A Randomised, Double-blind, Parallel-group, Multicentre, Phase III Study to Compare the Efficacy and Tolerability of Fulvestrant (FASLODEX) 500 mg With Anastrozole (ARIMIDEX) 1 mg as Hormonal Treatment for Postmenopausal Women With Hormone Receptor-Positive Locally Advanced or Metastatic Breast Cancer Who Have Not Previously Been Treated With Any Hormonal Therapy.
Phase: PHASE3
Conditions: Hormone Receptor Positive Breast Cancer
Sponsor: AstraZeneca

Revised Clinical Study Protocol
Drug Substance
Fulvestrant
Study Code
D699BC00001
Edition Number
6
Date
17 December 2021
A Randomised, Double-blind, Parallel-group, Multicentre, Phase III Study 
to Compare the Efficacy and Tolerability of Fulvestrant (FASLODEX™) 
500 mg with Anastrozole (ARIMIDEX™) 1 mg as Hormonal Treatment for 
Postmenopausal Women with Hormone Receptor-Positive Locally 
Advanced or Metastatic Breast Cancer Who Have Not Previously Been 
Treated With Any Hormonal Therapy (FALCON)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
The following Amendment(s) and Administrative Changes are included in this revised protocol: 
Amendment No.
Date of Amendment
Local Amendment No.
Date of local Amendment
001
05 December 2012
001 - US
14 January 2013
002
1 December 2017
003
17 December 2021
Administrative 
change No.
Date of Administrative 
Change
Local Administrative 
change No.
Date of local 
Administrative Change
001
002
003
27 June 2012
14 January 2013
18 January 2018
FASLODEX™and ARIMIDEX™are trademarks of the AstraZeneca group of companies

2(87)
VERSION HISTORY
Version 6.0, 17 December 2021 (Global CSP Amendment 003)
Changes to the protocol are summarised below
Change of final overall survival (OS) analysis trigger from when 75% of patients have 
died to: when at least 65% of patients have died and at least 8 years have passed since 
the last patient was enrolled
The final OS analysis in the FALCON study will be changed from the currently-planned 
trigger of when 75% of patients have died to: when at least 65% of patients have died and at 
least 8 years have passed since the last patient was enrolled. A 7-day window has been 
established for collection of these data, and it has been added that public websites can be 
searched.  The proposal is based on:
!
High uncertainty around when 75% of patients will have died. Newly proposed 
final OS analysis trigger is expected to occur in July 2022. With a minimum 
follow up period of 8 years and at least 65% of patients will have had the event, 
survival curves should be robustly characterised.
!
With continuing evolution in the standard of care, an extended follow-up for OS
analysis may not be clinically relevant. The treatment paradigms and current 
clinical guidelines including the National Comprehensive Cancer Network 
(NCCN Guidelines Breast Cancer 2021) have evolved to recommend the 
combination regimens of cyclin-D kinase 4/6 inhibitors plus endocrine agent 
(fulvestrant/aromatase inhibitors) as category I preferred treatment options over 
monotherapy.
All relevant sections of the protocol have been updated to reflect these changes.
Sections updated: Protocol Synopsis, Sections 3.1, 5.6, 6.1, 6.2.2.2, 6.4.4, 10, 12.2.1, and 
12.2.4. The statistical analysis detailed in Section 12.2.1 has been updated to reflect this 
change.
Also, references to ‘second data cut-off’ have been changed to ‘final data cut-off’.
Supply of investigational product after final database lock
Updated with details of provision of fulvestrant and anastrozole being supplied as a 
continued access phase after final database lock.
All relevant sections of the protocol have been updated to reflect these changes.
Sections updated: Protocol Synopsis, Sections 3.1, 5.5.1, and 9.5.

Revised Clinical Study Protocol Synopsis
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
3(87)
Check of Concomitant Medication During Survival Follow-up Phase
Concomitant medication continues to be checked during the survival follow-up phase; 
consequently this has been added to Table 2 in Section 3.1 and is mentioned in 
Section 6.2.2.2.
COVID-19
Noted in Section 5.6 that COVID-19 vaccination with authorised vaccines is permitted at 
the discretion of the investigator.
Added text to Section 13.2.1 to note that summaries of data relating to patients diagnosed 
with COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, 
delayed or discontinued IP, and other protocol deviations) may be generated.
SAE Reporting
To more accurately reflect the SAE reporting process, the wording has been changed to say 
that SAEs will be reported (not recorded) on a paper-based SAE form, and it is clarified that 
the form will be submitted as per instructions on the form.
Sections updated: Sections 6.1, 6.2.2.2, 6.4.3, and 6.4.4.
Study Timetable
To reflect the progress of the study, study timetable details have been updated in the 
Protocol Synopsis and in Section 9.5.
Change to CRO Name
Throughout, references to ‘Quintiles’ have been changed to ‘IQVIA’
Other minor corrections/updates were made throughout the document.

Revised Clinical Study Protocol Synopsis
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
4(87)
Version 5.0, 18 January 2018 (Correction of the editorial mistake in Revised CSP 
version 4.0)
Changes to the protocol are summarised below
Sections affected:
Appendix G :
Questionnaires, which due to the editorial mistake, were not included in Appendix G 
(edition 1.0 dated 19 Apr 2012) of the Revised CSP version 4.0 dated 01 Dec 2017 have 
been added in the corrected Appendix G of the Revised CSP version 5.0 dated 18 Jan 2018.
Version 4.0, 1 December 2017 (Global CSP Amendment 002)
Changes to the protocol are summarised below
Delay of final overall survival (OS) analysis to 75% maturity
The final OS analysis in the FALCON study will be delayed from the currently-planned 
50% maturity (approximately 231 events) to 75% (approximately 347 events).  This 
proposal is based on:
!
the observation that in previous fulvestrant studies, the OS curves split relatively 
late then maintain a clear treatment difference for the remainder of the study, 
suggesting that a later, more mature analysis of FALCON OS is more likely to 
demonstrate a difference between the treatment groups, if one exists
!
the unique mechanism of action of fulvestrant, which may explain the late 
separation of the OS curves
!
the fact that a delayed final analysis of OS will include a greater number of 
events, which will improve the statistical power to detect a difference between 
the treatment arms.
All relevant sections of the protocol have been updated to reflect these changes. Sections 
updated: Protocol Synopsis, Section 3.1, 5.6, 6.2.2.2, 10, 12.2.1, 12.2.4. 
Section 5.5.1:
Updated to describe IP supply in the post OS analysis phase. 
Section 6.1, 6.2, 6.4.3 and 6.4.4:
Updated to explain that SAEs will be recorded on a paper-based SAE report form in the 
post-OS analysis period

Revised Clinical Study Protocol Synopsis
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
5(87)
Version 3, 14 January 2013 (Local CSP Amendment 001, with Global Administrative 
Changes)
Version 3 of the CSP comprised local Amendment 001 along with administrative changes 
and, which was developed under a previous process where the changes were documented in 
a separate changes document and are not listed here.
Version 2, 5 December 2012 (Global CSP Amendment 001)
Version 2 of the CSP was developed under a previous process where the changes were 
documented in a separate changes document and are not listed here.
Version 1, 1 May 2012
Initial creation

Revised Clinical Study Protocol Synopsis
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
7(87)
Study period
Phase of development
Date of first patient enrolled
17 Oct 2012
III
Date of last patient enrolled
11 Jul 2014
Date of data cut-off for primary analysis of 
progression-free survival
11 Apr 2016
Estimated date of data cut-off for when at least 
65% of patients have died and at least 8 years 
have passed since the last patient was enrolled
Q3 2022
Objectives
Primary:
To demonstrate the superior progression-free survival (PFS) of patients treated with 
fulvestrant 500 mg versus patients treated with anastrozole 1 mg.
Secondary:
1.
To compare the overall survival (OS) of patients treated with fulvestrant 500 mg 
versus patients treated with anastrozole 1 mg.
2.
To compare the objective response rate (ORR), duration of response (DoR) and the 
expected duration of response (EDoR) of patients treated with fulvestrant 500 mg 
versus patients treated with anastrozole 1 mg.
3.
To compare the clinical benefit rate (CBR), the duration of clinical benefit (DoCB) 
and the expected duration of clinical benefit (EDoCB) of patients treated with 
fulvestrant 500 mg versus patients treated with anastrozole 1 mg.
4.
To compare the quality of life (QoL) of patients treated with fulvestrant 500 mg 
versus patients treated with anastrozole 1 mg.
5.
To compare the safety and tolerability of fulvestrant 500 mg treatment versus that 
of anastrozole 1 mg treatment.
Exploratory:
To explore how variations in tumour biomarkers (DNA, RNA and/or protein based) may be 
related to factors that may influence development of cancer and/or study treatment response 
and resistance.
Study design
This is a randomised, double-blind, double-dummy, international, multicentre study 
comparing the efficacy and tolerability of fulvestrant with anastrozole. Eligible patients will 

Revised Clinical Study Protocol Synopsis
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
8(87)
be randomised 1:1 to receive fulvestrant 500 mg or anastrozole 1 mg.  Patients will be 
stratified at randomisation based on whether (1) they have locally advanced or metastatic 
breast cancer (2) they have received prior chemotherapy for locally advanced or metastatic 
breast cancer or not and (3) they have measurable or non-measurable disease.
The primary analysis will be performed when approximately 306 events have occurred 
(defined as objective disease progression, surgery or radiotherapy to manage worsening of 
disease, or death by any cause in the absence of progression).  Upon objective disease 
progression, patients will enter the survival follow-up phase.  After the data cut-off for the 
primary analysis, all the remaining patients, regardless of whether they are still receiving 
randomised treatment, will enter the survival follow-up phase and will otherwise be managed 
as per standard clinical practice.  A survival analysis will be performed at the same time as the 
primary analysis and again when at least 65% of patients have died and at least 8 years have 
passed since the last patient was enrolled. After this point, data collection will cease for this 
study, the study database will close and the patient's treatment will be unblinded.  The end of 
the study is defined as the last visit of the last patient, occurring when the last patient has 
discontinued study therapy.
Following the final survival analysis, the patient’s treatment will be unblinded.  Patients are 
permitted to continue to receive open-label study treatment beyond the closure of the database 
as a continued access phase if, in the opinion of the investigator, they are continuing to receive 
benefit from treatment with fulvestrant or anastrozole and cannot access appropriate treatment 
outside of the clinical study protocol.  Placebo treatment will be discontinued at this point.  
During this period (ie, after the final OS analysis), there will be no further survival follow-up 
for the patient.
Target patient population
Postmenopausal women with hormone receptor-positive locally advanced or metastatic breast 
cancer (confirmed by histology), who have not previously been treated with any hormonal 
therapy, have a World Health Organisation (WHO) performance status of 0, 1 or 2 and at least 
one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline and 
is suitable for repeated assessment according to Response Evaluation Criteria in Solid 
Tumours (RECIST 1.1) guidelines.  Patients may have received one line of cytotoxic 
chemotherapy as previous treatment of breast cancer prior to enrolment but there must be 
evidence of progressive disease at this time if the chemotherapy was given for the metastatic 
or locally advanced disease.
Investigational product, dosage and mode of administration
Fulvestrant 500 mg will be administered as two 5 mL intramuscular injections, one in each
buttock, on Days 0, 14 (±3), 28 (±3) and every 28 (±3) days thereafter.  Placebo will also be 
given to match the anastrozole administration schedule.

Revised Clinical Study Protocol Synopsis
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
9(87)
Comparator, dosage and mode of administration
The comparator, anastrozole will be administered orally as a single daily tablet at a dose of 
1 mg/day.  Placebo will also be given to match the fulvestrant administration schedule.
Duration of treatment
Randomised treatment will continue until objective disease progression unless any of the other 
criteria for treatment discontinuation are met.
Disease progression will be assessed locally by each investigator according to RECIST 1.1. 
After objective disease progression, patients will enter the survival follow-up phase.  In order 
to facilitate a decision on the subsequent treatment options, investigators may request to be 
unblinded to treatment allocation, once randomised treatment has been discontinued, and 
progression has been formally documented in the electronic case report form (eCRF).
After the data cut-off for the primary analysis, all the remaining patients, regardless of 
whether they continue to receive randomised treatment, will enter the survival follow-up 
phase of the study, and will otherwise be managed as per standard clinical practice.
Following the final survival analysis, patients are permitted to continue to receive open-label 
study treatment beyond the closure of the database as a continued access phase if, in the 
opinion of the investigator, they are continuing to receive benefit from treatment with 
fulvestrant or anastrozole and cannot access appropriate treatment outside of the clinical study 
protocol.  Placebo treatment will be discontinued at this point. Alternative supply options will 
be discussed and may be implemented if they become available.
Outcome variable(s): 
!
Primary outcome variable
∀
Progression-free survival
!
Secondary outcome variables
∀
Overall survival (OS) (time from randomisation to death from any cause)
∀
Objective response (OR) (= complete response [CR] + partial response [PR] 
defined by RECIST 1.1 criteria)
∀
Clinical benefit (= CR + PR + {stable disease [SD] ≥24 weeks} defined by 
RECIST 1.1 criteria)
∀
Duration of response (DoR) (defined for patients with OR only, as the number 
of days from first response to date of progressive disease [PD], as defined by 
RECIST 1.1, or death) 

Revised Clinical Study Protocol Synopsis
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
10(87)
∀
Duration of clinical benefit (DoCB) (defined for patients with CB only, as the 
time in days from date of randomisation until date of PD as defined by 
RECIST 1.1 or death)
∀
Expected duration of response (EDoR) (from first response) (EDoR for patients 
who had OR assuming a log-normal distribution for the duration, multiplied by 
the proportion of patients who had OR)
∀
Expected duration of clinical benefit (EDoCB) (EDoCB for patients who had 
CB assuming a log-normal distribution for the duration, multiplied by the 
proportion of patients who had CB)
∀
Trial Outcome Index (TOI) derived from the Functional Assessment of Cancer 
Therapy for Breast Cancer (FACT-B) questionnaire, Total FACT-B score and 
patients' utility scores from the EQ-5D™(EuroQol Group) questionnaire
∀
Frequency and severity of adverse events (AEs) as assessed by Common 
Toxicity Criteria (CTC) grade (Version 4.0), pre-defined AEs of interest (joint 
disorders and back pain), laboratory assessments, electrocardiogram (ECG), 
physical examination (including WHO performance status), vital signs 
(including blood pressure and heart rate)
!
Exploratory
∀
to investigate biomarkers in tumour samples potentially using a number of 
different analytical platforms, eg, tumour-specific sequence changes.
Statistical methods
The primary statistical analysis will compare the PFS between fulvestrant 500 mg versus 
anastrozole 1 mg using the stratified log-rank test, at the 2-sided 5% significance level.  This 
analysis will be performed on the Intention to Treat population.  Results will be presented in 
terms of an estimate of the hazard ratio (HR) (fulvestrant 500 mg: anastrozole 1 mg), 
associated confidence interval (CI) and p-value.  A HR less than 1 would indicate that, on 
average, PFS is improved on fulvestrant 500 mg when compared with anastrozole 1 mg.  
Secondary analyses will examine OS, ORR, CBR, DoR, EDoR, DoCB, EDoCB, and 
patient-reported outcomes by use of FACT-B and EQ-5D questionnaires.  Analysis of OS will 
be done using the stratified log-rank test, similarly to the analysis of PFS.  ORR and CBR will 
be analysed using a logistic regression model and examination of the odds ratio of the 
2 treatment groups.  EDoR and EDoCB will be estimated using the methodology described by 
Ellis et al 2008.  For the health-related QoL endpoints (FACT-B total score and TOI), a time 
to deterioration analysis will be performed.  EQ-5D will be summarised only.
A multiple-testing procedure with an alpha-exhausting recycling strategy (Burman et al 2009) 
will be used in order to control strongly the Type I error at the 2-sided 5% significance level 
for the primary and key secondary endpoints. 

Revised Clinical Study Protocol Synopsis
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
11(87)
AEs will be summarised by preferred term and system organ class (using the Medical 
Dictionary for Regulatory Activities [MedDRA]).  Summaries of AEs by causality and CTC 
grade will also be presented.  Fisher’s exact test will be used in order to compare the incidence 
of pre-defined AEs of interest (joint disorders and back pain) between the two treatment 
groups.  All other safety variables will also be summarised.

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
12(87)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS.....................................................................................6
TABLE OF CONTENTS...................................................................................12
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.........................17
1.
INTRODUCTION .............................................................................................20
1.1
Background........................................................................................................20
1.2
Research hypothesis...........................................................................................21
1.3
Rationale for conducting this study ....................................................................21
1.4
Benefit/risk and ethical assessment ....................................................................22
2.
STUDY OBJECTIVES......................................................................................23
2.1
Primary objective...............................................................................................23
2.2
Secondary objectives..........................................................................................23
2.3
Exploratory objectives ....................................................................................... 24
3.
STUDY PLAN AND PROCEDURES ...............................................................24
3.1
Overall study design and flow chart ...................................................................24
3.2
Rationale for study design, doses and control groups..........................................34
4.
PATIENT SELECTION CRITERIA.................................................................. 35
4.1
Inclusion criteria ................................................................................................35
4.2
Exclusion criteria ............................................................................................... 36
5.
STUDY CONDUCT..........................................................................................38
5.1
Restrictions during the study..............................................................................38
5.2
Patient enrolment and randomisation and initiation of investigational 
product...............................................................................................................38
5.2.1
Procedures for enrolment ...................................................................................38
5.2.2
Procedures for randomisation.............................................................................38
5.3
Procedures for handling patients incorrectly enrolled or randomised or 
initiated on investigational product.....................................................................39
5.4
Blinding and procedures for unblinding the study...............................................39
5.4.1
Methods for ensuring blinding ...........................................................................39

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
13(87)
5.4.2
Methods for unblinding the study.......................................................................39
5.5
Treatments.........................................................................................................40
5.5.1
Identity of investigational products ....................................................................40
5.5.2
Doses and treatment regimens............................................................................41
5.5.3
Labelling............................................................................................................41
5.5.4
Storage...............................................................................................................42
5.6
Concomitant and post-study treatment(s) ...........................................................42
5.7
Treatment compliance........................................................................................44
5.7.1
Accountability....................................................................................................45
5.8
Discontinuation of investigational product .........................................................45
5.8.1
Procedures for discontinuation of a patient from investigational product 
and comparator ..................................................................................................46
5.9
Withdrawal from study.......................................................................................46
5.9.1
Randomised patients ..........................................................................................46
5.9.2
Screening failures...............................................................................................47
6.
COLLECTION OF STUDY VARIABLES........................................................47
6.1
Recording of data...............................................................................................47
6.2
Data collection at enrolment and follow-up ........................................................47
6.2.1
Enrolment procedures ........................................................................................47
6.2.2
Follow-up procedures.........................................................................................48
6.2.2.1
Discontinuation visit ..........................................................................................48
6.2.2.2
Survival follow-up phase....................................................................................48
6.3
Efficacy .............................................................................................................49
6.3.1
CT/MRI scans....................................................................................................49
6.3.2
Bone scan ..........................................................................................................50
6.3.3
Tumour assessments ..........................................................................................50
6.4
Safety................................................................................................................. 51
6.4.1
Definition of adverse events...............................................................................51
6.4.2
Definitions of serious adverse event ...................................................................51
6.4.3
Recording of adverse events...............................................................................52
6.4.4
Reporting of serious adverse events ...................................................................55
6.4.5
Laboratory safety assessment .............................................................................56
6.4.6
Physical examination .........................................................................................56
6.4.7
ECG...................................................................................................................56
6.4.8
Vital signs..........................................................................................................57
6.5
Patient reported outcomes (PRO) ....................................................................... 57
6.5.1
FACT-B.............................................................................................................57
6.5.2
EQ-5D™.............................................................................................................57
6.5.3
Administration of HRQoL questionnaires .......................................................... 57
6.6
Biomarker research ............................................................................................ 59

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
14(87)
6.6.1
Collection of tissue sections for biomarker research ........................................... 59
6.6.2
Optional tumour tissue sample for biomarker research .......................................59
7.
BIOLOGICAL SAMPLING PROCEDURES ....................................................59
7.1
Volume of blood................................................................................................ 59
7.2
Handling, storage and destruction of biological samples.....................................60
7.3
Labelling and shipment of biohazard samples ....................................................60
7.4
Chain of custody of biological samples ..............................................................60
7.5
Withdrawal of informed consent for donated biological samples........................61
8.
ETHICAL AND REGULATORY REQUIREMENTS.......................................61
8.1
Ethical conduct of the study ...............................................................................61
8.2
Patient data protection........................................................................................61
8.3
Ethics and regulatory review .............................................................................. 62
8.4
Informed consent ...............................................................................................62
8.4.1
Biomarker research informed consent (tumour tissue sample only) .................... 63
8.5
Changes to the protocol and informed consent form...........................................63
8.6
Audits and inspections ....................................................................................... 64
9.
STUDY MANAGEMENT BY ASTRAZENECA OR DELEGATE ..................64
9.1
Pre-study activities............................................................................................. 64
9.2
Training of study site personnel .........................................................................64
9.3
Monitoring of the study...................................................................................... 65
9.3.1
Source data ........................................................................................................ 65
9.4
Study agreements............................................................................................... 65
9.4.1
Archiving of study documents............................................................................ 65
9.5
Study timetable and end of study........................................................................65
10.
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE.....................66
11.
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE ................................................................... 67
11.1
Calculation or derivation of efficacy variables....................................................67
11.2
Calculation or derivation of safety variables.......................................................70
11.2.1
Other significant adverse events (OAE).............................................................. 70
11.3
Calculation or derivation of patient reported outcome variables..........................70
11.3.1
FACT-B.............................................................................................................70
11.3.1.1
Items to be reversed ...........................................................................................70
11.3.1.2
Missing data.......................................................................................................71
11.3.1.3
Visit responses...................................................................................................71

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
15(87)
11.3.1.4
Time to deterioration of Health related Quality of Life.......................................73
11.3.1.5
HRQoL compliance rates...................................................................................74
11.3.2
EQ-5D™.............................................................................................................74
11.4
Calculation or derivation of exploratory biomarker variables ............................. 74
12.
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
BY ASTRAZENECA OR DELEGATE............................................................. 75
12.1
Description of analysis sets ................................................................................75
12.1.1
Efficacy analysis set...........................................................................................75
12.1.2
Safety analysis set..............................................................................................75
12.2
Methods of statistical analyses ...........................................................................75
12.2.1
General principles..............................................................................................76
12.2.2
Efficacy .............................................................................................................78
12.2.2.1
Progression-free survival (PFS)..........................................................................78
12.2.2.2
Objective response rate (ORR)...........................................................................81
12.2.2.3
Overall survival (OS).........................................................................................81
12.2.2.4
Clinical benefit rate (CBR).................................................................................81
12.2.2.5
Duration of response (DoR) ...............................................................................81
12.2.2.6
Duration of clinical benefit (DoCB) ................................................................... 81
12.2.2.7
Expected duration of response (EDoR)...............................................................82
12.2.2.8
Expected duration of clinical benefit (EDoCB)...................................................82
12.2.3
Tolerability and safety........................................................................................82
12.2.3.1
Adverse events (AE) ..........................................................................................82
12.2.3.2
Health-related Quality of Life (HRQoL) ............................................................82
12.2.3.3
Other assessments..............................................................................................83
12.2.4
Interim analyses................................................................................................. 83
12.3
Determination of sample size .............................................................................83
12.4
Data monitoring committee................................................................................83
13.
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR .............................................................................................. 83
13.1
Medical emergencies and AstraZeneca contacts.................................................83
13.2
Overdose............................................................................................................84
13.3
Pregnancy ..........................................................................................................84
14.
LIST OF REFERENCES ...................................................................................84
LIST OF TABLES
Table 1
Study plan (for primary analysis) ..........................................................28
Table 2
Study plan (survival follow-up phase) ...................................................31

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
16(87)
Table 3
Laboratory safety variables ...................................................................56
Table 4
Volume of blood to be drawn from each patient ....................................59
Table 5
Summary of HRQoL visit responses .....................................................72
Table 6
Formal statistical analyses to be conducted and pre-planned 
sensitivity analyses................................................................................76
LIST OF FIGURES
Figure 1
Study flow chart....................................................................................27
Figure 2
Multiple testing procedure.....................................................................77
LIST OF APPENDICES
Appendix A
Signatures – Not Applicable
Appendix B
Additional Safety Information
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance 
Document
Appendix D
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours)
Appendix E
Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law
Appendix F
WHO Performance Status
Appendix G
Patient Reported Outcomes (FACT-B and EQ-5D™)
Appendix H
Biomarker Research

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
17(87)
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse event (see definition in Section 6.4.1)
AI
Aromatase inhibitor
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BCS
Breast Cancer Subscale
CBR
Clinical Benefit Rate
CI
Confidence Interval
CONFIRM
Comparison of FASLODEX in Recurrent or Metastatic Breast Cancer 
(Study D6997C00002)
CR
Complete Response
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Computed Tomography 
CTC
Common Terminology Criteria (National Institutes of Health, National 
Cancer Institute)
CTCAE
Common Terminology Criteria for Adverse Event
DoCB
Duration of Clinical Benefit
DoR
Duration of Response
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDoCB
Expected Duration of Clinical Benefit
EDoR
Expected Duration of Response
ER
Oestrogen receptor
EU
European Union
EWB
Emotional well-being
FACIT
Functional Assessment of Chronic Illness Therapy
FACT-B
Functional Assessment of Cancer Therapy – Breast
FACT-G
Functional Assessment of Cancer Therapy – General

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
18(87)
Abbreviation or 
special term
Explanation
FALCON
Fulvestrant and anastrozole compared in hormonal therapy naïve advanced 
breast cancer (Study D699BC00001)
FIRST
Fulvestrant first-line Study comparing endocrine Treatments
(Study D6995C00006)
FISH
Fluorescence in situ hybridisation 
FWB
Functional Well-being
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HER2
Human Epidermal Growth Factor Receptor 2
HR
Hazard ratio
HRQoL
Health-related Quality of Life
IATA
International Air Transport Association
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IHC
Immunohistochemistry
INR
International Normalised Ratio
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally. 
IP
Investigational Product 
IRB
Institutional Review Board
ITT
Intention to Treat
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LMWH
Low molecular weight heparin
MedDRA
Medical Dictionary for Regulatory Activities
MedID
Medication Identification (known as KitID in IVRS)
MRI
Magnetic Resonance Imaging
MTP
Multiple testing procedure
NCCN
National Comprehensive Cancer Network 
NE
Not evaluable
NTL
Non-target Lesion

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
19(87)
Abbreviation or 
special term
Explanation
OAE
Other Significant Adverse Event (see definition in Section 11.2.1)
OR
Objective Response
ORR
Objective Response Rate
OS
Overall Survival
PD
Progressive disease
PET
Paraffin-embedded tissue
PFS
Progression-free Survival
PgR
Progesterone Receptor
PhRMA
Pharmaceutical Research and Manufacturers of America
PI
Principal Investigator 
PR
Partial Response
PRO
Patient Reported Outcome
PWB
Physical Well-being
QoL
Quality of Life
RECIST 1.1
Response Evaluation Criteria In Solid Tumours, Version 1.1
SAE
Serious adverse event (see definition in Section 6.4.2).
SAP
Statistical analysis plan
SD
Stable Disease
SERM
Selective oestrogen receptor modulator
SWB
Social well-being
TL
Target lesion
TOI
Trial Outcome Index
TTP
Time to Progression
ULRR
Upper limit of reference range
USA
United States of America
WBDC
Web Based Data Capture
WHO
World Health Organization

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
20(87)
1.
INTRODUCTION
Investigators should be familiar with the current fulvestrant (ZD9238) Investigator's Brochure 
(IB). 
1.1
Background
Breast cancer is a common disease with significant morbidity and mortality.  Approximately 
30% of women diagnosed with breast cancer die of the disease.  Tumours that show oestrogen 
and/or progesterone receptors (ER or PgR) (hormone receptor positive disease) are suitable 
for hormonal therapy, which is generally less toxic than chemotherapy.  Interventions are 
possible at all stages of the disease: prevention in women with high risk, therapy adjuvant to 
surgery, and first and subsequent lines of therapy for advanced disease.  Early breast cancer is 
potentially curable (by surgery often combined with adjuvant therapy), while advanced 
disease is beyond the scope of curative surgery and is generally fatal.
Unmet needs for patients with advanced disease include higher response rates, prolonged 
duration of disease control, relief of symptoms, improvement in quality of life (QoL) and 
minimal toxicity associated with treatment.  Over the past decade, the standard of care for 
hormone-receptor positive breast cancer has changed, with aromatase inhibitors (AIs) largely 
replacing anti-oestrogens (selective oestrogen receptor modulators [SERMs]) for adjuvant 
therapy.  Sequential hormonal therapies are subsequently used in the advanced disease setting, 
progressing from non-steroidal AIs such as anastrozole (ARIMIDEX™) or letrozole 
(FEMARA®, Novartis Pharmaceuticals Corporation), to steroidal AIs such as exemestane 
(AROMASIN®, Pfizer Ltd) and then to fulvestrant (FASLODEX™)1.
Fulvestrant is an oestrogen receptor antagonist with no known agonist activity, administered 
as a monthly intramuscular injection of a depot formulation.  It binds the ER, renders it 
transcriptionally inactive and, because the fulvestrant-receptor complex is unstable, results in 
accelerated degradation of the receptor protein.  Fulvestrant’s pre-clinical and clinical 
characteristics are generally well established.  
Studies in which the fulvestrant 250 mg dose regimen was compared to AIs or other SERMs 
in patients with hormone-receptor positive advanced breast cancer, have shown generally 
comparable results in terms of progression-free survival (PFS)/time to progression (TTP) and 
overall survival (OS) (Howell et al 2002, Howell et al 2004, Osborne et al 2002, 
Chia et al 2008).  These studies were either in patients who had not previously received 
hormonal therapy for advanced disease, or in patients progressing after prior hormonal 
therapy.  
The CONFIRM study (Study D6997C00002) was a randomised, double-blind, Phase III study 
to compare 2 dose levels of fulvestrant (500 mg versus 250 mg) in postmenopausal women 
with ER-positive (ER +ve) advanced breast cancer who had either relapsed whilst on adjuvant 
                                               
1 FASLODEX™and ARIMIDEX™are trademarks of the AstraZeneca group of companies.

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
21(87)
endocrine therapy, or progressed whilst on first-line endocrine therapy for advanced disease 
(Di Leo et al 2010).  The observation that the fulvestrant 500 mg dose regimen showed an 
efficacy advantage over the 250 mg dose regimen in this potentially less responsive patient 
population is encouraging for the effectiveness of the higher dose in hormonal therapy-naïve 
patients.
Further evidence that the fulvestrant 500 mg dose regimen may provide a clinical advantage 
over AIs was provided by the FIRST study (Study D6995C00006).  This was a Phase II, 
randomised, open-label study of fulvestrant 500 mg versus anastrozole 1 mg in 205 women 
with advanced disease previously untreated with hormonal therapy or at least a year after 
completing adjuvant therapy.  There were 2 time points for analysis of data from the FIRST 
study: a primary analysis (6 months after the last patient was randomly assigned) and a 
follow-up analysis (when approximately 69% of patients had progressed).  Investigator 
assessment of radiographic scans was used for the main efficacy analyses.
At the time of the primary analysis, the primary response variable, clinical benefit rate (CBR), 
showed a numerical advantage for fulvestrant over anastrozole (72.5% versus 67.0%), but did 
not reach statistical significance (odds ratio=1.302; 95% confidence interval [CI]=0.717, 
2.380; p=0.386).  Despite the immaturity of the data at the primary analysis, TTP was 
significantly longer for fulvestrant versus anastrozole (hazard ratio [HR]=0.63; 95% CI=0.39, 
1.00; p=0.0496; median TTP not reached for fulvestrant versus 12.5 months for anastrozole) 
(Robertson et al 2009).  A post-hoc analysis of TTP using blinded independent review also 
showed a numerical benefit for fulvestrant over anastrozole (HR=0.79; 95% CI=0.45, 1.36).
A further assessment of TTP was performed at the follow-up analysis.  The TTP endpoint of 
the FIRST follow-up analysis was composed of progression events confirmed via Response 
Evaluation Criteria in Solid Tumours (RECIST) assessment (for patients who progressed prior 
to the primary trial data cut-off) and progressive disease (PD) in the Investigator's opinion (for 
patients who progressed after the primary trial data cut-off).  For patients who did not progress 
prior to the data cut-off for the primary analysis, TTP in the follow-up phase was calculated as 
the time from randomisation to progression, as per Investigator opinion.  A statistically 
significant difference in favour of fulvestrant was seen corresponding to a 35% reduction in 
risk of progression (HR=0.66; 95% CI =0.47, 0.92; p=0.01), with median TTP being 
10.3 months longer for fulvestrant than for anastrozole (23.4 versus 13.1 months, respectively) 
(Robertson et al 2010). 
1.2
Research hypothesis
The hypothesis to be tested for the primary objective is that the efficacy of fulvestrant 500 mg 
is superior to that of anastrozole 1 mg by assessment of PFS.
1.3
Rationale for conducting this study
Data from the Phase II open-label study, FIRST, suggest an efficacy benefit for 
fulvestrant 500 mg compared with anastrozole as first-line endocrine therapy for patients with 

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
22(87)
hormone receptor-positive metastatic and/or locally advanced breast cancer 
(Robertson et al 2009, Robertson et al 2010).
This Phase III study (FALCON) is therefore intended to extend and confirm the clinical 
benefit of fulvestrant 500 mg compared with anastrozole 1 mg in approximately 
450 postmenopausal women through the evaluation of the hypothesis that fulvestrant 500 mg 
per month will prove superior to anastrozole by the assessment of PFS.  The proposed patient 
population (patients with advanced disease who have not received any previous hormonal 
therapy) reflects the majority (75%) of patients who were studied in FIRST.
1.4
Benefit/risk and ethical assessment
Fulvestrant at the original dose of 250 mg, has received marketing approval in all 72 countries 
where submitted for the treatment of postmenopausal women with ER +ve locally advanced or 
metastatic breast cancer whose breast cancer recurred or progressed on previous endocrine 
therapy.  Fulvestrant, at a monthly dose of 250 mg, was well tolerated in clinical studies and 
the safety profile has been confirmed by analysis of post-marketing pharmacovigilance data.  
The CONFIRM study has since demonstrated that the fulvestrant 500 mg dose regimen has a 
clear clinically meaningful benefit over the fulvestrant 250 mg dose regimen, with a 
statistically significant prolongation of PFS and a 20% reduction in the risk of progressing for 
patients receiving the higher dose.  A pooled analysis of safety data has shown that the risks 
associated with fulvestrant 500 mg are generally similar to those of fulvestrant 250 mg.  
Injection site reaction and hypersensitivity (predominantly pruritus) are the only adverse drug 
reactions for which there is evidence of an increased risk for fulvestrant 500 mg compared 
with fulvestrant 250 mg. This is consistent with the increased number of injections required 
for the fulvestrant 500 mg dose regimen compared to fulvestrant 250 mg.
In November 2009 variations were submitted in the European Union (EU), United States of 
America (USA) and Canada to update the recommended dose of fulvestrant, with 250 mg 
being replaced by 500 mg.  In March 2010 the fulvestrant 500 mg dose was approved in the 
EU and approvals soon followed in Canada and the USA. The fulvestrant 500 mg dose is now 
approved in more than 60 markets worldwide.  Fulvestrant was first approved as a new 
chemical entity in Japan in September 2011 at the 500 mg dose.  Further worldwide 
submissions for the fulvestrant 500 mg dose are either ongoing or planned.
The safety profiles of fulvestrant and of anastrozole are well established.  The very common 
adverse reactions associated with fulvestrant 500 mg are nausea, elevated liver enzymes 
(alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatise 
[ALP]), asthenia and injection site reactions, while common reactions are urinary tract 
infections, hypersensitivity reactions, anorexia, headache, hot flushes, elevated bilirubin, 
vomiting, diarrhoea, and rash.  For anastrozole, very common adverse reactions include rash, 
headache, hot flushes, nausea, arthralgia, joint stiffness, arthritis and asthenia, while common 
adverse reactions are anorexia, hypercholesterolaemia, somnolence, carpal tunnel syndrome, 
diarrhoea, vomiting, increases in ALP, ALT and AST, bone pain, myalgia, hair thinning, 
allergic reactions, vaginal dryness and vaginal bleeding.  As anastrozole lowers circulating 

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
23(87)
oestrogen levels it may cause a reduction in bone mineral density with a possible consequent 
increased risk of fracture.
No significant differences were observed between the two treatment arms in the FIRST study 
for any of the individual pre-specified adverse events (AEs; endometrial dysplasia, 
gastrointestinal disturbances, hot flushes, ischaemia cardiovascular disorders, joint disorders, 
osteoporosis, thrombolic events, urinary tract infections, vaginitis and weight gain).  A higher 
number of events describing joint disorders were observed in the fulvestrant 500 mg arm and 
although this difference was not statistically significant, these events are known to be 
associated with anastrozole and will be further investigated in the present study.
The improved efficacy, and similar safety, tolerability and health-related QoL (HRQoL) that 
fulvestrant 500 mg offers compared with fulvestrant 250 mg, indicate that there is an 
improved benefit-risk profile for fulvestrant 500 mg in postmenopausal women with advanced 
breast cancer who have recurred or progressed after previous endocrine therapy.  Furthermore, 
the improvement for fulvestrant 500 mg compared with 250 mg was seen in all patient 
subgroups analysed. 
The FIRST study has provided evidence that a fulvestrant 500 mg dose regimen may provide 
a clinical advantage over AIs in women with advanced disease previously untreated with 
hormonal therapy for at least a year after completing adjuvant therapy.  Follow-up analysis 
indicated a statistically significant prolongation of the TTP with a 34% reduction in the risk of 
progressing for patients receiving the higher 500 mg dose (Robertson et al 2010).
The clinical benefit of fulvestrant 500 mg has been established; the results of this study will 
confirm whether it has a greater clinical benefit than anastrozole 1 mg in terms of PFS in the 
defined patient population.
2.
STUDY OBJECTIVES
2.1
Primary objective
The primary objective of this study is to demonstrate the superior PFS of patients treated with 
fulvestrant 500 mg versus patients treated with anastrozole 1 mg.
2.2
Secondary objectives
The secondary objectives of this study are:
1.
To compare the OS of patients treated with fulvestrant 500 mg versus patients 
treated with anastrozole 1 mg.
2.
To compare the objective response rate (ORR), duration of response (DoR), and the 
expected duration of response (EDoR) of patients treated with fulvestrant 500 mg 
versus patients treated with anastrozole 1 mg.

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
24(87)
3.
To compare the CBR, the duration of clinical benefit (DoCB) and the expected 
duration of clinical benefit (EDoCB) of patients treated with fulvestrant 500 mg 
versus patients treated with anastrozole 1 mg.
4.
To compare the QoL of patients treated with fulvestrant 500 mg versus patients 
treated with anastrozole 1 mg.
5.
To compare the safety and tolerability of fulvestrant 500 mg treatment versus that 
of anastrozole 1 mg treatment.
2.3
Exploratory objectives
The exploratory objective of the study is to explore how variations in tumour biomarkers 
(DNA, RNA and/or protein based) may be related to factors that may influence development 
of cancer and/or study treatment response and resistance.
3.
STUDY PLAN AND PROCEDURES
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures.
3.1
Overall study design and flow chart
This is a randomised, double-blind, double-dummy, international, multicentre study 
comparing the efficacy and tolerability of fulvestrant (500 mg) with anastrozole (1 mg) in 
postmenopausal women with hormone receptor-positive locally advanced or metastatic breast 
cancer (confirmed by histology), who have not previously been treated with any hormonal 
therapy.
Patients will be assessed for eligibility for the study based on local laboratory results for 
hormone receptor status.
Approximately 450 women will be randomised 1:1 (fulvestrant: anastrozole).  Patients will be 
stratified at randomisation based on whether (1) they have locally advanced or metastatic 
breast cancer (2) they have received prior chemotherapy for locally advanced or metastatic 
breast cancer or not and (3) they have measurable or non-measurable disease.  To maintain 
blinding, patients randomised to fulvestrant will also receive placebo tablets to match 
anastrozole and patients randomised to anastrozole will also receive placebo injections to 
match fulvestrant.  Patients will start study treatment on the day of randomisation (Day 0 
[Visit 2]).
Study visits will occur at screening (Day -28 to -1), randomisation (Day 0), Day 14, Weeks 4, 
8, 12, 16, 20, 24 and every 12 weeks thereafter (Table 1) until progression.  Up to the data 
cut-off for the primary analysis, all randomised patients will be assessed by computed 
tomography (CT) or magnetic resonance imaging (MRI) every 12 weeks relative to the date of 
randomisation, until documented evidence of objective disease progression (regardless of 

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
25(87)
whether on study treatment or not).  Patients with evidence of metastatic bone lesions at 
baseline must also have a bone scan/skeletal x-ray survey every 12 weeks.
Progression-free survival (PFS) will be determined based on tumour assessments performed
locally by each investigator according to RECIST 1.1 (see Appendix D).  Where surgery or 
radiotherapy is performed to manage worsening of disease, this will be captured as a 
progression event and documented in the electronic case report form (eCRF); these patients 
will continue to receive study medication and be scanned until imaging criteria for objective 
disease progression are met.  To ensure comparability, identical imaging techniques must be 
used for the assessment of response at baseline and throughout the study.  The single 
exception to this is where problems with global supplies of technetium-99m for bone scans 
may necessitate a switch to an alternative modality on prior discussion/agreement with the 
IQVIA Study Physician.
Treatment will continue until objective disease progression (see Section 6.3.3) unless any of 
the criteria for treatment discontinuation are met first (see Section 5.8).  Upon discontinuation 
of study treatment or objective disease progression, patients will enter the survival follow-up 
phase.  In addition, if surgery or radiotherapy is performed to manage worsening of disease 
this will be captured as a progression event. In order to facilitate decisions on subsequent 
treatment options, investigators may request to be unblinded to treatment allocation, 
once randomised treatment has been discontinued, and objective disease progression has been 
formally documented in the eCRF.
The primary analysis will be performed when approximately 306 progression events (see 
Section 6.3.3) have occurred.  After the data cut-off for the primary analysis, all the remaining 
patients, regardless of whether they are still receiving randomised treatment, will enter the 
survival follow-up phase.  
In the survival follow-up phase, study visits will be conducted in order to complete HRQoL 
assessments (at 3-monthly intervals prior to objective disease progression, at the treatment 
discontinuation visit, at 3-months post-progression, and thereafter at 6-monthly intervals 
post-progression until the data cut-off for the OS analysis), administer/dispense study 
medication (for patients still receiving randomised treatment), and to determine survival 
status.  Further collection of data on objective disease progression will stop after the data cut-
off for the primary analysis (ie, 12-weekly CT/MRI scans will no longer be recorded in the 
eCRF). During the survival phase of the study, patients will otherwise be managed according 
to standard clinical practice.  Patients who enter the survival follow-up phase while still 
receiving randomised treatment may continue to receive treatment for as long as they receive 
clinical benefit (until criteria for discontinuation are met).  Following confirmation of 
objective disease progression, follow-up may be conducted by telephone, and HRQoL 
questionnaires may be posted to patients for completion, if appropriate.
A survival analysis will be performed at the same time as the primary analysis and again when 
at least 65% of patients have died and at least 8 years have passed since the last patient was 
enrolled. After this point, data collection will cease for this study, the study database will 
close and the patient's treatment will be unblinded.

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
26(87)
Patients are permitted to continue to receive open-label study treatment beyond the closure of 
the database if, in the opinion of the investigator, they are continuing to receive benefit from 
treatment with fulvestrant or anastrozole and cannot access appropriate treatment outside of 
the clinical study protocol. Placebo treatment will be discontinued at this point.
After final database lock AstraZeneca will continue to supply fulvestrant and anastrozole as a 
continued access phase while the patient is benefiting, in the opinion of the investigator, but if 
the product development reaches a point where alternative options of supply become available 
these will be discussed with the investigator.  Where an alternative supply route is determined 
to be the better option, including commercial products available in some regions, AstraZeneca 
will work with the investigator to transition patients to this alternative supply.
Safety will be monitored based on the frequency and severity of AEs, as assessed by Common
Terminology Criteria (CTC) grade version 4.0, laboratory assessments, ECGs, physical 
examination (including World Health Organization [WHO] performance status) and vital 
signs (including blood pressure and heart rate).
An optional part of the study is the collection of archival and/or recent tumour samples 
(paraffin-embedded tissue [PET] block) if available, from either the primary tumour or a 
metastatic site for the purposes of biomarker analysis.  In addition, patients who consent to 
participate in this biomarker research will also be asked if they are willing to provide a further 
optional tumour sample at progression, if, in the opinion of the investigator, the biopsy 
procedure does not pose additional significant risks to the patient.  If a tumour sample is 
already available at the time of progression a further sample is not required.  The main aim of 
this research is to identify patients most likely to benefit from fulvestrant (versus AIs), to 
explain non-responders and to study the changes associated with the development of 
resistance to these agents.  Patients who do not consent to exploratory research on tumour 
samples may participate in all other aspects of the study. Details of the biomarker research are 
provided in Appendix H.
Approximately 180 to 220 international centres are planned in Asia, Europe, North America, 
South America and South Africa.  It is expected that each centre will recruit between 2 to 
20 patients over approximately a 27-month recruitment period.
The study flow chart is shown in Figure 1.  The Study Plan for the primary analysis is 
presented in Table 1, and the Study Plan for the survival follow-up phase is presented in 
Table 2.

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
27(87)
Figure 1
Study flow chart
CONSENT - Enrol patients in IVRS/IWRS1
(Day -28 to Day -7)
SCREENING ASSESSMENTS
(Day -28 to Day -1)
Fulvestrant 500 mg
(Anastrozole placebo)
Anastrozole 1 mg
(Fulvestrant placebo)
RANDOMISATION (Day 0)
START
Study medication and RECIST observations
PRIMARY (PFS) ANALYSIS
STOP
RECIST observations 
(includes patients still on study 
medication)
CONTINUE
RECIST observations in ALL patients:
those taking study medication 
AND
patients who have stopped study medication (but continue consent)
STOP
all observations in patients who 
withdraw consent
OBJECTIVE DISEASE 
PROGRESSION
STOP
study medication 
(if still on study medication)
STOP
RECIST observations
OVERALL SURVIVAL ANALYSIS
STOP
SURVIVAL observations
START SURVIVAL observations
DEATH
1IVRS/IWRS = Interactive Voice Response System/Interactive Web Response System

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
28(87)
Table 1
Study plan (for primary analysis)
Study plan
Refer to 
Section:
Screening 
Phase
Treatment Phase
Treatment 
Discon-
tinuation
Visit number
1
2
(Random
-isation)
3 
4
5
6
7
8
9
10 onwards 
(every 
12 weeks until 
progression)
99 (within 
35 days of 
last injection)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
Week(s)
-4 to 0
(Day -28 
to -1)
0
(Day 0)
2 
(Day 14)
4
8
12
16
20
24
36 and 
onwards
Informed consent
4.1, 5.2.1, 
8.4
X
Medical/surgical history
6.2.1
X
Demography
6.2.1
X
Inclusion/exclusion 
criteria
4
X
X
Tumour characteristics
6.2.1
X
Concomitant therapy
5.6, 6.2.1
X
X
X
X
X
X
X
X
X
X
Xa
Electrocardiogram (ECG)
6.2.1, 6.4.7
X
X
X
X
X
Physical examination 
(including WHO 
Performance Status)
6.2.1, 6.4.6
Appendix F
X
Vital signs
6.4.8
X
X
X
X
X
X
X
X
X
Height (Visit 2 only) and 
weight 
6.4.6
X
X
X
X
X
X
X
X
X
Haematology/
clinical chemistry
6.2.1, 6.4.5,
Table 3
X
X
X
X
X

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
29(87)
Table 1
Study plan (for primary analysis)
Study plan
Refer to 
Section:
Screening 
Phase
Treatment Phase
Treatment 
Discon-
tinuation
Visit number
1
2
(Random
-isation)
3 
4
5
6
7
8
9
10 onwards 
(every 
12 weeks until 
progression)
99 (within 
35 days of 
last injection)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
Week(s)
-4 to 0
(Day -28 
to -1)
0
(Day 0)
2 
(Day 14)
4
8
12
16
20
24
36 and 
onwards
CT/MRI scan of the chest, 
abdomen and pelvis 
(RECIST 1.1)
6.2.1, 6.3.1, 
6.3.3, 
Appendix D
X
X
X
X
X
Bone scan or skeletal 
x-ray surveyb
(RECIST 1.1)
6.2.1, 6.3.2, 
6.3.3
Appendix D
X
Xb
Xb
Xb
Xb
Anastrozole (or matching 
placebo) dispensed
5.5
X
X
X
X
Administration of 
fulvestrant (or matching 
placebo) 
5.5.2
X
X
X
X
X
X
X
X
X
Every 
28 (±3) days  
after Visit 9
Administration of 
anastrozole (or matching 
placebo)
5.5.2
Adverse events
6.2.1, 6.4
X
X
X
X
X
X
X
X
X
X
Xa
Informed consent for 
tissue biomarker research
8.4.1
X
←-------------------------Continuous once daily dosing-----------------------→

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
30(87)
Table 1
Study plan (for primary analysis)
Study plan
Refer to 
Section:
Screening 
Phase
Treatment Phase
Treatment 
Discon-
tinuation
Visit number
1
2
(Random
-isation)
3 
4
5
6
7
8
9
10 onwards 
(every 
12 weeks until 
progression)
99 (within 
35 days of 
last injection)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
Week(s)
-4 to 0
(Day -28 
to -1)
0
(Day 0)
2 
(Day 14)
4
8
12
16
20
24
36 and 
onwards
Optional tumour  tissue 
sample for biomarker 
analysis (if available)
6.6.2, 7.2
Appendix H
X
XC
FACT-B questionnaire
6.5.1, 6.5.3
Appendix G
X
X
X
X
X
EQ-5D™questionnaire
6.5.2, 6.5.3
Appendix G
X
X
X
X
X
a
Details of AEs and concomitant therapy should be collected for up to 8 weeks after the last injection of fulvestrant (or matching placebo).
b
Patients with metastatic bone lesions at baseline should have repeat bone scans or skeletal x-ray surveys every 12 weeks (±2 weeks) until progression (or
until the data cut-off for the primary analysis, whichever occurs first).  Patients who do not have metastatic bone lesions at baseline do not require 
follow-up bone scans or skeletal x-ray surveys unless a new lesion is suspected (clinically indicated). 
c
Only for consenting patients with disease progression who provided an optional tumour tissue sample at baseline, and for whom, in the opinion of the 
investigator, the biopsy procedure poses no additional significant risks.

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
31(87)
Table 2
Study plan (survival follow-up phase)
Study plan
Refer to 
Section:
PRIOR to 
Primary Analysis 
AFTER Primary Analysis and Up To OS Analysis
Patients have 
DISCONTINUED 
randomised treatmenta
Patients STILL ON randomised 
treatment
Patients have DISCONTINUED randomised 
treatmenta
Weeks from last scheduled 
visit
Every 12 weeks
Every 12 weeks
Treatment 
discontinuation
Week 12, 24, 48, 72 etc
Week 36, 60, 84 etc
Visit number
100, 101, 102 etc
200, 201, 202 etc
99 (within 
35 days of last 
injection)
300, 301, 303, 305 etc
302, 304, 306 etc
Visit window 
±2 weeks
±3 days
±2 weeks
±2 weeks
CT/MRI scan of the chest, 
abdomen and pelvis 
(RECIST 1.1) until objective 
progression 
6.3.1, 6.3.3
Appendix D
X
Bone scan or skeletal x-ray 
surveyb (RECIST 1.1) until 
objective progression 
(if indicated at baseline)
6.3.2, 6.3.3
Appendix D
X
Serious adverse events 
(SAEs)
6.4.2, 6.4.4
Xc
(Up to 8 weeks after 
last injection only)
X
X
Xc,d
(Up to 8 weeks after last 
injection only)
Concomitant therapy
5.6, 6.2.1
Xc
(Up to 8 weeks after 
last injection only)
X
X
Xc
(Up to 8 weeks after last 
injection only)
Anastrozole (or matching 
placebo) dispensed
5.5
X
Administration of fulvestrant 
(or matching placebo)
5.5.2
Every 28 (±3) days

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
32(87)
Table 2
Study plan (survival follow-up phase)
Study plan
Refer to 
Section:
PRIOR to 
Primary Analysis 
AFTER Primary Analysis and Up To OS Analysis
Patients have 
DISCONTINUED 
randomised treatmenta
Patients STILL ON randomised 
treatment
Patients have DISCONTINUED randomised 
treatmenta
Weeks from last scheduled 
visit
Every 12 weeks
Every 12 weeks
Treatment 
discontinuation
Week 12, 24, 48, 72 etc
Week 36, 60, 84 etc
Visit number
100, 101, 102 etc
200, 201, 202 etc
99 (within 
35 days of last 
injection)
300, 301, 303, 305 etc
302, 304, 306 etc
Visit window 
±2 weeks
±3 days
±2 weeks
±2 weeks
Administration of anastrozole 
(or matching placebo)
5.5.2
Continuous once
daily dosing
FACT-B questionnaire
6.5.1, 6.5.3, 
Appendix G
Xe
X
X
Xe
EQ-5D™questionnaire
6.5.2, 6.5.3, 
Appendix G
Xe
X
X
Xe
Survival status
6.2.2.2
X
X
X
X
X
Best response to first
subsequent breast cancer 
therapy and name, start and 
stop date of all subsequent 
breast cancer therapies
5.6
X
X
X
X
a
Follow-up may be conducted by telephone, and FACT-B and EQ-5D questionnaires posted to patients for completion, if appropriate.
b
Patients with metastatic bone lesions at baseline should have repeat bone scans or skeletal x-ray surveys every 12 weeks (±2 weeks) until progression (or 
until the data cut-off for the primary analysis, whichever occurs first).  Patients who do not have metastatic bone lesions at baseline do not require 
follow-up bone scans or skeletal x-ray surveys unless a new lesion is suspected (clinically indicated).
c
Details of SAEs and concomitant therapy should be collected for up to 8 weeks after the last injection of fulvestrant (or matching placebo).
d
After the final analysis, SAEs are to be sent directly to AstraZeneca Patient Safety using a paper-based SAE report form, and for up until 8 weeks after 
the last injection of fulvestrant (or matching placebo).

Revised Clinical Study Protocol
Drug Substance Fulvestrant
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
33(87)
e
FACT-B and EQ-5D questionnaires should be administered at 3 months post objective disease progression, then at 6-monthly intervals.  

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
34(87)
3.2
Rationale for study design, doses and control groups
The population included in this study (ie, postmenopausal women with hormone 
receptor-positive locally advanced or metastatic breast cancer who have not been treated with 
any hormonal therapy and have received no more than one line of cytotoxic chemotherapy) 
reflects the majority (75%) of patients who participated in the FIRST study 
(Robertson et al 2009, Robertson et al 2010).
The randomised, double-blind design has been adopted to enable a robust comparison of the 
treatment groups.  The double-blind, double-dummy administration of study medication has 
been selected to ensure rigorous comparison of the treatment effects in each arm that will 
include patient-reported outcomes.  The comparator is anastrozole 1 mg, taken once daily.
The primary response variable, PFS, has been selected as it provides an objective measure of 
efficacy based on tumour size and is an established surrogate for clinical benefit.  The 
secondary response variables of OS, ORR, CBR, DoR and DoCB are established variables in 
the assessment of cancer drugs.  The variables eDoR and eDoCB represent a new and useful 
methodology that assesses data for all randomised patients for eDoCB, and all evaluable 
patients for eDoR, rather than just the data for responders.  The collection of safety and 
tolerability data will allow the safety profiles of the 2 randomised treatments to be compared.  
HRQoL assessments provide a valuable source of additional information useful to both 
clinician and patient when making treatment decisions and the collection of best response to 
subsequent therapies will allow the outcome of subsequent therapies to be compared for each 
treatment group.
The dose regimens selected for this study are guided by the results of previous clinical trials, 
especially CONFIRM (Di Leo et al 2010) and FIRST.
The use of local, investigator review of scans to assess tumour response, rather than an 
independent central review, is consistent with the findings of a literature review of trials that 
used blinded independent central review, in which treatment efficacy was consistently 
estimated between local and central review despite relatively high discrepancy rates 
(Dodd et al 2008).  The position is also consistent with the recommendations of the 
Pharmaceutical Research and Manufacturers of America (PhRMA)-sponsored PFS 
Independent Working Group (Amit et al 2011).  It is not considered necessary to have an 
independent central review of CT/MRI scans in this study as it is considered to be sufficiently 
large, and adequately blinded, up to the point of objective disease progression, and the safety 
profiles of both hormonal agents at these doses are well established and similar.  There is no 
expectation that toxicities during this study will inadvertently unblind the study.
To be eligible for this study, patients must have breast cancer that is ER/PgR positive and 
human epidermal growth factor receptor 2 (HER2) negative.  Tumour samples will be 
analysed by local laboratories identified by principal investigators.  Hormone and HER2 
receptor status are standard and well recognised investigations.  They are well established as 
predictive tests for appropriate tumour therapy and will be carried out in this trial by local 
laboratories.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
35(87)
4.
PATIENT SELECTION CRITERIA
Investigator(s) should keep a record, the patient screening log, of patients who entered 
pre-study screening.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
4.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1.
Provision of signed, written informed consent prior to any study specific 
procedures.
2.
Histological confirmation of breast cancer.
3.
Positive hormone receptor status (ER +ve and/or PgR +ve) of primary or metastatic 
tumour tissue based on local laboratory assessment.
4.
Have EITHER
∀
locally advanced disease not amenable to surgery or radiotherapy of curative 
intent. Patients may have had one line of cytotoxic chemotherapy, following 
which they must remain unsuitable for therapy of curative intent.
OR
∀
metastatic disease
Patients may have received one line of cytotoxic chemotherapy as previous 
treatment of breast cancer but must show progressive disease prior to enrolment. 
5.
At least 1 lesion (measurable and/or non-measurable) that can be accurately 
assessed at baseline and is suitable for repeated assessment by CT, MRI or plain 
x-ray.
6.
Postmenopausal woman, defined as a woman fulfilling any 1 of the following 
criteria (based on the NCCN definition of menopause [National Comprehensive 
Cancer Network 2008]):
∀
Prior bilateral oophorectomy
∀
Age ≥60 years

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
36(87)
∀
Age <60 years and amenorrheic for 12 or more months in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle 
stimulating hormone and oestradiol in the postmenopausal range.
7.
WHO performance status 0, 1 or 2.
For inclusion in the optional biomarker research component of this study, patients should 
fulfil the following criterion:
!
Provision of informed consent for biomarker research.
If a patient declines to participate in the biomarker research, there will be no penalty or loss of 
benefit to the patient.  The patient will not be excluded from other aspects of the study 
described in this Clinical Study Protocol, so long as they consent to the main protocol.
4.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Presence of life-threatening metastatic visceral disease, defined as extensive hepatic 
involvement, or any degree of brain or leptomeningeal involvement (past or 
present), or symptomatic pulmonary lymphangitic spread.  Patients with discrete 
pulmonary parenchymal metastases are eligible, provided their respiratory function 
is not significantly compromised as a result of disease in the opinion of the 
investigator.
2.
Prior systemic therapy for breast cancer other than one line of cytotoxic 
chemotherapy (the last dose of chemotherapy must have been received more than 
28 days prior to randomisation).
3.
Radiation therapy if not completed within 28 days prior to randomisation (with the 
exception of radiotherapy given for control of bone pain, which must be completed 
prior to the day of randomisation, see Section 5.6).
4.
Herceptin-eligible (HER2 overexpression or gene amplification, ie, 
immunohistochemistry (IHC)3+ve or fluorescence in situ hybridisation (FISH)+ve, 
where appropriate).
5.
Prior treatment with a non-approved or experimental drug for breast cancer.
6.
Concomitant anticancer treatment (with the exception of 
bisphosphonates/denosumab, see Section 5.6).
7.
Prior hormonal treatment for breast cancer.
8.
Use of systemic oestrogen-containing hormone replacement therapy within the 
6 months prior to randomisation.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
37(87)
9.
Current or prior malignancy (other than breast cancer or adequately treated basal 
cell or squamous cell carcinoma of the skin or in situ carcinoma of the cervix) 
unless curatively treated with no evidence of disease within previous 5 years.
10.
Any of the following laboratory values within 4 weeks of randomisation:
∀
Platelets <100 × 109/L
∀
Total bilirubin >1.5 × upper limit of reference range (ULRR) (Patients with 
confirmed Gilbert’s syndrome may be included in the study)
∀
ALT or AST >2.5 × ULRR if no demonstrable liver metastases or >5 × ULRR 
in presence of liver metastases.
11.
History of:
∀
bleeding diathesis (ie, disseminated intravascular coagulation, clotting factor 
deficiency) or 
∀
long-term anticoagulant therapy (although patients treated with anti-platelet 
therapy and low dose warfarin or other anticoagulant agents such as 
acenocoumarol are eligible providing they have an international normalised 
ratio [INR] of ≤1.6).
12.
History of hypersensitivity to active or inactive excipients of FASLODEX™ or 
ARIMIDEX™ or castor oil.
13.
Any severe concomitant condition which makes it undesirable for the patient to 
participate in the trial or which would jeopardise compliance with the study 
protocol, eg, uncontrolled cardiac disease or uncontrolled diabetes mellitus.
14.
Previous randomisation in the present study.
15.
Involvement in the planning and/or conduct of the study (applies to AstraZeneca 
staff, its agents, and/or staff at the study site).
16.
Participation in a clinical study and/or receipt of any investigational drug within 
28 days prior to randomisation (participation in the survival follow-up period of a 
study is not an exclusion).
For procedures for withdrawal of incorrectly enrolled patients, see Section 5.3.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
38(87)
5.
STUDY CONDUCT
5.1
Restrictions during the study
The following restriction should be applied to patients in this trial:
!
Concomitant treatments listed in Section 5.6.
5.2
Patient enrolment and randomisation and initiation of
investigational product
5.2.1
Procedures for enrolment
Patients will be assessed to ensure that they meet the eligibility criteria before being entered 
into the study (see Sections 4.1 and 4.2).  
Written informed consent must be obtained prior to any study-specific assessments.  
Procedures that are part of standard of care may occur before informed consent is obtained.  A 
separate informed consent must be obtained for patients who agree to participate in the 
optional biomarker research component of the study.
Informed consent and enrolment using the centralised Integrated Voice/Web Response System 
(IVRS/IWRS) must occur no more than 28 days before randomisation (ie, Day -28) and no 
later than on Day -7 (in order to ensure availability of study drug at site by Day 0).
The Principal Investigator (PI) or delegate will contact the IVRS/IWRS by telephone or using 
the web to register the patient when she is entered into the study, and will record a unique 
enrolment code (E-code) assigned to the patient by IVRS/IWRS in the patient medical 
records.  The E-code is a 7-digit number made up of the centre number and the patient number 
within that particular centre (eg, the first patient screened at number 0001 would be assigned 
the E-code E0001001).  This number is the patient’s unique identifier and is used to identify 
the patient on the eCRF.
All screened patients are assigned an E-code and will be listed on the patient enrolment and 
identification log irrespective of whether or not they are subsequently randomised.  If the 
patient is not randomised the IVRS/IWRS should be contacted to allow the termination of the 
patient in the system.  If a patient withdraws from participation in the study, the patient 
E-code will not be reused.
5.2.2
Procedures for randomisation
Study treatment cannot be allocated until 7 days after the first patient at the site is registered in 
IVRS/IWRS.  Patients will start study treatment on the day of randomisation (Day 0 [Visit 2]).
The biostatistics group within AstraZeneca or its representative is responsible for generating 
the randomisation scheme.  The randomisation scheme will be produced by a computer 
software program that incorporates a standard procedure for generating random numbers.  
Patients will be stratified at randomisation based on whether (1) they have locally advanced or 

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
39(87)
metastatic breast cancer (2) whether they have received prior chemotherapy for locally 
advanced or metastatic breast cancer or not and (3) they have measurable or non-measurable 
disease.
Patient eligibility must be established before the patient is randomised through the 
IVRS/IWRS and drug is dispensed.  Patients will be randomised strictly sequentially, as 
patients are eligible for randomisation.  Once the eligibility of a patient has been confirmed, 
the Investigator (or nominated assistant) should contact the centralised IVRS/IWRS by 
telephone or using the web for the treatment allocation and dispensing of blinded treatment.  
Patients will be identified to the centralised IVRS/IWRS using patient E-code and date of 
birth (where local regulations allow collection of full date of birth).
5.3
Procedures for handling patients incorrectly enrolled or
randomised or initiated on investigational product
Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances, 
be enrolled or receive study medication.  There can be no exceptions to this rule.
Where patients that do not meet the inclusion criteria are enrolled in error or incorrectly 
started on treatment, or where patients subsequently fail to meet the study criteria post 
initiation, the Investigator should inform the IQVIA Study Physician immediately.  The 
IQVIA Study Physician is to ensure all such contacts are appropriately documented.
5.4
Blinding and procedures for unblinding the study 
5.4.1
Methods for ensuring blinding
Study drug will be labelled using a unique Medication Identification (MedID) number, which 
is linked to the randomisation scheme.  The active study drug and placebo for fulvestrant 
(pre-filled syringes) and anastrozole (tablets) will be identical and presented in the same 
packaging to ensure blinding of the study drug.
5.4.2
Methods for unblinding the study
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the investigator(s) or pharmacists from the IVRS/IWRS.  Routines 
for this will be described in the IVRS/IWRS user manual that will be provided to each centre.
The treatment code must not be broken unless requested by the Investigator once objective 
disease progression has been fully documented in the eCRF.  The treatment code may also be 
broken in cases of unacceptable toxicity to the study treatment or in medical emergencies 
when the appropriate management of the patient requires knowledge of the treatment 
randomisation.  The blind may also be broken if a patient withdraws consent and the 
appropriate management of the patient requires knowledge of the treatment randomisation.  In 
this case, all data for the patient must be fully documented in the eCRF before the blind is 
broken.
When unblinding due to a medical emergency, the Investigator must document and report the 
action to AstraZeneca or its delegate, without revealing the treatment allocation.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
40(87)
AstraZeneca retains the right to break the code for serious adverse events (SAEs) that are 
unexpected and are suspected to be causally related to an investigational product (IP) and that 
potentially require expedited reporting to regulatory authorities.
5.5
Treatments
5.5.1
Identity of investigational products
Investigational product
Dosage form and strength
Manufacturer
Fulvestrant
2 × 250 mg/5 mL solution for intramuscular 
injection; 500 mg fulvestrant
AstraZeneca
Placebo to match fulvestrant
2 × 5 mL solution for intramuscular 
injection, 0 mg fulvestrant
AstraZeneca
Anastrozole
Tablet, 1 mg anastrozole
AstraZeneca
Placebo to match anastrozole
Tablet, 0 mg anastrozole
AstraZeneca
AstraZeneca Pharmaceuticals Investigational Products will pack, label, and supply the IP for 
this study via IVRS/IWRS.  In the post-OS analysis phase (see Section 12.2.1), the IP will be 
supplied to sites manually outside of the IVRS/IWRS system.  During the post-final OS
analysis phase, drug dispensation and reconciliation will be handled by each site on each 
patient’s visit.
Fulvestrant will be supplied as a castor oil-based solution in clear neutral glass pre-filled 
syringes.  Each syringe will contain 250 mg of fulvestrant in 5 mL.  Matching placebo will be 
supplied as a castor oil-based solution in clear neutral glass pre-filled syringes.  Each syringe 
will contain 5 mL.  Fulvestrant (and matching placebo) will be packed into cartons containing 
2 syringes.  Two syringes must be administered to receive the 500 mg dose regimen. 
Anastrozole tablets (or placebo to match) will be supplied as film-coated tablets containing 
1 mg of active substance.  Tablets will be packed into bottles, each containing 112 tablets 
(3 months' supply).
Following the final survival analysis, patients are permitted to continue to receive open-label 
study treatment beyond the closure of the database as a continued access phase if, in the 
opinion of the investigator, they are continuing to receive benefit from treatment with 
fulvestrant or anastrozole, and cannot access appropriate treatment outside of the clinical 
study protocol.  Placebo treatment will be discontinued at this point.  During this period (ie, 
after the final OS analysis), there will be no further survival follow-up for the patient.  If the 
product development reaches a point where alternative options of supply become available 
these will be discussed with the investigator.  Where an alternative supply route is determined 
to be the better option, including commercial products available in some regions, AstraZeneca 
will work with the investigator to transition patients to this alternative supply.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
41(87)
5.5.2
Doses and treatment regimens
In order to support the double-blind, double-dummy design of this trial, each patient will 
receive both study treatments, one being placebo: 
!
Patients randomised to receive fulvestrant will also receive placebo to match the 
anastrozole schedule (tablets, once daily)
!
Patients randomised to receive anastrozole will also receive placebo to match the 
fulvestrant schedule (injections on Days 0, 14 (±3), 28 (±3) and every 28 [±3] days 
thereafter).
Fulvestrant
Fulvestrant 500 mg (or matching placebo) will be administered as two 5 mL intramuscular 
injections, one in each buttock, at each visit on Days 0, 14 (±3), 28 (±3) and every 
28 (±3) days thereafter until the patient permanently discontinues the treatment (refer to 
Section 5.8 for more details on discontinuation).
Each injection will be administered into the gluteus maximus muscle using an aseptic 
parenteral technique, and must be administered slowly over approximately 1 to 2 minutes. 
Following administration, the injection sites should be assessed by the Investigator for any 
local reaction.  The patient should be instructed to report complications to the Investigator.  
Appropriate measures such as the application of heat or cold should be instituted according to 
basic nursing intervention and institutional policy, and pressure should be applied where 
appropriate.  Any severe local site reaction should be treated with appropriate medical 
intervention.  
Dose reductions are not permitted.
For patients on warfarin or other anticoagulant agents such as acenocoumarol, refer to the 
precautions described in Section 5.6.
Anastrozole
Anastrozole (or matching placebo) will be taken orally as a single daily tablet at a dose of 
1 mg/day from randomisation on Day 0 until the patient permanently discontinues the 
treatment (refer to Section 5.8 for more details on discontinuation).  Anastrozole (or placebo 
to match) should be taken at the same time each day, swallowed whole with a drink of water.  
There are no food restrictions for the administration of anastrozole.
5.5.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirement for labelling.  Label 
text will be translated into the local language.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
42(87)
The label will include at least the following information: study code, randomisation number, 
storage conditions and any other market specific requirements. 
For fulvestrant packs, 2 labelled prefilled syringes will be packed into a single-dose carton. 
For anastrozole packs, one labelled bottle containing 112 tablets (3 months' dosing) will be 
supplied.
All packs will be labelled and blinded according to the randomisation scheme.
5.5.4
Storage
All study drugs should be kept in a secure place.  Fulvestrant must be stored in a refrigerator 
(2°C to 8°C) in the original packaging, to protect from light.  Anastrozole must be stored 
below 30°C.
5.6
Concomitant and post-study treatment(s)
All prior treatments for cancer and all drugs given to, or taken by, the patient at entry, during 
the study and up to 8 weeks after the last injection of fulvestrant (or matching placebo) must 
be clearly documented on the appropriate eCRF page.
The following treatment restrictions apply:
!
Patients who have received any prior systemic therapy for breast cancer other than 
one line of cytotoxic chemotherapy are ineligible for the study.  The last dose of 
prior cytotoxic therapy must have been received more than 28 days prior to 
randomisation.
!
No other non-approved or investigational agents for breast cancer are allowed 
concomitantly with study medication.  In addition, given the relatively long 
elimination terminal half-life of fulvestrant, no investigational agent should be 
given concomitantly with study medication, or within 8 weeks of final 
administration of study medication to avoid any potential unknown drug-drug 
interactions.
!
Radiotherapy given for control of bone pain must be completed prior to the day of 
randomisation.
!
Patients requiring radiotherapy or surgery for breast cancer to manage worsening of 
disease after randomisation will be considered to have progressed.  If radiation or 
surgery is performed for breast cancer for reasons other than objective disease 
progression, the patient will continue to receive study medication and be followed 
for objective disease progression.
!
Bisphosphonate/denosumab therapy for the prevention of skeletal related events in 
patients with bone metastases must be started prior to randomisation.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
43(87)
!
The use of herbal or traditional remedies should be discouraged while patients are 
on study treatment.
!
Patients must not receive any other concurrent anticancer therapy, including 
investigational agents, while on study treatment (with the exception of 
bisphosphonate/denosumab therapy for the prevention of skeletal related events 
started prior to randomisation) (see Section 4.2, Exclusion Criterion 6).
!
Sex hormone containing drugs such as hormone replacement therapy, progestational 
agents (megestrol acetate), dehydroepiandrosterone, other androgens (eg, 
oxandrolone) and SERMs (eg, raloxifene [Evista®]) are not permitted during the 
study.  In cases where patients suffer severe menopausal symptoms, management 
with non-hormonal agents, eg, clonidine or venlafaxine, is recommended.  In cases 
of atrophic vaginitis the use of non-hormonal vaginal moisturising or lubricating 
gels or creams is recommended.  Use of oestrogen-containing vaginal creams or 
other topical preparations is not allowed on the study, but use of controlled-release 
vaginal rings (eg, Estring®) may be considered at the Investigator’s discretion in 
severe cases or where all the other treatment possibilities have been exhausted and 
bearing in mind current advice on their use in combination with AIs.
!
In addition, other drugs than those mentioned above which may affect sex hormone 
status or disease response, such as systemic ketoconazole, systemic corticosteroids 
and adrenocortical suppressants are not allowed to begin after randomisation into 
the study.  However, the patient can continue to receive such drugs if they were 
taken before randomisation and the investigator is satisfied that the patient’s 
hormonal status is stable.  Hormone antagonists and related agents (eg, soy 
isoflavones) are not allowed.
The following treatment restrictions relating to anti-coagulant therapy apply:
!
Patients receiving long-term anti-coagulant therapy with warfarin or other 
anticoagulant agents such as acenocoumarol are ineligible for the study unless they 
are receiving a low dose and have an INR ≤1.6.  The INR should be checked to 
ensure that it is ≤1.6 prior to each injection of fulvestrant (or matching placebo).  If 
the INR is >1.6, the injections of fulvestrant (or matching placebo) should be 
withheld until the INR has returned to ≤1.6.  It is advised to apply direct pressure to 
the injection site in these patients.
!
Patients who need to begin anti-coagulant therapy while receiving study treatment 
may be treated, at the discretion of the Investigator, with low molecular weight 
heparin (LMWH).  The LMWH should be temporarily discontinued 12 to 24 hours 
prior to each injection of fulvestrant (or matching placebo) and then resumed 12 to 
24 hours later (depending on the particular LMWH used).  There is an increased 
risk of haemorrhage in these patients and the Investigator should decide whether 

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
44(87)
that risk is outweighed by the possible benefits of continued treatment.  It is advised 
to apply direct pressure to the injection site in these patients.
!
If, in the opinion of the Investigator, warfarin or other anticoagulant agents such as 
acenocoumarol are required instead of LMWH, it should be recognised that the risk 
of intramuscular haemorrhage may be increased.  In this situation, the dose of 
anticoagulant should be chosen according to the condition being treated and the 
INR should be monitored.  The INR should be checked prior to each injection of 
fulvestrant (or matching placebo) and the injections should be withheld if the INR 
>1.6.  It is advised to apply direct pressure to the injection site in these patients. 
!
Patients receiving antiplatelet therapy (acetylsalicylic acid, ticlopidine, clopidogrel, 
etc) may be at increased risk of bleeding from intramuscular injection.  The
Investigator should decide whether that risk is outweighed by the possible benefits 
of continued treatment.  It is advised to apply direct pressure to the injection site in 
these patients.
Other medication, which is considered necessary for the patient’s safety and wellbeing, may 
be given at the discretion of the Investigator and recorded in the appropriate sections of the 
eCRF.
COVID-19 vaccination with authorised vaccines is permitted at the discretion of the 
investigator.
Details of all subsequent breast cancer therapies received from the time of objective disease 
progression on randomised treatment, up to the date of data cut-off for the final OS analysis 
(when at least 65% of patients have died and at least 8 years have passed since the last patient 
was enrolled) must be collected (see Section 6.2.2.2).
5.7
Treatment compliance
The administration of all study medication (including investigational products) should be 
recorded in the appropriate sections of the eCRF.
Patients should be given clear instruction on how and when to take anastrozole or matching 
placebo tablets.  Patients will be asked to return all unused and empty bottles containing 
anastrozole or matching placebo.  Patients will be asked about compliance at each clinic visit 
and their tablet returns should be counted for compliance every 3 months at the time of each 
dispensing visit.  Discrepancies between the number of tablets returned and the expected 
number of tablets returned should be discussed with the patient and the reasons for 
non-compliance documented.  Patients judged to be non-compliant, may continue in the study, 
but should be counselled on the importance of taking their study medication as prescribed.  If 
the patient is not compliant after counselling on the importance of taking study drug as 
instructed, the Investigator may withdraw the patient from study treatment.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
45(87)
Patients must continue with both parts of their blinded treatment (oral tablet plus injection); 
permanently discontinuing one blinded treatment whilst continuing the other is not permitted.  
Any interruptions in treatment must be documented on the appropriate eCRF. 
5.7.1
Accountability
The study drug provided for this study must be used only as directed in the Clinical Study 
Protocol.
The study personnel will account for all study drugs dispensed to and returned from the 
patient.
Investigational product will only be delivered to the centre when the required regulatory 
approvals have been obtained.  Ethic committee approvals may also be required, depending on 
local regulations. It is the Investigator and/or institution’s responsibility to establish a system 
for handling study treatment, so as to ensure that:
!
Deliveries of products from AstraZeneca or their designee are correctly received by 
the Investigator or his or her designee;
!
Such deliveries are properly documented.
The Investigator must maintain accurate records accounting for the receipt and for the 
disposition of the IP.  It must be possible to reconcile delivery records with records of usage 
and returned stocks.  Any discrepancies must be accounted for.
Study site personnel will account for all received study drugs and return all unused study 
drugs to AstraZeneca, its representatives or to an authorised site following AstraZeneca 
approval to conduct destruction.  Certificates of delivery and return should be signed.  The 
destruction of IP will be done according to local requirements. 
5.8
Discontinuation of investigational product
Patients may be discontinued from IP in the following situations:
!
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.  Patients will continue to be followed for objective 
disease progression and survival.
!
AE
!
Severe non-compliance to study protocol
!
Incorrect enrolment and randomisation (see Section 5.3) 
!
Objective disease progression

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
46(87)
!
Patient lost to follow-up
!
Any other reasons not listed above as per Investigator discretion (the reason must be 
adequately documented)
5.8.1
Procedures for discontinuation of a patient from investigational product and 
comparator
Study treatment will continue until objective disease progression (see Section 6.3.3), or other 
criteria for discontinuation are met (see Section 5.8). Patients must stop both treatments 
(active and placebo) upon discontinuation. A patient who discontinues study treatment 
prematurely will always be asked about the reason(s) for discontinuation and the presence of 
any AEs.  Required assessments are detailed in the Study Plan (Table 1).  Ongoing SAEs and 
AEs will be followed up (See Sections 6.4.3 and 6.4.4). The patient should return any leftover 
study drug.
If a patient is withdrawn from study, see Section 5.9.
5.9
Withdrawal from study
5.9.1
Randomised patients
Patients will be considered to have withdrawn from the study only due to the following 
reason:
!
Patient decision (patient withdraws consent from participating in the study)
!
Death
!
Patient lost to follow-up (to declare a patient lost to follow-up, sites should make at 
least 3 attempts to reach out to the patient or the patient’s family.  The 3 attempts 
should be conducted at 3-month intervals)
Patients who choose to withdraw from the study should always be asked specifically whether 
they are withdrawing or continuing their consent for the optional biomarker research, and 
whether they would still allow contact for determination of survival follow-up.  The 
Investigator/delegate should inform AstraZeneca of the withdrawal from these aspects of the 
study. 
If a patient withdraws consent to survival follow-up, no further study procedures or follow-up 
assessments will be performed following withdrawal, and no further data will be collected 
with the exception of publically available death registry information where permitted locally 
(for patients whose termination reason is not death).  The reason for withdrawal from the 
study should be recorded on the eCRF.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
47(87)
5.9.2
Screening failures
Screening failures are patients who do not fulfil the eligibility criteria for the study and are 
therefore not randomised.  These patients should have their reason for study withdrawal 
recorded as ‘Incorrect Enrolment’ (ie, patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screening failures (not randomised 
patients).
6.
COLLECTION OF STUDY VARIABLES
6.1
Recording of data
The Inform Web Based Data Capture (WBDC) system will be used for data collection and 
query handling. The Investigator will ensure that data are recorded on the eCRFs as specified 
in this Clinical Study Protocol and in accordance with the instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
The Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be 
archived at the study site.
Patient-reported outcomes data (Functional Assessment of Cancer Therapy - Breast [FACT-B] 
and EQ-5D™) will be captured using paper questionnaires.
Note that in the period following the final OS analysis (when at least 65% of patients have 
died and at least 8 years have passed since the last patient was enrolled) (see Section 12.2.1), 
SAEs will be reported on a paper-based SAE form.
6.2
Data collection at enrolment and follow-up
6.2.1
Enrolment procedures
The following screening procedures will be performed within 28 days prior to the first dose of 
study drug.  Screening assessments may be performed over several days, if necessary, up to 
Day -1, as long as all results are available prior to randomisation.
!
Recording of demographic data (date of birth, race, ethnic group)
!
A standard medical and surgical history (including all previous, now resolved, 
significant medical conditions), date of diagnosis, extent of disease
!
Recording of tumour characteristics
!
Documentation of ER +ve and/or PgR +ve status and HER2 status (this can be 
based on an archival tumour sample, irrespective of age)

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
48(87)
!
Recording of concomitant medication (including details of previous anticancer 
therapy and prior use of hormone replacement therapy)
!
12-lead ECG
!
Physical examination (including WHO performance status)
!
A blood sample for standard clinical chemistry and haematology assessments 
!
Tumour assessment as per RECIST 1.1 (CT or MRI scan of the chest, abdomen and 
pelvis) 
!
For patients with locally advanced breast cancer, the reason that the patient's locally 
advanced breast cancer is not amenable to therapy of curative intent must be 
recorded in the eCRF.
!
Bone scan or skeletal x-ray survey (nuclear medicine bone scan is preferred) as per 
RECIST 1.1.  Patients who do not have metastatic bone lesions at baseline do not 
require follow-up bone scans or skeletal x-ray surveys.
!
Recording of AEs.
6.2.2
Follow-up procedures
6.2.2.1
Discontinuation visit
The discontinuation visit should take place at the time of the last dose of study drug, or within 
35 days of the last injection of study drug.  Details of AEs and concomitant therapy should be 
followed-up for 8 weeks following the last injection. 
Investigators should refer to the Study Plan (Table 1 and Table 2) for the list of procedures 
and assessments to be performed on discontinuation.
6.2.2.2
Survival follow-up phase
Patients who have progressed will enter the survival follow-up phase of the study, and 
otherwise be managed according to standard clinical practice.
At the time of the data cut-off for the primary analysis, patients who have not yet progressed 
will enter the survival follow-up phase of the study (see Table 2) and will continue to receive 
randomised treatment for as long as they obtain clinical benefit (until they meet the criteria for 
discontinuation).
Following discontinuation of randomised treatment, patients will be followed up for 
subsequent therapies, survival and QoL, unless they have withdrawn their consent.  SAEs and 
details of concomitant medication should be collected for up to 8 weeks after the last injection 
of fulvestrant (or matching placebo).

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
49(87)
After the data cut-off for the primary analysis, further data collection of objective disease 
progression will stop (ie, 12-weekly CT/MRI scans will no longer be recorded in the eCRF).
Patients will complete HRQoL assessments at 3-monthly intervals prior to objective disease 
progression, at the treatment discontinuation visit, at 3-months post-progression, and 
thereafter at 6-monthly intervals post-progression until the cut-off for the OS analysis.  
Following progression, patients should continue to have regular survival follow-up contacts 
every 12 (±2) weeks as detailed in the Study Plan (Table 2) until death or until the final 
survival analysis endpoint has been met, whichever occurs first.  Details of the best response 
to the first breast cancer therapy subsequent to progression will be collected together with the 
drug name and start/stop dates of the first and all subsequent breast cancer therapies.  
Following confirmation of objective disease progression, follow-up may be conducted by 
telephone, and HRQoL questionnaires may be posted to patients for completion, if 
appropriate.
An additional survival contact will be made just after the time of the data cut-off for the 
primary analysis (ie, when approximately 306 PFS events have been observed), regardless of 
when the last survival contact was made.  Another additional survival contact will be made 
around the time of the final data cut-off (when at least 65% of patients have died and at least 
8 years have passed since the last patient was enrolled).  This is to ensure that the survival 
information is as up to date as possible for the analysis of OS.  The patient, patient’s family, or 
the patient’s current physician will be contacted for the latest survival information (unless the 
patient withdraws consent), and public websites searched, if appropriate.
For patients receiving open-label study treatment after the final data cut-off and OS analysis, 
SAEs will be reported on a paper-based SAE report form.
6.3
Efficacy
6.3.1
CT/MRI scans
Patients must have a baseline CT or MRI scan of the chest, abdomen and pelvis, performed 
within 4 weeks before the start of treatment, to assess the level of tumour burden.
The methods of assessment of tumour burden used at baseline (CT or MRI scans of the chest, 
abdomen and pelvis) must be used at each subsequent follow-up assessment.
Following the baseline assessment, efficacy for all patients will be assessed by objective 
tumour assessments every 12 (±2) weeks relative to randomisation, until objective disease 
progression as defined by RECIST 1.1 or until the data cut-off for the primary analysis.  This 
includes patients who discontinue treatment prior to progression.  If an unscheduled tumour 
assessment is performed and the patient has not progressed, every attempt should be made to 
perform the subsequent assessments at the scheduled visits relative to baseline (ie, at 12 week 
[±2] week intervals).

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
50(87)
6.3.2
Bone scan
Patients should have a baseline bone survey performed within 4 weeks before treatment.  
Patients with metastatic bone lesions at baseline should have repeat bone scans or skeletal 
x-ray surveys every 12 weeks (±2 weeks) until progression (or until the data cut-off for the 
primary analysis, whichever occurs first).  Additional bone scans or skeletal x-ray surveys 
should be performed if clinically indicated.  Bone lesions should be followed by the same 
methodology (the single exception to this is where problems with global supplies of 
technetium-99m for bone scans may necessitate a switch to an alternative modality - see 
Section 3.1).  If an unscheduled tumour assessment is performed and the patient has not 
progressed, every attempt should be made to perform the subsequent assessments at the 
scheduled visits relative to baseline (ie, at 12 week [±2] week intervals).
6.3.3
Tumour assessments
RECIST 1.1 criteria will be used to assess patient response to treatment, up to the data cut-off 
for the primary analysis.  The RECIST 1.1 guidelines for measurable, non-measurable, target 
lesion (TL) and non-target lesions (NTLs) and the objective tumour response criteria 
(complete response [CR], partial response [PR], stable disease [SD] or progressive disease 
[PD]) are presented in Appendix D.  In patients with non-measurable disease care must be 
taken to explicitly describe the finding which will qualify for progressive disease.  To achieve 
unequivocal progression there must be an overall level of substantial worsening in non-target 
disease that is of a magnitude that the treating physician would feel it important to change 
therapy (Eisenhauer et al 2009).
Categorisation of objective tumour response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD and PD.  Target lesion (TL) progression will be calculated in 
comparison to when the tumour burden was at a minimum (ie, smallest sum of diameters 
previously recorded on study).  In the absence of progression, tumour response (CR, PR, SD) 
will be calculated in comparison to the baseline tumour measurements obtained before starting 
treatment.
For patients with non-measurable disease only at baseline, categorisation of objective tumour 
response assessment will be based on the RECIST 1.1 criteria of response: CR, PD and 
Non CR/Non PD.
If the Investigator is in doubt as to whether progression has occurred, particularly with respect 
to NTL or the appearance of a new lesion, treatment should continue until the next scheduled 
assessment or sooner if clinically indicated and the patient’s status should be reassessed.  If 
repeat scans confirm progression, then the date of the initial scan should be declared as the 
date of progression.
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  For patients with non-measurable disease only the increase in 
overall tumour burden based on the change in non-measurable disease should be comparable 

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
51(87)
to the increase that would be required to declare PD for measurable disease and merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more NTLs is usually 
not sufficient to qualify for unequivocal progression status.
Following progression, patients should continue to be followed up for survival every 
12 (±2) weeks as outlined in the Study Plan.
In addition, patients requiring radiation or surgery to manage worsening of disease after 
randomisation will be considered to have progressed, but will continue to receive study 
medication and be scanned until imaging criteria for objective disease progression are met.  
Progression due to surgery or radiotherapy will be recorded in the eCRF.  
6.4
Safety
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section.
6.4.1
Definition of adverse events 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product.  An undesirable medical condition can be 
symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the abnormal 
results of an investigation (eg, laboratory findings, ECG).  In clinical studies, an AE can 
include an undesirable medical condition occurring at any time, including run-in or washout 
periods, even if no study treatment has been administered.
Patients will be asked specifically about the presence or development of joint disorders 
(including pain and loss of movement in joints) and back pain at each visit or telephone 
contact.
The term AE is used to include both serious and non-serious AEs.
6.4.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (ie, treatment, follow-up), that fulfils one 
or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
!
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions
!
Is a congenital abnormality or birth defect

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
52(87)
!
Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study
Protocol.
6.4.3
Recording of adverse events
Time period for collection of adverse events
Prior to the data cut-off for the primary analysis non-serious AEs/SAEs will be collected from 
the time of signature of informed consent up until 8 weeks after the last injection of 
fulvestrant (or matching placebo).
During the survival follow-up phase only SAEs for patients still on randomised treatment will 
be recorded and reported.  SAEs for these patients should be collected for up until 8 weeks 
after the last injection of fulvestrant (or matching placebo).
Following the survival follow-up phase, for those patients that remain on study treatment, 
SAEs will be recorded and reported directly into AstraZeneca Patient Safety for up until 
8 weeks after the last injection of fulvestrant (or matching placebo).  In the post-OS analysis 
period (see Section 12.2.1), SAEs will be reported on a paper-based SAE report form.
AEs will be graded according to Common Terminology Criteria for Adverse Event (CTCAE) 
version 4.0.
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca or its representative retains the right to request additional information for 
any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum CTCAE Grade
!
Whether the AE is serious or not
!
Investigator causality rating against the IP (yes or no)
!
Action taken with regard to IP

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
53(87)
!
Outcome.
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date Investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalisation
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment in relation to other medication
!
Description of AE.
The grading scales found in the revised National Cancer Institute CTCAE version 4.0 will be 
utilised for all events with an assigned CTCAE grading.  For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used.  A copy of the CTCAE version 4.0 can be 
downloaded from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.4.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE.  On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE.
Assessment of causality
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
54(87)
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure, the causal relationship 
is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred (when possible) to the recording 
of lists of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report (CSR).  Deterioration as compared to baseline in protocol-mandated 
laboratory values and vital signs should therefore only be reported as AEs if they fulfil any of 
the SAE criteria or are the reason for discontinuation of treatment with the IP.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
should use the clinical, rather than the laboratory term (eg, anaemia rather than low 
haemoglobin value).  In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
Hy's Law
Cases where a patient shows an increase in AST or ALT or total bilirubin may need to be 
reported as SAEs, please refer to Appendix E ‘Actions required in cases of combined increase 
of aminotransferase and total bilirubin – Hy’s Law’, for further instructions. 
Disease progression
Objective disease progression is described in Section 6.3.3.  Disease progression and events 
that are unequivocally due to disease progression should not be reported as AEs during the 
study.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
55(87)
Deaths
All deaths (both cancer-related and other) that occur during the study and within 8 weeks after 
the last dose of randomised treatment must be reported as follows:
!
Death clearly resulting from unequivocal objective disease progression should be 
reported to the study monitor at the next monitoring visit and should be documented 
on the relevant eCRF but should not be reported as an AE or SAE.
!
When death is not due to progression of disease under study, the AE causing death 
must be reported to the study monitor as a SAE within 24 hours. The report should 
contain a comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign main and contributory causes of death.
In the event of death, the patient will be considered as having completed the study.
New cancers
The development of a new cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria.  New cancers are those that are not the primary reason for 
administration of study medication and have been identified after inclusion of the patient into
this clinical study.  They do not include metastases of the original cancer.  Symptoms of 
metastasis or the metastasis itself should not be reported as an AE/SAE as they are considered 
to be disease progression.
6.4.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the eCRF.  For details of how SAEs are 
reported using WBDC, please refer to the study specific Safety Handling Plan.  In the period 
following the final OS analysis (when at least 65% of patients have died and at least 8 years 
have passed since the last patient was enrolled) (see Section 12.2.1), SAEs will be reported on 
a paper-based SAE report form and submitted as per the instructions on the form.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives immediately, or no later than 24 hours from when 
he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately, or no later than 24 hours from when he or she 
becomes aware of it.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
56(87)
The reference document for definition of expectedness/listedness is the IB for fulvestrant and 
the local approved labelling for the active comparator, anastrozole.
6.4.5
Laboratory safety assessment
Blood samples for determination of clinical chemistry and haematology, will be taken at the 
times indicated in the Study Plan (see Table 1).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator/delegate.  The date, time of collection and results will be recorded on the 
appropriate eCRF.
The clinical chemistry and haematology will be performed at a local laboratory at or near to 
the Investigator site.  Sample tubes and sample sizes may vary depending on laboratory 
method used and routine practice at the site.  For blood volume see Section 7.1.
Table 3 lists the laboratory variables to be measured:
Table 3
Laboratory safety variables
Clinical Chemistry
Haematology
Alanine aminotransferase (ALT)
White blood cell count (total)
Aspartate aminotransaminase (AST)
Haemoglobin
Alkaline phosphatase 
Absolute neutrophil count
Creatinine
Platelet count
Total bilirubin 
INR (at Screening [Visit 1], and subsequently 
only when clinically indicated)
6.4.6
Physical examination
A complete physical examination will be performed at screening only and will include an 
assessment of the following: general appearance, respiratory, cardiovascular, abdomen, skin, 
head and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, abdomen, 
musculoskeletal (including spine and extremities), and neurological systems.
Performance status will be assessed using the WHO criteria (refer to Appendix F) at screening 
to check eligibility criteria (see Section 4.1 for inclusion criteria). 
Height (at first examination only) and weight will be recorded throughout the study. For 
timings of assessments refer to the Study Plan (Table 1).
6.4.7
ECG
Twelve-lead ECGs will be recorded throughout the study. For timings of assessments refer to 
the Study Plan (Table 1).  The same method of assessment should be used throughout.  ECGs 

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
57(87)
will be evaluated locally and the results recorded on the relevant eCRF page.  Any clinically 
significant abnormal findings observed and recorded during the study will be recorded as AEs.
6.4.8
Vital signs
Vital signs (blood pressure and heart rate) will be measured throughout the study.  For timings 
of assessments refer to the Study Plan (Table 1).  Blood pressure and heart rate will be 
measured after the patient has been sitting for 5 minutes and before any blood sampling.  
Blood pressure obtained at Day 0 (Visit 2) will be considered the baseline. The measurement 
at Day 0 (Visit 2) must take place prior to the first dose of randomised treatment.
6.5
Patient reported outcomes (PRO)
Patient-reported outcomes, specifically HRQoL questionnaires, must be administered to all 
patients according to the schedules in Table 1 and Table 2.  HRQoL questionnaires will 
continue to be administered to all patients (who have not withdrawn consent) at 3-monthly 
intervals prior to objective disease progression, at the treatment discontinuation visit, at 
3-months post-progression, and thereafter at 6-monthly intervals post-progression up until the 
data cut off for the final OS analysis.
6.5.1
FACT-B
Functional Assessment of Cancer Therapy-Breast (FACT-B) was developed to measure the 
effect of breast cancer and its treatment on HRQoL (Brady et al 1997).  It is a self-reported 
questionnaire, comprising 2 parts; Functional Assessment of Cancer Therapy-General 
(FACT-G) which is a generic questionnaire of 4 subscales (physical, emotional, social/family 
and functional well-being) which was developed for any tumour type, plus a 9-item breast 
cancer subscale specific to symptoms of breast cancer and its treatment.
6.5.2
EQ-5D™
The EQ-5D™questionnaire is a standardised measure of health status, developed by the 
EuroQoL Group in order to provide a simple, generic measure of health for clinical and 
economic appraisal (EuroQol Group 1990). The information can be converted into a single 
index value of health status, generally ranging from 0, representing a health state of being 
dead, to 1, representing a health state of full health. It consists of the EQ-5D™descriptive 
system (comprising 5 dimensions – mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression) plus an overall rating of health status measured on a visual analogue scale.  
For timings of assessments refer to the Study Plan (Table 1 and Table 2).
The EQ-5D™health utility status questionnaire is provided in Appendix G.
6.5.3
Administration of HRQoL questionnaires
HRQoL questionnaires will be administered using paper questionnaires.  The patient should 
complete the HRQoL questionnaires at the scheduled clinic visit at baseline, and throughout 
the study at the times specified in the Study Plan (Table 1 and Table 2).  The patient should 

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
58(87)
also complete a questionnaire at their treatment discontinuation visit.  If any scheduled 
HRQoL assessment is not completed the reason for non-completion should be recorded.
Each centre should allocate responsibility for HRQoL assessment to a specific individual 
(eg, a research nurse).  The AstraZeneca designee will provide training for the relevant 
personnel in the administration of the questionnaires.  Before patients are randomised, they 
must be informed of the rationale for the study and the study details, including the HRQoL 
questionnaires.  The patients should be instructed on how to complete the questionnaire and if 
necessary assisted with completion of a training questionnaire that must be destroyed after 
completion.
It is important that the value and relevance of HRQoL data are explained carefully to 
participating patients so that they are motivated to comply with data collection.  There is 
research evidence that patients with breast cancer value the opportunity to provide information 
on their QoL and health utility status.  The research nurse or appointed individual should also 
stress that the information is confidential.  Therefore, if the patient has any medical problems 
she should discuss them with the doctor or research nurse separately from their HRQoL 
assessment.
The instructions for completion of questionnaires are:
!
It must be completed before any investigations or discussions about the status of the 
patient’s disease with the clinic staff.
!
The patient must complete it herself without any intervention from family, friends, 
centre staff etc.
!
The only exception to this is if the patient is blind or illiterate.  In this case the 
questionnaire may be read to the patient verbatim, however the reader must not aid 
in the interpretation of questions or in the selection of answers.
!
Only one answer to every question should be checked.
!
Centre personnel should not review the responses to the questionnaire with the 
patient or with any other centre staff.
Following completion, the nurse or appointed individual may quickly scan the questionnaire 
visually for completeness and should confirm verbally with the patient that the questionnaire 
has been completed fully.  However, if appropriate, questionnaires may be posted to patients 
for completion following objective disease progression.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
59(87)
6.6
Biomarker research
6.6.1
Collection of tissue sections for biomarker research
Refer to Appendix H and the laboratory manual for details on exploratory biomarker sample 
collection, labelling, preparation, storage and shipment and for details of the type of testing 
that may be carried out on the tumour samples.
If no sample is available patients may still participate in the main part of the study.
6.6.2
Optional tumour tissue sample for biomarker research
Possible future analysis is likely to be performed retrospectively.  The results may be pooled 
with biomarker data from other studies on fulvestrant or anastrozole to generate and/or 
validate emerging hypotheses.
Pre-treatment tumour samples (archival and/or recent) will be collected on randomisation to 
the study for patients who consent to participate in the optional biomarker research.  In 
addition, patients who consent to participate in this biomarker research will also be asked if 
they are willing to provide an optional tumour sample at progression, if, in the opinion of the 
investigator, the biopsy procedure does not pose additional significant risks to the patient.  If a 
tumour sample is already available at the time of progression a further sample is not required.  
This progression tumour sample will enable comparison studies to understand the molecular 
changes in the tumour that are associated with the development of resistance to either 
fulvestrant or anastrazole.
Tumour samples provided by the investigational site may either be in the form of a PET block 
or as 20 pre-cut slides.  Tumour blocks or slides will be stored for potential retrospective 
analysis of biomarkers.
7.
BIOLOGICAL SAMPLING PROCEDURES 
7.1
Volume of blood
The total volume of blood that will be drawn from each patient in this study will depend on 
the length of time the patient receives study drug.  Table 4 is a guide to the approximate 
volume of blood that will be drawn from a patient who receives study treatment for 24 weeks.  
For schedule of required blood draws, see Table 1.
Table 4
Volume of blood to be drawn from each patient
Assessment
Sample volume 
(mL)
No. of samples
Total volume 
(mL)
Safety
Clinical chemistry
3.5
3
10.5
Haematology
2
3
6.0
Total
16.5

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
61(87)
7.5
Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed (or repatriated, if applicable), and the action documented.  If samples 
are already analysed, AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an optional part of the study, then the patient may 
continue in the study.
The PI:
!
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca or its representative
!
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed (or repatriated, if applicable), and the 
action documented
!
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed (or 
repatriated, if applicable), the action documented and the signed document returned 
to the study site
!
Ensures that the patient and AstraZeneca or its representative are informed about 
the sample disposal.
AstraZeneca or its representative ensures the central laboratory(ies) holding the samples is/are 
informed about the withdrawn consent immediately and that samples are disposed 
of/destroyed (or repatriated, if applicable) and the action documented and returned to the 
study site.
8.
ETHICAL AND REGULATORY REQUIREMENTS
8.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca 
policy on Bioethics and Human Biological Samples.
8.2
Patient data protection
The informed consent form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
62(87)
8.3
Ethics and regulatory review
An Ethics Committee (EC) or Institutional Review Board (IRB) should approve the final 
Clinical Study Protocol, including the final version of the ICF and any other written 
information and/or materials to be provided to the patients.  The Investigator will ensure the 
distribution of these documents to the applicable EC, and to the study site staff.
The opinion of the EC should be given in writing.  The Investigator should submit the written 
approval to AstraZeneca or its representative before enrolment of any patient into the study.
The EC should approve all advertising used to recruit patients for the study.
AstraZeneca or its representative should approve any modifications to the ICF that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the EC annually.
Before enrolment of any patient into the study, the final Clinical Study Protocol, including the 
final version of the ICF, is approved by the national regulatory authority or a notification to 
the national regulatory authority is done, according to local regulations.
AstraZeneca or its representative will handle the distribution of any of these documents to the 
national regulatory authorities.
AstraZeneca or its representative will provide Regulatory Authorities, ECs and PIs with safety 
updates/reports according to local requirements, including Suspected Unexpected Serious 
Adverse Reactions (SUSARs), where relevant.
If the PI is responsible (depending on local regulations) for providing the ECs/IRB with 
reports of any serious and unexpected adverse drug reactions from any other study conducted 
with the IP, AstraZeneca or its representative will provide this information to the PI so that 
he/she can meet these reporting requirements.
8.4
Informed consent
The PI(s) at each centre will:
!
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risks and benefits of the study
!
Ensure each patient is notified that they are free to discontinue from the study at any 
time
!
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
63(87)
!
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study
!
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File
!
Ensure a copy of the signed ICF is given to the patient
!
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC.
8.4.1
Biomarker research informed consent (tumour tissue sample only)
The pre-treatment tissue tumour sample for biomarker research is optional and the patient may 
participate in the main study without participating in the biomarker research.  To participate in 
the biomarker research component of the study the patient must sign and date both the ICF for 
the main study (non-biomarker research components of the study) and the biomarker research 
component of the study.  Patients who also consent to provide an additional (optional) tumour 
sample on progression must check the appropriate box indicating that they consent to provide 
this additional sample if it proves feasible to obtain such a sample at the time of progression 
(and if, in the opinion of the investigator, the biopsy procedure does not pose additional 
significant risks to the patient).
Copies of both signed and dated ICFs must be given to the patient and the original filed at the 
study centre.  The PI(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely discontinue the biomarker research aspect of the 
study at any time.
If modifications are made according to local requirements, the new version has to be approved 
by AstraZeneca.
8.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International 
co-ordinating Investigator, the PI, and AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant EC and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed 
for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each PI. For distribution to EC see Section 8.3.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
64(87)
If a protocol amendment requires a change to a centre’s ICF, AstraZeneca and the centre’s EC 
are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each EC.
8.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all 
study-related activities and documents, to determine whether these activities were conducted, 
and data were recorded, analysed, and accurately reported according to the protocol, GCP, 
guidelines of the ICH, and any applicable regulatory requirements.  The Investigator will 
contact AstraZeneca or its representative immediately if contacted by a regulatory agency 
about an inspection at the centre.
9.
STUDY MANAGEMENT BY ASTRAZENECA OR DELEGATE
9.1
Pre-study activities
Before the first patient is entered into the study, it is necessary for a representative of 
AstraZeneca or its representative to visit the investigational study site to:
!
Determine the adequacy of the facilities
!
Determine availability of appropriate patients for the study
!
Discuss with the Investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of
AstraZeneca or its representatives.  This will be documented in a CSA between 
AstraZeneca or its representative and the Investigator.
9.2
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC 
system utilised.
The PI will ensure that appropriate training relevant to the study is given to all of these staff, 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved.
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff).

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
65(87)
9.3
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
!
Provide information and support to the Investigator(s)
!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed
!
Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients.  This 
will require direct access to all original records for each patient (eg, clinic charts)
!
Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.3.1
Source data
Refer to the CSA for location of source data.
9.4
Study agreements
The PI at each centre should comply with all the terms, conditions, and obligations of the 
CSA, or equivalent, for this study.  In the event of any inconsistency between this Clinical 
Study Protocol and the CSA, the terms of Clinical Study Protocol shall prevail with respect to 
the conduct of the study and the treatment of patients and in all other respects, not relating to 
study conduct or treatment of patients, the terms of the CSA shall prevail.
Agreements between AstraZeneca or its representative and the PI should be in place before 
any study-related procedures can take place, or patients are enrolled.
9.4.1
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.5
Study timetable and end of study
The study is expected to start in Quarter 2 or 3, 2012.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
66(87)
The end of the study is defined as the last visit of the last patient, occurring when the last 
patient has discontinued study therapy.
An initial data cut-off for the primary analysis of Progression Free Survival will occur 
following completion of the last patient assessment / visit contributing to this analysis. Data 
analysis will be performed and clinical study report written. A subsequent final data cut-off 
will be performed for the survival follow-up analysis and will occur following the last patient 
assessment/visit contributing to the OS analysis. At this time point, the clinical study database 
will close to new data, data analysis will be performed and a Clinical Study Addendum Report 
written. Patients are however permitted to continue to receive open-label study treatment 
beyond the closure of the database as a continued access phase if, in the opinion of the 
investigator, they are continuing to receive benefit from treatment with fulvestrant or 
anastrozole and cannot access appropriate treatment outside of the clinical study protocol. If 
the product development reaches a point where alternative options of the supply become 
available these will be discussed with the investigator.  Where an alternative supply route is 
determined to be the better option, including commercial products available in some regions,
AstraZeneca will work with the investigator to transition patients to this alternative supply. 
Placebo treatment will be discontinued at this point.  For patients who do continue to receive 
study treatment beyond the time of this data cut-off, investigators will continue to report all 
SAEs to AstraZeneca Patient Safety up until 8 weeks after study treatment is discontinued, in 
accordance with Section 6.4.3 (Recording of Serious Adverse Events). Additionally, any SAE 
or non-serious AE that is ongoing at the time of this data cut-off must be followed up to 
resolution unless the event is considered by the investigator to be unlikely to resolve, or the 
patient is lost to follow-up.
The study may be terminated at individual centres if the study procedures are not being 
performed according to ICH GCP guidelines, or if recruitment is slow. AstraZeneca may also 
terminate the entire study prematurely for other reasons such as for safety if there are concerns 
within this study or in any other study with fulvestrant.
10.
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE
Data management will be performed by IQVIA.
Data will be entered in the WBDC system at the study site. Trained study personnel will be 
responsible for entering data on the observations, tests, and assessments specified in the 
protocol into the WBDC system and according to the eCRF instructions. The eCRF 
Instructions will also guide the study site in performing data entry. Data entered in the WBDC 
system will be immediately saved to a central database. All entries and any changes performed 
will be tracked to provide an audit trail.  Site personnel will enter the data in the eCRFs. The 
data will then be source data verified, reviewed, queried, and updated as needed.  Data queries 
will be raised for inconsistent, impossible, or missing data.
When all data have been coded and validated, medically reviewed by AstraZeneca or its 
representative, and signed by the Investigator, the data will be frozen and then locked to 

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
67(87)
prevent further editing and a clean file will be declared. A copy of the eCRF will be archived 
at the study site when the study has been locked.
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. The study Data Management Plan will also clarify the 
roles and responsibilities of the various functions and personnel involved in the data 
management process.
The study database will be closed and the final survival analysis will be performed when at 
least 65% of patients have died and at least 8 years have passed since the last patient was 
enrolled.
Dictionary coding
Medical Coding will be performed using the most current version of Medical Dictionary for 
Regulatory Activities (MedDRA) and AstraZeneca Drug Dictionary. All coding will be 
performed by IQVIA.
Serious adverse event (SAE) reconciliation
SAE reconciliation reports will be produced and reconciled with Patient Safety Database and / 
or the Investigational Site.
Biomarker data
For biomarker samples (ie, tumour tissue samples), the original date of biopsy (historical 
tumour/re-biopsy tissue samples) and details regarding sample tracking will be recorded in the 
CRF and database.
Management of external data
AstraZeneca or its representative determines the format of the data to be received from 
external vendors and coordinates the flow of data to an external environment or clinical 
database.  AstraZeneca or its representative will ensure that other data collection tools 
(eg, IVRS/IWRS) will be tested/validated as needed.  External data reconciliation will be done 
with the clinical database as applicable.
11.
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE
11.1
Calculation or derivation of efficacy variables
Patients will undergo regular tumour assessments until documented objective disease 
progression as defined by RECIST 1.1 (see Appendix D). 

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
68(87)
At each visit, patients will be programmatically assigned a RECIST visit response of CR, PR, 
SD or PD depending on the status of their disease compared with baseline and previous 
assessments.
If a patient has had a tumour assessment, which cannot be evaluated, then the patient will be 
assigned a visit response of not evaluable (NE) (unless there is evidence of progression in 
which case the response will be assigned as PD).
Progression-free survival (PFS)
Progression-free survival is defined as the time from randomisation until objective disease 
progression as defined by RECIST 1.1, or death (by any cause in the absence of progression).  
Where surgery or radiotherapy is performed to manage worsening of disease, this will be 
captured as a progression event and documented in the eCRF; these patients will continue to 
receive study medication and be scanned until imaging criteria for objective disease 
progression are met.  The PFS time will always be derived based on scan/assessment dates, 
not visit dates.
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied:
!
Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression 
!
When censoring a patient for PFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment.
Patients who have not progressed or died at the time of the cut-off for the primary statistical 
analysis will be censored at the time of their last evaluable RECIST assessment.  Patients who 
progress or die after 2 or more missed visits, will be censored at the time of the latest 
evaluable RECIST' assessment prior to the missed visits.  If a patient has no RECIST 
follow-up assessments or has no evaluable baseline assessment and is still alive at the time of 
the analysis cut-off with no surgery or radiotherapy to manage worsening of disease, then they 
will be censored at 0 days for PFS.  Symptomatic deterioration will not be regarded as a 
progression event.
If a patient discontinues treatment prior to objective disease progression and/or receives a 
subsequent therapy prior to progression then the patient will continue to be followed until 
evidence of objective disease progression (until the data cut-off for the primary analysis) as 
defined by RECIST 1.1 and their PFS time will be derived as defined above.
Overall survival (OS)
OS is defined as the time from randomisation until death by any cause.
Patients who have not died at the time of the statistical analysis will be censored at the time 
they were last known to be alive.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
69(87)
Objective response rate (ORR)
A patient is defined as having objective response (OR) if they have a visit response of CR or 
PR at some point during the study, prior to disease progression.  Objective Response Rate 
(ORR) is defined as the percentage of patients who have OR during the study.  The 
denominator in the calculation of the ORR for each treatment group will be the number of 
patients in the Intention to Treat [ITT] population with measurable disease at baseline.
A visit response of CR is defined when all TL and NTL lesions present at baseline have 
disappeared (with the exception of lymph nodes which must be <10 mm to be considered 
non-pathological) and no new lesions have developed since baseline.  A visit response of PR 
is defined when the sum of diameters of the TLs has decreased by 30% or more compared 
with baseline (with no evidence of progression) and the NTLs are at least stable with no 
evidence of new lesions. 
Duration of response (DoR)
DoR is defined only for patients who had OR, as the number of days from the date of first 
documentation of response (CR/PR) until the date of disease progression (see Section 6.3.3).
Any patient who has not progressed or died by the date of data cut-off, or who has been lost to 
follow-up, will be right-censored in the analysis at the date of their last disease assessment.
Expected duration of response (EDoR)
The EDoR will be estimated using the formula EDoR 
,where 
is the duration of 
response (DoR) as defined earlier for responders,
is the proportion of responders and 
is the mean duration of response for responders. The estimation can be completed by using the 
maximum likelihood estimates of 
and 
, as described by Ellis 
(Ellis et al 2008). The log normal distribution will be used for the duration of response and 
this assumption will be checked for appropriateness.
Clinical benefit rate (CBR)
A patient is defined as having clinical benefit (CB) if they have a visit response of CR or PR 
or stable disease (SD) for at least 24 weeks.  The clinical benefit rate (CBR) is defined as the 
proportion of patients who have CB for a minimum of 154 days (ie, 22 weeks with allowance 
for a 2-week visit window). The number of patients per treatment group in the ITT population 
will be used as the denominator in the calculation of the CBR.
Duration of clinical benefit (DoCB)
DoCB is defined only for patients who had clinical benefit, as the time in days from date of 
randomisation until the date of disease progression (see Section 6.3.3).
Any patient who has not progressed or died by the date of data cut-off, or who has been lost to 
follow-up, will be right-censored in the analysis at the date of their last disease assessment.
)
(x
pE
pf
#
x
p
)
(x
E
p
f
p
)
(x
E
pf

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
70(87)
Expected duration of clinical benefit (EDoCB)
The EDoCB will be calculated using the same approach as described above for EDoR, with
being the duration of clinical benefit (DoCB) as defined earlier for patients with clinical 
benefit,
the proportion of patients with clinical benefit and 
the mean duration of 
clinical benefit for patients with clinical benefit.
11.2
Calculation or derivation of safety variables
In addition to the safety variables mentioned in Section 6.4, the following will also be derived. 
11.2.1
Other significant adverse events (OAE)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs or discontinuations of IP due to AEs (DAEs).  
Based on the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant adverse 
events (OAEs) and reported as such in the CSR.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious) or significant 
additional treatment.
11.3
Calculation or derivation of patient reported outcome variables
11.3.1
FACT-B
The main outcome measure from the FACT-B will be the Trial Outcome Index (TOI), which 
is a summary score of the following subscales:
!
Physical well-being (PWB)
!
Functional well-being (FWB)
!
Breast cancer subscale (BCS)
The TOI is recommended as an efficient and precise summary measure of the physical and 
functional well-being of patients in clinical trials (Brady et al 1997).
The following measure will also be derived from the FACT-B:
!
The total FACT-B score comprising the sum of the scores from all the subscales; 
PWB, FWB, Social/family well-being (SWB), Emotional well-being (EWB), BCS.
11.3.1.1
Items to be reversed
!
Each question in the FACT-B questionnaires has a choice of 5 responses, “Not at 
all”, “A little bit”, “Somewhat”, “Quite a bit” and “Very much”. The scores range 
from 0 (“Not at all”) to 4 (“Very much”) for positively phrased questions. 
x
p
)
(x
E
pf

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
71(87)
Negatively phrased questions have a reverse scoring, from 0 (“Very much”) to 4 
(“Not at all”).  This results in a consistent approach, where higher scores indicate a 
better quality of life.
!
Note, questions that are reversed (via subtraction of the response from 4) are: 
GP1-7, GE1, GE3-6, B1-3 and B5-B8. The response to item P2 ‘I have certain parts 
of my body where I experience pain’ will not be included in the BCS total score, or 
any of the other derived quality of life scores since this item is not currently scored 
within the Functional Assessment of Chronic Illness Therapy (FACIT) scoring 
guidelines (version 4).
11.3.1.2
Missing data 
!
As per the FACIT scoring guidelines, more than 80% of questions in a 
questionnaire must be completed for the questionnaire to be evaluable. If 80% or 
less of questions are completed, the questionnaire is not evaluable, and the data will 
be listed, but not included in any summaries or analyses. 
!
For each domain (PWB, SWB, EWB, FWB and BCS) if more than 50% of the 
items were answered (e.g., a minimum of 4 of 7 items, 4 of 6 items, etc), the 
domain score can be prorated within each domain. This is done by multiplying the 
sum of the domain scores by the number of items in the domain, then dividing by 
the number of items actually answered. This can be done by using the formula 
below:
!
Prorated subscale score = [Sum of item scores] × [N of items in domain] ÷ [N of 
items answered]
!
If at least 50% of the domain items are missing, that domain will be treated as 
missing and thus non-evaluable. The total score for each variable (FACT-B TOI 
and Total FACT-B) is then calculated as the sum of the un-weighted prorated 
scores. If a domain score is non evaluable, any HRQoL variable which these 
domains contribute to is also termed non-evaluable. For example, for the FACT-B 
TOI variable, if PWB is non-evaluable at a visit, the FACT-B TOI variable is also 
non-evaluable at this visit. 
11.3.1.3
Visit responses
The last non-missing assessment before randomisation will be assigned to be the baseline 
assessment.
At each post-baseline visit, the following criteria as listed below in Table 5, will be used to 
assign a FACT-B TOI and FACT-B total score visit response.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
72(87)
Table 5
Summary of HRQoL visit responses
Score
Change from baseline
Visit Response
FACT-B TOI
(0-92 score range)
≥ +6 
Improved
≤ -6 or “Patient too affected by symptoms 
of disease under investigation” is answered 
as the reason for not completing HRQoL at 
visit.
Worsened
>-6 and < +6
No change
Not calculable
Not evaluablea
FACT-B total score
(0-144 score range)
≥ +8 
Improved
≤ -8 or “Patient too affected by symptoms 
of disease under investigation” is answered 
as the reason for not completing HRQoL at 
visit.
Worsened
>-8 and < +8
No change
Not calculable
Not evaluablea
a
The visit response will be classified as Non-Evaluable if ‘No’ has been ticked to the Question 
“Questionnaire completed” and the reason is one of: ‘Patient unwilling’, ‘Patient cannot understand 
instructions’, ‘Patient too sick, other than disease under investigation’, ‘Administrative failure to distribute 
questionnaire to Patient’ or ‘Other’, or if missing data is such that a score cannot be calculated (see section 
above on missing data).
The criteria for worsening of HRQoL, as measured by FACT-B TOI and FACT-B total score 
are based on Eton et al 2004.
Note for some patients it will not be immediately possible to obtain a PRO visit score 
response for a particular subscale, for example:
!
Patients with no baseline score for a particular subscale, or no baseline data at all
!
Patients whose baseline subscale score is close to the maximum or minimum 
possible score to allow an increase or decrease of the specific size to be observed.
∀
For patients whose baseline score is greater than the maximum possible score 
for that subscale minus the score needed to satisfy improvement, the best visit 
response possible will be “No Change”
∀
For patients whose baseline score is less than the threshold needed for 
worsening (eg, a baseline FACT-B TOI < 6) all post-baseline visit responses 
will be considered not-calculable.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
73(87)
11.3.1.4
Time to deterioration of Health related Quality of Life
Time to deterioration of HRQoL as measured by FACT-B TOI will be defined as the interval 
from the date of randomisation to the first assessment of worsened without an improvement in 
the next 12 weeks in FACT-B TOI, or the date of death (by any cause in the absence of 
symptom deterioration).  Time to deterioration as measured by FACT-B total score will be 
derived similarly.
A worsening is as described in Table 5, for example, for FACT-B TOI a decrease in score 
from baseline of greater than or equal to 6, or “Patient too affected by symptoms of disease 
under investigation” answered as the reason for not completing HRQoL at a post-baseline visit 
will constitute a deterioration. Improvement is also as defined within Table 5. 
A deterioration followed by an improvement within 12 weeks means that this first 
deterioration cannot be used in determining the time to deterioration of symptoms.  However, 
if a subsequent worsening is seen, with no improvement in the following 12 weeks, this 
second deterioration will be used to derive the time to deterioration. 
Progression will not be considered as deterioration in symptoms.
Note, under the same principles applied to the primary outcome variable (PFS), time to 
deterioration will be derived regardless of whether the patient withdraws from randomised 
therapy or receives another anti-cancer therapy prior to symptom deterioration.  In addition, 
similar to the analysis of PFS, if a patient either meets the criteria for deterioration, or dies but 
at a time point this is greater than 2 or more missed RECIST assessments of the last evaluable 
HRQoL assessment, then the patient will be censored at the time of the latest evaluable 
HRQoL assessment.
A number of situations will lead to a patient’s time to deterioration of HRQoL endpoints being 
censored.  These are:
!
Patients who have not met the criteria for symptom deterioration or died at the time 
of analysis will be censored at the time of the latest evaluable HRQoL assessment: 
∀
The censoring date will be the date of the last assessment that led to evaluable 
being assigned for the specific HRQoL variable (eg, it could be the case that 
FACT-B TOI was evaluable but FACT-B total score was not evaluable at a 
visit, and in this case FACT-B TOI and FACT-B total score would be censored 
at different time points).
!
Patients with no evaluable baseline or post-baseline data will be censored at 0 days 
unless they die within 2 visits of baseline
!
Patients whose baseline subscale score is close to the minimum possible

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
74(87)
∀
For patients whose baseline score is less than the threshold needed for 
worsening (eg, a baseline FACT-B TOI of < 6), time to worsening will be 
censored at 0 days unless they die within 2 visits of baseline.
The time to deterioration of HRQoL will always be derived based on assessment dates not 
visit dates.
11.3.1.5
HRQoL compliance rates
Summary measures of overall compliance and compliance over time will be derived.  These 
will be based upon:
!
Received forms = number of FACT-B forms received back plus the number not 
received back where the reason was ‘Patient too affected by symptoms of disease 
under investigation’
!
Expected forms = number of patients still in the study at the specified assessment 
time excluding patients in countries with no available translation
!
Evaluable forms = FACT-B forms with at least one subscale that can be 
determined; or where REVPRDI form is ticked ‘Patient too affected by symptoms 
of disease under investigation’
Thus the overall compliance rate is defined as number of patients with an evaluable baseline 
and at least one evaluable follow-up form (as defined above), divided by the number of 
patients expected to have completed at least a baseline FACT-B form.
Compliance over time will be calculated separately for each visit, including baseline, as the 
number of patients with an evaluable form at the time point (as defined above), divided by 
number of patients still expected to complete forms.  Similarly, the evaluability rate over time 
will be calculated separately for each visit, including baseline, as the number of evaluable 
forms (per definition above), divided by the number of received forms. 
Similar compliance rates will also be determined for TOI and FACT-B total score.
11.3.2
EQ-5D™
The EQ-5D™descriptive system comprises 5 questions (see Appendix G) which generate 
possible health states which can be converted into a weighted health status index by applying 
scores from the appropriate available ‘value sets’.
11.4
Calculation or derivation of exploratory biomarker variables
Analyses may be performed to investigate potential biomarkers that may help to define a more 
specific patient population that would benefit from fulvestrant or anastrozole. The results of 
such an analysis will be reported separately to the CSR. 

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
75(87)
12.
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION BY ASTRAZENECA OR DELEGATE
12.1
Description of analysis sets
12.1.1
Efficacy analysis set
The ITT population will include all randomised patients.  Patients in the ITT population will 
be analysed according to the treatment they were randomised to, regardless of the treatment 
actually received.  The ITT population will be used for the primary analysis for this study. 
12.1.2
Safety analysis set
All patients who received at least one dose of randomised treatment will be included in the 
Safety population.  Throughout the safety results sections, erroneously treated patients 
(eg, those randomised to treatment A but actually given treatment B) will be accounted for in 
the group corresponding to the actual treatment initially received (in case they receive the 
wrong treatment initially but subsequently receive the correct treatment).
12.2
Methods of statistical analyses
Table 6 summarises all formal statistical analyses planned for this study.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
76(87)
Table 6
Formal statistical analyses to be conducted and pre-planned sensitivity 
analyses
Endpoint analysed 
Analyses
Progression free survival (PFS) 
Based on RECIST 1.1 data from Investigator assessment, 
surgery/radiotherapy for worsening of disease, or death from 
any cause:
Stratified log-rank test (Primary analysis)
Sensitivity analyses:
Based on RECIST 1.1, or death from any cause
Cox proportional hazards regression model 
Censoring at time of treatment discontinuation/subsequent 
therapy
Analysis of midpoints to assess time evaluation bias
Subgroup analyses
Overall survival
Stratified log-rank test 
Objective response rate
Clinical benefit response 
Stratified logistic regression analysis
Stratified logistic regression analysis
Expected duration of response 
Expected duration of clinical benefit
Analysis following method described by Ellis et al 2008
Analysis following method described by Ellis et al 2008
Time to deterioration of HRQoL
Cox proportional hazards model of time to deterioration of 
FACT-B TOI 
Cox proportional hazards model of time to deterioration of 
FACT-B total score
Pre-specified AEs
Fisher’s exact test analysis of joint disorders and back pain
12.2.1
General principles
All descriptive statistics will be presented by treatment group.  Continuous variables will be 
summarised by the number of observations, mean, standard deviation, median, minimum, and 
maximum.  Categorical variables will be summarised by frequency counts and percentages for 
each category.  Unless otherwise stated, percentages will be calculated out of the population 
total for the corresponding treatment group.
Baseline will be the last assessment of the variable under consideration prior to first dose 
intake.
All data collected will be listed.
Efficacy data will be summarised and analysed on the ITT population.  Safety data will be 
summarised and analysed on the safety population.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
77(87)
There are no planned co-primary analyses.
The key secondary endpoints of OS and ORR will be tested using a multiple testing procedure 
(MTP) with an alpha-exhaustive recycling strategy (Burman et al 2009). With this approach, 
the endpoints of OS and ORR will be tested in a pre-defined order as shown below.  The 
secondary endpoints of CBR, EDoR, EDoCB, FACT-B and EQ-5D will not be included in
this MTP.
Figure 2
Multiple testing procedure
The primary endpoint (PFS) is tested at a single time point when approximately 
306 progression events have occurred. The secondary endpoints of OS and ORR will then be 
tested in the MTP using a weighted proportion of alpha (test mass; the total test mass equals 
alpha) and test mass that becomes available after each rejected hypothesis is recycled to 
secondary endpoints not yet rejected. This testing procedure stops when the entire test mass is 
allocated to non-rejected endpoints. Implementation of this pre-defined ordered testing 
procedure, including recycling, will strongly control the Type I error at 2.5% (1-sided), 
amongst the primary (PFS) and the key secondary (OS, ORR) endpoints.
PFS and ORR will be analysed at one time point only. However, OS will be analysed on 
2 occasions; at the time of the primary analysis and again when at least 65% of patients have 
died and at least 8 years have passed since the last patient was enrolled.  The available alpha 
will be controlled amongst the 2 OS analyses. Lan DeMets (Lan and DeMets 1983) spending 
function that approximates an O’Brien Fleming approach will be used for the interim analysis
where the significance level applied at the interim is dependent upon the proportion of 
information available.
For the final OS analysis, Haybittle-Peto alpha adjustment will be used to account for the 
actual proportion of information available at the interim analysis and alpha already spent. 
MTP is illustrated below:
PFS
ORR
OS
OS
ORR
0.5%
2%

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
78(87)
!
2% alpha was available for OS overall.
!
At the time of the primary analysis in 2016, 142 deaths had been observed and the 
final OS analysis was planned to take place when 50% of patients had died 
(approximately 231 events) as per the original study protocol. Therefore, 
142/231 = 0.6147 of the full death information was assumed to be available and 
0.301% one-sided significance level was used as per Lan DeMets spending 
function.
!
The final OS analysis trigger has changed since the primary analysis in 2016 and as 
per the latest update, the final OS will be triggered when at least 65% of patients 
have died and at least 8 years have passed since the last patient was enrolled. Using 
the steps below, 1.845% one-sided alpha is available for the final OS analysis:
∀
0.301% of alpha has already been spent at the time of the primary analysis
∀
approximately 310 death events are estimated to occur at the time of the final 
OS analysis in July 2022
∀
recalculated proportion of the information available at the time of the primary 
PFS analysis is 142/310 = 0.46
∀
using Haybittle-Peto to account for the recalculated proportion of information 
available at the primary analysis and alpha already spent, 1.845% one-sided 
alpha is available for the final OS
Patient disposition will be summarised for all patients.  A summary of the important protocol 
deviations will be produced.  Demography will be summarised on the ITT population. 
Depending on the extent of any impact, summaries of data relating to patients diagnosed with 
COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, delayed or 
discontinued IP, and other protocol deviations) may be generated.  More detail will be 
provided in the statistical analysis plan (SAP).
12.2.2
Efficacy
12.2.2.1
Progression-free survival (PFS)
The primary statistical analysis will compare the PFS between fulvestrant 500 mg versus 
anastrozole 1 mg using the stratified log-rank test using the Breslow method to handle ties 
(Breslow, 1974).  The HR and its CI can be estimated from the log-rank as follows 
(Berry et al 1991, Collett, 2003, Sellke and Siegmund 1983):
HR = exp(U/V)
95% CI for HR = (exp{U/V – 1.96/ √V}, exp{U/V + 1.96/ √V})

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
79(87)
Where U =
is the stratified log-rank test statistic obtained from the 
SAS LIFETEST procedure, √V=√
, is its standard deviation,
denotes the stratum 
and d1ki and e1ki are the observed and expected events in group 1, stratum k.
Results will be presented in terms of an estimate of the HR (fulvestrant 500 mg: anastrozole 
1 mg), associated CI and p-value.  A HR less than 1 would indicate that, on average, PFS is 
improved on fulvestrant 500 mg when compared with anastrozole 1 mg.
The decision as to whether or not the primary study objective has been achieved will be made 
upon the superiority test for PFS using the log-rank test in ITT population, at the 5% (2-sided) 
significance level.
The number of events at the time of analysis, as well as point estimates of the median, lower 
and upper quartile for PFS (when feasible to do so) will be presented for each treatment group 
and PFS will be displayed graphically using Kaplan-Meier plots.
Proportional hazards will be tested firstly by examining plots of complementary log-log (event 
times) versus log (time) and, if these raise concerns, by fitting a time dependent covariate to 
assess the extent to which this represents random variation.  If a lack of proportionality is 
evident, the variation in treatment effect will be described by presenting piecewise HR 
calculated over distinct time-periods. In such circumstances, the HR can still be meaningfully 
interpreted as an average HR over time unless there is extensive crossing of the survival 
curves.  If lack of proportionality is found, this may be as a result of treatment-by-covariate 
interactions, which will be investigated.
Sensitivity analyses
A sensitivity analysis using Cox Proportional Hazards regression will also be performed, with 
treatment and relevant baseline prognostic covariates included in the model.  The Efron 
method will be used to handle ties (Efron, 1977).  The covariates to be included are ER +ve 
and PgR +ve at baseline (no/yes), metastatic disease at baseline (no/yes), use of 
bisphosphonates as concomitant medication at baseline (yes versus no), measurable disease at 
baseline (yes versus no), prior chemotherapy for locally advanced or metastatic breast cancer 
(yes versus no) and geographic region (geographic split to be defined in SAP) and prior 
systemic oestrogen-containing hormone replacement therapy (no/yes).  This analysis will be 
performed on the ITT population.
A global interaction test will be performed to test if overall the treatment benefit was 
consistent across the covariates.  This will be done by fitting a model with treatment and the 
3 stratification factors and comparing that with the model with treatment, the 3 factors and the 
factor by treatment interactions. If the fit of the model is not significantly improved (at the 
10% level) then it will be concluded that overall the treatment effect is consistent across the 
covariates. 
)
,
(
1
1
ki
k
k
i
ki
k
e
d
U
∀
#
∃
∃∃
∃
k
k
V
k

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
80(87)
This test will be conducted by taking the difference in the log likelihood between the model 
containing all the covariates and 2-way interactions and the model without these interactions. 
The difference will be multiplied by -2 (ie, minus 2) and this statistic has a chi-squared 
distribution with degrees of freedom equal to the difference in the number of parameters 
between the two models.
If the global interaction test is significant, for each of the covariates listed above the covariate 
by treatment interaction will also be assessed individually and if the p-value for this is not 
significant (at the 10% level) then the treatment effect will be assumed to be consistent across 
the values of this covariate.  These tests will be carried out in the same way as the global 
interaction test.  Treatment effect may be investigated in groups as defined by these covariates 
to locate the source and nature of any interactions or if that would aid interpretation of the trial 
results.
A sensitivity analysis will be performed whereby patients are censored at the time they 
discontinue treatment and/or receive subsequent therapies prior to documented disease 
progression.
A sensitivity analysis will be performed based on RECIST 1.1, or death from any cause.
In order to assess evaluation-time bias, the primary PFS analysis will be repeated, but based 
on the midpoint of the time between progression detected and the previous visit. To support 
this analysis, the mean of patient-level average inter-assessment times will be tabulated for 
each treatment.
Subgroup analysis
Analysis of the following subgroups as defined by the 7 covariates will be performed, if 
numbers permit, for the ITT population:
!
ER +ve and PgR +ve at baseline (no/yes)
!
Metastatic disease at baseline (no/yes)
!
Used bisphosphonates as concomitant medication at baseline (no/yes)
!
Measurable disease at baseline (no/yes)
!
Prior chemotherapy for locally advanced or metastatic breast cancer (yes versus no)
!
Geographic region (geographic split to be defined in the SAP)
!
Prior systemic oestrogen-containing hormone replacement therapy (no/yes)
The subgroup analyses will be performed on the primary endpoint PFS only using the 
stratified log-rank test.  For each subgroup, the number and percentage of events at the time of 
analysis and the median PFS will be presented.  In addition, the HR and 95% CI for the 

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
81(87)
treatment group comparison will be presented and the data will be displayed graphically using 
a Kaplan-Meier plot for each subgroup.
A forest plot will be produced for PFS showing the hazard ratio with associated 95% CIs of 
each subgroup.
12.2.2.2
Objective response rate (ORR)
A summary of ORR will be presented by treatment group.  In addition, ORR will be analysed 
using a logistic regression model including the 3 stratification factors.  The results will be 
expressed in terms of the odds ratio and its associated CI and p-value.  The p-value will be 
based on twice the change in log-likelihood resulting from the addition of treatment factor to a 
model that contains the factors.  CIs will be profile likelihood intervals (eg, using option LRCI 
in SAS PROC GENMOD).
12.2.2.3
Overall survival (OS)
OS will be compared between fulvestrant 500 mg and anastrozole 1 mg using the stratified 
log-rank test.  Results will be presented in terms of an estimate of the HR (fulvestrant 500 mg: 
anastrozole 1 mg), associated CI and p-value.  HR and 95% CIs will be calculated using the 
same methodology as for PFS.  A HR less than 1 would indicate that, on average, OS is 
improved on fulvestrant 500 mg when compared with anastrozole 1 mg.
The number of events at the time of analysis, as well as point estimates of the median, lower 
and upper quartile for OS (when feasible to do so) will be presented for each treatment group 
and OS will be displayed graphically using Kaplan-Meier plots.
12.2.2.4
Clinical benefit rate (CBR)
A summary of CBR will be presented by treatment group.  In addition, CBR will be analysed 
using a logistic regression model including the 3 stratification factors.   The results will be 
expressed in terms of the odds ratio and its associated CI and p-value.  The p-value will be 
based on twice the change in log-likelihood resulting from the addition of treatment factor to a 
model that contains the 3 stratification factors.  CIs will be profile likelihood intervals 
(eg, using option LRCI in SAS PROC GENMOD).
12.2.2.5
Duration of response (DoR)
DoR will be presented graphically per treatment group using Kaplan-Meier plots.  Estimates 
of the median DoR for each treatment group and the corresponding 95% CI will also be 
presented.
12.2.2.6
Duration of clinical benefit (DoCB)
DoCB will be presented graphically per treatment group using Kaplan-Meier plots.  Estimates 
of the median DoCB for each treatment group and the corresponding 95% CI will also be 
presented.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
82(87)
12.2.2.7
Expected duration of response (EDoR)
An analysis of EDoR will be performed by calculating the ratio of the EDoR of fulvestrant 
500 mg to that of anastrozole 1 mg.  The 95% CI will also be provided.  By including all 
evaluable patients, this methodology allows an unbiased comparison of treatments for DoR 
(Ellis et al 2008).
12.2.2.8
Expected duration of clinical benefit (EDoCB)
An analysis of EDoCB will be performed by calculating the ratio of the EDoCB of fulvestrant 
500 mg to that of anastrozole 1 mg.  The 95% CI will also be provided.  By including all 
randomised patients, this methodology allows an unbiased comparison of treatments for 
DoCB (Ellis et al 2008).
12.2.3
Tolerability and safety
12.2.3.1
Adverse events (AE)
AE data will be summarised using MedDRA by preferred term and system organ class.  
Summaries will be produced based upon number of patients and number of AEs.  The number 
of patients who withdraw or die due to AEs will be summarised.  AEs will also be 
summarised by maximum reported CTCAE grade and Investigator's causality assessment.  A 
summary of the number of patients with a causally related AE will also be produced.  The 
number of patients with a causally related AE with an outcome of death will be presented.  A 
summary of all deaths and the primary cause of death will be produced.  A summary of the 
key information for deaths will also be produced.  SAEs and OAEs will be summarised.
The incidence of the pre-defined OAEs of interest (ie, joint disorders and back pain) will be 
compared between the two treatment groups using Fisher's exact test.  The analysis will be 
done on the Safety population.
12.2.3.2
Health-related Quality of Life (HRQoL)
For each applicable visit, a summary of the FACT-B scores, and also the change from baseline 
scores, will be summarised and presented graphically.  Specifically, the TOI, Total FACT-B, 
and the individual subscale scores will be summarised in this way.
The scores from other PRO assessments and their change from baseline will be summarised 
and presented graphically by visit. 
The analysis of time to deterioration of TOI and FACT-B total score will be as outlined for the 
primary PFS analysis. 
Change from baseline in all HRQoL subscale scores will be listed and summarised but no 
formal statistical analysis will be performed. 
The EQ-5D™ data will be listed and summarised only.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
84(87)
13.2
Overdose 
If an overdose occurs, routine supportive measures should be taken.
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives within
one day, ie, immediately, or no later than 24 hours from when he or she becomes aware of 
it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with an SAE, standard reporting timelines apply, see Section 6.4.4.  
For other overdoses, reporting should be done within 30 days.
13.3
Pregnancy
Only postmenopausal women are eligible to participate in this study.  Pregnancy should be 
ruled out prior to study start in case of doubt.
14.
LIST OF REFERENCES
Amit et al 2011
Amit O, Mannino F, Stone AM, Bushnell W, Denne J, Helterbrand J, et al.  Blinded 
independent central review of progression in cancer clinical trials: Results from a meta-
analysis.  Eur J Cancer 2011;47(12):1772–8.
Berry et al 1991
Berry G, Kitchin RM, Mock PA. A comparison of two simple hazard ratio estimators based 
on the logrank test. Statistics in Medicine 1991;10:749-755.
Brady et al 1997
Brady MJ, Cella DF, Mo F, Bonomi AE, Tulsky DS, Lloyd SR, et al. Reliability and validity
of the functional assessment of cancer therapy-breast (FACT-B) quality of life instrument. J 
Clin Oncol 1997;15:974–86.
Breslow, 1974
Breslow, NE. Covariance Analysis of Censored Survival Data. Biometrics 1974;30:89–99.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
85(87)
Burman et al 2009
Burman CF, Sonesson C, Guilbaud O.  A recycling framework for the construction of 
Bonferroni-based multiple tests.  Statistics in Medicine 2009:28;739–761.
Chia et al 2008
Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M et al.  Double-blind, 
randomized placebo controlled trial of fulvestrant compared with exemestane after prior 
nonsteroidal AI therapy in postmenopausal women with hormone receptor-positive, advanced 
breast cancer: results from EFECT.  J Clin Oncol 2008;26(10):1664–70.
Collett, 2003
Collett D.  Modelling Survival Data in Medical Research. 2nd ed. Boca Raton (FL): Chapman 
& Hall/CRC; 2003. (Available upon request)
Di Leo et al 2010
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al.  Results 
of the CONFIRM Phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in 
postmenopausal women with estrogen receptor–positive advanced breast cancer.  J Clin Oncol 
2010;28:4594–4600.
Dodd et al 2008
Dodd LE, Korn EL, Freidlin B, et al. Blinded independent central review of progression-free 
survival in phase III clinical trials: important design element or unnecessary expense? J Clin 
Oncol. 2008;26(22):3791–3796.
Efron, 1977
Efron, B. The Efficiency of Cox’s Likelihood Function for Censored Data. J Am Stat Assoc 
1977;72:557–565.
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer 
2009:45:228–247.
Ellis et al 2008
Ellis S, Carroll KJ, Pemberton K.  Analysis of duration of response in oncology trials, 
Contemp Clin Trials 2008;29:456–65.
Eton et al 2004
Eton DT, Cella D, Yost KJ, Yount SE, Peterman AH, Neuberg DS, Sledge GW, Wood WC. A 
combination of distribution- and anchor-based approaches determined minimally important 
differences (MIDs) for four endpoints in a breast cancer scale. Journal of Clinical 
Epidemiology 2004;57:898–910.

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
86(87)
EuroQol Group 1990
EuroQol–a new facility for the measurement of health-related quality of life. The EuroQol 
Group. Health Policy. 1990;16(3):199–208.
Fallowfield et al 1999
Fallowfield LJ, Leaity SK, Howell A, Benson S, Cella D. Assessment of quality of life in 
women undergoing hormonal therapy for breast cancer: validation of an endocrine symptom 
subscale for the FACT-B. Breast Cancer Research and Treatment 1999;55(2):189–199.
Howell et al 2002
Howell A, Robertson JFR, Quaresma Albano A, Aschermannova A, Mauriac L, Kleeberg UR, 
et al. Fulvestrant, formerly ICI 182, 780, is as effective as anastrozole in postmenopausal 
women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 
2002;20(16):3396–3403.
Howell et al 2004
Howell A, Robertson JFR, Abram P, Lichinitser MR, Elledge R, Bajetta E, et al.  Comparison 
of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal 
women previously untreated with endocrine therapy: a multinational, double-blind, 
randomized trial.  J Clin Oncol 2004;22(9):1605–13.
Lan and DeMets 1983
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70;3:659–63.
National Comprehensive Cancer Network 2008
National clinical practice guidelines in oncology: breast cancer. V2.2008. Available from: 
URL: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site
Osborne et al 2002
Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, et al.  Double-blind, 
randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in 
postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: 
results of a North American trial.  J Clin Oncol 2002;20(16):3386–95.
Robertson et al 2009
Robertson JFR, Llombart-Cussac A, Rolski J, Feltl D, Dewar J, Macpherson E, et al.  Activity 
of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast 
cancer: results from the FIRST study.  J Clin Oncol 2009;27:4530–5.
Robertson et al 2010
Robertson JFR, Lindemann JPO, Llombart-Cussac A, Rolski J, Feltl D, Dewar J, et al.  A 
comparison of fulvestrant 500 mg with anastrozole as first-line treatment for advanced breast 
cancer: follow-up analysis from the 'FIRST' study.  33rd Annual San Antonio Breast Cancer 
Symposium.  Abstract (S1–3).

Revised Clinical Study Protocol
Drug Substance Fulvestrant  
Study Code D699BC00001
Edition Number 6
Date 17 December 2021
87(87)
Sellke and Siegmund 1983
Sellke T and Siegmund D. Sequential analysis of the proportional hazards model. Biometrika 
1983;70:315–326.

 
 
Clinical Study Protocol Apendix B 
 
Drug 
Substance 
Fulvestrant 
 
Study 
Code 
D69BC01 
 
Edition 
Number 
1.0 
 
Date 
19 April 2012 
 
 
 
 
 
 
 
 
 
 
Apendix B 
Aditional Safety Information 
 

Clinical Study Protocol Apendix B 
Drug Substance Fulvestrant 
Study Code D69BC01 
Edition Number 1.0 
Date 19 April 2012 
3(3) 
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION 
The folowing factors should be considered 
when deciding if there is a “reasonable 
posibility” that an AE may have ben caused by the drug. 
x
Time Course. Exposure to suspect drug
. Has the subject actualy received the 
suspect drug? Did the AE ocur in a r
easonable temporal relationship to the 
administration of the suspect drug? 
x
Consistency with known drug profile. Was 
the AE consistent with the previous 
knowledge of the suspect drug (pharmacology
 and toxicology) or drugs of the same 
pharmacological clas? OR could the AE 
be anticipated from its pharmacological 
properties? 
x
Dechalenge experience. Did the AE resolv
e or improve on stoping the dose of the 
suspect drug? 
x
No alternative cause. The AE canot be 
reasonably explained by another aetiology 
such as the underlying disease, other drug
s, other host or environmental factors. 
x
Rechalenge experience. Did the AE reocur if the suspected drug was reintroduced 
after having ben stoped? AstraZenec
a would not normaly recomend or suport 
a rechalenge. 
x
Laboratory tests. A specific laboratory 
investigation (if performed) has confirmed 
the relationship? 
A “reasonable posibility” could be considered to exist for an AE where one or more of these 
factors exist. 
In contrast, there would not be a “reasonable posibility” of causality if none of the above 
criteria aply or where there is evidence of exposure and a reasonable time course but any 
dechalenge (if performed) is negative or ambigu
ous or there is another more likely cause of 
the AE. 
In dificult cases, other factors could be considered such as: 
x
Is this a recognised feature of overdose of the drug? 
x
Is there a known mechanism? 
Ambiguous cases should be considered as be
ing a “reasonable posibility” of a causal 
relationship unles further evidence becomes availa
ble to refute this. Causal relationship in 
cases where the disease under study has deteriorated
 due to lack of efect
 should be clasified 
as no reasonable posibility. 

 
 
Clinical Study Protocol Appendix C 
 
Drug Substance 
Fulvestrant 
 
Study Code 
D699BC00001 
 
Edition Number 
1.0 
 
Date 
19 April 2012 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix C 
International Airline Transportation Association (IATA) 6.2 Guidance 
Document 
 

Clinical Study Protocol Appendix C 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
2(3) 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm).  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus: 
x
are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name: 
x
UN 3373 – Biological Substance, Category B 
x
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
x
Clinical trial samples will fall into Category B or exempt under IATA regulations 
x
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm) 
x
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
x
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable 

Clinical Study Protocol Appendix C 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
3(3) 
x
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used. 

 
 
Clinical Study Protocol Appendix D 
 
Drug Substance 
Fulvestrant 
 
Study Code 
D699BC00001 
 
Edition Number 
1.0 
 
Date 
19 April 2012 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix D 
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours) 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
2(15) 
TABLE OF CONTENTS 
PAGE
 
TABLE OF CONTENTS.........................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS............................4 
1. 
INTRODUCTION ...................................................................................................5 
2. 
DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET 
AND NON-TARGET LESIONS.............................................................................5 
3. 
METHODS OF ASSESSMENT..............................................................................6 
3.1 
CT and MRI.............................................................................................................7 
3.2 
Clinical examination................................................................................................7 
3.3 
X-ray ........................................................................................................................7 
3.3.1 
Chest X-ray..............................................................................................................7 
3.3.2 
Plain X-ray...............................................................................................................7 
3.4 
Ultrasound................................................................................................................7 
3.5 
Endoscopy and laparoscopy.....................................................................................7 
3.6 
Tumour markers.......................................................................................................7 
3.7 
Cytology and histology............................................................................................8 
3.8 
Isotopic bone scan....................................................................................................8 
3.9 
FDG-PET scan.........................................................................................................8 
4. 
TUMOUR RESPONSE EVALUATION ................................................................9 
4.1 
Schedule of evaluation.............................................................................................9 
4.2 
Target lesions (TL) ..................................................................................................9 
4.2.1 
Documentation of target lesions ..............................................................................9 
4.2.2 
Evaluation of target lesions....................................................................................10 
4.3 
Non-target lesions (NTL).......................................................................................10 
4.3.1 
Evaluation of non-target lesions ............................................................................10 
4.4 
New lesions............................................................................................................11 
4.5 
Symptomatic deterioration.....................................................................................12 
4.6 
Evaluation of overall visit response.......................................................................12 
5. 
SPECIFICATIONS FOR RADIOLOGICAL IMAGING.....................................13 
5.1 
CT scan ..................................................................................................................13 
5.2 
MRI scan................................................................................................................14 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
3(15) 
5.3 
FDG-PET scans .....................................................................................................14 
5.3.1 
PET/CT scans.........................................................................................................15 
6. 
REFERENCES ......................................................................................................15 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
4(15) 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or special term 
Explanation 
CR 
Complete response 
CT 
Computed Tomography 
FDG-PET 
Fluorodeoxyglucose (18F) positron emission tomography 
iv 
intravenous 
MRI 
Magnetic Resonance Imaging 
NA 
Not applicable 
NE 
Not evaluable 
NTL 
Non-target lesion 
PD 
Progressive disease 
RECIST 1.1 
Response Evaluation Criteria In Solid Tumours, Version 1.1 
SD 
Stable disease 
TL 
Target lesion 
 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
5(15) 
1. 
INTRODUCTION 
This appendix details the implementation of Response Evaluation Criteria In Solid Tumours, 
(RECIST) Version 1.1 Guidelines (Eisenhauer et al 2009) for the FALCON study 
(Study D699BC00001) with regards to Investigator assessment of tumour burden including 
protocol-specific requirements for this study. 
2. 
DEFINITION OF MEASURABLE, NON-MEASURABLE, 
TARGET AND NON-TARGET LESIONS 
At least one lesion (measurable and/or non-measurable) that can be accurately assessed at 
baseline by computed tomography (CT), magnetic resonance imaging (MRI) and plain X-ray 
and is suitable for repeated assessment. 
Measurable: 
A lesion, not previously irradiated, that can be accurately measured at baseline as 10 mm in 
the longest diameter (except lymph nodes which must have short axis 15 mm) with CT or 
MRI and which is suitable for accurate repeated measurements. 
Non-measurable: 
x
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with 10 to <15 mm short axis at baseline*). 
x
Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or 
MRI. 
x
Previously irradiated lesions** 
x
Skin lesions assessed by clinical examination 
x
Brain metastasis 
* Nodes with <10 mm short axis are considered non-pathological and should not be recorded 
or followed as Non-target Lesions (NTL). 
**Localised post-radiation changes which affect lesion sizes may occur.  Therefore, lesions 
that have been previously irradiated will not be considered measurable and must be selected as 
NTL at baseline and followed up as part of the NTL assessment. 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
6(15) 
Special cases: 
x
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. Blastic lesions are considered non-measurable. 
x
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient; these should be selected as target lesions. 
Target lesions: 
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as 
target lesions (TL) at baseline. 
Non-target lesions: 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline. 
3. 
METHODS OF ASSESSMENT 
The same method of assessment and the same technique should be used to characterize 
each identified and recorded lesion at baseline and during follow-up visits. 
A summary of the methods to be used for RECIST assessment is provided below and those 
excluded from tumour assessments for this study are highlighted, with the rationale provided. 
Table 1: Summary of methods of assessment 
Target Lesions  
Non-Target Lesions 
New Lesions 
CT (preferred) 
MRI 
CT (preferred) 
MRI 
Clinical examination (for skin 
lesions only) 
X-ray, chest X-ray 
 
CT (preferred) 
MRI 
Clinical examination (for skin 
lesions only) 
X-ray, chest X-ray 
Ultrasound 
Bone scan(a) 
FDG-PET(a) 
a 
Can be used if also assessed at baseline (as per Section 3.8 and 3.9) 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
7(15) 
3.1 
CT and MRI  
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and identification 
of any new lesions.  
In this study it is recommended that CT examinations of the chest, abdomen, and pelvis will 
be used to assess tumour burden at baseline and follow-up visits.  CT examination with 
intravenous (iv) contrast media administration is the preferred method.  MRI should be used 
where CT is not feasible or it is medically contra-indicated.  For brain lesion assessment, MRI 
is the preferred method. 
3.2 
Clinical examination  
Clinical examination will not be used for assessment of TL in this study.  Clinically detected 
lesions can be selected as target lesions if they are assessed by CT or MRI scans.  Clinical 
examination can be used to assess NTL and to identify the presence of new lesions for skin 
lesions only. 
3.3 
X-ray 
3.3.1 
Chest X-ray 
Chest X-ray assessment will not be used for assessment of TL in this study, as they will be 
assessed by CT examination or MRI examination.  Chest X-ray can, however, be used to 
assess NTL and to identify the presence of new lesions. 
3.3.2 
Plain X-ray  
Plain X-ray may be used in this study as a method of assessment for bone NTL and to identify 
the presence of new bone lesions.  
3.4 
Ultrasound  
Ultrasound examination will not be used in this study for assessment of TL and NTL as it is 
not a reproducible method, does not provide an accurate assessment of tumour size and it is 
subjective and operator dependent.  Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed 
then new lesions should be confirmed by CT or MRI examination. 
3.5 
Endoscopy and laparoscopy  
Endoscopy and laparoscopy will not be used in this study for tumour assessments as they are 
not validated in the context of tumour assessment. 
3.6 
Tumour markers  
Tumour markers will not be used in this study for tumour response assessments as per 
RECIST 1.1. 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
8(15) 
3.7 
Cytology and histology  
Histology will not be used in this study as part of the tumour response assessment as per 
RECIST 1.1.  
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease.  In such circumstances, the cytology is necessary to differentiate between 
response / stable disease (an effusion may be a side effect of the treatment) and progressive 
disease (if the neoplastic origin of the fluid is confirmed).  Where cytology findings are not 
available, any effusion that significantly worsens (from trace to large) or appearance of 
clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTL, or disease progression due to new lesions.  
3.8 
Isotopic bone scan  
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or 
X-ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.   
In this study isotopic bone scans may be used as a method of assessment to identify the 
presence of new bone lesions at follow-up visits, provided a baseline scan is available.  New 
lesions will be recorded where a positive hot-spot that was not present on the baseline bone 
scan assessment is identified on a bone scan performed at any time during the study.  The 
Investigator should consider the positive hot-spot to be a significant new site of malignant 
disease and represent true disease progression in order to record the new lesion.  Confirmation 
by CT, MRI and X-ray is recommended where bone scan findings are equivocal. 
3.9 
FDG-PET scan  
Fluorodeoxyglucose (18F) positron emission tomography (FDG-PET) scans may be used in 
this study as a method for identifying new lesions (provided a baseline scan is available), 
according with the following algorithm:  new lesions will be recorded where there is positive 
FDG uptake* not present on baseline FDG-PET scan or in a location corresponding to a new 
lesion on CT/MRI at the same follow-up visit.  If there is no baseline FDG-PET scan 
available, and no evidence of new lesions on CT/MRI scans then follow-up CT/MRI 
assessments should be continued, scheduled as per protocol or clinical indicated, in order to 
confirm new lesions. 
* A positive FDG-PET scan lesion should be reported only when an uptake greater than twice 
that of the surrounding tissue is observed. 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
9(15) 
4. 
TUMOUR RESPONSE EVALUATION  
4.1 
Schedule of evaluation 
Baseline assessments should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based 
on signs and symptoms of individual patients and should be performed no more than 28 days 
before the start of study treatment.  Follow-up assessments will be performed every 
12 (±2) weeks after randomisation, until objective disease progression as defined by 
RECIST 1.1.  Any other sites at which new disease is suspected should also be adequately 
imaged at follow-up. 
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimise any unintentional bias caused by some patients 
being assessed at a different frequency than other patients. 
4.2 
Target lesions (TL) 
4.2.1 
Documentation of target lesions 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved should be identified as TL at baseline.  
TLs should be selected on the basis of their size (longest diameter for non-nodal lesions or 
short axis for nodal lesions), but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected. 
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters.  At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters.  At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters. 
Special cases: 
x
For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis.  
x
If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan. 
x
If a lesion has completely disappeared, the longest diameter should be recorded as 
0 mm. 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
10(15) 
x
If a TL splits into two or more parts, then record the sum of the diameters of those 
parts.  
x
If two or more TLs merge then the sum of the diameters of the combined lesion 
should be recorded for one of the lesions and 0 mm recorded for the other lesion(s).   
x
If a TL is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned.  If an accurate measure can be given, this 
should be recorded, even if it is below 5 mm. 
x
If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion.  
x
When a TL has had any intervention eg, radiotherapy, embolisation, surgery etc., 
during the study, the size of the TL should still be provided where possible. 
4.2.2 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumour visit 
response for TL. 
Table 2: Evaluation of target lesions 
Complete response (CR) 
Disappearance of all target lesions since baseline.  Any 
pathological lymph nodes selected as target lesions must have a 
reduction in short axis to <10 mm. 
Partial response (PR) 
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD 
Progressive disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 
Not evaluable (NE) 
Only relevant if any of the target lesions were not assessed or not 
evaluable or had a lesion intervention at this visit. Note:  If the 
sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a target lesion 
response 
4.3 
Non-target lesions (NTL) 
4.3.1 
Evaluation of non-target lesions 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.  At each visit an overall assessment of the NTL response should be 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
11(15) 
recorded by the Investigator.  This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit. 
Table 3: Evaluation of non-target lesions 
Complete response (CR) 
Disappearance of all non-target lesions since baseline. All lymph 
nodes must be non-pathological in size (<10 mm short axis). 
Non CR/Non PD 
Persistence of one or more NTL  
Progression (PD) 
Unequivocal progression of existing non-target lesions.  
Unequivocal progression may be due to an important progression 
in one lesion only or in several lesions.  In all cases the 
progression MUST be clinically significant for the physician to 
consider changing (or stopping) therapy. 
Not evaluable (NE) 
Only relevant when one or some of the non-target lesions were not 
assessed and, in the Investigator's opinion, they are not able to 
provide an evaluable overall non-target lesion assessment at this 
visit. 
Note:  For patients without target lesions at baseline, this is 
relevant if any of the non-target lesions were not assessed at this 
visit and the progression criteria have not been met. 
 
To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target lesions, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  For patients with non-measurable disease only the increase in 
overall tumour burden based on the change in non-measurable disease should be comparable 
to the increase that would be required to declare PD for measurable disease and merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target lesions 
is usually not sufficient to qualify for unequivocal progression status. 
4.4 
New lesions 
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression.  
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour. 
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
12(15) 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan. 
4.5 
Symptomatic deterioration 
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy. 
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed. 
4.6 
Evaluation of overall visit response 
The overall visit response will be derived using the algorithm shown in Table 4. 
Table 4: Overall Visit Response 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non CR/Non PD  
No 
PR 
CR 
NE 
No  
PR 
PR 
Non PD or NE 
No 
PR 
SD  
Non PD or NE 
No 
SD 
NA 
Non CR/Non PD 
No 
SD (Non CR/Non PD) 
NE 
Non PD or NE 
No 
NE 
NA 
NE 
No  
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, NE = not evaluable, NA = not applicable (only relevant if there were no TL/NTLs at 
baseline). 
In addition, if not all TL measurements are recorded for a particular visit, but the sum of 
recorded TLs is sufficiently increased to result in a 20% increase, and an absolute increase of 
at least 5mm from nadir, even assuming that the non-recorded TLs have disappeared, then the 
overall visit response will be assigned to PD. 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
13(15) 
5. 
SPECIFICATIONS FOR RADIOLOGICAL IMAGING 
These notes are recommendations for use in clinical studies.  The use of standardised 
protocols for CT and MRI allows comparability both within and between different studies, 
irrespective of where the examination has been undertaken. 
5.1 
CT scan 
CT scans of the chest, abdomen, and pelvis should be contiguous throughout all the anatomic 
region of interest. 
The most critical CT image acquisition parameters for optimal tumour evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval. 
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the chest, 
abdomen and pelvis. Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual patients.  Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up time points.  This will enable better 
consistency not only of tumour measurements but also identification of new disease. 
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumours requires consistent administration (dose and rate) of IV contrast as well as timing of 
scanning.  Typically, most abdominal imaging is performed during the portal venous phase 
and (optimally) about the same time frame after injection on each examination.  An adequate 
volume of a suitable contrast agent should be given so that the metastases are demonstrated to 
best effect and a consistent method is used on subsequent examinations for any given patient.  
It is very important that the same technique be used at baseline and on follow-up examinations 
for a given patient.  For patients who develop contraindications to contrast after baseline 
contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or non-
enhanced) should be performed should also be based on the tumour type, anatomic location of 
the disease and should be optimised to allow for comparison to the prior studies if possible.  
Each case should be discussed with the radiologist to determine if substitution of these other 
approaches is possible and, if not, the patient should be considered not evaluable from that 
point forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions, since the same lesion may appear to 
have a different size using a new modality.  Oral contrast is recommended to help visualise 
and differentiate structures in the abdomen.  
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study then the recommended methods are:  CT thoracic examination without 
contrast and abdominal and pelvis MRI with contrast.  If MRI cannot be performed then CT 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
14(15) 
without i.v. contrast is an option for the thorax, abdomen and pelvis examination.  For brain 
lesions assessment, MRI is the preferred method.  
c. Slice thickness and reconstruction interval: It is recommended that CT scans be 
performed at 5 mm contiguous slice thickness and this guideline presumes a minimum 5 mm 
thickness in recommendations for measurable lesion definition.  Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses greater than 5 mm.  If 
this occurs, the minimum size of measurable lesions at baseline should be twice the slice 
thickness of the baseline scans. 
All window settings should be included in the assessment, particularly in the thorax where 
lung and soft tissue windows should be considered.  When measuring lesions, the TL should 
be measured on the same window setting for repeated examinations throughout the study.  All 
images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion. 
5.2 
MRI scan 
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement.  Furthermore, the availability of MRI is variable globally.  The modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  Generally, axial imaging of the abdomen and 
pelvis with T1 and T2 weighted imaging along with gadolinium-enhanced imaging should be 
performed.  The field of view, matrix, number of excitations, phase encode steps, use of fat 
suppression and fast sequences should be optimised for the specific body part being imaged as 
well as the scanner utilised.  It is beyond the scope of this appendix to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques if possible. 
For these reasons, CT is the imaging modality of choice. 
5.3 
FDG-PET scans  
FDG-PET has gained acceptance as a valuable tool for detecting, staging and restaging several 
malignancies.  If  FDG-PET scans are included in a protocol, an FDG uptake period of 60 min 
prior to imaging has been decided as the most appropriate for imaging of  patients with 
malignancy.  Whole-body acquisition is important since this allows for sampling of all areas 
of interest and can assess if new lesions have appeared thus determining the possibility of 
interval progression of disease.  Images from the base of the skull to the level of the mid-thigh 
should be obtained 60 min post injection.  PET camera specifications are variable and 
manufacturer specific, so every attempt should be made to use the same scanner, or the same 
model scanner, for serial scans on the same patient.  Whole-body acquisitions can be 

Clinical Study Protocol Appendix D 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
15(15) 
performed in either 2- or 3-dimensional mode with attenuation correction, but the method 
chosen should be consistent across all patients and serial scans in the clinical trial. 
5.3.1 
PET/CT scans 
At present, low dose or attenuation correction CT portions of a combined PET–CT are of 
limited use in anatomically based efficacy assessments and it is therefore suggested that they 
should not be substituted for dedicated diagnostic contrast enhanced CT scans for tumour 
measurements by RECIST 1.1.  In exceptional situations, if a site can document that the CT 
performed as part of a PET–CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast) then the CT portion of the PET–CT can be used for RECIST measurements.  
However, this is not recommended because the PET portion of the CT introduces additional 
data that may bias an investigator if it is not routinely or serially performed. 
6. 
REFERENCES 
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R.  New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer 
2009; 45: 228–247. 

 
 
Clinical Study Protocol Appendix E 
 
Drug Substance 
Fulvestrant 
 
Study Code 
D699BC00001 
 
Edition Number 
1.0 
 
Date 
19 April 2012 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix E 
Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin - Hy’s Law 
 

Clinical Study Protocol Appendix E 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
2(6) 
TABLE OF CONTENTS 
PAGE
 
TABLE OF CONTENTS.........................................................................................2 
1. 
INTRODUCTION ...................................................................................................3 
2. 
DEFINITIONS.........................................................................................................3 
3. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES...................................3 
4. 
FOLLOW-UP ..........................................................................................................4 
4.1 
Potential Hy’s Law Criteria not met ........................................................................4 
4.2 
Potential Hy’s Law Criteria met ..............................................................................4 
5. 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES...............4 
6. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL 
HY’S LAW ..............................................................................................................6 
7. 
REFERENCES ........................................................................................................6 
 

Clinical Study Protocol Appendix E 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
3(6) 
1. 
INTRODUCTION 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes. 
2. 
DEFINITIONS 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT)  3x Upper Limit of 
Normal (ULN) and Total Bilirubin (TBL)  2xULN at any point during the study irrespective 
of an increase in Alkaline Phosphatase (ALP).  The elevations do not have to occur at the 
same time or within a specified time frame. 
Hy’s Law (HL) 
AST or ALT  3x ULN and TBL  2xULN, where no other reason, other than the IMP, can 
be found to explain the combination of increases, eg, elevated ALP indicating cholestasis, 
viral hepatitis, another drug.  The elevations do not have to occur at the same time or within a 
specified time frame. 
3. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
x
ALT  3xULN 
x
AST  3xULN 
x
TBL  2xULN 

Clinical Study Protocol Appendix E 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
4(6) 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
x
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits 
x
Promptly enter the laboratory data into the laboratory CRF 
4. 
FOLLOW-UP 
4.1 
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
x
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
4.2 
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
x
Notify the AstraZeneca representative who will then inform the central Study Team  
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will: 
x
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated  
x
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician 
x
Complete the three Liver CRF Modules as information becomes available  
x
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
5. 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES 
The instructions in this Section should be followed for all cases where PHL criteria were met. 

Clinical Study Protocol Appendix E 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
5(6) 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.   
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
x
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
x
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
x
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
x
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
x
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review 

Clinical Study Protocol Appendix E 
Drug Substance Fulvestrant 
Study Code D699BC00001 
Edition Number 1.0 
Date 19 April 2012 
6(6) 
6. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF 
POTENTIAL HY’S LAW 
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.   
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
x
Was the alternative cause for the previous occurrence of PHL criteria being met 
chronic or progressing malignant disease? 
If No: follow the process described in Section 4.2 of this Appendix 
If Yes: 
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met 
x
If there is no significant change no action is required 
x
If there is a significant change follow the process described in Section 4.2 of this 
Appendix 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty. 
7. 
REFERENCES 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 

 
 
Clinical Study Protocol Appendix F 
 
Drug Substance 
Fulvestrant 
 
Study Code 
D699BC00001 
 
Edition Number 
1.0 
 
Date 
19 April 2012 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix F 
WHO Performance Status 
 

Clinical Study Protocol Appendix F 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
2(2) 
WHO PERFORMANCE STATUS 
Description 
Status 
Fully active, able to carry out all usual activities without restrictions and 
without the aid of analgesia. 
0 
Restricted in strenuous activity, but ambulatory and able to carry out 
light work or pursue a sedentary occupation. This group also contains 
subjects who are fully active, as in grade 0, but only with the aid of 
analgesics 
1 
Ambulatory and capable of all self-care, but unable to work. Up and 
about more than 50% of waking hours 
2 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours 
3 
Completely disabled, unable to carry out any self-care and confined 
totally to bed or chair 
4 
 

Clinical Study Protocol (CSP) Addendum, ANGEL
Version 2.0
Template Form Doc ID: AZDoc0026014
Parent Doc ID: SOP AZDoc0018580
Clinical Study Protocol – Addendum #1
Drug Substance
Fulvestrant
Study Code
D699BC00001
Addendum Version 1
Date
23January 2018
Addendum #1 to the Revised CSP v 4,0 dated 01Dec2017
A Randomised, Double-blind, Parallel-group, Multicentre, Phase III Study 
to Compare the Efficacy and Tolerability of Fulvestrant (FASLODEX™) 500 
mg with Anastrozole (ARIMIDEX™) 1 mg as Hormonal Treatment for 
Postmenopausal Women with Hormone Receptor-Positive Locally Advanced 
or Metastatic Breast Cancer Who Have Not Previously Been Treated With 
Any Hormonal Therapy (FALCON)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden

Clinical Study Protocol – Global Addendum
Drug Substance Fulvestrant
Study Code D699BC00001
Version 1
Date 23January 2018
2 (2)
VERSION HISTORY
Version 1, 23 January 2018 (Global Addendum #1 to the Revised CSP v 4,0 dated 
01Dec2017)
Sections of the Revised CSP v 4,0 dated 01Dec2017 affected: 
-
Appendix G
Description of the update:
Due to an editorial mistake, Patient Reported Outcomes questionnaires (FACT-B and EQ-
5D™), were not included in Appendix G (edition 1,0 dated 19 Apr 2012) of the revised CSP 
version 4,0 dated 01 Dec 2017.
To correct and document this omission an Addendum #1 has been developed. 
The corrected Appendix G (edition 1,0 dated 19 Apr 2012) including Patient Reported 
Outcomes questionnaires (FACT-B and EQ-5D™) is attached to this document. 
Attachement:
Appendix G (edition 1,0 dated 19 Apr 2012) Patient Reported Outcomes (FACT-B and EQ-
5D™)

Clinical Study Protocol Appendix G
Drug Substance
Fulvestrant
Study Code
D699BC00001
Edition Number
1.0
Date
19 April 2012
Appendix G
Patient Reported Outcomes (FACT-B and EQ-5D™)

FACT-B (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright 1987, 1997 
Page 1 of 3 
 
 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy .......................................................
0 
1 
2 
3 
4 
GP2 
I have nausea......................................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family.........................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain..........................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .........................
0 
1 
2 
3 
4 
GP6 
I feel ill ...............................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed........................................
0 
1 
2 
3 
4 
 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends....................................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends.............................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ....................................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness..................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ..............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life ............................................
0 
1 
2 
3 
4 

FACT-B (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright 1987, 1997 
Page 2 of 3 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel sad ..............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness..........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness..................
0 
1 
2 
3 
4 
GE4 
I feel nervous.......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying.............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse............................
0 
1 
2 
3 
4 
 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GF1 
I am able to work (include work at home) ..........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling.....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life..........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness...................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ...............................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now..............
0 
1 
2 
3 
4 
 

FACT-B (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright 1987, 1997 
Page 3 of 3 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
B1 
I have been short of breath..................................................
0 
1 
2 
3 
4 
B2 
I am self-conscious about the way I dress...........................
0 
1 
2 
3 
4 
B3 
One or both of my arms are swollen or tender....................
0 
1 
2 
3 
4 
B4 
I feel sexually attractive ......................................................
0 
1 
2 
3 
4 
B5 
I am bothered by hair loss ...................................................
0 
1 
2 
3 
4 
B6 
I worry that other members of my family might 
someday get the same illness I have ...................................
 
0 
 
1 
 
2 
 
3 
 
4 
B7 
I worry about the effect of stress on my illness ..................
0 
1 
2 
3 
4 
B8 
I am bothered by a change in weight ..................................
0 
1 
2 
3 
4 
B9 
I am able to feel like a woman ............................................
0
1 
2 
3
4
P2 
I have certain parts of my body where I experience pain....
0 
1 
2 
3 
4 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+HDOWK4XHVWLRQQDLUH

(English version for the UK) 
(validated for use in Eire) 
 

 
 
2
 
By placing a tick in one box in each group below, please indicate which statements 
best describe your own health state today. 
 
Mobility 
I have no problems in walking about 
 
I have some problems in walking about 
 
I am confined to bed 
 
 
Self-Care 
I have no problems with self-care 
 
I have some problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities 
 
I have some problems with performing my usual activities 
 
I am unable to perform my usual activities 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
I have moderate pain or discomfort 
 
I have extreme pain or discomfort 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
I am moderately anxious or depressed 
 
I am extremely anxious or depressed 
 

 
 
3
 
 
To help people say how good or bad a health state is, we 
have drawn a scale (rather like a thermometer) on which 
the best state you can imagine is marked 100 and the 
worst state you can imagine is marked 0. 
 
We would like you to indicate on this scale how good 
or bad your own health is today, in your opinion. 
Please do this by drawing a line from the box below to 
whichever point on the scale indicates how good or 
bad your health state is today. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Your own 
health state 
today 
9 
0 
8 
0 
7 
0 
6 
0 
5 
0 
4 
0 
3 
0 
2 
0 
1 
0 
100 
Worst 
imaginable 
health state 
0 
Best  
imaginable 
health state 

 
 
Clinical Study Protocol Appendix H 
 
Drug Substance 
Fulvestrant 
 
Study Code 
D699BC00001 
 
Edition Number 
1.0 
 
Date 
19 April 2012 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix H 
Biomarker Research 
 

Clinical Study Protocol Appendix H 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
2(10) 
TABLE OF CONTENTS 
PAGE
 
TABLE OF CONTENTS.........................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS............................3 
1. 
BACKGROUND .....................................................................................................4 
1.1 
Rationale for research ..............................................................................................4 
2. 
RESEARCH OBJECTIVES ....................................................................................4 
3. 
RESEARCH PLAN AND PROCEDURES.............................................................5 
3.1 
Research plan...........................................................................................................5 
3.2 
Selection of biomarker research population.............................................................5 
3.2.1 
Study selection record..............................................................................................5 
3.2.2 
Withdrawal of patients from this biomarker research..............................................5 
3.2.2.1 
Procedures for withdrawal .......................................................................................5 
4. 
MEASUREMENTS AND CO-VARIABLES.........................................................5 
4.1 
Summary of objectives and analysis........................................................................5 
4.2 
Collection of samples for Biomarker research.........................................................6 
4.2.1 
Tumour samples.......................................................................................................6 
4.3 
Chain of custody of biological samples...................................................................7 
5. 
MANAGEMENT OF RESEARCH DATA.............................................................7 
6. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE .........................................................................................................................8 
7. 
STUDY MANAGEMENT ......................................................................................8 
7.1 
Monitoring ...............................................................................................................8 
7.2 
Training of staff .......................................................................................................8 
7.3 
Study agreements.....................................................................................................8 
8. 
ETHICS....................................................................................................................9 
8.1 
Ethics review............................................................................................................9 
8.2 
Ethical conduct of the study.....................................................................................9 
8.3 
Informed consent .....................................................................................................9 
8.4 
Patient data protection..............................................................................................9 
9. 
REFERENCES ........................................................................................................9 
 

Clinical Study Protocol Appendix H 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
3(10) 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or special term 
Explanation 
CSR 
Clinical study report 
EC 
Ethics Committee 
ER 
oestrogen receptor 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
PgR 
progesterone receptor 
PI3K 
phosphoinositide 3-kinase 
PTEN 
phosphatase and tensin homolog 
 

Clinical Study Protocol Appendix H 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
4(10) 
1. 
BACKGROUND 
As part of the clinical drug development programmes for fulvestrant and anastrozole 
AstraZeneca is investigating variations in biomarker profiles and their relationship to drug 
effect and toxicity.  These biomarkers may be derived from DNA, RNA, proteins and 
metabolites and potentially be predictive markers of response or potential toxicity.  By 
generating this information, we aim to better understand the impact of variation between 
individuals and how this knowledge can be utilised to bring the right drugs to the right patient.  
To achieve this goal a systematic collection of biological samples including those taken from 
patients' tumours will be undertaken where appropriate. 
1.1 
Rationale for research 
AstraZeneca may perform biomarker research in the fulvestrant and anastrozole clinical 
development programmes to explore how variations in biomarkers (DNA, RNA and/or protein 
based) may be related to fulvestrant, anastrozole and other factors that may influence 
development of cancer. 
Recent studies have demonstrated that it is possible to predict which patients are most likely to 
gain benefit from therapy via molecular profiling of the tumour (Paik et al 2004:  
Ring et al 2006).  For example complex gene expression profiles derived from solid tumour 
samples can be translated into simple scores that predict which patients are most likely to 
benefit from treatment (Paik et al 2006).  Non-heritable, tumour-specific alterations to DNA 
have also been linked to prognosis and to potential treatment benefit (Wu et al 2007,  
Yoshida et al 2007, Sunaga et al 2007, Massarelli et al 2007 and Beauclair et al 2007).  
Astrazeneca is committed to delivering the right drug to those patients most likely to gain 
clinical benefit. The ability to acquire appropriate consent to collect biological samples and 
perform exploratory analysis is of the utmost importance to the success of this initiative.  
Samples will be used to both support the development of fulvestrant and anastrozole and also 
new projects targeting the breast cancer disease area.  
The benefits of being able to explore associations between biomarker variations and clinical 
outcomes within the fulvestrant and anastrozole programmes are potentially many; for 
example, the possibility to identify patients most likely to benefit from treatment, explain 
potential outliers, such as non-responders or to explain potential adverse reactions related to 
drug exposure. 
2. 
RESEARCH OBJECTIVES 
Biomarker technologies enable the measurement of many different molecules, such as DNA, 
RNA, proteins and metabolites, within a sample.  The objective of this research is to explore 
how variations in tumour biomarkers (DNA, RNA and/or protein based) may be related to 

Clinical Study Protocol Appendix H 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
5(10) 
factors that may influence development of cancer and/or study treatment response and 
resistance. 
3. 
RESEARCH PLAN AND PROCEDURES 
3.1 
Research plan 
In the study the following samples will be requested: 
x
Tumour sample(s) (archival and/or recently acquired formalin-fixed 
paraffin-embedded specimens) 
3.2 
Selection of biomarker research population 
3.2.1 
Study selection record 
All patients who take part in the study will be asked to participate in this (optional) biomarker 
research. 
3.2.2 
Withdrawal of patients from this biomarker research 
3.2.2.1 
Procedures for withdrawal 
Patients who withdraw from the main study should always be asked specifically whether they 
are withdrawing or continuing their consent for this biomarker research.  It must be 
established whether the patient: 
x
Agrees to the biomarker samples and any preparations derived from the sample 
being kept for research in the future 
x
Withdraws consent for the samples to be kept for biomarker research in the future 
and wishes the samples to be destroyed.  If a patient withdraws consent to the use of 
donated biological samples, then the samples will be disposed of/destroyed, and the 
action documented.  If samples are already analysed, AstraZeneca is not obliged to 
destroy the results of this research. 
The Principal Investigator is responsible for providing written notification to AstraZeneca of 
any patient who has withdrawn consent for the use of the sample taken for biomarker 
research.  AstraZeneca will provide written confirmation to the investigator of the actions 
taken with the sample, which must be filed in the investigator study file. 
4. 
MEASUREMENTS AND CO-VARIABLES 
4.1 
Summary of objectives and analysis 
The purpose of this research is to generate data for use in futher retrospective analyses.  These 
analyses will explore factors, which may influence the disposition, efficacy, safety and 

Clinical Study Protocol Appendix H 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
6(10) 
tolerability to fulvestrant or anastrozole and/or susceptibility to or prognosis of cancer.  The 
results of this research may not form part of the clinical study report for the main study.  The 
results may be pooled with data from other studies on fulvestrant or anastrozole to generate 
hypotheses to be tested in future studies. 
4.2 
Collection of samples for Biomarker research 
AstraZeneca or its designee will act as the central laboratory for sample logistics and 
laboratory analysis. Details of sample collection, processing, shipping and storage are 
described in the Laboratory Manual. 
The samples and data for analysis in this research will be coded and will not be labelled with 
any personal details.  Each sample will be identified with the study number and patient 
enrolment number.  In this way biomarker data may be correlated with clinical data, samples 
destroyed in the case of withdrawal of consent and regulatory audit enabled.  However, only 
the investigator will be able to link the biomarker sample to the individual patient.  
Where genetic analysis will be undertaken the processes adopted for the coding and storage of 
samples will be more stringent in order to maintain patient confidentiality.  As an added 
precaution for all samples the DNA sample will be assigned a unique number replacing the 
information on the sample tube.  Thereafter, the DNA sample will be identifiable by the 
unique DNA number only.  The DNA number will be used to identify the sample and 
corresponding data at the AstraZeneca genetics laboratories, or at the designated contract 
laboratory.  No personal details identifying the individual will be available to any AstraZeneca 
employee (or employee’s of contract laboratories etc.) working with the DNA.  No analysis of 
heritable genetic changes will be performed, only changes that have occurred somatically in 
the tumour and which may have a bearing on tumour response eg, mutations in the 
phosphoinositide 3-kinase (PI3K) gene or loss of phosphatase and tensin homolog (PTEN) 
may be analysed. 
Samples taken previously, as part of routine care, will remain the property of the donating 
organisation. 
4.2.1 
Tumour samples 
Collection of optional tumour sample for biomarker research 
Pre-treatment tumour sample(s) (archival and/or recent) will be obtained only once consent 
has been given by the patient.  The sample(s) may be analysed for a range of oncology 
biomarkers eg, oestrogen receptors (ER), progesterone receptors (PgR) and other exploratory 
factors thought to be associated with response and resistance to study treatment.  
Patients who consent to participate in the biomarker study and allow the analysis of their 
pre-treatment tumour tissue for biomarkers will be asked if they consent to a second optional 
biopsy procedure, if, in the opinion of the investigator, the biopsy procedure does not pose 
additional significant risks to the patient.  If a tumour sample is already available at the time 
of progression, a further sample is not required.  This optional biopsy procedure is for 

Clinical Study Protocol Appendix H 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
7(10) 
consideration in the event that the patient progresses while on the trial and has a lesion which 
is accessible by standard biopsy procedures at the time of progression.  This biopsy tissue 
would be obtained after disease progression while on the trial would be collected for 
biomarker research on the exploratory factors thought to be associated with resistance to either 
fulvestrant or anastrazole. 
The tumour samples (both the pre-treatment and the optional post-progression biopsy) will 
preferably be in the form of a formalin fixed paraffin embedded block.  If this is not possible, 
20 slides of freshly prepared unstained 5 micron sections from the tumour block/s may be 
provided.  Further details on sample processing, handling and shipment are provided in the 
investigators Laboratory Manual. 
4.3 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.  
The principal investigator at each centre keeps full traceability of collected biological samples 
from the subjects while in storage at the centre until shipment and keeps documentation of 
receipt of arrival.  
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of.  
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.  
Samples retained for further use are registered in AstraZeneca bio bank or external laboratory 
provider systems during the entire life cycle.  Unless repatriation is requested, samples will be 
stored for a maximum of 25 years from clinical study report completion after which they may 
be destroyed.  
5. 
MANAGEMENT OF RESEARCH DATA 
Some of the dataset from the main study may be duplicated within AstraZeneca for 
exploratory analyses in combination with the biomarker data.  Neither the patient’s name nor 
any other personal identifiers will be part of this dataset.  Biomarker data may not be reported 
in the clinical study report (CSR). Only the date the patient gave consent to participation in the 
research and the date and time the biological sample(s) (if applicable) was taken from the 
patient will be recorded in the electronic case report form and database. 
AstraZeneca will not provide biomarker research results to patients, their family members, 
any insurance company, an employer, clinical study investigator, general physician or any 
other third party, unless required to do so by law.  The patient’s samples will not be used for 
any purpose other than those described in the study protocol.  

Clinical Study Protocol Appendix H 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
8(10) 
Individual patients will not be identified in any report or publication resulting from this work. 
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient’s name nor any other personal identifiers will appear in any publication or 
report.  
6. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The number of patients who will agree to participate in the research and the number of whom 
will have any particular clinical outcome are unknown.  It is therefore not possible to establish 
whether a statistically relevant number of patients will consent to provide sufficient data to be 
collected to allow a formal statistical evaluation or whether only descriptive statistics will be 
generated.  A statistical analysis plan will be prepared where appropriate.  
7. 
STUDY MANAGEMENT 
7.1 
Monitoring 
Before first patient entry into the study, a representative of AstraZeneca will visit the 
investigational study centre.  The requirements described in the main study and this biomarker 
research will be discussed.  
During the study, a representative of AstraZeneca will have regular contacts with the 
investigational centres.  One of the purposes of these visits will be to perform source 
verification of the informed consent of participating patients and to ensure that the 
investigational team are adhering to the specific requirements of this biomarker research.  
7.2 
Training of staff 
Before the first patient is entered into the study the investigational staff will have an 
opportunity to discuss the procedures associated with the collection of samples and biomarker 
research with a representative of AstraZeneca.  The requirements for the collections of the 
patients’ sample will also be made clear. 
7.3 
Study agreements 
The principal investigator at each study centre must comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement for this research.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
Clinical Study Protocol shall prevail.  Specific reference to requirements relating to this 
biomarker research will be included in the study agreement(s).  

Clinical Study Protocol Appendix H 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
9(10) 
8. 
ETHICS 
8.1 
Ethics review 
Ethics Committee (EC)/Institutional Review Board (IRB) approval of the study with this 
biomarker research must be obtained and documented from the relevant EC. 
8.2 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca 
policy on Bioethics. 
8.3 
Informed consent 
To participate in the biomarker component of the study the patient must sign and date the 
main study consent form and the biomarker research consent form.  Patients who also consent 
to provide an additional (optional) tumour sample on progression must check the appropriate 
box indicating that they consent to provide this additional sample.  Copies of signed and dated 
consent forms must be given to the patient and the originals filed at the study centre in the 
investigator’s study file.  The principal investigator is responsible for ensuring that consent is 
given freely. 
8.4 
Patient data protection 
All data protection and confidentiality principles, described in the main study protocol, are 
applicable to this biomarker research. 
Due to the exploratory nature of this biomarker research, there will be no routine 
communication of results to patients.  AstraZeneca will not provide individual results to 
patients, any insurance company, any employer, their family members, general physician or 
any other third party, unless required to do so by law. 
9. 
REFERENCES 
Beauclair et al 2007 
Beauclair S, Formento P, Fischel J, Lescaut W, Largillier R, Chamorey E, et al. Role of the 
HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-
related cardiotoxicity. Ann Oncol 2007;18:1335–41. 
Massarelli et al 2007 
Massarelli E, Varella-Garcia M, Tang X, Xavier AC, Ozburn NC, Liu DD, et al. KRAS 
mutation is an important predictor of resistance to therapy with epidermal growth factor 
receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res 
2007;13:2890–6. 

Clinical Study Protocol Appendix H 
Drug Substance Fulvestrant 
Study Code D699BC00001  
Edition Number 1.0 
Date 19 April 2012 
10(10) 
Paik et al 2004 
Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict 
recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:2817–
26. 
Paik et al 2006 
Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, et al. Gene expression and benefit of 
chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin 
Oncol 2006;24:3726–34. 
Ring et al 2006 
Ring BZ, Seitz RS, Beck R, Shasteen WJ, Tarr SM, Cheang MC, et al. Novel prognostic 
immunohistochemical biomarker panel for estrogen receptor-positive breast cancer. J Clin 
Oncol 2006;24:3039–47. 
Sunaga et al 2007 
Sunaga N, Tomizawa Y, Yanagitani N, Iijima H, Kaira K, Shimizu K et al. Phase II 
prospective study of the efficacy of gefitinib for the treatment of stage III/IV non-small cell 
lung cancer with EGFR mutations, irrespective of previous chemotherapy. Lung Cancer 
2007;56:383–9. 
Wu et al 2007 
Wu YL, Zhong WZ, Li LY, Zhang XT, Zhang L, Zhou CC et al. Epidermal growth factor 
receptor mutations and their correlation with gefitinib therapy in patients with non-small cell 
lung cancer: a meta-analysis based on updated individual patient data from six medical centers 
in mainland China. J Thorac Oncol 2007;2:430–9. 
Yoshida et al 2007 
Yoshida K, Yatabe Y, Park JY, Shimizu J, Horio Y, Matsuo K, et al. Prospective validation 
for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in 
patients with non-small cell lung cancer. J Thorac Oncol 2007;2:22–8.