Clinical trial NCT04588298
Conditions: HER2-negative Breast Cancer
Keywords: Breast cancer Breast carcinoma Estrogen-Receptor-positive breast cancer HER2-negative breast cancer
Sponsor: AstraZeneca
Start date: 2020-11-02; Completion date: 2023-06-19
Enrollment: 135 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomised, open-label, parallel-group, pre-surgical study aimed to investigate the biological effects, safety, tolerability, and pharmacokinetics (PK) of different doses of oral AZD9833 in post-menopausal women with primary breast cancer

Detailed description:
The study will be conducted in approximately 20 study centers across 3 countries and will be conducted in three stages (stage 1, stage 2 and stage 3). After the screening visit and confirmation of eligibility, evaluable participants will be enrolled across treatment groups. In stage 1, up to 24 evaluable participants across two treatment groups will be enrolled. A Safety and Data Monitoring Committee will convene to review stage 1 data and decide whether further treatment groups are required in stage 2. Stage 2 will include participants across up to 3 treatment groups. Stage 3 will include two treatment groups:

Stage 1 Group 1: AZD9833 Dose A once daily Group 2: AZD9833 Dose B once daily

Stage 2 Group 1: AZD9833 Dose A once daily Group 2: AZD9833 Dose B once daily Group 3: AZD9833 Dose C once daily

Stage 3 Group 1: AZD9833 Dose A once daily Group 2: AZD9833 Dose B once daily

Adverse events and concomitant medications information will be collected throughout the study. Thereafter there will be 28-day follow-up visit after discontinuation of study treatment

Arms: arm 1: Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 1 of the study. arm 2: Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 1 of the study. arm 3: Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 2 of the study. arm 4: Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 2 of the study. arm 5: Post-menopausal participants will receive once daily oral dose C of AZD9833 in stage 2 of the study. arm 6: Post-menopausal participants will receive once daily oral dose A of AZD9833 in stage 3 of the study. arm 7: Post-menopausal participants will receive once daily oral dose B of AZD9833 in stage 3 of the study.
Interventions: intervention 1: AZD9833
Intervention descriptions: intervention 1: AZD9833 tablets will be administered orally.

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol 
Drug Substance
AZD9833 (INN: camizestrant)
Study Code
D8530C00003
Version
3.0
Date
04 July 2022
A Randomised, Open-Label, Parallel-Group, Pre surgical Study to 
Investigate the Biological Effects of AZD9833 in Women with 
ER-positive, HER2-negative Primary Breast Cancer (SERENA-3)
Sponsor Name: AstraZeneca
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden 
Regulatory Agency Identifier Number(s)
EudraCT number: 2020-001079-33
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: D8530C00003
Amendment Number: 2
Study Intervention: AZD9833
Study Phase: Phase 2


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Short Title: A Randomised, Pre-surgical Study to Investigate the Biological Effects of 
AZD9833 in Women with ER-positive, HER2 negative Primary Breast Cancer
SERENA-3
Medical Monitor Name and Contact Information will be provided separately
International Co-ordinating Investigator:
Professor John Robertson
Graduate Entry Medicine & Health School
University of Nottingham, Royal Derby Hospital
Uttoxeter Road, Derby, DE22 3DT, UK.


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date of Issue
Version 3.0 (Global Amendment 2)
04-Jul-2022
Version 2.0 (Global Amendment 1)
28-Sep-2021
Original Protocol
11-Jun-2020
Overall Rationale for Amendment 2.0:
This global amendment has been issued in order to investigate longer duration dosing of 
AZD9833 and in order to implement recommendations made by the SDMC.
Section Number 
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Sections 1.1; 1.2; 1.3; 
2.1; 2.2.2; 2.3.2; 3; 4.1; 
4.3
Text has been amended to allow for 
addition of Stage 3 of the CSP, with 
a longer duration of 12 to 15 days. 
Assessments and text related to the 
addition of Stage 3 have been added 
throughout
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 1.1 
Text has been added to account for 
increased duration of treatment (12 
to 15 days) in Stage 3 of the CSP. 
This includes updates to show 
change in sampling times for 
Stage 3, given longer treatment 
period, updated sample size to 
account for addition of Stage 3 and 
requirement for patients in Stage 3 
to show a 
 
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 1.2
New schema added (Figure 3) with 
accompanying text added to 
describe Stage 3
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 1.3
New SoA added (Table 2) to 
describe Stage 3
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 2.1
Rationale updated to confirm 
current status of SERENA-3 study 
and rationale for addition of Stage 3 
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 2.2.2
Paragraph relating to preliminary 
data from SERENA-1 study deleted
Data are superseded by 
updated data from 
SERENA-1, new data from 
SERENA-2 and interim 
data from Stages 1 and 2 of 
the SERENA-3 study
Substantial
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Section Number 
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Section 2.2.2.1
Section updated using data from a 
pooled analysis of SERENA-1, and 
SERENA-2  
Safety data in larger 
population included to 
provide more confidence on 
the safety profile for 
AZD9833.
Substantial
Section 2.2.2.3
New section providing data for the 
pool of data for SERENA-1 and 
SERENA-2 at the 15-day exposure 
timepoint
Safety data at longer 
exposures added to provide 
more confidence on the 
safety profile for AZD9833. 
Substantial
Section 2.2.2.8 
New section from the interim 
analysis of PD data from Stages 1 
and 2 of the SERENA-3 study.
Biological activity data 
provided for a treatment 
period of 5 to 7 days with 
AZD9833, to justify that a 
longer treatment is needed, 
to achieve maximal PD 
effect
Substantial
Section 2.2.2.9 
New section from the interim 
analysis of safety data from Stages 
1 and 2 of the SERENA-3 study.
Data provided for Stages 1 
and 2 of the SERENA-3 
study 
 
 
 
 
 
 
 
 
 
 
 
 
Substantial
Section 2.3.2
Section updated to require patients 
in Stage 3 
 
 
Section also updated to show 
change in sampling times for 
Stage 3, given longer treatment 
period and updated sample size to 
account for addition of Stage 3
 
 
 
 
 
Substantial
Section 3
Objectives table updated to account 
for addition of Stage 3 to the study
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 4.1
Design updated to account for 
addition of Stage 3 to the study
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 4.1.3
New subsection to describe Stage 3
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
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Section Number 
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Section 4.3
Justification of dose updated to 
account for longer treatment period 
allowed in Stage 3 to the study
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 5.2
Exclusion criterion 5b updated to 
require patients in Stage 3 
 
 
Change based on 
 
 summarised 
which showed the potential 
for a higher proportion of 
patients to be impacted by 
an 
risk of AEs of 
Substantial
Section 6.1.1
Updated to confirm investigational 
product to be used in Stage 3
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 6.6.1
New table of dose modifications 
added for Stage 3
Change based on 
 
 summarised 
which showed the potential 
for a higher proportion of 
patients to be impacted by 
an 
 risk of AEs of 
.
Substantial
Section 8.6
Updated to show change in 
sampling times for Stage 3, given
longer treatment period
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 9.2
Updated sample size for Stage 3
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 9.2.1
Confirmation of definition of an 
evaluable patient for Stage 3
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
AE = Adverse event; bpm = Beats per minute; CSP = Clinical study protocol; CSR = Clinical study report; 
ERα = Oestrogen receptor alpha; PD = Pharmacodynamic(s); PK = Pharmacokinetics; SDMC = Safety and Data 
Monitoring Committee; SoA = Schedule of Activities.
Additionally, minor changes were made throughout the protocol to clarify the SoAs to be used 
for Stage 1 and 2 and for Stage 3 where appropriate.
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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 3
TABLE OF CONTENTS...................................................................................................... 6
1
PROTOCOL SUMMARY................................................................................ 12
1.1
Synopsis ........................................................................................................... 12
1.2
Schema............................................................................................................. 19
1.3
Schedule of Activities....................................................................................... 20
2
INTRODUCTION............................................................................................ 24
2.1
Study Rationale ................................................................................................ 24
2.2
Background ...................................................................................................... 25
2.2.1
ER-positive HER2-negative Breast Cancer ....................................................... 25
2.2.2
AZD9833.......................................................................................................... 26
2.2.2.1
Safety and Tolerability...................................................................................... 27
2.2.2.2
Safety from Short Duration AZD9833 Monotherapy (7 days): Stages 1 and 2... 31
2.2.2.3
Safety from Short Duration AZD9833 Monotherapy (15 days): Stage 3............ 39
2.2.2.4
Pharmacokinetics.............................................................................................. 46
2.2.2.5
Biological Activity and Clinical Efficacy from D8530C00001 (SERENA-1) .... 46
2.2.2.6
Biological Activity from Stage 1 of SERENA-3, and Justification for Stage 2 
Dose Selection.................................................................................................. 47
2.2.2.7
Safety Data from Stage 1 of SERENA-3, and Justification for Stage 2 Dose 
Selection........................................................................................................... 50
2.2.2.8
Biological Activity from Stage 1 and 2 of SERENA-3, and Justification for 
Selection Stage 3 Dose and Duration of Dosing ................................................ 51
2.2.2.9
Safety data from Stage 1 and 2 of SERENA-3, and Justification for Stage 3 
Dose Selection and Duration of Exposure ......................................................... 54
2.3
Benefit/Risk Assessment................................................................................... 58
2.3.1
AZD9833.......................................................................................................... 58
2.3.1.1
Potential Benefits.............................................................................................. 58
2.3.1.2
Potential Risks.................................................................................................. 58
2.3.2
Overall Benefit/Risk and Ethical Assessment.................................................... 59
3
OBJECTIVES AND ENDPOINTS................................................................... 61
4
STUDY DESIGN ............................................................................................. 63
4.1
Overall Design.................................................................................................. 63
4.1.1
Stage 1.............................................................................................................. 63
4.1.2
Stage 2.............................................................................................................. 64
4.1.2.1
Post-menopausal Women.................................................................................. 65
4.1.3
Stage 3.............................................................................................................. 66
4.1.3.1
Post-menopausal Women.................................................................................. 67
4.1.4
Study Conduct Mitigation During Study Disruptions Due Cases of Civil Crisis, 
Natural Disaster, or Public Health Crisis........................................................... 67




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8.1.1
Performance Status........................................................................................... 83
8.2
Safety Assessments........................................................................................... 84
8.2.1
Clinical Safety Laboratory Assessments............................................................ 84
8.2.2
Physical Examinations...................................................................................... 85
8.2.3
Vital Signs........................................................................................................ 85
8.2.4
Electrocardiograms........................................................................................... 86
8.2.4.1
Triplicate 12-lead Digital ECGs........................................................................ 86
8.2.5
........................................................................... 87
8.3
Adverse Events and Serious Adverse Events..................................................... 88
8.3.1
Method of Detecting AEs and SAEs ................................................................. 88
8.3.2
Time Period and Frequency for Collecting AE and SAE Information................ 88
8.3.3
Follow-up of AEs and SAEs ............................................................................. 89
8.3.4
Adverse Event Data Collection ......................................................................... 89
8.3.5
Causality Collection.......................................................................................... 89
8.3.6
Adverse Events Based on Signs and Symptoms ................................................ 90
8.3.7
Adverse Events Based on Examinations and Tests............................................ 90
8.3.8
Hy’s Law.......................................................................................................... 90
8.3.9
Disease Progression.......................................................................................... 91
8.3.10
Deaths .............................................................................................................. 91
8.3.11
Reporting of Serious Adverse Events................................................................ 91
8.3.12
Medication Error............................................................................................... 92
8.4
Overdose .......................................................................................................... 93
8.4.1
AZD9833.......................................................................................................... 93
8.5
Human Biological Samples............................................................................... 93
8.5.1
Pharmacokinetics.............................................................................................. 93
8.5.1.1
Determination of Drug Concentration ............................................................... 94
8.5.1.2
Storage and Destruction of Pharmacokinetic Samples....................................... 94
8.5.2
Pharmacodynamics........................................................................................... 95
8.6
Human Biological Sample Biomarkers ............................................................. 95
8.6.1
Blood Samples for Circulating Tumour DNA ................................................... 95
8.6.2
Blood Samples for Exploratory Biomarkers ...................................................... 95
8.6.3
Tumour Biopsy................................................................................................. 95
8.7
................................................................ 98
8.8
Medical Resource Utilization and Health Economics........................................ 98
9
STATISTICAL CONSIDERATIONS............................................................... 98
9.1
Statistical Hypotheses....................................................................................... 98
9.2
Sample Size Determination............................................................................... 99
9.2.1
Definition of an Evaluable Patient................................................................... 100
9.3
Populations for Analyses ................................................................................ 100
9.4
Statistical Analyses......................................................................................... 100
9.4.1
Definition of Endpoints................................................................................... 101
9.4.2
Pharmacodynamic Analyses ........................................................................... 101
9.4.3
Safety Analyses .............................................................................................. 101
9.4.3.1
Adverse Events............................................................................................... 102
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9.4.3.2
Other Significant Adverse Events (OAEs) ...................................................... 102
9.4.3.3
Other Safety Data ........................................................................................... 102
9.4.4
Pharmacokinetic Analyses .............................................................................. 103
9.4.5
Other Analyses ............................................................................................... 103
9.4.5.1
Exploratory Analyses...................................................................................... 103
9.4.6
Methods for Multiplicity Control .................................................................... 103
9.5
Interim Analyses............................................................................................. 103
9.6
Safety and Data Monitoring Committee.......................................................... 103
10
REFERENCES............................................................................................... 105
11
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................... 107
LIST OF FIGURES
Figure 1
Study Design: Stage 1.............................................................................. 19
Figure 2
Study Design: Stage 2.............................................................................. 20
Figure 3
Study Design: Stage 3.............................................................................. 20
Figure 4
Pharmacodynamic Effect of 5 to7 Days Treatment with 75 mg or 150 mg 
AZD9833 on ERα, PgR, and Ki-67 Expression........................................ 48
Figure 5
Pharmacodynamic Effect of 5 to7 Days Treatment with 75 mg, 150 mg 
or 300 mg AZD9833 on ERα, PgR, and Ki-67 Expression....................... 52
Figure 6
Percent Change from Baseline of ERα, PgR, and Ki-67 Expression Upon 
treatment with 75 mg, 150 mg or 300 mg AZD9833 
 
. ............................................................................................... 53
Figure 7
 
........................................... 57
Figure 8
Schematic Illustrating the Relative Timings and Windows for Biopsy 
and PK Sampling..................................................................................... 94
Figure 9
Diagnostic Biopsy Decision Tree............................................................. 97
LIST OF TABLES
Table 1
Schedule of Activities: Stages 1 and 2...................................................... 21
Table 2
Schedule of Activities: Stage 3 ................................................................ 22
Table 3
Duration of Exposure – AZD9833 Monotherapy (SERENA-1 and 
SERENA-2)............................................................................................. 28
Table 4
Summary of Adverse Events in Study AZD9833 monotherapy 
(SERENA-1 and SERENA-2).................................................................. 29
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Table 5
AZD9833-related AEs (Investigator Opinion) Occurring in ≥10% 
(SERENA-1 and SERENA-2).................................................................. 30
Table 6
Summary of Causally Related AEs by SOC/PT in Study DC8530C0001 
– First 7 Days of Treatment ..................................................................... 33
Table 7
 
........................................ 37
Table 8
 
................................................................................... 38
Table 9
........................................................................ 39
Table 10
Summary of Most Common (≥5% in Total for any SOC) Causally 
Related AEs by SOC/PT (SERENA-1 and SERENA-2); First 15 Days of 
Treatment ................................................................................................ 41
Table 11
 
................................................. 44
Table 12
 
..................... 45
Table 13
 
................... 46
Table 14
ANCOVA Analysis for ERα, PgR, and Ki-67 (Adjusted for Key 
Covariates) .............................................................................................. 49
Table 15
ANCOVA Analysis for ERα, PgR, and Ki-67 (Adjusted for Key 
Covariates) .............................................................................................. 52
Table 16
Summary of Adverse Events from Interim Analysis of Data for Stage 1 
and Stage 2 of SERENA-3 Study............................................................. 55
Table 17
Summary of Causally Related Adverse Events from Interim Analysis of 
Data for Stage 1 and Stage 2 of SERENA-3 Study................................... 56
Table 18
Objectives and Endpoints......................................................................... 61
Table 19
Study Treatments in Stage 1 and Stage 3.................................................. 74
Table 20
Study Treatments in Stage 2..................................................................... 75
Table 21
AZD9833 Dose Discontinuation Guidance (AZD9833-related); 
Stages 1 and 2.......................................................................................... 79
Table 22
AZD9833 Dose Discontinuation Guidance (AZD9833-related); Stage 3.. 80
Table 23
Blood Sample Volumes ........................................................................... 83
Table 24
Laboratory Safety Variables..................................................................... 85
Table 25
Study Populations.................................................................................. 100
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Table 26
Drugs Known to be 
.......................................... 109
Table 27
Drugs Known to be 
........................................... 110
Table 28
Examples of 
........................... 111
Table 29
 with Label Advice Regarding Combination with 
 
............................................................................................... 112
LIST OF APPENDICES
Appendix A
Guidelines Regarding Potential Interactions of AZD9833 with 
Concomitant Medications ...................................................................... 108
Appendix B
Regulatory, Ethical and Study Oversight Considerations........................ 113
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 119
Appendix D
Adverse Event Definitions and Additional Safety Information............... 124
Appendix E
Handling of Human Biological Samples ................................................ 129
Appendix F
Genetics................................................................................................. 131
Appendix G
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis, including 
COVID19 Outbreak............................................................................... 135
Appendix H
Abbreviations ........................................................................................ 140
Appendix I
Protocol Amendment History................................................................. 144
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title:
A Randomised, Open-Label, Parallel-Group, Pre-surgical Study to Investigate the Biological 
Effects of AZD9833 in Women with ER positive, HER2 negative Primary Breast Cancer 
(SERENA-3).
Short Title: A Randomised, Pre-surgical Study to Investigate the Biological Effects of 
AZD9833 in Women with ER positive, HER2 negative Primary Breast Cancer (SERENA-3).
Rationale:
The oestrogen receptor alpha (ERα) is a well-established drug target in ER-positive breast 
cancer and anti-hormonal endocrine therapies have become the mainstay of treatment (Early 
Breast Cancer Trialists’ Collaborative Group 2005). The selective oestrogen receptor 
down-regulator and degrader (SERD) fulvestrant is used as a standard-of-care treatment for 
ER positive metastatic breast cancer, both alone and in combination with cyclin-dependent 
kinase 4 and 6 (CDK4/6) inhibitors (Cardoso et al 2018).
While fulvestrant has demonstrated superior clinical efficacy to other endocrine therapies and 
is approved for use in the metastatic breast cancer setting, it is not orally bioavailable and the 
monthly intramuscular (IM) route of administration may limit its efficacy (Robertson 2007, 
Robertson et al 2014).
AZD9833 is an orally bioavailable SERD which is being developed for the treatment of 
patients with ER-positive and human epidermal growth factor receptor 2 (HER2)-negative 
breast cancer.
A first-in-human study (SERENA-1, D8530C00001, NCT03616587) evaluating AZD9833 in 
women with advanced breast cancer has completed its monotherapy dose escalation phase. 
This study evaluated multiple ascending doses of AZD9833 administered once daily to pre- or 
post-menopausal women. Subsequent parts of this study are examining AZD9833 in several 
combinations. Study D8530C00001 established that AZD9833 doses of 25, 75, 150, 300 and 
450 mg administered once daily were safe and exhibited dose-dependent tolerability in that 
population. Indications of efficacy were observed with AZD9833, with evidence of clinical 
benefit and target engagement observed at all dose levels, including patients pre-treated with 
CDK4/6 inhibitors and fulvestrant, and those with oestrogen receptor 1 (ESR1) mutations 
(Hamilton et al 2020). 
SERENA-2 (D8530C00002, NCT04214288) is a global Phase 2, randomised, open-label 
study enrolling post-menopausal women who are suitable for fulvestrant therapy and with 


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disease progression after no more than one line of endocrine therapy for advanced disease, no 
more than one line of chemotherapy for advanced disease, and no prior fulvestrant or other 
oral SERD in the advanced disease setting. The study will evaluate the efficacy and safety of 
AZD9833 monotherapy doses once daily versus fulvestrant (administered according to its 
label). The primary objective is to determine the clinical efficacy of AZD9833 versus 
fulvestrant, as assessed by progression-free survival (PFS). Secondary objectives include 
objective response rate (ORR), duration of response, clinical benefit rate at 24 weeks (CBR24) 
and overall survival (OS). Effects of AZD9833 and fulvestrant on patients’ health-related 
quality of life (HRQoL) will also be assessed. Exploratory endpoints include analysis of 
serially sampled circulating tumour DNA (ctDNA) and 
.
This study, SERENA-3 (D8530C00003) is a randomised, open-label, parallel-group, 
pre-surgical study to investigate the biological effects of different doses of AZD9833 in 
post-menopausal (and potentially pre-menopausal) women with primary breast cancer. Stage 1 
of the study will examine the effects of AZD9833 at 75 and 150 mg administered once daily
for 5 to 7 days. An on-treatment tumour biopsy will be assessed for ER, progesterone receptor 
(PgR) and Ki-67 expression by immunohistochemistry (IHC) and compared with the 
diagnostic biopsy assessed by the same IHC method. 
A Safety and Data Monitoring Committee (SDMC) will review the data from Stage 1 with 
reference to the SDMC charter, where guidelines regarding progress to, and dose-selection in, 
Stage 2 will be provided. Stage 2 will only occur in the United Kingdom after approval of a 
substantial protocol amendment including details of the rationale, the doses of AZD9833 
and/or fulvestrant, and the study populations that will be evaluated in Stage 2 as recommended 
by the SDMC. In general, if Stage 1 doses produce a high degree of pharmacodynamic (PD) 
modulation versus historical fulvestrant control data, Stage 2 will likely focus on lower 
AZD9833 doses. Conversely, if Stage 1 doses produce a similar or lower degree of PD 
modulation compared with historical fulvestrant control data, Stage 2 will likely focus on 
higher AZD9833 doses. An alternative scenario is that the precision of the estimate of the 
primary endpoint from Stage 1 is insufficient, and the inclusion of additional patients in Stage 
2 at the same doses from Stage 1 will provide additional clarity. Therefore, Stage 2 of the 
study makes provision for the examination of the biological effects of several different dose 
levels of AZD9833, or to evaluate additional patients at the dose levels examined in Stage 1. 
A fulvestrant control group was not included in Stage 1, as several pre-surgical studies have 
been conducted, which include a fulvestrant control or experimental arms (eg, Robertson et 
al 2013, Robertson et al 2019), allowing a cross-study comparison of AZD9833 with 
fulvestrant historical control data. Provision was made in Stage 2 for a supplementary 
fulvestrant control group, if the SDMC advise that a concurrent fulvestrant control group 
would add to the scientific understanding of the study in Stage 2.
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•
To evaluate the PK of AZD9833 in this 
patient population.
•
Plasma concentrations of AZD9833 on the 
biopsy day.
For exploratory objectives and endpoints, see Section 3 of the protocol.
Overall Design
This is a three-stage, randomised, open-label, parallel-group, multicentre study to investigate 
the biological effects of different doses of daily, orally administered (PO) AZD9833 in 
women with primary breast cancer awaiting curative-intent surgery. Women with 
histologically proven, ER-positive, HER2-negative invasive breast cancer involving a 
palpable tumour of any size, or a tumour with an ultrasound of ≥ 1.0 cm and fulfilling all the 
inclusion criteria and none of the exclusion criteria will be enrolled in the study. 
Stage 1 of the study will include 2 treatment groups, to which post-menopausal patients will 
be randomised 1:1. 
Stage 2 of the study will include 3 treatment groups (post-menopausal women; 3 AZD9833 
groups). 
Stage 3 of the study will include 2 treatment groups, to which post-menopausal patients will 
be randomised 1:1.
Stage 1:
After the screening visit and confirmation of eligibility, patients will be randomly assigned in 
a 1:1 ratio to receive one of the following two treatments for 5 to 7 days: 

Group 1: AZD9833 75 mg once daily (n = 12 evaluable post-menopausal patients)

Group 2: AZD9833 150 mg once daily (n = 12 evaluable post-menopausal patients)
The SDMC will convene to review the Stage 1 data, potentially alongside the ongoing Phase 1 
and 2 studies. The SDMC will make a decision as to whether to proceed to Stage 2, based on 
the SDMC charter, where guidelines regarding progress to, and dose-selection for Stage 2 will 
be provided. 
Stage 2:
The SDMC reviewed the Stage 1 data and advised that Stage 2 will comprise: 

Group 1: AZD9833 Dose 75 mg once daily; approximately n = 24 evaluable patients

Group 2: AZD9833 Dose 150 mg once daily; approximately n = 24 evaluable patients

Group 3: AZD9833 Dose 300 mg once daily; approximately n = 12 evaluable patients


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The randomisation will be stratified by country such that the UK will recruit approximately 
24 evaluable patients across Groups 1 and 2, and Georgia and Mexico will recruit 
approximately 36 evaluable patients across Groups 1, 2, and 3.
Patients will attend a study visit on Day 5, 6, or 7 for an on-treatment imaging-guided biopsy. 
Following a washout period of a minimum of 5 days, the patients will undergo curative-intent 
surgery. 
Stage 3:
The SDMC has advised that an additional Stage 3 will evaluate the biological effects of 
AZD9833 with longer duration of AZD9833 treatment (12 to 15 days) at doses of 75 and 
150 mg once daily.
Stage 3 will comprise: 

Group 1: AZD9833 Dose 75 mg once daily; approximately n = 24 evaluable patients

Group 2: AZD9833 Dose 150 mg once daily; approximately n = 24 evaluable patients
Patients will attend a study visit on Day 12, 13, 14, or 15 for an on-treatment imaging-guided 
biopsy. Following a washout period of a minimum of 5 days, the patients will undergo 
curative-intent surgery. 
Safety Assessments 
Throughout the study, patients will be asked to report AEs and the use of concomitant 
medications.
Stages 1 and 2:
Safety assessments (physical examination, vital signs) will be performed at screening. Clinical 
safety laboratory assessments will be performed at screening and on the biopsy visit day. 
ECGs and supine blood pressure measurement will be performed at screening (to ensure 
 at screening), on the day of biopsy (Day 5 to 7; ie, Visit 3) and on 
the day of surgery (to ensure 
 prior to surgery). Patients will wear a 
heart rate monitor from Day 1 to the Surgery Visit day.
Stage 3:
Safety assessments (physical examination, vital signs) will be performed at screening. Clinical 
safety laboratory assessments will be performed at screening and on the biopsy visit day. 
ECGs and supine blood pressure measurement will be performed at screening (to ensure 
 at screening), on the day of biopsy (Day 12 to 15; ie, Visit 4), and 
on the day of surgery (to ensure 
 prior to surgery). In Stage 3 an 
additional safety assessment will be performed on Day 7 (+3 days), specifically to assess heart 
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rate (by triplicate ECG) and blood pressure. Patients will wear a heart rate monitor from Day 1 
to the Surgery Visit day. 
Blood and Plasma Samples
Stages 1 and 2:
Blood and plasma samples for ctDNA will be collected at screening, on the day of the biopsy 
(Day 5 to 7), and the day of surgery. Where a decision to perform surgery is delayed for any
reason (eg, neoadjuvant therapy, COVID-19-related reasons, adverse drug reaction) the 
‘surgery day’ visit should be conducted on Day 13 (+ 3 days). Blood samples for exploratory 
circulating biomarkers will be collected at screening, on the day of the biopsy (Day 5 to 7), 
and the day of surgery.
Stage 3:
Blood and plasma samples for ctDNA will be collected at screening, on the day of the biopsy 
(Day 12 to 15) and the day of surgery. Where a decision to perform surgery is delayed for any 
reason (eg, neoadjuvant therapy, COVID-19-related reasons, adverse drug reaction), the 
‘surgery day’ visit should be conducted on the 6th day following the last dose of AZD9833 
(with a + 3 day window). Blood samples for exploratory circulating biomarkers will be 
collected at screening, on the day of the biopsy (Day 12 to 15), and the day of surgery.
All Stages
Blood samples will be collected for assessment of pharmacokinetics (PK) on the day of the 
biopsy, one sample prior to the biopsy and the other sample 1 to 3 hours after biopsy. 
For patients who provide optional consent, an additional blood sample will be collected at 
screening, Day 1, or day of biopsy for future genetic research.
Study Period:
Estimated date of first patient enrolled: Q3 2020.
Estimated date of last patient completed (end of Stage 3): Q2 2023.
Number of Participants:
In Stage 1 of the study, approximately 28 post-menopausal patients will be screened 
(assuming a screen failure rate of approximately 15%), in order to randomise 24 evaluable 
patients into two treatment groups in a 1:1 ratio. Non-evaluable patients may be replaced.
In Stage 2 of the study, approximately 70 post-menopausal patients will be screened 
(assuming a screen failure rate of approximately 15%), in order to randomise up to 
60 evaluable post-menopausal patients into 3 treatment groups. Non-evaluable patients may 
be replaced.


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In Stage 3 of the study, approximately 56 post-menopausal patients will be screened 
(assuming a screen failure rate of approximately 15%), in order to randomise approximately 
48 evaluable post-menopausal patients into 2 treatment groups. Non-evaluable patients may 
be replaced.
Treatments and Treatment Duration:
In Stages 1 and 2 patients will receive AZD9833 for 5 to 7 days. 
In Stage 1, AZD9833 will be administered PO once daily in the morning at the same time:

75 mg: 
 tablets

150 mg: 
 tablet + 
 tablets
In Stage 2, AZD9833 will be administered once daily in the morning at the same time at the 
doses selected by the SDMC, ie:

75 mg: 
 tablets

150 mg: 
 tablet + 
 tablets

300 mg: 
 tablet
In Stage 3, patients will receive AZD9833 for 12 to 15 days. AZD9833 will be administered 
PO once daily in the morning at the same time:

75 mg: 
 tablets

150 mg:
 tablet + 
 tablets
Safety and Data Monitoring Committee:
An independent AstraZeneca SDMC was to consider the Stage 1 data from this study prior to 
commencing Stage 2.
Stage 2 will only start enrolling in the UK after approval of a substantial protocol amendment 
including details of the rationale, the doses of AZD9833 and the study population that will be 
evaluated in Stage 2 as recommended by the SDMC. 
The SDMC convened on 06 July 2021 and reviewed the Stage 1 data. The SDMC decided to
proceed with Stage 2, based on the guidelines outlined in the charter and, selected three 
treatment groups as noted above. The charter is provided as a separate document. 
The SDMC met on 27 June 2022 to review data arising from Stage 1 and 2.  The SDMC has 
advised that an additional Stage 3 of the study will examine the effects of AZD9833 at 75 and 
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150 mg administered once daily for 12 to 15 days. The details and justification for Stage 3 are
given in Section(s) 2.2.2.8 and 2.2.2.9; and Section 6.1.1.
Statistical Methods:
Statistical methods for the study will be as described in Section 9.
1.2
Schema
The general study design for Stage 1 is summarised in Figure 1. The study design for Stage 2 
is shown in Figure 2 and the study design for Stage 3 is shown in Figure 3.
Figure 1
Study Design: Stage 1


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Figure 2
Study Design: Stage 2
The SDMC has advised Stage 2 should be conducted as follows: 
Figure 3
Study Design: Stage 3
The SDMC has advised Stage 3 should be conducted as follows: 
1.3
Schedule of Activities
Table 1 indicates the Schedule of Activities throughout the study for Stage 1 and Stage 2. 
Table 2 indicates the Schedule of Activities throughout the study for Stage 3.


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Table 1
Schedule of Activities: Stages 1 and 2
Stage 1 and 2
Screening
Day 1
Biopsy 
day
Surgery 
daya
28-day 
safety
CSP 
section 
Visit
1
2
3
4
5b
Study Day
-21 to 1
1
5 to 7
≥11
28 ± 3
Informed consent and eligibility criteria
X
5.1, 5.2
Demography, medical/surgical history, 
baseline disease characteristics 
(including ECOG)
X
5.1, 8.1.1
Clinical chemistry, haematology, 
urinalysis
X
X
8.2.1
Troponin and NT-proBNP
X
X
8.2.1
Physical examination, neurological 
exam, weight, height, temperature, pulse 
rate
X
8.2.2
Triplicate digital ECGc + supine blood 
pressure
X
X
X
8.2.4
Wearable heart rate monitor
Continuous
8.2.5
Randomisation
X
6.3
AZD9833 (allocated dose PO)
Daily
6.1.1
Concomitant medications
At every visit
6.5
Adverse events
At every visit
8.3
AZD9833 PK sample pre-biopsy
X
8.5.1
AZD9833 PK sample post-biopsy 
(1 to 3 hours)
X
8.5.1
Diagnostic tumour tissue retrieval
X
8.6.3
Tumour biopsy
(X)d
X
8.6.3
Blood sample for ctDNA 
X
X
X
8.6.1
Blood sample for exploratory biomarkers 
X
X
X
8.6.2
Genetic blood sample
(X)
8.7
a
Surgery must be scheduled after a minimum of 5 days washout period from the last dose of study medication. In the 
event that a patient is undergoing longer-term neoadjuvant therapy rather than surgery, the 'surgery day' visit should be 
conducted on Day 13 (+ 3 days).
b
Adverse events and concomitant medications information may be collected by telephone at the safety follow-up visit.
c
Heart rate will be assessed by central review of the mean of triplicate ECG at all assessment timepoints except on the 
day of surgery, where it will be assessed by the treating physician prior to planned surgery.
d
Mandatory tumour biopsy if diagnostic biopsy taken > 6 weeks prior to the screening visit date or patients consent to 
biopsy for fresh tumour tissue.


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Table 2
Schedule of Activities: Stage 3
Stage 3
Screening
Day 1
Day 7
Biopsy 
day
Surgery 
daya
28-day 
safety
CSP 
section 
Visit
1
2
3
4
5
6b
Study Day
-21 to 1
1
7 
(+ 3 days)
12 to 15
≥18a
28 ± 3 days 
after last 
dose
Informed consent and 
eligibility criteria
X
5.1, 5.2
Demography, 
medical/surgical history, 
baseline disease 
characteristics (including 
ECOG)
X
5.1, 
8.1.1
Clinical chemistry, 
haematology, urinalysis
X
X
8.2.1
Troponin and NT-proBNP
X
X
8.2.1
Physical examination, 
neurological exam, weight, 
height, temperature, pulse 
rate
X
8.2.2
Triplicate digital ECGc + 
supine blood pressure
X
X
X
X
8.2.4
Continuous
8.2.5
Randomisation
X
6.3
AZD9833 (allocated dose 
PO)
Daily
6.1.1
Concomitant medications
At every visit
6.5
Adverse events
At every visit
8.3
AZD9833 PK sample 
pre-biopsy
X
8.5.1
AZD9833 PK sample 
post-biopsy (1 to 3 hours)
X
8.5.1
Diagnostic tumour tissue 
retrieval
X
8.6.3
Tumour biopsy
(X)d
X
8.6.3
Blood sample for ctDNA 
X
X
X
8.6.1
Blood sample for 
exploratory biomarkers 
X
X
X
8.6.2
Genetic blood sample
(X)
8.7
a
Surgery must be scheduled after a minimum of 5 days washout period from the last dose of study medication. In the 
event that a patient is undergoing longer-term neoadjuvant therapy rather than surgery, the 'surgery day' visit should be 
conducted on the 6th day following the last dose of AZD9833 (with a + 3 day window).
b
Adverse events and concomitant medications information may be collected by telephone at the safety follow-up visit.
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c
Heart rate will be assessed by central review of the mean of triplicate ECG at all assessment timepoints except on the 
day of surgery, where it will be assessed by the treating physician prior to planned surgery.
d
Mandatory tumour biopsy if diagnostic biopsy taken > 6 weeks prior to the screening visit date or patients consent to 
biopsy for fresh tumour tissue.


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2
INTRODUCTION
2.1
Study Rationale
Anti-hormonal endocrine therapies targeting ERα have become treatments of choice in breast 
cancer (Early Breast Cancer Trialists’ Collaborative Group 2005). The SERD fulvestrant is 
used as a standard-of-care treatment for ER positive metastatic breast cancer 
(Cardoso et al 2018).
While fulvestrant has demonstrated superior clinical efficacy to other endocrine therapies and 
is approved for use in the metastatic breast cancer setting, it is not orally bioavailable and the 
monthly IM route of administration may limit its efficacy (Robertson 2007, 
Robertson et al 2014).
AZD9833 is an orally bioavailable SERD which is being developed for the treatment of 
patients with ER-positive breast cancer. AZD9833 has the potential to provide superior 
clinical benefit to existing endocrine therapies through enhanced bioavailability, target 
engagement and modulation in patients with ER positive breast cancer.
A first-in-human study (SERENA-1, D8530C00001, NCT03616587) evaluating multiple 
ascending doses of AZD9833 established that doses of 25, 75, 150, 300, and 450 mg once 
daily were safe and exhibited dose-dependent tolerability in pre- and post-menopausal 
women. Indications of efficacy were observed with AZD9833, with evidence of clinical 
benefit and target engagement observed at all dose levels, including patients pre-treated with 
CDK4/6 inhibitors and fulvestrant, and those with ESR1 mutations (Hamilton et al 2020). 
SERENA-2 (D8530C00002, NCT04214288) is a global Phase 2, randomised, open-label 
study evaluating the efficacy and safety of AZD9833 monotherapy versus fulvestrant. The 
primary objective is to determine the clinical efficacy of AZD9833 versus fulvestrant, as 
assessed by PFS. Secondary endpoints include ORR, duration of response, CBR24 and OS. 
Exploratory endpoints include analysis of serially sampled ctDNA and CTCs. This study 
started recruiting patients in Q2 2020 and aims to enrol 288 patients in approximately 
100 sites in up to 16 countries.
This study, SERENA-3 (D8530C00003) is a randomised, open-label, parallel-group, 
pre-surgical study to investigate the biological effects of different doses of AZD9833 in 
post-menopausal (and potentially pre-menopausal) women with primary breast cancer. Stage 1 
will examine AZD9833 at 75 and 150 mg once daily for 5 to 7 days. An on-treatment tumour 
biopsy will be assessed for ER, PgR and Ki-67 expression by IHC, and compared with the 
diagnostic biopsy assessed by the same IHC method. The SDMC will review the data from 
Stage 1 to decide whether to proceed to Stage 2, in line with the SDMC charter, where 
guidelines regarding progress to and dose-selection will be provided. Stage 2 of the study may 
examine the biological effects of different dose levels of AZD9833 or provide an option for 


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further patients at the dose levels examined in Stage 1. Stage 2 will only occur in the UK after 
approval of a substantial protocol amendment including details of the rationale, the doses of 
AZD9833, and the study populations that will be evaluated in Stage 2 as recommended by the 
SDMC.
Randomisation to Stage 1 was completed on 10 March 2021 and the SDMC met on 
06 July 2021 to review the overall Stage 1 data in detail. On the basis of that review, the 
SDMC has advised that Stage 2 will comprise of: 1) additional patients at both the 75 and
150 mg doses of AZD9833, and 2) an additional arm examining a higher dose of 300 mg 
AZD9833. The details and justification for these Stage 2 doses is given in Sections 2.2.2.6, 
2.2.2.7 and Section 6.1.1.
Randomisation to Stage 2 (Georgia and Mexico) was completed on 08 December 2021. 
Patients were dosed at the following 3 doses of AZD9833: 75, 150, and 300 mg. The UK 
portion of Stage 2 is currently ongoing at the following 2 doses of AZD9833: 75 and 150 mg. 
The SDMC met on 27 June 2022 to review data arising from Stage 1 and 2.  The SDMC has 
advised that an additional Stage 3 of the study will examine the effects of AZD9833 at 75 and 
150 mg administered once daily for 12 to 15 days. Stage 3 of the study will examine the 
effects of AZD9833 at 75 and 150 mg administered once daily for 12 to 15 days. An on-
treatment tumour biopsy will be assessed for ERα, PgR, and Ki-67 expression by IHC and 
compared with the diagnostic biopsy assessed by the same IHC method. The details and 
justification for these Stage 3 doses and treatment duration are given in Sections 2.2.2.8 and
2.2.2.9; and Section 6.1.1.
SERENA-3 is key to understanding the PD dose response for AZD9833, and in concert with 
the clinical efficacy and safety determined from SERENA-2, will support dose selection for 
further clinical development in the early and advanced breast cancer settings.
2.2
Background
2.2.1
ER-positive HER2-negative Breast Cancer
Breast cancer is the second most common cancer in the world and the most frequent cancer in 
women. An estimated 1.67 million new breast cancer cases were diagnosed in 2012, 
accounting for 25% of all cancers (Ferlay et al 2013). According to 2017 estimates, over 
253000 women in the United States were diagnosed with breast cancer and 41000 died from 
the disease (Siegel et al 2017). In Europe, it is estimated that 367000 women were diagnosed 
with breast cancer in 2012 and 91000 died from breast cancer (Ferlay et al 2013). 
Approximately 80% of post-menopausal women with breast cancer have ER positive disease 
(Clark et al 1984).


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Endocrine therapy has been shown to improve prognosis for patients with ER-positive breast 
cancer and is a standard-of-care for this patient group (Davies et al 2011). However, disease 
recurrence occurs steadily through the years subsequent to diagnosis and initial treatment, 
with a risk of recurrence in 10% to 41% of cases within 20 years, depending on tumour stage 
and grade (Pan et al 2017). Patients with recurrent or advanced disease have a median survival 
of 2 to 3 years, and a 5-year survival rate of 25% (Cardoso et al 2018).
Current guidelines (Cardoso et al 2018) indicate that the preferred first-line endocrine therapy 
for post-menopausal women with advanced disease is an AI, tamoxifen, or fulvestrant.
Options for second-line therapy depend on which agents were used in earlier lines of therapy; 
the optimal sequence of agents is uncertain. Options include AIs, tamoxifen, 
fulvestrant + palbociclib, AIs + everolimus, tamoxifen + everolimus, fulvestrant, megestrol 
acetate, and oestradiol.
New, more effective endocrine therapies, for use both alone and in combination, are needed 
for the treatment of ER-positive breast cancer. AZD9833 has the potential to provide superior 
clinical benefit to existing endocrine therapies through enhanced oral bioavailability and target 
engagement and modulation in patients with ER-positive breast cancer.
2.2.2
AZD9833
AZD9833 (INN: camizestrant) is a selective, non-steroidal, and potent SERD that can be 
administered orally. Pre-clinically, the drug has demonstrated equivalent maximal ERα 
degradation to fulvestrant in a panel of ER-positive breast cancer cell lines and complete 
antagonism of oestradiol induced gene expression changes in vitro. Furthermore, AZD9833 
did not cause any agonism of ER activity in the absence of oestradiol in ER-positive breast 
cancer nor in uterine endothelial models in vitro and in vivo. AZD9833 caused significant 
anti-tumour effects in several patient-derived xenograft models of ER-positive breast cancer, 
including those bearing clinically relevant mutations in ESR1, the gene that encodes ERα.
The first-in-human study (D8530C00001) evaluating AZD9833 in women with advanced ER 
positive HER2-negative breast cancer has completed its monotherapy dose escalation phase 
(SERENA-1) (Hamilton et al 2020).
The AZD9833 programme has now recruited 
 patients; the safety information 
presented below, and in the current version of the Investigator’s Brochure remains 
representative.
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2.2.2.1
Safety and Tolerability 
Safety and Efficacy in Humans
To-date, evaluation of AZD9833 monotherapy has occurred in study D8530C00001 
(SERENA-1) and study D8530C00002 (SERENA-2) in patients with advanced breast cancer. 
The clinical safety data summarised below are described separately, as follows:

AZD9833 safety at doses of 75 to 300 mg, administered daily in patients with advanced 
breast cancer (irrespective of duration of exposure); (N =
; SERENA-1 and 
SERENA-2).

AZD9833 safety at doses of 75 to 300 mg, administered daily for the first 7 days only
(N =
; SERENA-1 study).

AZD9833 safety at doses of 75 to 300 mg, administered daily for the first 15 days only. 
(N =
; SERENA-1 and SERENA-2)
The short duration safety data (7-day and 15-day exposure) is of most clinical relevance to the 
exposure and, in turn, the likely safety profile that will be observed in SERENA-3, where 
AZD9833 will be administered for a period of 5 to7 or 12 to 15 days.
The primary objective of SERENA-1 (D8530C00001) was to investigate the safety and 
tolerability of AZD9833, and to define the doses for further clinical evaluation by assessment 
of DLTs, AEs, vital signs, ECGs and clinical chemistry and haematology parameters. Enrolled 
patients were dosed once daily from study start through to disease progression, or to study 
withdrawal if that occurred before disease progression. The DLT evaluation period was 
28 days.  
The primary objective of SERENA-2 (D8530C00002) was to determine the clinical efficacy 
(as assessed by PFS) of AZD9833 at 75, 150 and 300 mg once daily when compared to 
fulvestrant in women with advanced ER-positive HER2-negative breast cancer.  SERENA-2 
is ongoing. While the study is open-label, it is blinded to the study team in terms of aggregate 
efficacy.
Overall Safety: AZD9833 Monotherapy (SERENA-1 and SERENA-2)
Durations of exposure at each dose level are provided in Table 3.
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Table 3
Duration of Exposure – AZD9833 Monotherapy (SERENA-1 and 
SERENA-2)
AZD9833 monotherapy
75 mg
150 mg
300 mg
Total 
(monotherapy)
Subject exposure,
days
Mean
SD
Median
Min
Max
Months n (%)
< 3 months
3 to 6 months
≥6 months
DCO = Data cut-off; SD = Standard deviation.
Source: Studies D8530C00001 (SERENA-1) and D8530C00002 (SERENA-2) combined preliminary data 
(DCO:
).
The observed AE profile is described in Table 4 and Table 5 below.
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Table 4
Summary of Adverse Events in Study AZD9833 monotherapy (SERENA-1 and SERENA-2)
75 mg
150 mg
300 mg
Total (monotherapy)
Any AE
Any causally related AEa
Any AE of CTCAE Grade 3 or higher
Any causally related AEa of CTCAE grade 3 or higher
Any AE leading to dose interruption
Causally related AEa leading to dose interruption
AE leading to dose reduction
Causally related AEa leading to dose reduction
AE leading to discontinuation
Causally related AEa leading to discontinuation
Any SAE
Causally related SAEa
Any AE with outcome = death
Causally related AEa with outcome = death
a
Causally related to AZD9833, as assessed by the Investigator.
The AEs are reported if occurred during period from first dose to the end of safety follow-up or got worse during treatment.
AE = Adverse event; CTCAE = Common terminology criteria for adverse events; DCO = Data cut-off; SAE = Serious adverse event.
Source: Studies D8530C00001 (SERENA-1) and D8530C00002 (SERENA-2) combined preliminary data (DCO:
).
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The highest dose tested in SERENA-1 was 450 mg once daily; following review of the safety 
data described, the SRC for that study declared 300 mg once daily was likely to be highest 
dose appropriate for long-term dosing in future clinical development with advanced/metastatic 
breast cancer. SERENA-2 and SERENA-3 investigate doses of 75, 150 and 300 mg once 
daily. 
 
 In 
addition, 
 associated with AZD9833 was observed, including 
following 
; this is also considered in further detail 
below.
2.2.2.2
Safety from Short Duration AZD9833 Monotherapy (7 days): Stages 1 and 2
This section has been left unchanged to reflect the data available at the start of the study and 
where the planned SERENA-3 exposure period was 5 to 7 days.
AZD9833 will be evaluated in a short duration (5 to 7 days) window of opportunity study in 
patients with newly diagnosed breast cancer. To optimally characterise the safety profile of 
AZD9833 after a short duration of exposure, the safety data in 80 patients treated with 
AZD9833 at doses of 25, 75, 150, 300 and 450 mg administered for 7 days in the ongoing 
Phase 1 AZD9833 monotherapy study was evaluated. 
At the time of writing Version 1 of this CSP, it had not been decided which doses (if any) 
might be evaluated in Stage 2 of the SERENA 3 window of opportunity study; and that this 
would be determined after Stage 1 by the SDMC. In Stage 1 AZD9833 doses of 75 and 
150 mg only were evaluated. In Stage 2 up to 60 patients may be evaluated with AZD9833 
including doses unchanged, higher or lower than those in Stage 1 (75 and 150 mg). As 
described in Section 6.1.1, the SDMC has advised doses of AZD9833 of 75, 150, and 300 mg 
once daily for Stage 2.
In total, in the Phase I, SERENA-1 study, 
%) patients had an AZD9833 causally 
related AE during 7 days of treatment. 
 
 
 respectively. The patient with 
 
 
 
The most commonly occurring AZD9833-related AEs by system organ class term were 
 
 and 
 occurring in 
%) and 
%) of patients, 
respectively. The most common AZD9833-related AEs during 1-7 days of treatment occurring 
in ≥ 2 patients were: 
 
 and 
.
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A summary of AZD9833 causally related AEs occurring during the first 7 days of treatment is 
detailed below (Table 6).
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Table 6
Summary of Causally Related AEs by SOC/PT in Study DC8530C0001 – First 7 Days of Treatment 
MedDRA SOC a/PT b
AZD9833 monotherapy
25 mg
75 mg
150 mg
300 mg
450 mg
Total
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Table 6
Summary of Causally Related AEs by SOC/PT in Study DC8530C0001 – First 7 Days of Treatment 
MedDRA SOC a/PT b
AZD9833 monotherapy
25 mg
75 mg
150 mg
300 mg
450 mg
Total
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Table 6
Summary of Causally Related AEs by SOC/PT in Study DC8530C0001 – First 7 Days of Treatment 
MedDRA SOC a/PT b
AZD9833 monotherapy
25 mg
75 mg
150 mg
300 mg
450 mg
Total
a
SoC number represents the number of patients with AEs (eg, with AZD9833 150 mg, 
),
b
Preferred term number represents the number of AEs reported in patients (eg, with AZD9833 150 mg, 
 AEs were reported in 
). 
Source: t 36b_caus_rel_AE_soc_7d_V.
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AZD9833 Monotherapy (7-days Exposure): 
1
 
 
 
 
 
 
 
 
.
 
 
                                               
1 This has now changed to ‘
’; Refer to the AZD9833 IB (version 4.0) for justification of this 
change.
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Table 8
AZD9833 monotherapy
25 mg
75 mg
150 mg
300 mg
450 mg
Total
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AZD9833 will be evaluated in a 12 to 15 day duration in Stage 3 of this window of 
opportunity study in patients with newly diagnosed breast cancer. To optimally characterise 
the safety profile of AZD9833 after a 1 to 15-day exposure (ie, longer than the 5 to 7 days 
examined in Stages 1 and 2) the safety data in 251 patients treated with AZD9833 at doses of 
75, 150, and 300 mg administered for 1 to 15 days in the ongoing SERENA-1 and SERENA-2 
studies were evaluated. 
A summary of AZD9833 causally related AEs occurring during the first 15 days of treatment 
is detailed below (Table 10).


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Table 10
Summary of Most Common (≥5% in Total for any SOC) Causally Related AEs by SOC/PT (SERENA-1 and 
SERENA-2); First 15 Days of Treatment 
MedDRA SOC a/PT
AZD9833 monotherapy
Number (%) of patients
75 mg
150 mg
300 mg
Total
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Table 10
Summary of Most Common (≥5% in Total for any SOC) Causally Related AEs by SOC/PT (SERENA-1 and 
SERENA-2); First 15 Days of Treatment 
MedDRA SOC a/PT
AZD9833 monotherapy
Number (%) of patients
75 mg
150 mg
300 mg
Total
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Table 10
Summary of Most Common (≥5% in Total for any SOC) Causally Related AEs by SOC/PT (SERENA-1 and 
SERENA-2); First 15 Days of Treatment 
MedDRA SOC a/PT
AZD9833 monotherapy
Number (%) of patients
75 mg
150 mg
300 mg
Total
a
SoC number represents the number of patients with AEs (eg, with AZD9833 150 mg, 
 patients had 
),
AE = Adverse event; DCO = Data cut-off; MedDRA = Medical Dictionary for Regulatory Activities; PT = Preferred term; SOC = System organ classification.
Source: Studies D8530C00001 (SERENA-1) and D8530C00002 (SERENA-2) combined preliminary data (DCO:
).
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28 February 2020, 11 patients across 5 dose cohorts (25, 75, 150, 300 and 450 mg once daily) 
had evaluable tumour biopsy samples. All patients, across all doses, displayed PD effects and 
reduction of ERα following treatment with AZD9833. Reduction of the ER downstream 
transcriptional target PR and functional proliferation biomarker (Ki-67) was also observed 
across the dose cohorts.
RECIST ORR in patients with measurable disease at baseline, along with CBR24 for those 
evaluable, indicate ORR ranges from 11.1% at 25 mg to 20.0% at 300 mg, and CBR24 ranges 
from 23.1% for 300 mg to 50.0% for 450 mg.
Overall, the observed modulation of key PD markers, along with evidence of clinical efficacy 
is considered to be a strong indicator of the potential clinical utility of AZD9833 in this 
Phase 1 setting, and that warranted further investigation in a Phase 2 SERENA-2 study. 
SERENA-3 will further characterise the modulation of key PD markers in an early breast 
cancer context in patients without prior therapy. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD9833 is 
provided in the Investigator’s Brochure.
2.2.2.6
Biological Activity from Stage 1 of SERENA-3, and Justification for Stage 2 
Dose Selection
 
 
 
 
Biopsy pairs from 3 patients were not evaluated due to: 

failure to process the on-treatment biopsy correctly (n = 1).

technical reasons in relation to biopsy processing (n = 1).

on-treatment biopsy taken > 12 hours after the final AZD9833 dose (n = 1).
Additionally, one patient was determined to be HER2-positive by central assessment and was 
therefore excluded from further analysis. This resulted in 11 evaluable paired biopsies from 
patients treated with 75 mg AZD9833, and 10 from patients treated with 150 mg AZD9833. 
Paired pre-treatment/on treatment biopsies were analysed by IHC for ERα, PgR, and Ki-67 
and the data are presented in Figure 4 and Table 14. 
These data demonstrate that both doses of AZD9833 examined in Stage 1 caused ERα
degradation, and PgR and Ki-67 downregulation. 
 
 
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 (middle panel of Figure 4 and 
Table 14).
 
 
Furthermore, 
 
 
 These data indicate that 
 
 
 The SDMC therefore regarded 
 
 
to be an important goal for Stage 2.
Figure 4
Pharmacodynamic Effect of 5 to7 Days Treatment with 75 mg or 
150 mg AZD9833 on ERα, PgR, and Ki-67 Expression. 
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Table 14
ANCOVA Analysis for ERα, PgR, and Ki-67 (Adjusted for Key 
Covariates)
75 mg AZD9833
150 mg AZD9833
n
LS mean 
80% CI 
n
LS mean 
80% CI 
% change from baseline in 
ERα H-score
11
10
% change from baseline in 
PgR H-score 
8
8
% change from baseline in 
Ki67 % positive a
8
10
a
Back transformed from log scale
Note: Table contents sourced from SERENA-3 Stage 1 PD data.
Least squares means were derived from an ANCOVA model adjusting for day of biopsy, baseline score, and 
treatment. 
Note: Patients with a baseline H-score <10 on PgR or baseline labelling index <5% for Ki67 were excluded from 
the PgR or Ki-67 analysis, respectively. 
CI = Confidence interval; ERα = Oestrogen receptor alpha; Ki-67 = Antigen Ki-67; PgR = Progesterone receptor.
The SDMC additionally recognised 
 
 
 
 The SDMC advised that it would be scientifically valuable to 
examine the 
. Therefore, the SDMC advised that it was key to 
increase the precision of the estimates of the PD effects at the 75 and 150 mg doses and 
examine the PD effect of a higher dose.
The appropriate higher dose for Stage 2 is considered to be 300 mg. The linear dose-exposure 
relationship of AZD9833 over the dose range 25 to 300 mg means that increasing the dose 
from 150 mg to 300 mg would represent a doubling of exposure which could reasonably be 
expected to cause an observable increase in PD effect.
The SDMC specifically considered how many patients might be included in the 300 mg dose 
group and advised that 12 patients would be appropriate. This could be expected to provide 
sufficient understanding regarding the shape of the dose-response curve beyond 150 mg.
 
 
 
 
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The SDMC considered that the 5-day 
washout period is safe, reasonable, and sufficient for Stage 2 conduct as proposed.
2.2.2.8
Biological Activity from Stage 1 and 2 of SERENA-3, and Justification for 
Selection Stage 3 Dose and Duration of Dosing 
 
 
 
 
 
 
Biopsy pairs from 4 patients were not evaluated due to: 

Failure to process the on-treatment biopsy correctly (n = 1).

Insufficient tumour in the on-treatment sample (n=2).

On-treatment biopsy taken > 12 hours after the final AZD9833 dose (n = 1).
This resulted in 24 evaluable paired biopsies from patients treated with 75 mg AZD9833, 
25 from patients treated with 150 mg AZD9833 and 11 from patients treated with 300 mg 
AZD9833. Additionally, one patient treated at 75mg was determined to be HER2-positive by 
central assessment and was therefore excluded from further analysis. 
Paired pre-treatment/on treatment biopsies were analysed by IHC for ERα, PgR, and Ki-67 
and the data are presented in Figure 5 and Table 15. 
These data demonstrate that all doses of AZD9833 examined in Stage 1 and Stage 2 (Georgia 
and Mexico) caused ERα degradation, and PgR and Ki-67 downregulation. They also suggest 
that, while there is no apparent difference between the degree of ERα degradation nor the 
reduction in PgR expression caused by the different doses of AZD9833, 150 mg and 300 mg 
may be more effective than 75 mg AZD9833 at reducing Ki-67 levels. 
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Figure 5
Pharmacodynamic Effect of 5 to7 Days Treatment with 75 mg, 150 mg 
or 300 mg AZD9833 on ERα, PgR, and Ki-67 Expression
Note: In lower graphs of the above plot, line represents least squares mean and error bars 80% confidence 
interval.
+ve = positive; ERα = Oestrogen receptor alpha; Ki67 = Antigen Ki-67; PgR = Progesterone receptor.
a
Back transformed from log scale
Least squares means were derived from an ANCOVA model adjusting for day of biopsy, baseline score, and 
treatment. Note: Patients with a baseline H-score <10 on PgR or baseline labelling index <5% for Ki-67 were 
excluded from the PgR or Ki-67 analysis, respectively. 
ANCOVA = Analysis of covariance; CI = Confidence interval; ERα = Oestrogen receptor alpha; 
Ki-67 = Antigen Ki-67; LS = Least squares; PD = Pharmacodynamic(s); PgR = Progesterone receptor.
Note: Table contents sourced from SERENA-3 Stage 1 + 2 interim analysis PD data.
Table 15
ANCOVA Analysis for ERα, PgR, and Ki-67 (Adjusted for Key 
Covariates)
75 mg AZD9833
150 mg AZD9833
300 mg AZD9833
n
LS 
mean 
80% CI 
n
LS 
mean
80% CI 
n
LS 
mean 
80% 
CI 
% change from baseline in 
ERα H-score
23
25
11
% change from baseline in 
PgR H-score 
17
20
8
% change from baseline in 
Ki-67 % positivea
15
23
11
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These data suggest that the maximal PD effect of AZD9833 
may not have been achieved when tumour biopsies were collected on Day 5 to 7 of treatment, 
which may be a confounding factor in interpreting the effect of different doses of AZD9833. 
Therefore, the SDMC have advised to examine the PD effect of different doses of AZD9833 
at longer treatment durations. 
 
 the SDMC recommended that it would be appropriate to test the extended 
dosing period at 75 and 150 mg AZD9833.
In the IMPACT study, the effect of the endocrine therapies anastrozole, tamoxifen and the 
combination of the two agents on reductions in Ki-67 expression after 2 and 12 weeks of 
treatment was assessed (Dowsett et al 2005). While these are two drugs that target ER 
indirectly and directly respectively, there was no difference between the level of Ki-67 
reduction seen at 2 and 12 weeks for either drug, suggesting that the maximal PD effect of ER 
inhibition is achieved after 2 weeks of dosing. As changes in Ki-67 is the most distant from 
target engagement of the 3 biomarkers assessed in SERENA-3, it is considered that a 12 to 
15 day treatment period with AZD9833 is sufficient to achieve maximal PD effect on all three 
biomarkers. 
2.2.2.9
Safety data from Stage 1 and 2 of SERENA-3, and Justification for Stage 3 
Dose Selection and Duration of Exposure
No safety concerns were identified during the conduct of Stages 1 and 2. Table 16 and 
Table 17 below show the key AE data from the interim analysis of Stages 1 and 2. 
 
 
 
 
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Table 16
Summary of Adverse Events from Interim Analysis of Data for Stage 1 
and Stage 2 of SERENA-3 Study 
AZD9833 Monotherapy
Number (%) of patients
75 mg
150 mg
300 mg
Total
Any AE
Any AE possibly related a to treatment
Any AE of CTCAE Grade 3 or higher
Any AE of CTCAE Grade 3 or 
higher possibly relateda to treatment
Any AE with outcome = death
AEa with outcome = death possibly related 
to treatment
Any SAE (including events with outcome 
= death)
Any AE leading to discontinuation of 
treatment
Any AE leading to discontinuation of 
treatment, possibly relateda to treatment
Any AE leading to dose modification of 
treatment
a
Possibly related to AZD9833, as assessed by the Investigator.
AE = Adverse event; CTCAE = Common terminology criteria for adverse events; DCO = Data cut-off.
Source: Table 14.3.2.1 Study D8530C00003 (SERENA-3) interim analysis (DCO: 
).
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Table 17
Summary of Causally Related Adverse Events from Interim Analysis 
of Data for Stage 1 and Stage 2 of SERENA-3 Study 
AZD9833 Monotherapy
Number (%) of patients
75 mg
150 mg
300 mg
Total
Any AE possibly related a to treatment
a
Possibly related to AZD9833, as assessed by the Investigator.
AE = Adverse event; DCO = Data cut-off; MedDRA = Medical Dictionary for Regulatory Activities; PT = 
Preferred term; SOC = System organ class.
Source: Table 14.3.2.8 Study D8530C00003 (SERENA-3) interim analysis (DCO: 
). 
No AEs of 
 were reported.  
 
 
 
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2.3
Benefit/Risk Assessment
2.3.1
AZD9833
2.3.1.1
Potential Benefits
AZD9833 is unlikely to provide clinical benefit to patients in this pre-surgical window setting. 
The data presented above support potential benefit in a wider ER positive breast cancer setting 
at the doses under investigation in this study. 
2.3.1.2
Potential Risks
Risks Identified in Pre-clinical Studies
Based on non-clinical toxicology studies, 
 
 
 
 
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Further information regarding non-clinical toxicology data is provided in the Investigator’s 
Brochure. 
Risks Identified in Clinical Studies
The Phase 1 study has identified 
, as 
important risks, as described in detail above. 
 
 
 
 
 Please refer to the Investigator’s Brochure 
for further information regarding the potential risks for AZD9833 in a clinical setting.
2.3.2
Overall Benefit/Risk and Ethical Assessment
Whilst biomarker changes may be observed in tumours from these patients receiving 5 to 
15 days of AZD9833, there is no data to support that short-term pre-/peri-operative changes in 
biomarkers translate into clinical benefit in patients with primary breast cancer. As such, 
short-term administration of endocrine therapy prior to surgery for primary breast cancer is 
not considered a standard-of-care treatment. 
Similar smaller window-of-opportunity studies of other anti-hormonal or growth factor 
inhibitor agents in patients with early stage ER-positive breast cancer have been conducted 
(De Friend et al 1994, Robertson et al 2013, Robertson et al 2019, Robertson et al 2020a, 
Robertson et al 2020b) and found to be acceptable to the planned patient population. These 
studies have been central to the clinical development of SERDs, in particular to appropriate 
dose selection for later-phase clinical studies.
The investigation of AZD9833 in women with primary ER-positive HER2-negative breast 
cancer is considered acceptable, based upon:

The clinical safety and efficacy data obtained from D8530C00001, D8530C00002 and 
D8530C00003

The short duration of treatment with AZD9833 of 5 to 15 days in terms of side effect 
profile, 
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
The strength and importance of the scientific hypothesis under evaluation
Overall, the study provides an important clinical and scientific opportunity to investigate the 
PD effect of a new oral SERD at different doses. The study has the potential to substantially 
impact on the later clinical development of AZD9833 and other new endocrine treatments for 
women with breast cancer. There is an unmet clinical need for new therapeutic agents for 
patients with breast cancer and this study substantially facilitates rational drug development in 
that field. On balance, it is considered that the study presents an overall positive risk/benefit 
profile.
Stage 1 data support the overall risk/benefit and ethical assessment above, and the statements 
are unmodified for the conduct of Stage 2.
The combined Stage 1 and 2 data support the overall risk/benefit and ethical assessment 
above, and the statements are modified where appropriate to support the conduct of Stage 3.
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Table 18
Objectives and Endpoints
markers and circulating biomarkers such as 
tumour DNA, mRNA, proteins or immune 
biomarkers (eg, autoantibodies). 
circulating biomarkers such as tumour DNA, 
mRNA, proteins, or immune biomarkers.
•
To collect and store plasma and serum samples 
for possible retrospective exploratory biomarker 
analysis which may include, but will not be 
limited to, understanding mechanisms of 
response to treatment (where response is defined 
broadly to include biomarker change, 
tolerability, or safety). This may include the 
analysis of tumour-specific and circulating 
biomarkers such as tumour DNA, proteins, 
antibodies or metabolites.
•
Results from future exploratory biomarker 
analysis may be reported outside of the CSR.
•
To collect and store DNA for future exploratory 
research into genes/genetic variation that may 
influence response (ie, distribution, safety, 
tolerability and efficacy) to AZD9833 and/or 
susceptibility to breast cancer.
•
Results from future exploratory research may be 
reported outside of the CSR.


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4
STUDY DESIGN
4.1
Overall Design
This is a three-stage, randomised, open-label, parallel-group, multicentre study to investigate 
the biological effects of different doses of daily PO AZD9833 in post-menopausal women 
with primary breast cancer. Participants will be newly diagnosed with histologically ER-
positive, HER2-negative invasive breast cancer involving a palpable tumour of any size, or a 
tumour with an ultrasound of ≥ 1.0 cm and fulfilling all the inclusion criteria and none of the 
exclusion criteria will be included. Stage 1 of the study comprises two treatment groups, to 
which post-menopausal patients will be randomised (Figure 1). Stage 2 of the study may 
include up to four optional treatment groups, in which post-menopausal patients will be 
randomised in an allocation ratio to be determined (Figure 2). Stage 3 of the study comprises 
two treatment groups, to which post-menopausal patients will be randomised (Figure 3). All 
efficacy and safety assessments will be performed as described in the SoA for Stages 1 and 2 
(Table 1), and the SoA for Stage 3 (Table 2) and Section 8.
4.1.1
Stage 1
After the screening visit (up to Da 21ys prior to randomisation) and confirmation of eligibility, 
patients will be randomly assigned in a 1:1 ratio to receive one of the following two 
treatments for 5 to 7 days:

AZD9833 (75 mg, PO, once daily for 5 to 7 days)

AZD9833 (150 mg, PO, once daily for 5 to 7 days)
During the treatment period, patients will attend study visits on:

Day 1

Day of biopsy (Day 5, 6 or 7)

Day of surgery (following a washout from AZD9833 for at least 5 days; ie, if AZD9833 
was taken for the last time on morning of Day 5, then Days 6, 7, 8, 9 and 10 are washout 
days and surgery can be scheduled for Day 11 onwards). In the event that a patient is 
undergoing longer-term neoadjuvant therapy rather than surgery, the 'surgery day' visit 
should be conducted on Day 13 (+ 3 days).
A treatment window of 5 to 7 days, along with a washout period of 5 days is considered to 
permit curative intent surgery within existing standard of care timeframes.
Throughout the study, patients will be asked to report AEs and the use of concomitant 
medications.


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Safety assessments (physical examination, vital signs, ECGs, clinical safety laboratory 
assessments) will be performed at screening. An additional ECG and supine blood pressure 
measurement will be performed on the day of biopsy (Day 5 to 7; ie, Visit 3) and on the day of 
surgery. 
Patients will wear a portable heart rate monitor continuously from Day 1 to the Surgery Visit 
day. 
Blood and plasma samples for ctDNA will be collected at screening, on day of biopsy and the 
day of surgery. An additional blood sample (plasma and serum) to assess exploratory 
biomarkers will also be collected at screening, on the day of biopsy and on the day of surgery. 
Patients may be replaced until 12 evaluable paired biopsies are collected within each treatment 
group (see Section 9.2.1 for definition of an evaluable patient).
Blood samples will be collected for PK assessment on the day of biopsy. 
 
 
After the treatment period, patients will have a telephone 28-day safety follow-up visit to 
report any AEs and the use of concomitant medication.
4.1.2
Stage 2
Following the completion of the last patient visit in Stage 1 and availability of the IHC data, 
the SDMC will convene to review the Stage 1 data, potentially alongside the emerging data 
from any relevant ongoing AZD9833 studies. The SDMC will make a decision on whether to 
proceed with Stage 2, based on the guidelines outlined in the charter. If the decision is to 
proceed, the SDMC will then select the number of treatment groups in Stage 2 and at which 
doses, and confirm whether a pre-menopausal patient treatment group should be included, and 
at which dose of AZD9833. Stage 2 will only occur in the UK after approval of a substantial 
protocol amendment including details of the rationale, the doses of AZD9833 and/or 
fulvestrant, and the study populations that will be evaluated in Stage 2 as recommended by the 
SDMC.
See Section 2.2.2.6and 2.2.2.7 for a summary of Stage 1 data, and the SDMC 
recommendations. 
After the screening visit (up to 21 days prior to randomisation) and confirmation of eligibility, 
patients will be randomly assigned in a 1:1 or 1:1:1 ratio to receive one of the following two 
or three treatments (based on the geographical stratification factor) for 5 to 7 days:

AZD9833 (75 mg, PO, once daily for 5 to 7 days)
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
AZD9833 (150 mg, PO, once daily for 5 to 7 days)

AZD9833 (300 mg, PO, once daily for 5 to 7 days)
During the treatment period, patients will attend study visits on:

Day 1

Day of biopsy (Day 5, 6 or 7)

Day of surgery (following a washout from AZD9833 for at least 5 days; ie, if AZD9833 
was taken for the last time on morning of Day 5, then Days 6, 7, 8, 9, and 10 are washout 
days and surgery can be scheduled for Day 11 onwards). In the event that a patient is 
undergoing longer-term neoadjuvant therapy rather than surgery, the ‘surgery day’ visit 
should be conducted on Day 13 (+ 3 days)
A treatment window of 5 to 7 days, along with a washout period of 5 days is considered to 
permit curative intent surgery within existing standard of care timeframes. Throughout the 
study, patients will be asked to report AEs and the use of concomitant medications. 
Safety assessments (physical examination, vital signs, ECGs, supine blood pressure, and 
clinical safety laboratory assessments) will be performed at screening. An additional ECG and 
supine blood pressure measurement will be performed on the day of biopsy (Day 5 to 7; ie, 
Visit 3) and on the day of surgery. Additional clinical safety laboratory assessments will be 
performed on the day of biopsy. Patients will wear a portable heart rate monitor continuously 
from Day 1 to the day of surgery, or the Day 13 ‘surgical visit’ in the case of patients 
proceeding to neoadjuvant therapy rather than surgery. Blood and plasma samples for ctDNA 
will be collected at screening, on day of biopsy, and the day of surgery. An additional blood 
sample (plasma and serum) to assess exploratory biomarkers will also be collected at 
screening, on the day of biopsy, and on the day of surgery. Patients may be replaced until 
approximately 12 or 24 evaluable paired biopsies are collected within each treatment group 
(see Section 9.2.1 for definition of an evaluable patient). Blood samples will be collected for 
PK assessment on the day of biopsy. 
 
 
After the treatment period, patients will have a telephone 28-day safety follow-up visit to 
report any AEs and the use of concomitant medication.
4.1.2.1
Post-menopausal Women
After the screening visit and confirmation of eligibility, post-menopausal women with a 
pre-treatment diagnostic biopsy will be randomly assigned to one of up to 3 treatment groups 
(three AZD9833 dose groups). Following the SDMC recommendation, patients will be 
randomised to one of two (UK) or one of three (Georgia and Mexico) AZD9833 dose groups. 
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Treatment will be administered for 5 to 7 days using exactly the same inclusion/exclusion 
criteria and schedule of assessments as in Stage 1.
4.1.3
Stage 3
After the screening visit (up to 21 days prior to randomisation) and confirmation of eligibility, 
patients will be randomly assigned in a 1:1 ratio to receive one of the following two 
treatments for 12 to 15 days:

AZD9833 (75 mg, PO, once daily for 12 to 15 days)

AZD9833 (150 mg, PO, once daily for 12 to 15 days)
During the treatment period, patients will attend study visits on:

Day 1

Day 7 (+ 3 days)

Day of biopsy (Day 12, 13, 14, or 15)

Day of surgery (following a washout from AZD9833 for at least 5 days; ie, if AZD9833 
was taken for the last time on morning of Day 12, then Days 13, 14, 15, 16, and 17 are 
washout days and surgery can be scheduled for Day 18 onwards). In the event that a 
patient is undergoing longer-term neoadjuvant therapy rather than surgery, the 'surgery 
day' visit should be conducted on the 6th day following the last dose of AZD9833 (with a 
+ 3 day window).
If, at the Day 7 (+ 3 days) visit, a patient is observed to have a mean of triplicate heart rate of 
< 50 bpm, she will be scheduled to undergo her biopsy day visit at Day 12; she will then 
commence her washout from AZD9833 following her daily dose on Day 12. In the event that 
it is not possible to schedule her biopsy on Day 12, the patient will begin her washout 
immediately at the Day 7 (+ 3 days) visit and will not be required to undergo biopsy. Patients 
may be replaced until approximately 24 evaluable paired biopsies are collected within each 
treatment group of Stage 3.
A treatment window of 12 to 15 days, along with a washout period of 5 days is considered to 
permit curative intent surgery within existing standard of care timeframes.
Throughout the study, patients will be asked to report AEs and the use of concomitant 
medications.
Safety assessments (physical examination, vital signs, ECGs, clinical safety laboratory 
assessments) will be performed at screening. An additional ECG and supine blood pressure 
measurement will be performed at the Day 7 (+ 3 days) visit, on the day of biopsy (Day 12 to 
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Patients will wear a portable heart rate monitor continuously from Day 1 to the Surgery Visit 
day. 
Blood and plasma samples for ctDNA will be collected at screening, on the day of biopsy and 
the day of surgery. An additional blood sample (plasma and serum) to assess exploratory 
biomarkers will also be collected at screening, on the day of biopsy and on the day of surgery. 
Patients may be replaced until approximately 24 evaluable paired biopsies are collected within 
each treatment group (see Section 9.2.1 for definition of an evaluable patient).
Blood samples will be collected for PK assessment on the day of biopsy. 
 
 
After the treatment period, patients will have a telephone 28-day (± 3 days) safety follow-up 
visit to report any AEs and the use of concomitant medication.
4.1.3.1
Post-menopausal Women
After the screening visit and confirmation of eligibility, post-menopausal women with a 
pre-treatment diagnostic biopsy will be randomly assigned to one of two AZD9833 dose 
groups. Treatment will be administered for 12 to 15 days. The SOA for patients participating 
in Stage 3 is described in Table 2.
4.1.4
Study Conduct Mitigation During Study Disruptions Due Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis 
(eg, during quarantines and resulting site closures, regional travel restrictions, and 
considerations if site personnel or study participants become infected with severe acute 
respiratory syndrome coronavirus-2 [SARS-CoV-2] or similar pandemic infection), which 
would prevent the conduct of study-related activities at study sites, thereby compromising the 
study site staff or the participant’s ability to conduct the study. The investigator or designee 
should contact the study Sponsor to discuss whether the mitigation plans below should be 
implemented.
To ensure continuity of the clinical study during the COVID-19 outbreak, temporary changes 
may be implemented to ensure the safety of study patients, maintain compliance with GCP, 
and minimise risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies or local government), these temporary changes may include the 
following options:
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
Obtaining consent for the mitigation procedures (note, in the case of verbal consent, the 
ICF should be signed at the patient’s next contact with the study site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened patients (see 
Section 5.5).

Home or remote visit: Performed by a site-qualified HCP or HCP provided by a third 
party vendor (TPV).

Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.

At-home study treatment administration: Performed by a site-qualified HCP, HCP 
provided by a TPV, or by the patients or the patient’s caregiver, if possible. Additional 
information related to the visit can be obtained via telemedicine.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix G.
4.2
Scientific Rationale for Study Design
An open-label clinical design is adopted to minimise patient tablet burden and given that the 
primary endpoint is measurement of tumour biopsy pharmacodynamics, where the IHC 
reading will be conducted blinded to group allocation and sequence (diagnostic versus on 
treatment).
The primary endpoint for this study is percent change from baseline in ER expression, 
measured by IHC and assessed by the manual H-score method. The PD relationship will be 
further evaluated with secondary endpoints (ie, percent change from baseline in PgR H-score 
and Ki-67 labelling index measured by IHC). Ki-67 labelling index will be calculated as the 
number of Ki-67 stained nuclei counted/total number of all invasive nuclei counted. These PD 
endpoints have proven informative for the clinical development of the SERDs 
(Robertson 2007, Robertson et al 2020b) and are considered appropriate here.
4.3
Justification for Dose
The selection of the two dose levels of AZD9833 (75 and 150 mg) for Stage 1 is supported by 
the PK, PD, safety and efficacy data collected during D8530C00001, and represent the lower 
two of the three doses selected for the Phase 2 PFS study (D8530C00002).
The initial two-stage design provides flexibility to obtain an early read-out on what are 
considered to be the most-likely AZD9833 doses for further clinical development, whilst 
preserving the option to investigate further doses in Stage 2, as informed by the results of 
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The maximum daily dose to be considered for Stage 2 will not exceed 450 mg, which is the 
maximum dose examined in D8530C00001.
The absence of a control arm in Stage 1 has been explained earlier. The provision for a 
supplementary fulvestrant control arm has been justified above.
Pre-menopausal women with ER-positive breast cancer require induction of either surgical or 
medical menopause when a third generation AI is being prescribed. Furthermore, women with 
high risk, hormone receptor-positive, primary breast cancer have been shown to benefit by 
adding medical ovarian ablation to tamoxifen in the adjuvant setting. SERDs that are 
sufficiently potent to be able to obviate this requirement for ovarian ablation in 
pre-menopausal patients would present a substantial improvement in standard of care.
The Stage 1 and 2 on-treatment interval of 5 to 7 days prior to biopsy is based on a) PK 
modelling in relation to time for AZD9833 to reach steady-state exposure, and b) pre-clinical 
PD modelling relating to the rate of onset of ER expression reduction, and is set to be as short 
as feasible, ie, 5 days. This is also consistent with the recent STAKT study in the same setting 
where short-term treatment, albeit with a different class of agent, demonstrated significant 
dose-dependent PD effects that could be measured after 4.5 days of drug administration 
(Robertson et al 2020a). Dosing up to 7 days allows flexibility in clinical scheduling to ensure 
that both the Day 1 on-treatment visit and the biopsy day visit can occur on weekdays. 
Data emerging from Stages 1 and 2 indicated that PD steady state, particularly in relation to 
Ki-67 at the 75 mg dose, may not have been reached and it is important to understand this 
potential time-dependency to fully characterise the PD effect at longer exposure intervals, 
ie, the 12-to-15-day exposure period stipulated for Stage 3. Detailed justification is given in 
Sections 2.2.2.8 and 2.2.2.9; and Section 6.1.1.
 
 
 
See Sections 2.2.2.6 and 6 for a summary of Stage 1 data and SDMC recommendations. There 
is no change to the justification text above as a consequence of the readout of data from 
Stage 1.
4.4
End of Study Definition
The end of study is defined as the last expected visit or contact of the last patient undergoing 
the study. A patient is considered to have completed the study when she has completed the 
28-day follow-up visit after discontinuation of study treatment.
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5
STUDY POPULATION
5.1
Inclusion Criteria
Informed Consent
2
Provision of signed and dated, written informed consent prior to any mandatory study 
specific procedures, sampling, and analyses. Patients are also required to provide consent 
for the provision of archival tumour biopsies
3
For patients who consent, provision of signed and dated written genetic informed consent 
prior to collection of samples for genetic analysis
Age and Gender
4
Female patients aged at least 18 years
Menopausal Status
5
Post-menopausal status defined as meeting at least one of the following criteria:
(a) Have undergone a bilateral oophorectomy
(b) Age ≥ 60 years
(c) Age ≥ 50 and < 60 years and with cessation of menses ≥ 12 months and FSH and 
oestradiol levels in the post-menopausal range (utilising ranges from the local 
laboratory facility) and with an intact uterus in the absence of oral contraception or 
hormone replacement therapy prior to the diagnosis of breast cancer
Disease Characteristics
6
Female patients with newly diagnosed primary breast cancer scheduled to undergo 
treatment with curative intent by surgery and irrespective of clinical node status
(a) Patients who are scheduled to start neoadjuvant therapy can still participate in the 
study but must have their core tumour biopsies performed before commencing 
neoadjuvant therapy
7
Histologically confirmed invasive breast cancer involving a palpable tumour of any size, 
or a tumour with an ultrasound assessed diameter of ≥ 1.0 cm
8
Multifocal tumours (including bilateral tumours) are allowed, assuming one lesion is 
designated as the ‘target lesion’ (at the Investigator’s discretion) and tumour evaluations 
and pre- and on-treatment biopsies are performed on that lesion
9
Patients with adequately treated non-melanoma skin cancer, curatively treated in-situ 
cancer of the cervix, or other solid tumours curatively treated with no evidence of disease 
for ≥ 3 months can be considered for the study 
(a) Any endocrine or other anti-cancer therapies must have been received at least 
12 months prior to enrolment
10 According to the local laboratory parameters and where those laboratory parameters are 
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Oncology/College of American Pathologists Guideline Recommendations for 
Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer 
[Hammond et al 2010]) patients must have (where available, assessment of ER and HER2 
status should be based on the most recent tumour biopsy sample):
(a) ER positive breast cancer
(b) HER2-negative breast cancer, defined as an IHC Score 0 or 1+ or negative by in situ 
hybridisation (ISH; FISH/CISH/SISH); if IHC 2+, ISH negativity is required 
11 ECOG performance status 0 to 1
5.2
Exclusion Criteria
Prior/Concomitant Therapy
1
Previous systemic or local treatment for the new primary breast cancer currently under 
investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments) 
2
Intervention with any of the following:
(a) Use of sex-hormone-containing drugs within 6 months prior to the first dose of study 
treatment (including oral contraceptive pills, hormone replacement therapy, 
oestrogen-containing vaginal creams or other topical preparations, and controlled-
release vaginal rings and sex hormone-containing intra-uterine systems)
(b) Medications or herbal supplements known to be strong inhibitors/inducers of 
CYP3A4/5, sensitive CYP2B6 substrates (commonly prescribed drugs are listed in 
Appendix A), and drugs which are substrates of CYP2C9 and/or CYP2C19 which 
have a narrow therapeutic index ie, 
 
 
 as specified in Appendix A, prior to receiving the first dose of study treatment
(c) Drugs that are known to prolong QT and have a known risk of torsades de pointes, as 
indicated in Appendix A.
Medical Conditions
3
Inflammatory breast cancer
4
Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension and active bleeding diatheses, or eg, infection requiring intravenous 
antibiotic therapy, which in the Investigator’s opinion makes it undesirable for the patient 
to participate in the study or which would jeopardise compliance with the protocol, or 
active infection including hepatitis B, hepatitis C, and HIV
Note: Active viral infection is defined as requiring antiviral therapy. Screening for 
chronic conditions is not required 
5
Any of the following cardiovascular criteria:
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(a) Mean resting QTcF > 470 msec obtained from screening triplicate ECG
(b) Resting heart rate of < 50 bpm, obtained from central review of the average of 
triplicate ECGs taken at screening for Stages 1 and 2;
Resting heart rate of < 60 bpm, obtained from central review of the average of 
triplicate ECGs taken at screening for Stage 3
(c) Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG (eg, complete left bundle branch block, second- and third-degree heart 
block), or clinically significant sinus pause, or sick sinus syndrome. Patients with 
controlled atrial fibrillation can be enrolled
(d) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as symptomatic heart failure, congenital long QT syndrome, immediate family 
history of long QT syndrome, or unexplained sudden death at < 40 years of age; 
hypertrophic cardiomyopathy and clinically significant stenotic valve disease; 
clinically significant hypokalaemia, hyperkalaemia, hypo- and hypermagnesemia, 
hypo- and hypercalcaemia
(e) Known left ventricular ejection fraction < 50%, and/or experience of any of the 
following procedures or conditions in the preceding 6 months: coronary artery bypass 
graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris, 
congestive heart failure New York Heart Association (NYHA) Grade ≥ 2, 
cerebrovascular accident, or transient ischaemic attack
(f) Uncontrolled hypertension. Hypertensive patients may be eligible, but blood pressure 
must be adequately controlled at baseline. Patients may be re-screened regarding the 
blood pressure requirement
(g) Symptomatic hypotension
6
Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following laboratory values:
(a) ANC < 1.5 × 109/L
(b) Platelet count < 100 × 109/L
(c) Hb < 90 g/L
(d) ALT > 2.5 × ULN)
(e) AST > 2.5 × ULN
(f) TBL > 1.5 × ULN or > 3 × ULN in the presence of documented Gilbert’s Syndrome 
(unconjugated hyperbilirubinemia)
(g) eGFR < 50 mL/min
7
Refractory nausea and vomiting, uncontrolled chronic gastrointestinal diseases, inability 
to swallow the formulated product, or previous significant bowel resection that would 
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Other Exclusions
8
History of hypersensitivity to active or inactive excipients of AZD9833 or drugs with a 
similar chemical structure or class to AZD9833.
9
Involvement in the planning and conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site)
10 Previous randomisation in the present study
11 Judgement by the Investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements
12 Male patients are excluded from this study. Women of childbearing potential are excluded 
from Stage 1.
5.3
Enrolled and Randomised Patients
In this protocol, “enrolled” patients are defined as those who sign informed consent.
"Randomised" patients are defined as those who undergo randomisation and receive a 
randomisation number. Each patient should meet all of the inclusion criteria and none of the 
exclusion criteria for this study in order to be assigned/randomised to a study intervention. 
Patients who are enrolled and do not meet the entry requirements are screen failures, refer to 
Section 5.5.
For procedures for withdrawal of incorrectly enrolled patients see Section 7.1.2. Prospective 
approval of protocol deviations to inclusion/exclusion criteria, also known as protocol waivers 
or exemptions, is not permitted.
5.4
Lifestyle Considerations
5.4.1
Contraceptive Measures 
All Stages will include post-menopausal women only. If a woman has had bilateral 
oophorectomy, alone or along with hysterectomy and/or bilateral salpingectomy, she would be 
regarded as having been rendered post-menopausal.
5.4.2
Meals and Dietary Restrictions
Patients should abstain from eating large amounts of grapefruit and Seville oranges (and other 
products containing these fruits [eg, grapefruit juice or marmalade]) during the study (eg, no 
more than a small glass of grapefruit juice [120 mL], half a grapefruit, or 1 to 2 teaspoons 
[15 g] of Seville orange marmalade daily).
There are no food restrictions for AZD9833 (ie, AZD9833 may be taken with or without 
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5.5
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study treatment. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet the 
CONSORT publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria and any 
serious adverse event (SAE).
Screen failures may be rescreened. Rescreened patients should be assigned the same patient 
number as for the initial screening. However, rescreening should be documented, so that its 
effect on study results, if any, can be assessed. Patients must re consent to the study and all 
screening procedures out of screening period window must be repeated. Laboratory values 
re-tested within the 21-day screening period are not considered rescreening and are allowed. 
In case of multiple laboratory data within the screening period, the most recent data should be 
used to confirm eligibility.
Patients failing screening should have the reason for study withdrawal recorded in the CRF.
6
STUDY INTERVENTION
Study intervention is defined as any product(s) (including marketed product comparator) 
intended to be administered to a study participant, according to the study protocol. Study 
intervention in this study refers to AZD9833.
6.1
Study Interventions Administered
6.1.1
Investigational Products
Details of the investigational products are provided in Table 19 (Stage 1 and Stage 3) and 
Table 20 (Stage 2).
Table 19
Study Treatments in Stage 1 and Stage 3
Treatment 1
Treatment 2
Treatment name
AZD9833
Dosage formulation
 tablets
Dosage level(s)
75 mg once daily
150 mg once daily
Route of administration
PO
Dosing instructions
 tablets
 tablet
 tablets
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Table 19
Study Treatments in Stage 1 and Stage 3
Treatment 1
Treatment 2
Packaging and labelling
AZD9833 will be provided in bottles. Each bottle will be labelled in 
accordance with country regulatory requirements.
Provider
AstraZeneca
Table 20
Study Treatments in Stage 2
Treatment 1
Treatment 2
Treatment 3
Treatment name
AZD9833
Dosage formulation
 tablets
Dosage level(s)
75 mg once daily
150 mg once daily
300 mg once daily
Route of administration
PO
Dosing instructions
 tablets
 tablet
 tablets
 tablets
Packaging and labelling
AZD9833 will be provided in bottles. Each bottle will be labelled in 
accordance with country regulatory requirements.
Provider
AstraZeneca
6.1.2
Medical Devices
No medical devices are planned for use in this study. A portable heart rate monitor will be 
used in all patients to record heart rate (see Section 8.2.5). Data will be collected from the 
heart monitor on an ongoing basis but will be reviewed only at the end of each stage of the 
study, ie, data will not be available in real-time.
6.2
Preparation/Handling/Storage/Accountability of Interventions
1
AZD9833 should be stored in the pack provided, protected from light and at the 
recommended storage condition of below 30 °C, and used according to the instructions on 
the label. 
2
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.
3
Only patients enrolled in the study may receive study treatment and only authorised site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the Investigator and 
authorised site staff.
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4
The study personnel at the investigational sites will account for all drugs dispensed and 
for appropriate destruction. Certificates of delivery and destruction should be signed.
5
If the investigational site does not have the capabilities for destroying unused drugs, the 
drugs will be sent to a third-party vendor for proper disposal. Certificates of delivery and 
return should be signed.
6
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
6.3
Measures to Minimise Bias: Randomisation and Blinding
This is an open-label study. All patients will receive active treatment.
To reduce potential bias during the study, eligible patients will be randomly allocated at a 1:1 
ratio to receive one of the two study treatments in Stage 1 and 3. 
In Stage 2, eligible patients will be randomly allocated to one of two (UK) or three (Georgia 
and Mexico) treatment groups. The randomisation will be stratified based on country (UK / 
Georgia and Mexico). As per the SDMC recommendation the randomisation will be 
controlled such that approximately 24 evaluable patients are randomised in the UK across 
Groups 1 and 2, and approximately 36 evaluable patients are randomised in both Georgia and 
Mexico across Groups 1, 2 and 3.
Patients will be randomised as they become eligible. Once the eligibility of a patient has been 
confirmed, the Investigator (or designee) will notify the centralised IWRS. Randomisation 
should take place as close to the start of study treatment as possible.
Biopsies will be scored in a blinded manner both in terms of which arm of the study the 
patient was allocated to and also which is the pre- and the on-treatment biopsy being assessed, 
and the data will be read out at the end of Stage 1, at the end of Stage 2, if applicable, and at 
the end of Stage 3. 
If a patient withdraws from the study, then her enrolment/randomisation code cannot be 
reused. For information relating to withdrawn patients, see Section 7.1, Discontinuation of 
Study Intervention.
6.4
Study Treatment Compliance
The study treatment should only be used as directed in this protocol. Details of study 
treatment for each patient will be recorded in the CRF. Any change from the dosing schedule, 
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Patients should return all unused study treatment and empty containers to the Investigator. The 
Investigator is responsible for ensuring that the patient has returned all unused study 
treatment.
6.5
Concomitant Therapy
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrolment or receives 
during the study must be recorded along with:

Reason for use.

Dates of administration including start and end dates.

Dosage information including dose and frequency.
6.5.1
 
6.5.2
 
 
6.5.3
 
 
 
 
6.5.4
Medications that 
 
Drugs that are known
 
 
6.5.5
Medications Known to 
Drugs that are known to reduce 
 are allowed, but new prescriptions or dose 
increments while on study should be discussed with the clinical study team, as indicated in 
Appendix A.
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6.5.6
Anti-cancer Treatments
Patients must not receive any other anti-cancer therapy, including investigational agents, while 
on study.
6.5.7
 
 
6.5.8
Drugs Containing Sex Hormones or Affecting Sex Hormone Status
Sex hormone-containing drugs such as oral contraceptive pills, hormone replacement therapy, 
progestational agents (megestrol acetate), dehydroepiandrosterone, other androgens (eg, 
oxandrolone) and selective ER modulators (eg, raloxifene [Evista®]) are not permitted during 
treatment (Day 1 to the biopsy day). 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 during treatment.
In addition, drugs other 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 up the biopsy day. 
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.
6.5.9
Other Concomitant Treatment
Treatments other than those described above, which are considered necessary for the patient’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the CRF. 
The use of herbal or traditional remedies should be discouraged while patients are on study 
treatment.
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6.6
Dose Modification
6.6.1
Dose Modification for AZD9833
For AZD9833, guidance for dose modifications (dose discontinuation) in case of toxicities 
that are not attributable to the disease or disease-related processes is summarised in Table 21
(for Stages 1 and 2) and Table 22 (for Stage 3).
Table 21
AZD9833 Dose Discontinuation Guidance (AZD9833-related);
Stages 1 and 2
Toxicity
Details
Actions
 
 
 
 
 
 
 
 
 
 
Any CTCAE Grade > 3 or clinically significant AE (considered to be possibly 
related to AZD9833 by the Investigator)
Discontinue AZD9833
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Table 22
AZD9833 Dose Discontinuation Guidance (AZD9833-related); Stage 3
Toxicity
Details
Actions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any CTCAE Grade > 3 or clinically significant AE (considered to be 
possibly related to AZD9833 by the Investigator)
Discontinue AZD9833
6.7
Intervention after the End of the Study
Subsequent treatment will be at the discretion of the patient's treating physician.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
Patients may be discontinued from study treatment in the following situations:

Patient decision: the patient is at any time free to discontinue treatment, without prejudice 
to further treatment.

AE.

Severe non-compliance with the clinical study protocol, as judged by the Investigator 
and/or AstraZeneca.

Patients incorrectly initiated on study treatment (see Section 7.1.2, Procedures for 
Handling Patients Incorrectly Initiated on Study Treatment).
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See the SoA tables (Table 1 and Table 2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed.
7.1.1
Temporary Discontinuation and Re-challenge
Not applicable.
7.1.2
Procedures for Handling Patients Incorrectly Initiated on Study 
Treatment
When patients who do not meet the eligibility criteria, are enrolled in error, or incorrectly 
started on study treatment, the Investigator should inform the AstraZeneca Study Physician 
immediately for consideration of the reasonableness of continuing study treatment.
7.1.3
Procedures for Discontinuation of Study Treatment
Patients are at any time free to withdraw consent from study treatment without prejudice to 
further treatment. The Investigator should instruct the patient to contact the site before or at 
the time if study treatment is stopped. A patient that decides to discontinue study treatment 
will always be asked about the reason(s) and the presence of any AEs. The date of last intake 
of study treatment should be documented in the CRF. All study treatment should be returned 
by the patient at their next on-site study visit or unscheduled visit. If possible, they will be 
seen by an Investigator and undergo the assessments and procedures scheduled for the post 
study assessment.
Patients who have withdrawn from study treatment cannot be re-enrolled.
7.2
Participant Withdrawal from the Study
A participant may withdraw from the study (eg, withdraw consent), at any time at her own 
request, without prejudice to further treatment. Participants who are withdrawn from the study 
will be replaced.
If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a patient withdraws from the study, she may request destruction of any samples taken, and 
the Investigator must document this in the site study records.
See the SoA tables (Table 1 and Table 2) for data to be collected at the time of study 
discontinuation and 28-day follow-up.
7.3
Lost to Follow-up
A patient will be considered potentially lost to follow-up if she fails to return for scheduled 
visits and is unable to be contacted by the study site.


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The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:

The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule.

Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient or next of kin (eg, by repeat telephone calls, 
certified letter to the patient´s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the patient’s medical record. 

Should the patient be unreachable at the end of the study the patient should be considered 
lost to follow-up.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in SoA tables (Table 1 and Table 2).
The Investigator will ensure that data are recorded on the CRFs. A WBDC system will be 
used for data collection and query handling.
The Investigator will ensure the accuracy, completeness, legibility and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The Investigator will sign the completed CRFs. A copy of the completed CRFs 
will be archived at the study site.
Immediate safety concerns should be discussed with the Sponsor upon occurrence or 
awareness to determine if the patient should continue or discontinue study treatment.
Adherence to the study requirements, including those specified in the SoA tables, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure.
Procedures conducted as part of the patient’s routine clinical management and obtained before 
signing of the ICF may be utilised for screening or baseline purposes provided the procedures 
met the protocol-specified criteria and were performed within the time frame defined in the 
SoA.


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The total amount of mandatory blood samples collected from each patient is estimated to a 
maximum of 103 mL (Table 23). Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples.
Table 23
Blood Sample Volumes
Visit
Safetya
PK
(AZD9833)
ctDNA
Exploratory 
biomarkers
Screening 
15 + 2
Day 1
6c
Day of biopsy
6c
AZD9833 
treatment 
groups
2 × 2
Day of surgery
b
A volume of 15 mL is estimated for the Safety samples, assuming 6 mL for clinical chemistry, and 9 mL for 
haematology. In addition, 2 mL will be drawn for coagulation tests. Sample tubes and sample sizes may vary, 
depending on laboratory method used and routine practice at the site. The number of samples/blood volumes is 
therefore subject to site-specific change.
8.1
Efficacy Assessments
Not applicable.
8.1.1
Performance Status
Performance status will be assessed at the visits indicated in the SoA tables (Table 1 and 
Table 2), according to ECOG/WHO criteria as follows:
0
Fully active, able to carry on all pre-disease activities without restrictions.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (eg, light housework, office work).
2
Ambulatory and capable of self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
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8.2
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA tables (Table 1 and 
Table 2).
8.2.1
Clinical Safety Laboratory Assessments
See Table 24 for the list of clinical safety laboratory tests to be performed and the SoA for the 
timing and frequency. All protocol-required laboratory assessments, as defined in the table, 
must be conducted in accordance with the Laboratory Manual and the SoA.
The Investigator should assess the available results with regard to clinically relevant 
abnormalities. The laboratory results should be signed and dated and retained at each site as 
source data for laboratory variables.
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate CRF.
The clinical chemistry/haematology analysis and urinalysis 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.


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Table 24
Laboratory Safety Variables
Haematology (whole blood)
Clinical chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total (TBL)
B-Haematocrit
S/P-Conjugated bilirubin
B-Red blood cell count
S/P-Unconjugated bilirubin
B-Leukocyte differential count (absolute count)
S/P-Alkaline phosphatase (ALP)
Neutrophils
S/P-Aspartate transaminase (AST)
Lymphocytes
S/P-Alanine transaminase (ALT)
Monocytes
S/P-Creatine kinase (CK)
Basophils
S/P-Albumin
Eosinophils
S/P-Calcium, total
B-Platelet count
S/P-Potassium
Coagulation parameters
S/P-Sodium
Prothrombin time (PTT)
S/P-Glucose
Activated partial thromboplastin time (aPTT)
S/P-Magnesium
International normalised ratio (INR)
S/P-Phosphate
Urinalysis (dipstick)
S/P-Urea or Urea Nitrogen
U-Glucose
S/P-Protein, total
U-Protein
S/P-Troponin
U-Blood
NB. In case a patient shows an AST or ALT ≥ 3× ULN together with total bilirubin ≥ 2× ULN please refer to 
Appendix C ‘Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of Hy’s Law’, for 
further instructions.
8.2.2
Physical Examinations
A complete physical examination, including a standard neurological examination, body 
weight, and height, will be performed at screening, as indicated in the SoA tables (Table 1 and 
Table 2).
Investigators should pay special attention to clinical signs related to previous serious illnesses, 
new or worsening abnormalities may qualify as AEs, see Section 8.3.6 for details.
8.2.3
Vital Signs
Vital signs (including blood pressure, pulse rate, and body temperature), will be assessed at 
the timepoints indicated in the SoA (Table 1 and Table 2) as follows:
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
Blood pressure and pulse measurements will be assessed in supine position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.

Blood pressure, body temperature, and pulse measurements should be preceded by at least 
10 minutes of rest for the patient in a quiet setting without distractions (eg, television, cell 
phones).

Vital signs (to be taken before blood collection for laboratory tests) will consist of one 
pulse and three blood pressure measurements (three consecutive blood pressure readings 
will be recorded at intervals of at least 1 minute). The average of the three blood pressure 
readings will be recorded on the CRF.

Following screening only blood pressure will be measured prior to blood collection for 
laboratory tests and the ECG.
8.2.4
Electrocardiograms
8.2.4.1
Triplicate 12-lead Digital ECGs
Triplicate 12-lead digital ECGs will be obtained as outlined in the SoA using standardised 
ECG machines that automatically calculate the heart rate and measure RR, PR, QRS, QT, and 
QTcF intervals:

ERT, as the responsible company for the centralised ECG assessments, will provide the 
study sites with standardised ECG equipment and supplies, specific training and written 
instructions.

The ECGs will be collected after 10 minutes of rest in supine position, where applicable 
before blood pressure, PK and ctDNA sampling.

At each timepoint, three individual ECG tracings should be obtained in succession, no 
more than 2 minutes apart. The full set of triplicates should be completed within 
5 minutes.

Following an acquisition of a quality ECG tracing, the Investigator or designee will 
electronically transfer the data to ERT.
The ECG parameters to be determined will include (but will not be limited to) the following:

Heart rate (ERT mean of triplicate ECG).

RR interval: duration in msec between two R peaks of two consecutive QRS complexes.

PR interval: duration in msec from the beginning of wave P to onset of ventricular 
depolarisation (Q and R).

QRS interval: duration in msec of the QRS complex.

QT interval: duration in msec from the beginning of Q wave to the end of the T wave.

QTcF: QT interval corrected for heart rate using Fridericia’s formula 
(QT[msec]/RR[sec]1/3).


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Any abnormal finding in the ECG tracing will be evaluated by the Investigator and will be 
specifically documented and registered in the CRF. Throughout the study, clinically relevant 
new findings or worsening of a pre-existing finding in the ECGs (parameters or abnormal 
findings in the tracing) must be considered an AE and must be recorded in the AE CRF form. 
For information on how AEs based on ECG results should be recorded and reported, see 
Section 8.3.7. For ECG-related treatment modifications, see Section 6.6.1.
8.2.5
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.3
Adverse Events and Serious Adverse Events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix D.
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorised representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow up AEs see 
Section 8.3.3.
8.3.1
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about AE 
occurrences.
8.3.2
Time Period and Frequency for Collecting AE and SAE Information 
AEs will be collected from time of signature of ICF, throughout the treatment period and 
including the safety follow-up period (28 days after last dose of study treatment). 
SAEs will be recorded from the time of signing of the ICF.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix D. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs in former study patients. 
However, if the Investigator learns of any SAE, including a death, at any time after a patient’s 
last visit and he/she considers the event to be reasonably related to the study treatment or 
study participation, the Investigator shall, without undue delay, report the SAE to the Sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix D.
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8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
at subsequent visits/contacts. All AEs/SAEs will be followed until resolution, stabilisation, the 
event is otherwise explained, or the patient is lost to follow-up 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the CRF. 
AstraZeneca 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.
8.3.4
Adverse Event Data Collection
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

CTCAE grade (version 5.0)

Whether the AE is serious or not

Investigator causality rating against the study treatment (yes or no)

Action taken with regard to study treatment

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 (state reason)

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 to other medication
8.3.5 Causality Collection
The Investigator will assess causal relationship between study treatments 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?’


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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 D.
8.3.6 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study site staff: ‘Have you/the patient had any health problems since 
the previous visit/you were last asked?’ or revealed by observation will be collected and 
recorded in the CRF. When collecting AEs, the recording of diagnoses is preferred (when 
possible) to recording a list 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.
8.3.7 Adverse Events Based on Examinations and Tests
The results from the protocol-mandated laboratory tests and vital signs will be summarised in 
the 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 study treatments or are considered to be clinically relevant as 
judged by the Investigator (which may include, but not limited to, consideration as to whether 
treatment or non-planned visits were required or other action was taken with the study 
treatment, eg, dose adjustment or drug interruption).
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 
uses the clinical, rather than the laboratory term (eg, anaemia versus low Hb 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, unless unequivocally 
related to the disease under study, see Sections 8.3.9 and 8.3.11.
8.3.8 Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may need 


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to be reported as SAEs. Please refer to Appendix C for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s law.
8.3.9 Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the investigational product is being studied. It may be an increase in 
the severity of the disease under study and/or increases in the symptoms of the disease. The 
development of ER-positive HER2-negative breast cancer should be considered as disease 
progression and not an AE. Events, which are unequivocally due to disease progression, 
should not be reported as an AE during the study.
8.3.10 Deaths
All deaths that occur during the treatment period including the 28-day safety follow-up period 
should be reported as follows:

The AE causing the death should be reported to the study monitor as an SAE within 
24 hours. The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign a single primary cause of death, 
together with any contributory causes.

Deaths with an unknown cause should always be reported as an SAE, but every effort 
should be made to establish a cause of death. A post-mortem may be helpful for the cause 
of death assessment and, if performed, a copy of the post-mortem results (with translation 
of important parts into English) should be reported in an expedited fashion to an 
AstraZeneca representative within the usual timeframes.
8.3.11
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of 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 adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. investigators or other site personnel inform 
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within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert will be sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site staff will report 
a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
Regulatory reporting requirements for SAEs
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study treatment under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/IEC, and Investigators.
For all studies except those utilising medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary.
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it along with the Investigator’s Brochure or and will notify the IRB/IEC, if appropriate 
according to local requirements.
For further guidance on the definition of a SAE, see Appendix D.
8.3.12
Medication Error
If any medication error occurs in the course of the study, then the Investigator or other site 
personnel will inform the appropriate AstraZeneca representatives within 1 day (ie, 
immediately but no later than 24 hours) of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.12) and within 30 days for all other 
medication errors.


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The definition of a medication error can be found in Appendix D.
8.4
Overdose
All overdoses should be recorded as follows:

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on an AstraZeneca study treatment occurs in the course of the study, then the 
Investigator or other site personnel will inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 8.3.2. For other overdoses, reporting must occur within 30 days.
8.4.1
AZD9833
For this study, any dose of AZD9833 greater than the intended dosage will be considered an 
overdose.
AstraZeneca does not recommend specific treatment for an AZD9833 overdose. Any patient 
who receives a dose higher than intended should be monitored closely, managed with 
appropriate supportive care.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific Laboratory Manual. Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality. For further details on Handling of Human 
Biological Samples see Appendix E.
8.5.1
Pharmacokinetics
Venous blood samples of approximately 2 mL will be collected from patients receiving 
AZD9833 for measurement of plasma concentrations of AZD9833 as specified in the SoA. 
For AZD9833, two PK blood samples will be taken as illustrated in Figure 8: 

One PK sample will be taken at least 1 hour post-dose, and as close to the biopsy as 
possible.


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
The second PK sample should be taken 1 to 3 hours post biopsy. 
Figure 8
Schematic Illustrating the Relative Timings and Windows for Biopsy 
and PK Sampling
Samples may be collected at additional timepoints or no longer collected during the study if 
warranted and agreed upon between the Investigator and the Sponsor. Instructions for the 
collection and handling of biological samples will be provided by the Sponsor or analytical 
test site. The actual date and time (24-hour clock time) of each sample will be recorded.
Samples collected for analyses of AZD9833 plasma concentration may also be used to 
evaluate safety concerns arising during or after the study (ie, PK samples may be repurposed 
if required).
Any changes in the timing, addition or removal of timepoints, for any planned study 
assessments must be documented and approved by the relevant study team member and then 
archived in the Sponsor and site study files but will not constitute a protocol amendment.
8.5.1.1
Determination of Drug Concentration
Samples for determination of AZD9833 drug concentration in plasma will be analysed by 
analytical test sites by or on behalf of AstraZeneca, using an appropriate bioanalytical method. 
Full details of the analytical method used will be described in a separate Bioanalytical Report.
8.5.1.2
Storage and Destruction of Pharmacokinetic Samples
Details on sample processing, handling, shipment, and storage are provided in the Laboratory 
Manual. Samples containing AZD9833 for analysis should be protected from light to avoid 
photo-degradation.
PK samples will be disposed of after the Bioanalytical Report finalisation or 6 months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses.
In the event that PK samples destruction is required, they may be disposed of or destroyed and 
anonymised by pooling. Additional analyses may be conducted on the anonymised, pooled PK 


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samples to further evaluate and validate the analytical method. Any results from such analyses 
may be reported separately from the CSR.
8.5.2
Pharmacodynamics
PD measurements are described in Section 8.6.
8.6
Human Biological Sample Biomarkers
Biomarkers (ER, PgR and Ki-67) will be tested in tumour samples using a variety of methods 
for the primary, secondary and exploratory objectives.
The following samples for biomarker research are required and will be collected from all 
patients in this study, as specified in the SoA:

Diagnostic tumour tissue and tumour biopsy (Stage 1 and 2: Day 5 to 7; Stage 3: Day 12 
to 15) for analysis of biomarkers including, but not limited to, ER, PgR, and Ki-67 protein 
levels and ER-regulated genes and mutational profile, as follows:

Blood samples for ctDNA

Blood samples for exploratory biomarkers
8.6.1
Blood Samples for Circulating Tumour DNA
Two 10 mL whole blood samples will be taken at screening, for the isolation of plasma and 
buffy coat to enable the assessment, analysis and interpretation of ctDNA. One 10 mL blood 
sample will be taken at all of the other timepoints indicated in the SoA to provide plasma 
only. 
8.6.2
Blood Samples for Exploratory Biomarkers
Two 5 mL blood samples will be taken at each of the three timepoints indicated in the SoA to 
provide one sample of plasma and one sample of serum per timepoint. The samples will be 
collected and stored to permit retrospective exploratory biomarker analysis which may 
include, but will not be limited to, understanding mechanisms of response and resistance to 
treatment (where response is defined broadly to include biomarker change, tolerability or
safety) and for diagnostic purposes. This may include the analysis of circulating biomarkers, 
such as tumour DNA, mRNA, proteins, metabolites or immune biomarkers (eg, 
autoantibodies).
8.6.3
Tumour Biopsy 
Paired tumour biopsies will be collected from a minimum of 12 patients in each treatment 
group in Stage 1, approximately 12 (300 mg Stage 2 arm) or 24 (75 and 150 mg Stage 2 arms) 
evaluable patients in each treatment group in Stage 2, and approximately 24 patients in each 
treatment group in Stage 3. 


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The paired tumour biopsies will be the diagnostic tumour tissue and an on-treatment biopsy 
sample, taken on Day 5, 6, or 7 of treatment for Stages 1 and 2, and Day 12, 13, 14, or 15 of 
treatment for Stage 3. All biopsies should be taken from the same tumour lesion.
The diagnostic tumour tissue sample will have been taken from tumour tissue using a core cut 
or tru cut device as a standard hospital diagnostic procedure at baseline. Patients must consent 
to the use of their diagnostic FFPE biopsy sample and fresh frozen tissue sample (if available) 
if the biopsy was taken within 6 weeks of the planned start of study treatment.
If the diagnostic biopsy was taken ≥ 6 weeks prior to starting treatment or was taken within 
6 weeks but was not likely to provide adequate tissue sections for the biomarker assays (eg, 
technical artefact or too little tumour present in the diagnostic core), patients will require a 
new biopsy to be taken prior to starting treatment. Up to four core cut or tru cut biopsy 
samples will be taken via imaging-guided biopsy. The first core should be processed for 
FFPE, the second as fresh frozen and the third and fourth for FFPE. If fewer than 4 cores are 
obtained, the first core should be processed for FFPE the second as fresh frozen and any 
subsequent cores as FFPE. 
If the diagnostic biopsy was taken within 6 weeks prior to starting treatment, but a fresh 
frozen tissue sample is not available from the initial diagnostic biopsy, patients may also 
consent to an optional new pre-treatment biopsy to provide a fresh frozen tissue sample. Up to 
four core cut or tru cut biopsy samples will be taken via imaging-guided biopsy. The first core 
should be processed for fresh frozen tissue and subsequent cores processed for FFPE. These 
possibilities are summarised in Figure 9.


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Figure 9
Diagnostic Biopsy Decision Tree
Diagnostic FFPE tumour samples will preferably be in the form of a FFPE block. If this is not 
possible, freshly prepared unstained slides (minimum of 10, but preferably 20) 5 micron 
sections from the tumour block will be accepted if tumour blocks cannot be submitted. Fresh 
frozen core biopsies will be used for research purposes, unless the fresh frozen biopsy is 
required for initial diagnostic purposes.
The treatment biopsy samples should be taken on treatment Day 5, 6, or 7 for Stages 1 and 2, 
and on treatment Day 12, 13, 14, or 15 for Stage 3. In AZD9833-treated groups this should 
preferably be 2 to 4 hours after the last dose of AZD9833 but must be between 1 and 12 hours 
after the last dose of AZD9833. Up to four core cut or tru cut biopsy post-treatment samples 
will be taken via imaging-guided biopsy. The first core should be processed for FFPE, the 
second as fresh frozen and the third and fourth for FFPE. If fewer than 4 cores are obtained, 
the first core should be processed for FFPE the second as fresh frozen and any subsequent 
cores as FFPE. 
The date and exact time of AZD9833 last dose and date and exact time of collection of 
on-treatment tumour biopsies and PK samples must be carefully recorded in the CRFs. 


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All tissues should be either formalin-fixed, or fresh frozen, immediately following biopsy. 
Routine paraffin-wax embedding of formalin fixed biopsies will be carried out at the local 
investigational site (general guidance is provided in the Laboratory Manual). 
The date and exact time of the last dose AZD9833, and date and exact time of collection of 
on-treatment tumour biopsies and PK samples must be carefully recorded in the CRFs. 
All tissues should be either formalin-fixed or fresh frozen immediately following biopsy. 
Routine paraffin-wax embedding of formalin fixed biopsies will be carried out at the local 
investigational site. Full details regarding the collection, processing, labelling, storage and 
shipping of FFPE and fresh frozen samples is provided in the Laboratory Manual.
The results of this biomarker research will be reported either in the CSR itself or as an 
addendum, or separately in a scientific report or publication. The results of this biomarker 
research may be pooled with biomarker data from other studies with the study treatment(s) to 
generate hypotheses to be tested in future research.
8.7
 
 
 
 
 
 
 
8.8
Medical Resource Utilization and Health Economics
Medical Resource Utilisation and Health Economics parameters are not evaluated in this 
study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The primary objective is to obtain an estimation of the change in ER following treatment with 
different doses of AZD9833.
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9.2
Sample Size Determination
The study is designed as an exploratory estimation of ER knockdown of different AZD9833 
doses, as assessed by the manual H-score method. The sample size is based on the primary 
endpoint, percent change from baseline in ER expression in each dose group. Assuming a 
drop-out rate of 15%, approximately 14 patients will be recruited per treatment group, to 
allow 12 evaluable patients per treatment group for the analysis of the primary endpoint at the 
end of Stage 1.
For Stage 1, a total of 12 evaluable patients per treatment group will provide an 80% chance 
of obtaining an 80% CI, where one half of the CI is at most 14 for the mean percent change 
from baseline in ER. This is under the assumption of a true standard deviation of 29 
(Robertson et al 2020a, Robertson et al 2020b).
For Stage 2, following the SDMC review of Stage 1 data, approximately 24 evaluable patients 
will be recruited to each of Group 1 (AZD9833 75 mg) and Group 2 (AZD9833 150 mg), and 
approximately 12 evaluable patients to Group 3 (AZD9833 300 mg). For completeness, with
further patients recruited to the same two dose groups under Stage 2 of the study, 
approximately 36 evaluable patients may be included. A total of 36 evaluable patients per 
treatment group will provide an 80% chance of obtaining an 80% CI where one half of the CI 
is at most 7 for the mean percent change from baseline in ERα.
As per Sections 2.2.2.6 and 6, in Stage 2 of the study, approximately 12 patients in Group 1 
(AZD9833 75 mg) and Group 2 (AZD9833 150 mg) will be recruited from the UK to enable 
additional understanding of the homogeneity of the dose-response curves across the two 
geographies. The operating characteristics with 12 patients per dose group will mirror the 
Stage 1 precision above.
For Stage 3, a total of 24 evaluable patients per treatment group will provide an 80% chance 
of obtaining an 80% CI, where one half of the CI is at most 9 for the mean percent change 
from baseline in ER. This is under the assumption of a true standard deviation 
of 29 (Robertson et al 2020a; Robertson et al 2020b). In relation to the key secondary 
endpoint of Ki-67, a total of 24 evaluable patients per treatment group will provide an 80% 
chance of obtaining an 80% CI, where one half of the CI is at most 0.312 on the log scale, 
which if a geometric mean of -80% for Ki-67 was observed, the expected CI would be 
(-85%, -73%). 
 
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9.2.1
Definition of an Evaluable Patient
A patient is evaluable for the primary endpoint if:
1
Patient has taken a minimum of 5 consecutive daily doses of AZD9833 (as per Section 
6.1.1) for Stages 1 and 2, and a minimum of 12 consecutive daily doses prior to, and 
including, the biopsy day for Stage 3.
2
Patient received the last dose of AZD9833 within 12 hours of on-treatment biopsy
3
Biopsy pair evaluable as below:
(a) The diagnostic and on-treatment biopsy pair is considered evaluable by central 
pathology assessment, defined as containing >100 tumour cells in each FFPE biopsy 
and
(b) A minimum of 2 slides to allow measurement of ER 
4.Has no protocol deviations that may impact the biomarker analysis
On an ongoing basis and prior to final database lock, patient data will be reviewed on a case-
by-case basis to determine if the patient is evaluable. Non-evaluable patients may be replaced.
9.3
Populations for Analyses
Analysis populations are defined in Table 25. Full details of the analysis populations and 
reporting will be provided in the SAP:
Table 25
Study Populations
Population
Description
Primary endpoint analysis set
See Section 9.2.1
Safety analysis set
All patients who received at least one dose of AZD9833 
Pharmacokinetics (PK) 
analysis set
All patients who received at least one dose of AZD9833 and had at least one 
reportable plasma concentration
9.4
Statistical Analyses
Analyses will be performed by AstraZeneca or its representatives, including CROs. All data 
will be summarised by treatment group and time point. The data from all stages will be 
combined and reported together where appropriate. Continuous data will be reported using n 
(number of observations), mean, standard deviation (SD), median, minimum, and maximum 
values. Categorical data will be reported using number and percentage of patients. A 
comprehensive SAP will be developed and finalised before database lock and will describe the 
patient populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data. This section is a summary of the planned statistical analyses of the 


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primary and secondary endpoints at each stage of the study. Any deviations from this plan 
which occur prior to the database lock for the primary analysis will be included in the SAP. 
Those which occur post-database lock will be reported in the CSR.
9.4.1
Definition of Endpoints
Derivation of Biomarker Variables 
The following primary biomarker variable will be calculated: 

Percent change from baseline in ER expression assessed by the manual H-score method 
after 5 to 7 consecutive days of AZD9833 treatment for Stage 1 and 2, and after 12 to 15 
consecutive days for Stage 3.
The following secondary biomarker variables will be calculated:

Percent change from baseline in PgR expression as assessed by manual H-score method 
after 5 to 7 consecutive days of AZD9833 treatment for Stage 1 and 2, and after 12 to 15 
consecutive days for Stage 3.

Percent change from baseline in Ki-67 labelling index after 5 to 7 days of consecutive 
AZD9833 treatment for Stage 1 and 2, and after 12 to 15 consecutive days for Stage 3.
Other exploratory variables may be investigated.
9.4.2
Pharmacodynamic Analyses
The primary endpoint (percent change from baseline in ER expression) and the secondary 
endpoints (percent change from baseline in PgR expression and change in Ki-67 labelling 
index) will be listed and summarised appropriately, based on the PD analysis set. If data 
permit, an ANCOVA model will be fitted to each endpoint, with baseline value, day of biopsy 
and dose group included in the model. Estimates of the LS mean percent change taken from 
the model will be presented together with 80% CIs. Normality of the data will be assessed, 
and if it is judged that the data do not adequately follow a normal distribution, then the use of 
the natural log transformed data (ratio), or a non-parametric approach could replace the 
untransformed analysis as the primary approach. It is expected that the distribution of the 
Ki-67 index data will not be normally distributed (Robertson et al 2013, Robertson et al 
2020b), hence Ki-67 index data will be naturally log-transformed before being analysed.
Sensitivity analyses, eg, a non-parametric approach may be performed as necessary and will 
be fully detailed in the SAP, along with any subgroup analyses.
9.4.3
Safety Analyses
All safety analyses will be performed on the safety analysis set. Safety data will not be 
analysed formally.


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Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs and ECGs. These will be collected for all patients. Appropriate summaries of 
these data will be presented.
9.4.3.1
Adverse Events
AEs will be listed individually by patient and treatment group. For patients who undergo a 
dose modification, all AEs (due to drug or otherwise) will be assigned to the initial dose 
group. 
Events will be defined as treatment-emergent if they onset or worsen (by Investigator report of 
a change in intensity), during the treatment period (defined from date of first dose of any study 
treatment to the date of the last dose of any study treatment) or during the safety follow-up 
period (28 days after last dose of study treatment). The MedDRA (version 22.1 or later) will 
be used to code AEs.
Summary tables for AEs will only include TEAEs. AEs occurring prior to dosing or starting 
more than 28 days after discontinuation of study treatment will be listed separately but not 
included in the summaries.
9.4.3.2
Other Significant Adverse Events (OAEs)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to treatment discontinuation. 
Based on the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered OAEs and reported as 
such in the CSR. A similar review of laboratory/vital signs/ECG data and other safety 
assessments will be performed for identification of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment.
9.4.3.3
Other Safety Data
Duration of exposure will be summarised appropriately. 
Clinical chemistry, haematology, urinalysis, and vital signs will be listed individually by 
patient and appropriately summarised. For all laboratory variables that are included in the 
CTCAE (version 5.0), the CTCAE grade will be calculated.
The ECG parameters (PR, QRS, RR, QT, QTcB, and QTcF) will be summarised over time in 
terms of absolute values and change from baseline.
Details of any death will be listed for all patients.


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9.4.4
Pharmacokinetic Analyses
PK concentrations of AZD9833 will be summarised by treatment group, and PK concentration 
data will be listed for each patient in the PK analysis set. Data will be summarised by 
timepoint using appropriate descriptive statistics. Geometric mean (± geometric SD) 
concentration-time data will be presented (if applicable). 
AZD9833 plasma concentration data from this study may be combined with data from other 
studies to conduct population PK exploratory analysis and may be detailed in a separate PK 
plan and reported separately.
9.4.5
Other Analyses 
The PK, PD, demographic and safety data collected in this study may also be combined with 
similar data from other studies and explored using exploratory population PK and/or PK-PD 
methods. The results of any such analyses will be presented separately from the main CSR.
9.4.5.1
Exploratory Analyses
Exploratory endpoints will not be reported in the CSR.
9.4.6
Methods for Multiplicity Control 
Not applicable.
9.5
Interim Analyses 
There will be no interim statistical analyses during the conduct of Stage 1, except that which 
will be planned and reviewed by the SDMC at the completion of Stage 1. In Stage 2, there 
may be an interim analysis conducted once all patients have completed treatment in 
Georgia/Mexico (and with provision to include any patients who have been recruited from the 
UK at the date of data cut off) and on completion of recruitment. Analyses will be defined in 
the SAP.
9.6
Safety and Data Monitoring Committee
The SDMC will undertake review of the Stage 1 data prior to Stage 2 commencing. The 
doses, specific arms and sample size for Stage 2 will be determined by the SDMC based on 
data from Stage 1 and potentially using data on AZD9833 from other studies. A SDMC 
charter will include further detail outlining the membership and guidelines for transition from 
Stage 1 to Stage 2. Stage 2 will only occur in the UK after approval of a substantial protocol 
amendment including details of the rationale, the doses of AZD9833 and the study 
populations that will be evaluated in Stage 2 as recommended by the SDMC. Note that a 
fulvestrant arm will not be included in Stage 2 as decided by the SDMC.


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In general, if Stage 1 doses produce a high degree of PD modulation versus historical 
fulvestrant control data, Stage 2 will likely focus on lower AZD9833 doses. Conversely, if 
Stage 1 doses produce a similar or lower degree of PD modulation compared with historical 
fulvestrant control data, Stage 2 will likely focus on higher AZD9833 doses. An alternative 
scenario is that the precision of the estimate of the primary endpoint from Stage 1 is 
insufficient, and the inclusion of additional patients in Stage 2 at the same doses from Stage 1 
will provide additional clarity. Therefore, Stage 2 of the study makes provision for the 
examination of the biological effects of several different dose levels of AZD9833, or to 
evaluate additional patients at the dose levels examined in Stage 1.
Analysis of tumour samples will be batched and the resulting data reviewed on an ongoing 
basis throughout the study. 
The rationale for the remit and scope of the SDMC will be summarised in the SDMC charter. 
The key data from Stage 1, and the SDMC advice is summarised in Sections 2.2.2.6 and 6.


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SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS








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Table 28 below provides examples of 
 drugs. This list is not 
exhaustive.
Table 28
Examples of 
 Drugs
-
In vitro, it has been shown that AZD9833 is an inhibitor of 
.
 should not be combined with AZD9833 
.
 should be stopped at least 2 weeks before the first dose of AZD9833.
Preliminary PK data from 
 
 of SERENA-1 
 
 Therefore, prescribing advice for drugs 
that are known 
 
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Appendix B
Regulatory, Ethical and Study Oversight Considerations
B 1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines

Applicable ICH and GCP Guidelines

Applicable laws and regulations.
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC.

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures.

Providing oversight of the conduct of the study at the site and adherence to requirements 
of Title 21 of the CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for 
clinical studies (if applicable), and all other applicable local regulations.
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.


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
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for SUSAR, according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements.
B 2
Financial Disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
B 3
Informed Consent Process
The Investigator or his/her representative will explain the nature of the study to the patient or 
her legally authorised representative and answer all questions regarding the study.
Patients must be informed that their participation is voluntary. Patients or their legally 
authorised representative will be required to sign a statement of informed consent that meets 
the requirements of Title 21 of the CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, where applicable, and the IRB/IEC or study centre.
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date when the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorised 
representative.
 
 
Patients who are rescreened are required to sign a new ICF.
 
CCI
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B 4
Data Protection
Each patient will be assigned a unique identifier by the Sponsor. Any patient records or data 
sets transferred to the Sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred.
The patient must be informed that her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient.
The patient must be informed that her medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
B 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with the AstraZeneca Patient Safety department. 
Issues identified will be addressed; for instance, this could involve amendments to the CSP 
and letters to Investigators.
An independent AstraZeneca SDMC will consider the Stage 1 data from this study, and prior 
to commencing Stage 2.
B 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical study and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.
B 7
Data Quality Assurance
All patient data relating to the study will be recorded on electronic CRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
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verifying that data entries are accurate and correct by physically or electronically signing the 
CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. The sponsor assumes accountability for actions delegated to 
other individuals (eg, CROs).
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
B 8
Source Documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.


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Source data includes all information in original records and certified copies of original records 
or clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.
B 9
Study and Site Closure
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. The study may be stopped if, in the 
judgement of AstraZeneca, trial patients are placed at undue risk because of clinically 
significant findings that:

Meet individual stopping criteria or are otherwise considered significant

Are assessed as causally related to study treatment

Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study site closure visit has 
been performed.
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines.

Inadequate recruitment of participants by the Investigator.

Discontinuation of further study treatment development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.


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B 10
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments.
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.


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Appendix C
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
C 1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s law (PHL) cases and Hy’s law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.
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 PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.
The Investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the study treatment.
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
C 2
Definitions
Potential Hy’s Law (PHL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point during the study 
following the start of study medication, irrespective of an increase in ALP.
Hy’s law (HL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than 
the study treatment, can be found to explain the combination of increases, (eg, elevated ALP 
indicating cholestasis, viral hepatitis, another drug).


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur.
C 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:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative. 

Determine whether the patient meets PHL criteria (see Appendix C 2 for definition) by 
reviewing laboratory reports from all previous visits.

Promptly enter the laboratory data into the laboratory CRF.
C 4
Follow-Up
C 4.1
Potential Hy’s Law Criteria Not Met
If the patient does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the patient has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
C 4.2
Potential Hy’s Law Criteria Met
If the patient does meet PHL criteria, the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team. 

Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting.

For patients that met PHL criteria prior to starting study treatment, the Investigator is not 
required to submit a PHL SAE unless there is a significant change in the patient’s 
condition.


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Note: 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 TBL) 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.

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up (including any further laboratory testing) and 
the continuous review of data.

Subsequent to this contact the Investigator will:

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. Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.

Complete the 3 Liver CRF Modules as information becomes available.
C 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible 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 
study treatment, to ensure timely analysis and reporting to health authorities within 15 
calendar days from the date PHL criteria were met. The AstraZeneca Global Clinical Lead or 
equivalent and Global Safety Physician will also be involved in this review together with 
other patient matter experts as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where 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:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF.


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
If the alternative explanation is an AE/SAE, update the previously submitted PHL SAE 
and AE CRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study treatment:

Send updated 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 15 calendar days 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:

Provides any further update to the previously submitted SAE of PHL (report term now 
‘Hy’s law case’) ensuring causality assessment is related to study treatment and 
seriousness criteria is medically important, according to CSP process for SAE reporting.

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 still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
C 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:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease)?
If No: Follow the process described in Appendix C 4.2 for reporting PHL as an SAE.


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If Yes: Determine if there has been a significant change in the patient’s condition compared 
with when PHL criteria were previously met.

If there is no significant change, no action is required.

If there is a significant change, follow the process described in Appendix C 4.2 for 
reporting PHL as an SAE.
Note: 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 TBL) 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.
REFERENCES
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’.


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Appendix D
Adverse Event Definitions and Additional Safety Information
D 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
D 2
Definitions of Serious Adverse Event
A SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 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 or incapacity 

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardise the patient or may require medical 
treatment to prevent one of the outcomes listed above
AEs for malignant tumours reported during a study should generally be assessed as serious
AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a 
non-serious AE. For example, if the tumour is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalisation, may be assessed as non-serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 


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is being treated by the investigational product under study and is not the development of new 
or progression of existing metastasis to the tumour under study). Malignant tumours that – as 
part of normal, if rare, progression – undergo transformation (eg, Richter’s transformation of 
B cell chronic lymphocytic leukaemia into diffuse large B cell lymphoma) should not be 
considered a new malignant tumour.
All SAEs must be recorded and reported to the Sponsor or designee within 24 hours.
D 3
Life-Threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the 
patient’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
D 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the patient was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.
D 5
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment.

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine.

Intensive treatment in an emergency room or at home for allergic bronchospasm.

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation.

Development of drug dependency or drug abuse.


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D 6
Intensity Rating Scale
The grading scales found in the revised National Cancer Institute CTCAE latest version (at the 
start of the study) will be utilised for all events with an assigned CTCAE grading. This version 
will be used throughout the study, irrespective of whether a later version becomes available. 
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 can be downloaded from the Cancer Therapy Evaluation Program website 
(http://ctep.cancer.gov). Version 5.0 of CTCAE will be used.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix D 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 unless it meets the criteria 
shown in Appendix D 2. 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 when it satisfies the criteria 
shown in Appendix D 2.
D 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

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 class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered, such as:

Is this a recognised feature of overdose of the drug? 


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
Is there a known mechanism?
Causality of ‘related’ is made if, following a review of the relevant data, there is evidence for 
a ‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
D 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study treatment that either causes harm to the 
participant or has the potential to cause harm to the participant.
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error:  

Occurred;

Was identified and intercepted before the participant received the drug;

Did not occur, but circumstances were recognised that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion.

Dispensing error (eg, medication prepared incorrectly) even if it was not actually given to 
the participant.

Drug not administered as indicated, for example, wrong route or wrong site of 
administration.

Drug not taken as indicated (eg, tablet dissolved in water when it should be taken as a 
solid tablet).

Drug not stored as instructed (eg, kept in the fridge when it should be at room 
temperature).

Wrong participant received the medication (excluding IWRS errors).

Wrong drug administered to participant (excluding IWRS errors).


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Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IWRS – including those which lead to one of the above 
listed events that would otherwise have been a medication error. 

Participant accidentally missed drug dose(s) (eg, forgot to take medication).

Accidental overdose (will be captured as an overdose).

Participant failed to return unused medication or empty packaging.

Errors related to background and rescue medication, or standard-of-care medication in 
open-label studies, even if an AZ product.
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.


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Appendix E
Handling of Human Biological Samples
E 1
Chain of Custody of Biological Samples
A full chain of custody is maintained for all samples throughout their life-cycle.
The Investigator at each site keeps full traceability of collected biological samples from the 
patients while in storage at the site until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks and will 
be registered by the AstraZeneca Biobank Team during the entire life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
E 2
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, and the action documented. If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research.
The Investigator:

Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca.

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented.

Ensures the organisation(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented, 
and the signed document returned to the study site.

Ensures that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the action 
documented, and the signed document returned to the study site.


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E 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
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 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:

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, 
HIV types 1 and 2. They are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B.

are to be packed in accordance with UN3373 and IATA 650.
Exempt – all other materials with minimal risk of containing pathogens.

Clinical trial samples will fall into Category B or exempt under IATA regulations.

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).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content.

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.

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.


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Appendix F
Genetics
F 1
Use/Analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease aetiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting patients.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.
In addition, collection of DNA samples from populations with well-described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the patient´s DNA (ie, the 
entire genome). 
The results of genetic analyses may be reported in the CSR or in a separate study summary.
The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on AZD9833 continues but no longer than 
15 years or other period as per local requirements.
F 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population
Study Selection Record
All patients will be asked to participate in this genetic research. Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit. The patient will 
not be excluded from any aspect of the main study.


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Inclusion Criteria
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described 
in the main body of the CSP and provide informed consent for the genetic sampling and 
analyses.
Exclusion Criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant.

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection.
Withdrawal of Consent for Genetic Research
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7 of the main 
CSP.
Collection of Samples for Genetic Research
The blood sample for genetic research will be obtained from the patients at screening or on 
Day 1. Although DNA is stable, early sample collection is preferred to avoid introducing bias 
through excluding patients who may withdraw due to an AE, such patients would be important 
to include in any genetic analysis. If for any reason the sample is not drawn at screening or on 
Day 1, it may be taken at any visit until the day of surgery. Only one sample should be 
collected per patient for genetics during the study. Samples will be collected, labelled, stored, 
and shipped as detailed in the Laboratory Manual.
Coding and Storage of DNA Samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples will be stored for a maximum of 
15 years, from the date of last-patient-last-visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable only by the second, unique number. This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 


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organisation. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).
The link between the patient enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix B.
Informed Consent
The genetic component of this study is optional, and the patient may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study. Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study site. The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely withdraw from the genetic aspect of the study at any 
time.
Patient Data Protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data. In addition, Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
Data Management
 
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Statistical Methods and Determination of Sample Size
The number of patients that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. An SAP may be 
prepared where appropriate.
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Appendix G
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis, including COVID19 Outbreak
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions, and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from the Sponsor. 
G 1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections G 2 to G 5. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
G 2
Rescreening of Participants to Reconfirm Study Eligibility 
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
study clinical lead.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participants and either enrolment into the study or commencing of dosing with study 
intervention. If this delay is outside the screening window specified in Section 1.3 the 
participant will need to be rescreened to reconfirm eligibility before commencing study 
procedures. This will provide another opportunity to rescreen a participant in addition to that 
detailed in Section 5.5. The procedures detailed in Section 5.5 must be undertaken to confirm 
eligibility using the same randomisation number as for the participant.


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G 3
Home or Remote Visit to Replace On-site Visit (Where 
Applicable)
A qualified HCP from the study site or TPV service may visit the participants home/or other 
remote location as per local SOPs, as applicable. Supplies will be provided for a safe and 
efficient visit. The qualified HCP will be expected to collect information per the CSP.
G 4
Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix, the term telemedicine visit refers to remote contact with the participants 
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow AEs and concomitant medication to be reported and 
documented.
G 5
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site or TPV service in the source documents, or by the participant 
themselves.
G 6
COVID-19 Risk Assessment 
The safety of participants is of primary importance. Any potential risks of participating in the 
study, particularly with the added challenges due to the COVID-19 outbreak, should be 
weighed against the anticipated benefit (see also principle 2.2 of ICH GCP). Investigators are 
advised to use clinical judgment in determining infection prevention precautions for study 
participants.
The emergence of SARS-CoV-2 presents a potential safety risk for cancer patients. 
Participants enrolling in this study may require more frequent visits to the site for study 
treatment administration and for study assessments compared to participants receiving 
standard of care. Therefore, several risk mitigation factors have been implemented related to 
study conduct during the COVID-19 outbreak, for patient management in an event of 
COVID-19, and actions to be taken on study treatment (see Section G 9). 
Notably, participants with active COVID-19 infection confirmed by local laboratory testing
will not be eligible for study enrolment (see CSP Section 5.2, Exclusion Criterion 4). 


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G 7
Potential Risks During COVID-19
Every effort should be made to follow the CSP. Section G 10 provides a dose modification 
and management plan for participants with confirmed or suspected COVID-19 who are being 
treated with study intervention AZD9833. The risk-benefit assessment should be carefully 
considered for each participant enrolling in the study based on the known safety risks related 
to COVID-19, individual needs, and local guidelines and restrictions. Investigators must 
continue to use their best clinical judgment in determining the most optimal care for 
participants and utmost diligence in determining their eligibility for study participation, 
continued study treatment, and overall assessment of benefit/risk of study treatment or 
participation.
The Sponsor must be promptly notified of a site’s inability to perform study activities due to 
COVID-19 outbreak in order to minimise any potential risks.
G 8
New Participant Enrolment
Study sites may continue to recruit new participants into the study provided the following 
activities to preserve study integrity can be met:

Upon discussion with the site monitor, the study site has confirmed the ability to enrol 
and manage new participants effectively and in compliance with the protocol.

Data will continue to be entered into the eCRF and queries resolved in a timely manner. 
Per CSP Exclusion Criterion 4 (see CSP Section 5.2), participants with severe or uncontrolled 
systemic diseases, including but not limited to, ongoing or active infection are not eligible for 
the study participation and hence such participants (including those who have confirmed 
COVID-19) should not be included for study participation.
G 9
Study Treatment Administration
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
participants’ treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the CSP.
Adverse events, SAEs, cycle delays, and/or treatment suspensions associated with COVID-19 
along with logistical issues should be reported according to the eCRF Completion Guidelines. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should 
be followed, and the End of Treatment Form(s) completed


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G 10
Ongoing Participants
Participants receiving study intervention should continue to undergo safety assessments prior 
to dosing in accordance with the CSP. In case it is not feasible to perform safety assessments, 
study intervention should be interrupted until such assessments can be completed.
G 10.1
If a Participant has an Event Suspected to be COVID-19
Delay or omit study intervention as appropriate and test for COVID-19 per local health 
authority or institutional guidance. 

Signs and symptoms of COVID-19 include but are not limited to new onset of fever, 
new or worsening cough, shortness of breath, difficulty breathing, and sometimes 
abnormal chest imaging and may be similar to those of an imAE. 

In accordance with the CSP and the TMGs for imAEs, thorough evaluation should be 
performed to accurately identify the underlying pathology in case an AE is 
encountered for a participant. 

If COVID-19 is ruled out, study intervention may be resumed per the CSP.

If COVID-19 is confirmed or diagnosis still suspected after evaluation, manage 
COVID-19 per local guidance until full recovery. 
G 10.2
Participants with Confirmed COVID-19
Participants with confirmed COVID-19 (by local laboratory testing and/or combination of 
key symptoms) should have study intervention withheld and COVID-19 managed per local 
guidance.
In case of confirmed COVID-19 and a simultaneous imAE requiring treatment, investigators 
are advised to apply clinical judgement regarding the use of corticosteroids. This also includes 
the consideration of alternate immunosuppressive agents other than corticosteroids for imAE 
management, depending on the individual participant’s presentation (Curigliano et al 2020).
G 10.3
Restarting Study Intervention
Study intervention must not be resumed until recovery from COVID-19 (eg, confirmed by 
imaging, lab testing, and/or absence of symptoms) and COVID-19-specific treatment has been 
completed per local guidance.
The study clinical lead should be contacted if any additional guidance or clarification is 
needed.


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G 10.4
Vaccination Against COVID-19
Protocol restrictions applying to live attenuated vaccines are relevant for live attenuated 
COVID-19 vaccines as well. Investigators should apply their discretion assessing the 
risk-benefit of other types of COVID-19 vaccines for participants in clinical trials. Ideally, 
administration of the vaccine should be done on a different day other than the day of study 
drug administration to differentiate any potential AEs seen from the vaccine and study drug. 
The administration of the vaccine and any potential AEs associated with the vaccine are to be 
documented on the concomitant medication and AE eCRFs, respectively.
G 11
References
Curigliano et al 2020 
Curigliano G, Banerjee S, Cervantes A, Garassino MC, Garrido P, Girard N, et al. Managing 
cancer patients during the COVID-19 pandemic: an ESMO multidisciplinary expert 
consensus. Ann Oncol. 2020;31(10):1320-35.


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Appendix H
Abbreviations
Abbreviation 
or special term
Explanation
ADL
Activities of daily living
AE
Adverse event
AI
Aromatase inhibitor
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase
AUC0-8h
Area under the plasma concentration-time curve from time of dose to 8 hours
AUC0-24h
Area under the plasma concentration-time curve from time of dose to 24 hours
AUC0-inf
Area under the plasma concentration-time curve from time of dose to infinity
AUC0-last
Area under the plasma concentration-time curve from time of dose to last timepoint when 
PK sample taken
B
Blood
bpm
Beats per minute
CBR
Clinical benefit rate
CBR24
Clinical benefit rate at 24 weeks
CDK4/6
Cyclin-dependent kinase 4 and 6
CFR
Code of Federal Regulations
CI
Confidence interval
CIOMS
Council for International Organisations of Medical Sciences
CISH
Chromogenic in situ hybridization
CK
Creatine kinase
Cmax 
Maximum plasma drug concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus 2019 disease
CRF
Case report form (electronic/paper)
CRO
Contract Research Organisation
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumour DNA
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Abbreviation 
or special term
Explanation
CYP
Cytochrome P450
DCO
Data cut-off
DILI
Drug-induced liver injury
DLT
Dose-limiting toxicity
DMPK
Drug Metabolism and Pharmacokinetics
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eGFR
Estimated glomerular filtration rate
EOT
End of treatment
ER
Oestrogen receptor
ERα
Oestrogen receptor alpha
ERT
E-Research Technology
ESR1
Oestrogen receptor 1
FAS
Full analysis set
FFPE
Formalin-fixed paraffin-embedded
FISH
Fluorescence in situ hybridization
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
Hb
Haemoglobin
HCP
Health care professional
HER2
Human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HL
Hy’s law
HR
Hazard ratio
IATA
International Airline Transportation Association
ICF
Informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (formerly International Conference on Harmonisation)
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IM
Intramuscular
imAE
Immune-mediated adverse event
INN
International Non-proprietary Name
INR
International normalised ratio


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Abbreviation 
or special term
Explanation
IRB/IEC
Institutional Review Boards/Independent Ethics Committees
ITT
Intention-to-treat
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
IRB/IEC
Institutional Review Boards/Independent Ethics Committees
ITT
Intention-to-treat
ISH
In situ hybridisation
IWRS
Interactive web response system
Ki-67
Antigen Ki-67
LS mean
Least-squares mean
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare Products Regulatory Agency
mRNA
Messenger ribonucleic acid
NEI VFQ-25
National Eye Institute 25-Item Visual Function Questionnaire
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
PD
Pharmacodynamic(s)
PFS
Progression-free survival
PGI-BR
Patient Global impression of Benefit-Risk
PGIC
Patient Global Impression of Change
PGIS
Patient global impression of severity
PGI-TT
patient global impression of treatment tolerability
PgR
Progesterone receptor
PHL
Potential Hy’s law
PK
Pharmacokinetic(s)
PO
Per os (oral administration)
QD
Once daily
QTcB
QT interval corrected for heart rate using Bazett’s formula
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event 
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Abbreviation 
or special term
Explanation
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus-2
SDMC
Safety and Data Monitoring Committee
SERD
Selective oestrogen receptor down-regulator/degrader
SISH
Silver in situ hybridisation
SoA
Schedule of Activities
SmPC
Summary of product characteristics
SOC
System organ class
SOP
Standard operating procedure
S/P
Serum/plasma
SRC
Safety Review Committee
SUSAR
Suspected unexpected serious adverse reactions
t1/2
Terminal elimination half-life
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
tmax
Time to reach maximum plasma concentration 
TPV
Third party vendor
U
Urine
ULN
Upper limit of normal
USPI
United States prescribing information
WBDC
Web-based data capture
WHO
World Health Organization


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Appendix I
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the TOC.
Amendment 1 (28 Sep 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the EU.
This global amendment has been issued in order to implement recommendations made by the 
SDMC and to consolidate into the global CSP, local changes made to the CSP in response to 
requests from the MHRA.
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Sections 1.1; 
1.3 (Table 1); 2.1; 2.3.2; 
3; 4.1.1; 4.1.2; 4.1.2.1; 
6.1.1; 8 (text and Table 
14); 8.5.1 (text and 
Figure 4); 9.2.1; 
9.3 (Table 16); 9.4.4; 
and 9.6
Text has been amended to confirm 
Stage 2 will only occur in the UK 
after approval of a substantial 
protocol amendment including 
details of the rationale, the doses of 
AZD9833 and/or fulvestrant, and 
the study populations that will be 
evaluated in Stage 2 as 
recommended by the SDMC. 
Assessments and text related to the 
Stage 2 fulvestrant arm have been 
deleted.
As advised by the MHRA
Substantial
Sections 1.1 and 3 
(Table 10)
The objectives have been modified 
to remove fulvestrant treatment 
from the first of the secondary 
objectives and the last of the 
exploratory objectives.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 1.1
The number of patients randomised 
to each dose group has been 
updated.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 1.1, 6.3, and 
4.1.2.1
The randomisation will be stratified 
based on country (UK / Georgia 
and Mexico).
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 1.1
The estimated date of last patient 
completed (end of Stage 2) has 
been updated to Q1 2023.
To reflect current 
recruitment timelines
Non-substantial
Sections 1.1 and 4.1.1
Heart rate monitor text reworded 
for consistency with the SoA and 
Section 8.2.5.
To improve clarity
Non-substantial


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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Sections 1.1; 1.3 
(Table 1); and 4.1.1 and 
4.1.2.
Clarification regarding the timing 
of the follow-up visit after the 
biopsy visit for patients going on to 
subsequent neoadjuvant therapy is 
provided.
To provide clarification on 
the timing of the follow-up 
visit in patients planned to 
receive neoadjuvant therapy 
prior to planned surgery.
Non-substantial
Sections 1.1; 
1.2 (Figure 2); 
1.3 (Table 1); 4.1; 
4.1.2.2; 5.1; and 6.3.
Text/sections regarding the optional 
treatment group in pre-menopausal 
women in Stage 2 of the study have 
been removed.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 1.2 (Figure 2)
Figure has been amended to show 
the Stage 2 doses as advised by the 
SDMC for Stage 2.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Sections 1.1; 1.3 
(Table 1); and 2.3.2
‘Study entry’ updated to ‘the 
screening visit date’/ ‘screening’.
To provide clarification
Non-substantial
Sections 2.1; 2.2.2.2; 
2.2.2.5; 2.2.2.6; 4.1.2; 
6.1.1 (Table 12); and 
9.2
Updated to include details of the 
rationale and the doses of AZD9833 
that will be evaluated in Stage 2.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 2.2.2
Clarification that safety information 
remains representative despite 
recruiting over 500 patients to the 
study.
To provide clarification
Non-substantial
Section 2.2.2.3
After a single AZD9833 dose, the 
time to reach tmax was achieved 
approximately 2 to 4 hours 
post-dose, with a t1/2 of 
approximately 11 (previously 10) to 
15 (previously 13) hours across all 
dose groups.
Updated data
Non-substantial
Sections 2.2.2.4 and 9.2
ER updated to ERα.
For clarification
Non-substantial
Section 2.3.2 
Fulvestrant (applicable 
to Stage 2 only); 
Section 6.6.2 Dose 
Modification for 
Fulvestrant; 
Section 6.5.1 Drugs 
Affecting 
 
; and 
Section 8.4.2 
Fulvestrant
Sections/text deleted.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 2.3.2 Overall 
Benefit/Risk and 
Ethical Assessment 
(previously 
Section 2.3.3)
Text updated to confirm that 
Stage 1 data support the overall 
risk/benefit and ethical assessment 
above, and the statements are 
unmodified for the conduct of 
Stage 2.
Updated information
Non-substantial
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 4.1.2
Section heading moved to include 
final paragraph of Section 4.1.1. 
Text added to explain Stage 2 of the 
study.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Sections 4.1.3 and 11 
(Appendix G)
New sections added to provide 
guidance on changes related to 
mitigation of study disruptions due 
to cases of civil crisis, natural 
disaster, or public health crisis, 
including COVID 19 outbreak.
As per revised AZ template
Substantial
Section 5.2 (Exclusion 
criterion 8)
‘History of hypersensitivity to 
active or inactive excipients of 
fulvestrant for Stage 2 if relevant’ 
has been deleted.  
As per, or as a consequence 
of, recommendations by the 
SDMC
Non-substantial
Section 5.4.1
Text relating to contraceptive 
measures has been deleted in line 
with the removal of pre-menopausal 
women from the protocol.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 5.4.2
‘There are no food restrictions for 
fulvestrant (if applicable in 
Stage 2).’ was deleted.  
As per, or as a consequence 
of, recommendations by the 
SDMC
Non-substantial
Sections 6.2; 8.5.1.1; 
and 8.5.1.2.
Text relating to the storage of 
fulvestrant, and the handling of 
samples for fulvestrant PK analyses 
have been deleted.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 6.3
Text related to the randomisation of 
patients for Stage 2 has been 
updated.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 6.5.3 
 
New section added presenting 
preliminary PK data from 
SERENA-1 suggesting the 
possibility that AZD9833 may 
 
New information
Substantial
Section 6.5.8
Text modified to clarify that sex 
hormone containing drugs or other 
drugs that may affect sex hormone 
status or disease response are not 
permitted during treatment (Day 1 
to the biopsy day).
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 8.3.12 
Pregnancy
Section deleted. Note this has 
resulted in the Medication Error 
section being renumbered to 8.3.12.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
CCI
CCI
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Clinical Study Protocol – 3.0
AstraZeneca
AZD9833 (INN: camizestrant) - D8530C00003
CONFIDENTIAL AND PROPRIETARY
147 of 147
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 8.6.3
Additional details on the number of 
patients for whom paired tumour 
biopsies will be collected has been 
added for Stage 2 of the study. 
Reference to the collection of 
biopsy samples in Stage 2 patients 
receiving fulvestrant has been 
deleted.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Sections 1.1 and 9.2
Update of the sample size 
determination in line with the 
revised dose groups to be included 
in the study.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 9.4.5.1
Confirmation that exploratory 
endpoints will not be reported in the 
CSR.
Correction of typo
Non-substantial
Section 9.5
It has been added that an interim 
analysis may be conducted once all 
patients have completed treatment 
in Georgia/Mexico (and with 
provision to include any patients 
who have been recruited from the 
UK at the date of data cut off) and 
on completion of recruitment.
As per, or as a consequence 
of, recommendations by the 
SDMC
Substantial
Section 10 References
The reference list has been moved 
from Section 11 to come before the 
appendices (Supporting 
Documentation and Operational 
Considerations)
To maintain consistency 
with the AstraZeneca CSP 
template
Non-substantial
Section 11 (Appendix 
A3)
The appendix has been modified to 
provide advice regarding the 
concomitant use of 
.
New information
Substantial
Section 11 (Appendix 
D2)
The wording in this section has 
been modified to change 
‘congenital abnormality or birth 
defect’ to ‘congenital anomaly or 
birth defect’.
To maintain consistency 
within the document
Non-substantial
Section 11 (Appendix I)
A new appendix has been created 
which will be used to include the 
details of any prior global 
amendment.
To maintain consistency 
with the AstraZeneca CSP 
template
Non-substantial
CSR = Clinical study report; 
; ERα = Oestrogen receptor alpha; MHRA =Medicines 
and Healthcare Products Regulatory Agency; Q1 = Quarter 1; 
; PK = Pharmacokinetics; 
SDMC = Safety and Data Monitoring Committee; SoA = Schedule of Activities; t½ = Terminal elimination half-
life; tmax = Time to reach maximum plasma concentration; UK = United Kingdom
CCI
CCI
CCI


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d8530c00003-csp-v3
Document Title:
D8530C00003 Clinical Study Protocol version 3
Document ID:
Doc ID-004227561
Version Label:
3.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
06-Jul-2022 15:34 UTC
Content Approval
06-Jul-2022 14:18 UTC
Author Approval
06-Jul-2022 13:02 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
PPD

SAP_001.pdf: 
Parexel International
AstraZeneca
D8530C00003
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 4.0
Effective Date:  26 Nov 19
Project Document Effective Date: Date of last signature
Related to:  SOP-GDO-WW-019
Page 1 of 34
Parexel International
AstraZeneca
D8530C00003
A Randomised, Open-Label, Parallel-Group, Pre surgical Study to Investigate the Biological Effects 
of AZD9833 in Women with ER-positive, HER2-negative Primary Breast Cancer (SERENA-3)
Statistical Analysis Plan
Version: Final 4.0
Parexel Project Number: 247887


Parexel International
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D8530C00003
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
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Project Document Effective Date: Date of last signature
Related to:  SOP-GDO-WW-019
Page 2 of 34
TABLE OF CONTENTS
1
INTRODUCTION................................................................................................................. 8
2
STUDY OBJECTIVES ......................................................................................................... 8
2.1 PRIMARY OBJECTIVE............................................................................................................ 8
2.2 SECONDARY OBJECTIVES...................................................................................................... 9
2.3 EXPLORATORY OBJECTIVES.................................................................................................. 9
3
INVESTIGATIONAL PLAN.............................................................................................. 10
3.1 STAGE 1............................................................................................................................. 10
3.2 STAGE 2............................................................................................................................. 11
3.3 STAGE 3............................................................................................................................. 12
3.4 END OF STUDY................................................................................................................... 13
3.5 PLANNED ANALYSIS........................................................................................................... 13
4
STATISTICAL METHODS ............................................................................................... 14
4.1 DATA QUALITY ASSURANCE............................................................................................... 14
4.2 GENERAL DATA PRESENTATION CHARACTERISTICS ............................................................ 14
4.3 GENERAL VARIABLES......................................................................................................... 15
4.3.1
Study Day Definitions ................................................................................................ 15
4.3.2
Handling missing data............................................................................................... 16
4.4 SOFTWARE......................................................................................................................... 17
4.5 ANALYSIS SETS.................................................................................................................. 17
4.6 STUDY PATIENTS................................................................................................................ 19
4.6.1
Disposition of Patients............................................................................................... 19
4.6.2
Protocol Deviations................................................................................................... 19
4.6.3
Demographic and Other Baseline Characteristics ..................................................... 20
4.7 MEDICAL AND SURGICAL HISTORY..................................................................................... 21
4.8 CONCOMITANT MEDICATIONS AND TREATMENT ................................................................. 21
4.9 CURATIVE INTENT SURGERY ............................................................................................... 22
4.10
PHARMACODYNAMIC EVALUATION................................................................................. 22
4.10.1
ER and PgR ........................................................................................................... 22
4.10.2
Ki-67 Labelling Index ............................................................................................ 24
4.11
SAFETY EVALUATION..................................................................................................... 25
4.11.1
Extent of Exposure................................................................................................. 25
4.11.2
Adverse Events....................................................................................................... 26
4.11.3
Deaths ................................................................................................................... 27
4.11.4
Clinical Laboratory Evaluation.............................................................................. 27
4.11.5
Physical Examination findings............................................................................... 28
4.11.6
Vital Signs.............................................................................................................. 29
4.11.7
ECG Variables....................................................................................................... 29
4.11.8
................................................................................ 30
4.12
PHARMACOKINETIC EVALUATION................................................................................... 30
4.13
SAMPLE SIZE CONSIDERATIONS ...................................................................................... 31
4.14
SDMC ANALYSIS AND REPORTING................................................................................. 32
4.15
INTERIM ANALYSIS......................................................................................................... 33
4.16
OTHER ANALYSIS........................................................................................................... 33
5
REFERENCES.................................................................................................................... 33
CCI


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Project Document Version No. 4.0
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Page 3 of 34
REVISION HISTORY
Version No.
Effective Date
Summary of Change(s)
1.0
13 Nov 2020
New document
2.0
4 Apr 2022
Updated throughout to remove reference to fulvestrant and 
clarify Stage 2 design following protocol Version 2.0
Section 4.3.1; Table 2
Corrected the Visit 5, Analysis visit as  ‘Follow-up’
Section 4.5; Table 5 
Updated footnote to clarify reporting analysis sets.
Section 4.6.3
The age group categories revised to < 50, 50-59, 60-69, ≥ 70.
‘breast’ is added as primary cancer location.
The presentation of neurological assessment was updated to 
‘listing only’.
Section 4.8
‘concomitant procedures’ were added to the summary list.
Section 4.9
New section 4.9 Curative intent surgery was added.
Section 4.10
Updated the section with the strategy to handle multiple tumour 
blocks data at a single visit.
Section 4.10.1
Additional sensitivity analyses for HER2 positive patients were
added.
Section 4.10.2
Additional sensitivity analysis criteria for Ki67 was added.
Section 4.11.2
References to treatment emergent adverse events or TEAEs
were updated to adverse events or AEs throughout.
All references to ‘casually’ related AEs were updated to 
‘possibly’ related AEs.
Section 4.11.7
The section has been updated to include box plots for 
percentage change from baseline


Parexel International
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Project Document Effective Date: Date of last signature
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Page 4 of 34
Appendix A
Appendix A: Table of contents with the list of deliverables was
added.
3.0
03 Jan 2023
Section 1
Added the treatment duration for Stage 3
Added the sample collection strategies for Stage 3.
Updated the CSP version to 3.0 
Updated eCRF version to 7 (Sep 5, 2022)
Section 2
Updated with Stage 3 treatment objective (12 to 15 days of 
treatment)
Section 3
Updated with Stage 3 investigational plan. Added figure 3.
Section 3.5
Corrected the number of patients for interim analysis to 60 in 
Table 1
Section 4.2
Added a paragraph explaining how the data from Stage 1 , 2 and 
3 will be summarised and presented.
Section 4.3.1
Added analysis visit mapping table for Stage 3
Section 4.6.1, 4.6.3, 4.10.1, 4.10.2, 4.11, 4.11.6, 4.11.7, 4.12
Elaborated how the respective data from Stages 1,2 and 3 will 
be summarized.
Section 4.10.1, 4.10.2
Added how the percentage change from baseline in biomarker 
scores will be analysed and least square means will be 
presented.
Section 4.15
Added the following sentence
No formal interim analysis will be performed during Stage 3.
4.0
Date 
of 
last 
signature
Section 4.10.2
Added the following sensitivity analysis to the Ki67 labelling 
index

Any patients with an ER H-score < 10 on their pre-
treatment biopsy.


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
Any patients with an ER H-score < 10 on their pre-
treatment biopsy or any patients with a Ki-67 labelling 
index < 5% from their pre-treatment biopsy.
Added a new Table 4 summary of deviations and actions. 
Updated the table number of subsequent tables.
Updated the eCRF version with the latest version number and 
date.
Added Final stage 3 analysis to Table 1 summary of analyses 
during study conduct.
Section 4.5
Elaborated the conditions for subjects to be included in the PD 
analysis set


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LIST OF ABBREVIATIONS
AEs
adverse events
AESI
adverse events of special interest
ALP
alkaline phosphatase
ALT
alanine transaminase
ANCOVA
analysis of covariance
AST
aspartate transaminase
AZ
AstraZeneca
BLQ
below the limit of quantification
BMI
body mass index
CI
confidence interval
CK
creatine kinase
cm
centimetres
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse events
CV
coefficient of variation
DBP
diastolic blood pressure
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic Case Report Form
ER
oestrogen receptor
ESR 1
oestrogen receptor 1 
FAS
full analysis set
GE
Georgia
HER2
epidermal growth receptor 2
IHC
immunohistochemistry
kg
kilogram
LLoQ
lower limit of quantification
MedDRA
Medical Dictionary or Regulatory Affairs
mmHg
millimeter of mercury
mRNA
messenger ribonucleic acid
MX
Mexico
NC
not calculable
NE
not evaluable
NQ
not quantifiable
NR
not reportable
NS
no sample
OAEs
other significant adverse events
PD
pharmacodynamic
PgR
progesterone receptor
PK
pharmacokinetic
PO
orally administered
PT
preferred term


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Statistical Analysis Plan
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Page 7 of 34
PTT
prothrombin time
PXL
PAREXEL®
QTcB
QT interval corrected for heart rate using Bazett’s formula
QTcF
QT interval corrected for heart rate using Fridericia's formula
RDI
Relative Dose Intensity
SAEs
serious adverse events
SBP
systolic blood pressure
SD
standard deviation
SDMC
Safety and Data Monitoring Committee
SOC
system organ class
TBL
total bilirubin
TEAE
treatment emergent adverse events
TMF
trial master file
UK
United Kingdom
ULN
upper limit of normal
ULoQ
upper limit of quantification
WHO
World Health Organisation
WHODD
World Health Organisation Drug Dictionary


Parexel International
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D8530C00003
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Page 8 of 34
1
INTRODUCTION
This is a randomised, open-label, parallel-group, multicentre study which has three stages to help 
investigating the biological effects of different doses of AZD9833 orally administered (PO) once 
daily (QD), in women with primary breast cancer awaiting curative-intent surgery, for 5 to 7 days 
consecutively in Stage 1 and 2; for 12 to 15 days consecutively in Stage 3. Women with histologically 
proven, oestrogen receptor-positive (ER-positive), human epidermal growth receptor 2-negative 
(HER2-negative) invasive breast cancer involving a palpable tumour of any size, or a tumour with an 
ultrasound assessed diameter ≥ 1.0 cm and fulfilling all the inclusion criteria and none of the exclusion 
criteria will be enrolled in the study. 
In Stage 1, approximately twenty-four evaluable post-menopausal women will be randomly assigned 
in a 1:1 ratio to two dose groups (75 mg PO QD for 5 to 7 days and 150 mg PO QD for 5 to 7 days) 
of AZD9833. Following completion of Stage 1 and availability of immunohistochemistry (IHC) data, 
the Safety and Data Monitoring Committee (SDMC) will review the Stage 1 data, potentially 
alongside the emerging data from any relevant ongoing AZD9833 studies and decide whether to 
proceed with Stage 2 based on the guidelines provided in the SDMC charter. 
Following the review of the Stage 1 data, the SDMC has advised that Stage 2 will comprise of 
approximately thirty-six evaluable post-menopausal women from Georgia (GE) and Mexico (MX),
randomly assigned in a 1:1:1 ratio to three dose groups (75 mg PO QD for 5 to 7 days, 150 mg PO 
QD for 5 to 7 days and 300 mg PO QD for 5 to 7 days) of AZD9833 and approximately twenty-four 
post-menopausal women from the United Kingdom (UK) randomly assigned in a 1:1 ratio to two 
AZD9833 dose groups (75 mg PO QD for 5 to 7 days and 150 mg PO QD for 5 to 7 days). 
Following the interim analysis after Georgia and Mexico completed recruitment in Stages 1 and 2, 
the SDMC has advised that Stage 3 of the study should be conducted to include forty-eight evaluable 
post-menopausal women from Georgia (GE) and Mexico (MX), randomly assigned in a 1:1 ratio to 
two AZD9833 dose groups (75 mg PO QD for 12 to 15 days, 150 mg PO QD for 12 to 15).
This statistical analysis plan (SAP) provides the technical elaboration of the statistical analysis of 
pharmacodynamic (PD), safety and pharmacokinetic (PK) data.
The analyses described in this SAP are based upon the following study documents:

Study Protocol, Version 3.0 (04 July 2022)

electronic Case Report Form (eCRF), D8530C00003 Version 8.0 (Nov 30, 2022)
Specifications for tables, figures and listings are contained in a separate document.
2
STUDY OBJECTIVES
2.1
Primary Objective
Primary Objective:
Endpoint/Variable:
To explore the ER pharmacodynamic effects of 
AZD9833 between pre-
and on-treatment 
tumour samples in women with early breast 
cancer after 5 to 7 consecutive days of AZD9833 
treatment for Stage 1 and 2, and after 12 to 15 
Change from baseline in ER expression between 
pre- and on-treatment tumour samples measured 
by immunohistochemistry (IHC) and assessed 
by the manual H-score method.


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Page 9 of 34
consecutive days of AZD9833 treatment for 
Stage 3.
2.2
Secondary Objectives
Secondary Objectives:
Endpoint/Variables:
To explore the progesterone receptor (PgR) and 
Ki-67 pharmacodynamic effects of AZD9833 
between pre- and on-treatment tumour samples 
in women with early breast cancer after 5 to 7 
consecutive days of AZD9833 treatment for 
Stage 1 and Stage 2, and after 12 to 15 
consecutive days of AZD9833 treatment for 
Stage 3.
Change from baseline in PgR expression 
between pre- and on-treatment tumour 
samples measured by IHC and assessed 
by the manual H-score method. 
Change from baseline in Ki-67 labelling 
index between pre- and on-treatment 
tumour samples measured by IHC.
To evaluate the safety and tolerability of
AZD9833 in this patient population.
Adverse Events (AEs) / Serious Adverse 
Events (SAEs). 
Vital signs.
Electrocardiograms (ECG).
To evaluate the PK effect of AZD9833 in the 
patient population.
Plasma concentrations of AZD9833 on the 
biopsy day.
2.3
Exploratory Objectives
Exploratory Objectives:
Endpoint/Variables:
To assess the effects of AZD9833 in tumour 
tissue on ER, PgR and Ki-67 assessed by image 
analysis of pathological specimens.
Change from baseline in ER and PgR expression 
and Ki-67 labelling index, assessed by image 
analysis after 5 to 7 days of AZD9833 treatment
for Stage 1 and Stage 2; and 12 to 15 days of 
AZD9833 of treatment for Stage 3.
To assess the effects of AZD9833 in tumour 
tissue on ER, PgR and Ki-67 in patient 
subgroups including, but not limited to, baseline 
(pre-surgical) Ki-67 expression and 
 
Change from baseline in ER, PgR, and Ki-67, as 
assessed by manual and computerized methods 
after 5 to 7 days of AZD9833 for Stage 1 and
Stage 2; and 12 to 15 days of AZD9833 
treatment for Stage 3 in patients according to 
other baseline characteristics, for example 
To assess the effects of AZD9833 on ER 
expression and PgR expression in tumour tissue, 
based on alternative methods of analysis, such 
as, but not limited to, Western blot and mass 
spectrometry methods.
Change from baseline in ER and PgR 
expression, based on alternative methods of 
analysis such as, but not limited to, Western blot 
and mass spectrometry methods.
To assess the effects of AZD9833 on messenger 
ribonucleic 
acid 
(mRNA)
expression 
of 
Change from baseline in mRNA expression of 
ESR1 and a panel of oestrogen-regulated genes 
CCI
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Page 10 of 34
oestrogen receptor 1 (ESR1) and a panel of 
oestrogen-regulated genes in tumour tissue.
after 5 to 7 days of AZD9833 treatment for 
Stage 1 and Stage 2; and 12 to 15 days of 
AZD9833 treatment for Stage 3.
To assess the effects of AZD9833 on other 
tumour biomarkers including deoxyribonucleic 
acid (DNA), mRNA or proteins in tumour tissue.
Change from baseline in tumour tissue markers 
and circulating biomarkers, such as tumour 
DNA, mRNA, proteins or immune biomarkers 
(e.g. autoantibodies).
To explore the relationship between AZD9833 
plasma exposure and changes in tumour tissue 
markers and circulating biomarkers such as 
tumour DNA, mRNA, proteins or immune 
biomarkers (e.g. autoantibodies). 
PK/PD modelling of AZD9833 plasma exposure 
and changes in tumour tissue markers and 
circulating biomarkers such as tumour DNA, 
mRNA, proteins, or immune biomarkers.
To collect and store plasma and serum samples 
for possible retrospective exploratory biomarker 
analysis which may include, but will not be 
limited to, understanding mechanisms of 
response to treatment (where response is defined 
broadly 
to 
include 
biomarker 
change, 
tolerability, or safety). This may include the 
analysis of tumour-specific and circulating 
biomarkers such as tumour DNA, proteins, 
antibodies or metabolites.
Results from future exploratory biomarker 
analysis may be reported outside of the clinical 
study report (CSR).
To collect and store DNA for future exploratory 
research into genes/genetic variation that may 
influence response (i.e., distribution, safety, 
tolerability and efficacy) to AZD9833 and/or 
susceptibility to breast cancer. 
Results from future exploratory research may be 
reported outside of the CSR.
All exploratory endpoints will be reported outside of the CSR and are therefore not described further 
within this SAP.
3
INVESTIGATIONAL PLAN
3.1
Stage 1
After the screening visit and confirmation of eligibility, patients will be randomly assigned in a 1:1 
ratio to receive one of the following two treatments for 5 to 7 days: 
Group 1: AZD9833 75 mg once daily (n = 12 evaluable post-menopausal patients)
Group 2: AZD9833 150 mg once daily (n = 12 evaluable post-menopausal patients)
During the treatment period the patients will attend visits on:
Day 1
Day 5, 6 or 7 for an on-treatment imaging-guided biopsy
Day of surgery (following a washout period of at least 5 days after taking the last dose of 
AZD9833 on Day 5, 6 or 7, the patients will undergo curative-intent surgery i.e. study day ≥ 
11)


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28 day safety follow-up (after last dose of the study treatment for AZD9833)
The general study design of Stage 1 is summarised in Figure 1
Figure 1 : Study Design Stage 1
3.2
Stage 2
After the screening visit (up to 21 days prior to randomisation) and confirmation of eligibility, patients 
will be randomly assigned in a 1:1 or 1:1:1 ratio to receive one of the following two or three treatments 
(based on the geographical stratification factor) for 5 to 7 days:
Group 1: AZD9833 (75 mg, PO, once daily for 5 to 7 days; approximately 24 evaluable 
patients [12 UK])
Group 2: AZD9833 (150 mg, PO, once daily for 5 to 7 days; approximately 24 evaluable
patients [12 UK])
Group 3: AZD9833 (300 mg, PO, once daily for 5 to 7 days; approximately 12 evaluable 
patients)
During the treatment period, patients will attend study visits on:
Day 1
Day of biopsy (Day 5, 6 or 7)
Day of surgery (following a washout from AZD9833 for at least 5 days; ie if AZD9833 was 
taken for the last time on morning of Day 5, then Days 6, 7, 8, 9 and 10 are washout days and 
surgery can be scheduled for Day 11 onwards).  In the event that a patient is undergoing 
longer-term neoadjuvant therapy rather than surgery, the ‘surgery day’ visit should be 
conducted on Day 13 (+ 3 days)  
28 day safety follow-up (after last dose of the study treatment for AZD9833)
A treatment window of 5 to 7 days, along with a washout period of 5 days is considered to permit 
curative intent surgery within existing standard of care timeframes.
The general study design of Stage 2 is summarised in Figure 2.


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Figure 2: Study Design Stage 2
3.3
Stage 3
The SDMC has advised that an additional Stage 3 will evaluate the biological effects of AZD9833 
with longer duration of AZD9833 treatment (12 to 15 days) at doses of 75 and 150 mg once daily.
After the screening visit (up to 21 days prior to randomisation) and confirmation of eligibility, patients 
will be randomly assigned in a 1:1 ratio to receive one of the following two treatments for 12 to 15
days:
Group 1: AZD9833 (75 mg, PO, once daily for 12 to 15 days; approximately 24 evaluable 
patients).
Group 2: AZD9833 (150 mg, PO, once daily for 12 to 15 days; approximately 24 evaluable 
patients).
During the treatment period, patients will attend study visits on:
Day 1
Day 7
Day of biopsy (Day 12, 13, 14 or 15)
Day of surgery (following a washout from AZD9833 for at least 5 days; ie if AZD9833 was 
taken for the last time on morning of Day 12, then Days 13, 14, 15, 16 and 17 are washout 
days and surgery can be scheduled for Day 18 onwards).  In the event that a patient is 
undergoing longer-term neoadjuvant therapy rather than surgery, the ‘surgery day’ visit 
should be conducted on 6th day following the last dose of AZd9833 (with a +3 day window).
28 day safety follow-up (after last dose of the study treatment for AZD9833)
The general study design of Stage 3 is summarised in Figure 3


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Figure 3: Study Design Stage 3
3.4
End of Study
The end of study is defined as the last expected visit or contact of the last patient undergoing the 
study. A patient is considered to have completed the study when she has completed the 28-day follow-
up visit after discontinuation of study treatment.
3.5
Planned Analysis
The study is open-label, and so all AstraZeneca (AZ) and Parexel (PXL) team members involved in 
this study will be unblinded throughout. The details of the analyses planned during the conduct of 
this study are outlined in Table 1.
Table 1: Summary of Analyses during Study Conduct
Analysis
Trigger/Timepoint
Data included
End of Stage 1: Review by 
the SDMC
Upon completion of Stage 1 and 
availability of IHC data. 
Data from Stage 1, including:
Primary endpoint 
Key secondary endpoints
Key safety data
Interim analysis Stage 2 
Upon study completion of all 
patients recruited from Georgia
and Mexico  
Key data from Stage 1 and Stage 
2, to include approximately 60 
patients 
from 
Georgia 
and 
Mexico, and any available data 
from the UK patient population.  
Data to include: 
Primary endpoint 
Key secondary endpoints
Key safety data
Final Stage 3 analysisa
Upon study completion of all 
patients recruited from   Georgia 
and Mexico  
Key data from Stage 3, to include 
approximately 48 patients from 
Georgia and Mexico, and any 
available data from the UK 
patient population.  Data to 
include: 
Primary endpoint 


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Key secondary endpoints
Key safety data
Final analysis and CSRa
Following completion of the 
study and final database lock
All data from Stage 1, Stage 2 and 
Stage 3
a In the event that UK stage 2 completes ahead of stage 3, a UK stage 2 specific interim analysis may be performed; 
Final stage 3 analysis and final analysis may be combined if appropriate
4
STATISTICAL METHODS
4.1
Data Quality Assurance
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Parexel procedures.
4.2
General Data Presentation Characteristics
The data from all countries and stages will be combined and reported together. Stage 1 and Stage 2 
data combined and Stage 3 data alone will also be reported separately. All data will be summarised
by treatment group and timepoint. 
Continuous data will be summarised using descriptive statistics (the number of patients [n], mean, 
standard deviation [SD], median, 25th and 75th percentiles [where appropriate], minimum and
maximum unless otherwise stated). For log-transformed data it is more appropriate to present 
geometric mean (gmean), geometric coefficient of variation (CV), median, minimum and maximum.
For continuous data, the mean, median and gmean will be rounded to one additional decimal place 
compared to the original data. The SD and geometric CV will be rounded to two additional decimal 
places compared to the original data. Minimum and maximum will be displayed with the same 
accuracy as the original data. The maximum number of decimal places reported will be four for any 
summary statistic.
Categorical data will be summarised in terms of the number of patients providing data at the relevant 
time point (n), frequency counts and percentages. Percentages will not be presented for zero counts.
Unless otherwise stated, percentages will be calculated using the number of patients included in the 
analysis set for that treatment group as denominator and presented to one decimal place.
Confidence intervals (CIs), when presented, will generally be constructed at the 2 sided 80% level.
CIs will be presented to one additional decimal place compared to the original data.
For safety, PD, and PK endpoints the last observation prior to the first dose of study treatment will 
be considered the baseline measurement unless otherwise specified. For assessments on the day of 
first dose where time is not captured, a nominal pre-dose indicator, if available, will serve as evidence 
that the assessment occurred prior to first dose. Assessments on the day of first dose where neither 
time nor a nominal pre-dose indicator are captured will be considered prior to first dose if such 
procedures are required by the protocol to be conducted before first dose.
Any information taken after first dose/administration of study medication will be regarded as post 
baseline information. If two visits are equally eligible to assess patient status at baseline (e.g., 
screening and baseline assessments both on the same date prior to first dose/administration), the 
average should be taken as the baseline value. For non-numeric laboratory tests (i.e. some of the 
urinalysis parameters) where taking an average is not possible then the best value will be taken as 
baseline as this is the most conservative. Where safety data are summarised over time, study day will 
be calculated in relation to date of first treatment. If no value exists before the first dose/administration, 
then the baseline value will be treated as missing.


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In all summaries:
Change from baseline = post-baseline value - baseline value. 
Percent change from baseline = (post-baseline value - baseline value)/baseline value × 100
For any variable subject to log transformation, the back transformed change from baseline, calculated 
and summarised on the log scale, will be presented as ‘baseline scaled ratio’ (BSR). Percentage 
change will then be calculated as (BSR – 1) x 100.
4.3
General Variables
4.3.1
Study Day Definitions
Study day 1 is defined as the date of first dose of study treatment.
For visits (or events) that occur on or after first dose of study treatment:
Study day = Date of visit [event] – Date of first dose of study treatment + 1.
For visits (events) that occur prior to first dose:
Study day = Date of visit [event] – Date of first dose of study treatment.
There is no study day 0 defined for this study.
For listings (such as AEs) that include the derivation “Days since last dose”, days will be defined as:
Days since last dose = Event date – Date of last dose.
Where “Date of last dose” is defined as the date of dosing immediately preceding the event 
occurrence. Events that occur on the same day as the last dose of study treatment will therefore be 
described as occurring zero days from last dose of study treatment.
All visit-based summaries will use eCRF visits as shown in Table 2. There won’t be any visit 
windowing defined for on-treatment visits for this study. If there is more than one value per patient 
within an analysis visit then the closest value to the intended visit date will be summarised, or the 
earlier, in the event the values are equidistant from the protocol intended visit date. The 28th day 
safety follow-up is from the last day of dose administration of AZD9833. Any adverse event and 
concomitant medication data collected after the last dose of study treatment until 28 ± 3 days will be 
included in the relevant summaries. For summaries of the minimum or maximum observed value 
whilst on treatment, all data recorded at any time point (including unscheduled visits) will have the 
potential to be summarised. All results will be presented by treatment group and by visit with 
descriptive statistics appropriate to the nature of the variables.
Table 2: Analysis visit mapping
For Stage 1 and Stage 2
eCRF visit 
Protocol visit
Protocol visit window
Analysis visit 
Visit 1
Screeninga
Day -21 to Day 1 (pre-dose)
Baseline 
Visit 2
First day of dosinga
Day 1 (pre-dose)
Visit 3
Biopsy Day
Day 5, Day 6 or Day 7
Biopsy day
Visit 4
Surgery Day
≥ Day 11
Surgery day
Visit 5
28 Day follow-up after the last 
dose of the study treatment
≥Biopsy Day +25 days to 
≤Biopsy Day +31 days 
Follow-up
a The last non missing value obtained prior to the first dose/administration of study medication will be considered as 
baseline.


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For Stage 3
eCRF visit 
Protocol visit
Protocol visit window
Analysis visit 
Visit 1
Screeninga
Day -21 to Day 1 (pre-dose)
Baseline 
Visit 2
First day of dosinga
Day 1 (pre-dose)
Visit 3
Day 7
Day 7 (+ 3 days)
Day 7
Visit 4
Biopsy day
Day 12, Day 13, Day 14 or 
Day 15
Biopsy day
Visit 5
Surgery Day
≥ Day 18
Surgery day
Visit 6
28 Day follow-up after the last 
dose of the study treatment
≥Biopsy Day +25 days to 
≤Biopsy Day +31 days 
Follow-up
a The last non missing value obtained prior to the first dose/administration of study medication will be considered as 
baseline.
Listings will display all values contributing to a time point for a patient. The values used in the 
summary table for a patient will be highlighted, wherever applicable.
4.3.2
Handling missing data
Missing safety data will not be imputed. 
Missing pharmacodynamics biomarker data will not be imputed since no missing data are expected 
for the primary pharmacodynamics biomarker variables. Patients are required to have evaluable 
paired tumour samples for the primary endpoint by central pathology assessment, patients who don’t 
meet this criterion will be replaced.
In general, other than for the below described, or where otherwise specified in the particular analysis, 
missing data will not be imputed and will be treated as missing.
4.3.2.1
Imputation of Adverse Event and Concomitant Medication Start Date 
Missing day: impute with the 1st of the month unless month and year are same as month and 
year of first dose of study drug then impute first dose date.
Missing day and month: impute with 1st January unless year is the same as first dose date 
then impute first dose date.
Completely missing: impute with date of first dose of study treatment, unless the end date 
suggests it could have started prior to this in which case impute with 1st January of the same 
year as the end date.
When imputing a start date ensure that the new imputed date is sensible i.e. is prior to the end date 
of the AE or medication. 
4.3.2.2
Imputation of Adverse Event and Concomitant Medication End Date
Missing day: impute with the last day of the month, unless month and year are the same as 
month and year of last dose of study treatment, then impute with the last treatment date in that 
month.
Missing day and month: impute with 31st of December unless the year is the same as the year 
of last dose of the study treatment, then impute with the last treatment date of that year. 
Completely missing: assume the event is still ongoing and do not impute any date.
Generally, the imputation of dates is to decide if an observation is treatment emergent for AEs or 
concomitant for medications. Flags will be retained in the database indicating where any 


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programmatic imputation has been applied, and in such cases, durations and study days will not be 
calculated.
4.3.2.3
Imputation of Laboratory Values Outside of Quantification Range
Values of the form of “< x” (i.e., below the lower limit of quantification [LLoQ]) or > x (i.e. above 
the upper limit of quantification [ULoQ]) will be imputed as “x” in the calculation of summary 
statistics but displayed as “< x” or “> x” in the listings. Values of “≤x” or “≥x” will be imputed as 
well. 
4.4
Software
All report outputs will be produced using SAS® version 9.4 or later in a secure and validated 
environment
4.5
Analysis Sets
The Enrolled Analysis Set will include all patients who sign the informed consent form.
The Full Analysis Set (FAS) is defined as all randomised patients, with treatment groups assigned 
in accordance with the randomisation, regardless of the actual treatment received. Patients who are 
randomised, but do not subsequently receive treatment will be included in the FAS. If a patient is 
allocated the incorrect study treatment as per the study randomisation list, patients will be summarised
and analysed ‘as randomised’ i.e., by randomised treatment group.
There will be not statistical analyses of the FAS dataset as the primary endpoint analysis and 
summaries will be based on the PD analysis set.
PD analysis set.
A patient is considered to be evaluable for the PD analysis set if:

the patient has taken a minimum of 5 consecutive daily doses of AZD9833 for Stage 1 and 
Stage 2; and the patient has taken a minimum of 12 consecutive daily doses of AZD9833 for
Stage 3.

the patient received the last dose of AZD9833 within 12 hours of on-treatment biopsy;

the diagnostic and on-treatment biopsy pair are considered evaluable as below:
o
The diagnostic and on-treatment biopsy pair is considered evaluable by central 
pathology assessment, defined as containing > 100 tumour cells in each FFPE biopsy, 
and
o
A minimum of 2 slides to allow measurement of ER

has no protocol deviations that may impact the biomarker analysis.
The PD analysis set will include all patients who have a pair of any of ER, PgR or Ki67 results and 
will show a missing category when no results are available for an individual biomarker. Note that, 
from Stage 1 and Stage 3, all evaluable patients were evaluable for all 3 markers. For all non-
evaluable patients, all were non-evaluable for all 3 biomarkers, e.g. no tumour tissue.
For the PD analysis set, if a patient is allocated the incorrect study treatment as per the study 
randomisation list, patients will be summarised ‘as treated’, i.e., patients randomised to AZD9833 
who received an incorrect AZD9833 dose at the randomisation visit, will be accounted for in the 
treatment group corresponding to the first AZD9833 dose they received.
The Safety Analysis Set is defined as all patients who received any amount of study treatment, 
regardless of whether that was the randomised therapy intended or whether they received therapy 
without being randomised. If a patient is allocated the incorrect study treatment as per the study 


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randomisation list, patients will be summarised ‘as treated’ i.e., patients randomised to AZD9833
who received an incorrect AZD9833 dose at the randomisation visit will be accounted for in the 
treatment group corresponding to the first AZD9833 dose they received. The safety summaries will 
be based on safety analysis set. Safety data will not be formally analysed.
PK summaries will be based on the PK Analysis Set. The PK Analysis Set is defined as all patients 
who received at least one dose of AZD9833 per protocol, for whom there is at least one reportable 
PK concentration. If a patient is allocated the incorrect study treatment as per the study randomisation 
list, patients will be summarised ‘as treated’ i.e., patients randomised to AZD9833 who received an 
incorrect AZD9833 dose at the randomisation visit, will be accounted for in the treatment group 
corresponding to the first AZD9833 dose they received.
Upon database release, protocol deviation and analysis set outputs will be produced and will be sent 
to AZ and the ICI for review. Prior to database lock, an analysis set classification meeting will be 
arranged, involving AZ and the ICI, to discuss the outputs and decide which patients and/or patient 
data will be excluded from certain analyses, these decisions will be documented. A similar review to 
determine PD analysis set classification will take place prior to the production of outputs for the 
SDMC and the Stage 2 interim analysis.
A summary on which analysis set will be used for each outcome variable is provided in Table 3.
Table 3: Summary of Outcome Variables and Analysis Sets
Outcome Variable
Analysis Set
Study Population/Demography Data
Disposition of patients
Enrolled
Demography characteristics
FAS*/Safety
Baseline and disease characteristics
FAS*/Safety
Important protocol deviations
FAS*/Safety
Medical/surgical history
FAS*/Safety
Previous anti-cancer therapy 
FAS*/Safety
Concomitant medications/procedures
Safety
Subsequent anti-cancer therapy
Safety
PK Data
PK concentrations
PK
Pharmacodynamic Data
ER, PgR, Ki-67
PD
Safety**
Safety Data
Exposure
Safety
AEs
Safety
Laboratory measurements
Safety
Vital signs
Safety
ECGs
Safety
ER = oestrogen receptor; FAS = Full Analysis Set; PgR = progesterone receptor; PK = pharmacokinetic.
*Summary will be provided for safety analysis set; listings will be produced for the FAS analysis set.
**Pharmacodynamic data summaries will be based on PD analysis set, but listings will be provided for safety analysis set


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4.6
Study Patients
4.6.1
Disposition of Patients
Patient disposition will be summarized by treatment group for all patients byStage 1 and Stage 2 
combined, Stage 3 alone and by stages 1, 2 and 3 combined. Important protocol deviations and
analysis sets will be tabulated using the safety analysis set (see Section 4.5). The number and
percentages of patients will be presented for the following categories: 

All enrolled

Randomised to study treatment

Not randomised to study treatment (and reason)

Received study treatment

Did not receive study treatment (and reason)

Completed study treatment 

Discontinued from study treatment (and reason)

Completed study 

Prematurely withdrawn from study (and reason).
The number of patients recruited in each country and each centre will be presented by treatment group 
and total.
Additional listings and summaries on patients affected by the COVID-19 pandemic will also be 
presented.
4.6.2
Protocol Deviations
Important protocol deviations are defined as those deviations from the protocol likely to have a large 
impact on the interpretation of any analysis based on addressing the primary and secondary objectives 
of the trial.
The following general protocol deviation categories will be programmatically derived from the 
electronic case report form (eCRF) data. These deviations will be reviewed and assessed on a case-
by-case basis by the study team to determine importance. Deviations considered to be important will 
be listed and discussed in the CSR as appropriate. All decisions on importance will be made ahead of 
database lock and will be documented prior to the analysis being conducted. Deviations will include, 
but are not limited to: 

Patients who deviate from inclusion /exclusion criteria per the Clinical Study Protocol (CSP) 
(Deviation 1).

Patients who fail to sign the correct informed consent form, except the genetic informed 
consent form, before randomisation (Deviation 2).

Patients whose baseline safety assessments as per CSP are missing (Deviation 3).

Patients who received prohibited medications during the study (Deviation 4). Refer to the CSP 
Section 6.5 for those medications that are detailed as being ‘excluded’ from permitted use 
during the study. This will be used as a guiding principle for the physician review of all 
medications prior to database lock.

Patients who don’t have a baseline biopsy (Deviation 5).

Patients who don’t have an on-treatment biopsy (Deviation 6).

Patients randomised who received an incorrect dose to that which they were randomised to 
(Deviation 7).

Received AZD9833 and had an on-treatment biopsy more than 12 hours after last AZD9833 
dose (Deviation 8).


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
Pre- or on-treatment FFPE samples contain ≤ 100 tumour cells (Deviation 9).

No on-treatment FFPE blocks provided (Deviation 10).

Received AZD9833 and had an on-treatment biopsy without a minimum of 5 consecutive 
dosing days (Deviation 11).

A minimum of 2 slides are not available from either the baseline or on-treatment biopsy
(Deviation 12).
The following will be checked for analysis purposes and will not be included as part of the deviations 
to be recorded in the protocol deviations log during the study:

Patients randomised but who did not receive any study treatment (Deviation 13).

Patient vomits on the day of PK sampling and within 8 hours of AZD9833 dosing (Deviation 
14). These will be reviewed on a case-by-case basis to determine whether any exclusion from 
the PK analysis set is deemed necessary.

Non-invasive tumour biopsy scorings (Deviation 15).
Patients who received the wrong treatment at any time will be included in the analysis set as described 
in Section 4.5. During the study, decisions on how to handle errors in treatment dispensing (with 
regards to continuation/discontinuation of study treatment or, if applicable, analytically) will be made 
on an individual basis with written instruction from the study team leader and/or statistician.
Important protocol deviations will be listed and summarised by randomised treatment group. 
Important protocol deviations related to COVID-19 will be summarised separately.
Table 4: Summary of Deviations and Actions
Deviation
Action
Deviation 13
Exclusion from the Safety Analysis Set
Deviations 5, 6, 8-11 and 12
Patient becomes non-evaluable and to exclusion from the PD 
analysis set
Deviation 15
Exclusion of non-invasive tumour biopsy scorings from analysis
Other/further deviations
Will not lead to patients being excluded from the analysis sets 
described in Section 4.5 unless the deviation is considered to 
impact upon pharmacodynamic data. Non-evaluable patients 
will be replaced.
A per-protocol analysis excluding patients with specific important protocol deviations is not planned, 
however a sensitivity analysis may be performed on the key PD endpoints if > 10% of patients in any 
treatment group have any other significant deviation deemed to affect the primary endpoint which 
haven’t already led to exclusion from the PD analysis set.
The need for such a sensitivity analysis will be determined following review of the protocol 
deviations ahead of database lock and will be documented prior to the analysis being conducted.
In addition to the programmatic determination of deviations above, other study deviations captured 
from the eCRF module for inclusion/exclusion criteria will be tabulated and listed. Any other 
deviations from monitoring notes or reports will be reported in an appendix to the CSR.
A full list of protocol deviations can be found in the study-specific Protocol Deviation Specification.
4.6.3
Demographic and Other Baseline Characteristics
No formal statistical analysis of baseline data will be provided for this study. Demographic and other 
baseline disease characteristics will be summarised and listed by treatment group for all patientsby


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Stage 1 and Stage 2 combined, Stage 3 alone, and  by Stages 1, 2 and 3  combined in the safety 
analysis set as follows:

Demographics (age [years], age group[<50; 50-59; 60-69; ≥ 70], sex [only female patients are
expected in this study], race and ethnicity).

Patient characteristics at baseline (height [cm], weight [kg], and body mass index [BMI] 
[kg/m2]).

Previous non-breast related treatment modalities.

Disease characteristics at baseline (Eastern Cooperative Oncology Group [ECOG] 
performance status, primary tumour location (breast), histology type, tumour grade, tumour 
stage /AJCC stage, receptor status [ER/PgR/Ki67/HER2]).

Tumour, node and metastasis (TNM) classification at baseline.

Neurological assessment (listed only).

Time from diagnosis of primary breast cancer to randomisation.
4.7
Medical and Surgical History
Disease related medical history and relevant surgical history will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). All disease related medical history (past and 
current) will be listed and the number and percentage of patients with any disease related medical 
history will be summarised for the safety analysis set by system organ class (SOC) and preferred term 
(PT).
All relevant surgical history will be listed and summarised similarly.
4.8
Concomitant Medications and Treatment
Information on any treatment that the patient is receiving at the time of enrolment and all concomitant 
treatments given up to 28 days after discontinuation of study treatment, with reasons for the treatment
will be recorded in the eCRF. Any form of anti-cancer treatments, investigational agents, disallowed 
medications and radiotherapy should not be given while the patient is on study treatment. See 
Section 6.5 of CSP for a list of prohibited medications and anti-cancer treatments.
Treatments (including surgery), received prior to, concomitantly, or post-treatment will be coded 
using the Word Health Organisation (WHO) Drug Dictionary (WHODD) Anatomical Therapeutic 
Chemical (ATC) classification codes. Concomitant medications will be summarised for the safety 
analysis set by ATC classification codes.
For the inclusion in prior and/or concomitant medication or treatment summaries, incomplete 
medication or treatment start and stop dates will be imputed as detailed in Section 4.3.2.1 and
Section 4.3.2.2.

Prior medications are those taken prior to study treatment with a stop date prior to first dose 
of study treatment.

Concomitant medications are those with a stop date on or after the first dose date of study 
treatment (and could have started prior to or during treatment).

Post treatment medications are those with a start date after the last dose date of study 
treatment.
The following summaries will be produced:

Cancer therapies prior to this study.

Disallowed concomitant medications (as identified during physician review described in
Section 4.6.2, deviation 4).


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
Allowed concomitant medications.

Concomitant procedures.

Post-discontinuation cancer therapy.
The number and percentage of patients who took any previous cancer treatments will be summarised 
by therapy class (i.e. immunotherapy, hormonal therapy, cytotoxic chemotherapy, systemic therapy 
and other). The prior cancer (non-breast) therapy regimens will be listed.
Listings of prior, concomitant and post treatment medications, will be provided; and the timing of the 
medications will be marked clearly as ‘prior’, ‘concomitant’ or ‘post’.
4.9
Curative intent surgery
Curative intent surgery details will be listed. If the reasons for no surgery/delay in surgery for a 
patient is not collected on CRF, data management lead will provide the reasons in a separate MS 
Excel sheet after contacting study sites, which will subsequently be reviewed and approved by
study medical monitor. This excel sheet will be used for curative intent surgery listings and excel 
sheet will be filed in the TMF at the end of the study. 
4.10 Pharmacodynamic Evaluation
Biopsy samples will be sectioned and assessed for tumour content. Pathologist scoring for ER, PgR 
and Ki-67 expression will be carried out at a contracted external good clinical practice (GCP) 
accredited laboratory. Sections will be scored for ER, PgR and Ki-67 expression in tumour by a 
contracted independent pathologist who will be blinded to treatment groups.
For patients where more than one tumour block has been provided for a single timepoint, a weighted 
mean score based on the percentage (%) of tumour cells in each section will be used as the score for 
that timepoint. Non-invasive tumour biopsy scorings will be excluded from the PD summaries and 
listings. 
For example: If i=1, 2, 3 …n is the number of tumour blocks provided for a single patient for a 
particular tumour assessment visit; and the sample has corresponding percentage tumour tissues ti
and H-scores hi (total H-score for ER and PgR expressions, and percentage tumour cells with positive 
nuclei for Ki-67 expression), then the weighted mean score for that patient for that particular visit is 
calculated as follows:
∑


∑


	
  ℎ


   where i=1,2, 3….n
The weighted mean score will be used as is in the analyses, where the score will be rounded off to 
the nearest integer before presenting in the summary tables.
Pathology scoring will be summarised and listed by treatment group for all patients by Stage 1 and 
Stage 2 combined, Stage 3 alone, and  by Stages 1, 2 and 3  combined by actual treatment group and 
by visit.
The receptor status will be listed for safety analysis set by ER and PgR total H-score, Ki67 labelling 
index, and HER2 IHC positive staining.
4.10.1 ER and PgR
ER and PgR expression will be determined by the percentage of positively stained tumour nuclei in 
each staining category, i.e., negative ‘-/-’, weak ‘+’, moderate ‘++’, strong ‘+++’. The sum of the 


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percentages of these 4 staining categories will be 100%. Then, ER and PgR expression will be 
assessed using the following manual H-score method, which yields to a manual H-score range of 0 
to 300.
H-score = (1 * % of +) + (2 * % of ++) + (3 * % of +++).
When a biopsy contains only 0-100 tumour cells, then H-score is not reported and not evaluable (NE) 
will be stated.
The primary and secondary pharmacodynamic biomarker variables of percentage change from 
baseline in ER and PgR expressions after 5 to 7 days of AZD9833 treatment for Stage 1 and Stage 2; 
and after 12 to 15 days of AZD9833 treatment for Stage 3 will be listed and summarised based on the 
PD analysis set (see Section 4.5).
The primary objective of the study will be assessed using percent change in ER expression, however 
data will be summarised and analysed for the percent change and absolute change from baseline, and 
will also be analysed based on the log transformed values. This is to ensure comparability with the 
different methods of reporting used within the literature. For all summaries and analyses, baseline 
values equal to zero will be set to one and corresponding biopsy day ER expression value will be 
incremented by 1. The same will hold for the reporting of PgR expression. For listings, original values 
will be reported. 
For percent change in ER, and PgR expression, if data permits, three separate analyses of covariance 
(ANCOVA) models will be fitted, one utilizing data from stage 1 and 2 only (5-7 days exposure), 
one utilizing data from stage 3 only (12-15 days exposure) and one utilizing data from all stages
combined with on-treatment biomarker expression score as a dependent variable, baseline expression 
score as a covariate, and day of biopsy and treatment group as fixed effects.
An exploratory analysis utilizing data from all stages may also be performed with on-treatment 
biomarker expression score as a dependent variable, baseline expression score as a covariate, day of 
biopsy and treatment group as fixed effects and an interaction between day of biopsy and treatment 
group. Other covariates such as stage and country may be explored as well as interactions between 
covariates.
Least squares means (LS-means) estimates of the treatment effect will be calculated together with 
80% CIs for all treatment durations (5 to 7 consecutive days of AZD9833 treatment for stage 1 and 
stage 2, and 12 to 15 consecutive days of AZD9833 treatment for stage 3), as per the model fitted.
To calculate the percentage change, mean changes from baseline will be converted to percentage of 
initial staining by dividing mean changes by the overall mean score at baseline (Robertson et al 2013).
The three ANCOVA models will be repeated based on the absolute change from baseline.
If the distribution of ER and PgR expressions manual H-score is normal, these data will be analysed 
as described previously and this will form the primary analysis. If data does not adequately follow a 
normal distribution, then the use of the natural log transformed data (i.e., ratio) will replace the 
untransformed analysis as the primary approach. Log transformed ANCOVA analyses will be 
produced including the same covariates as specified for the untransformed analyses, but with the log 
transformed baseline value replacing the untransformed value. The estimated treatment effect and its 
80% CIs will be back transformed to the original scale prior to reporting. The values equal to zero 
(0) on the original scale will be set to 1, and corresponding baseline / biopsy day expressions scores 
will be incremented by 1 before natural log transformation.
The normality of the distribution of the data will be tested using a Shapiro-Wilk test. In case of a two-
sided p-value > 0.20, there will be evidence that the data is normally distributed. Additional plots and 


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statistics will be provided to measure the severity of the deviations from normality if 
necessary.Sensitivity analyses for ER and PgR
If necessary, the following sensitivity analysis will be conducted on a subset of the PD analysis set
by excluding:
From ER analysis 

Any patients who are HER2 positive by central assessment.

Any patients with an ER H-score < 10 on their pre-treatment biopsy.
From PgR analysis

Any patients who are considered to be HER2 positive by central assessment.

Any patients with a PgR H-score < 10 on their pre-treatment biopsy.
If considered necessary, further cuts and sensitivity analyses may be performed. 
If following transformation of the data an ANCOVA model is still not appropriate, a non-parametric 
approach may be considered.
4.10.2 Ki-67 Labelling Index
Ki-67 labelling index will be assessed and expressed as the average percentage of tumour cells with 
counted positive nuclei, following the International Ki-67 in Breast Cancer Working Group 
Recommendations. Ki-67 labelling index will be scored by increments of 1% and can range from 0 
– 100. When the number of tumour cells per section for a counted biopsy is less than 100 tumour 
cells, then the Ki-67 labelling index is not reported and NE will be stated.
The secondary pharmacodynamic biomarker variables of change from baseline in Ki-67 labelling 
index after 5 to 7 days of AZD9833 treatment for Stage 1 and Stage 2; and after 12 to 15 days of 
AZD9833 treatment for Stage 3 will be listed and summarised based on the PD analysis set (see 
Section 4.5).
It is expected that the distribution of the Ki-67 labelling index data will not be normally distributed 
(Robertson et al 2013, Robertson et al 2020b), hence Ki-67 labelling index data will be naturally log-
transformed before being analysed. Ki-67 will be analysed similarly to ER and PgR, using a 
parametric ANCOVA on natural log transformed data. Values equal to zero on the original scale will 
be set to one (1), and one will be added to the corresponding baseline/biopsy day labelling index 
value before natural log transformation. Log transformed baseline score will be included as a 
covariate, and day of biopsy and treatment group included as fixed effects. The estimated treatment 
effect together with 80% CIs for all treatment durations (5 to 7 consecutive days of AZD9833 
treatment for stage 1 and stage 2, and 12 to 15 consecutive days of AZD9833 treatment for stage 3), 
as per the model fitted will be back transformed to the original scale for reporting. For listings, 
original values will be reported.
Sensitivity analyses for Ki-67 labelling index
If necessary, sensitivity analysis will be conducted on a subset of the PD analysis set by excluding:

Any patients who are considered to be HER2 positive by central assessment.

Any patients with a Ki-67 labelling index < 5% from their pre-treatment biopsy.

Any patients with an ER H-score < 10 on their pre-treatment biopsy.

Any patients with an ER H-score < 10 on their pre-treatment biopsy or any patients with 
a Ki-67 labelling index < 5% from their pre-treatment biopsy.
If considered necessary, further cuts and sensitivity analyses may be performed.


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If, following transformation of the data, an ANCOVA model is still not appropriate, a non-parametric 
approach may be considered.
4.11 Safety Evaluation
All safety summaries will be based upon the Safety Analysis Set and presented for all patients by 
Stage 1 and Stage 2 combined, Stage 3 alone and Stages 1, 2 and 3 combined by actual treatment 
group.
4.11.1 Extent of Exposure 
Extent of exposure for AZD9833 will be defined in terms of the number of days the treatment is 
received.
Exposure (i.e., duration of treatment) will be defined as follows:
Total exposure = min (last day of dosing, date of death, date of withdrawal) – first dose date + 1.
Actual exposure = total exposure of study treatment – total duration of dose interruptions
where total exposure will be calculated as above, and a dose interruption is defined as any length of 
time (number of days) where the patient has not taken any of the planned daily dose. This should be 
taken from the patient diary cards. 
RDI is defined as the percentage of the actual dose delivered relative to the intended dose through to 
treatment discontinuation. Relative dose intensity will be calculated as follows:
RDI(%)=
d
D ×100, 
where 
d 
the actual cumulative dose delivered (which will be taken from the patient diary card)
D 
the intended cumulative dose (duration of intended dose will be calculated from Day 1 to the 
planned biopsy day. D is the total dose that would have been delivered if there were no 
modification to dose or schedule).
If a patient permanently discontinues study treatment, then the date of last administration of study 
medication recorded on eCRF will be used to program the RDI. If a patient permanently discontinues 
study treatment during a treatment interruption, then the date of last administration of study 
medication recorded on the eCRF will be used to program the RDI.
Summaries
The exposure data will be summarised and listed for the safety analysis set including all data from 
the diary card (see Section 4.5).
For AZD9833 treatment groups, actual treatment duration, total treatment duration, RDI, and the 
number and percentage of patients that received at least 5 consecutive days of dosing for Stage 1 and 
Stage 2; and at least 12 consecutive days of treatment for Stage 3 will be summarised. In addition, 
the number and percentage of patients who received the planned starting dose of AZD9833, with no 
interruption, with dose interruption or discontinuation and with both dose interruption and 
discontinuation will be presented. Reason for dose interruption and dose discontinuation will also be 
summarised. 


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4.11.2 Adverse Events
AEs and SAEs will be collected throughout the study from date of informed consent until the end of 
the safety follow-up period (28 days after last dose of study treatment). The latest version of MedDRA
will be used to code the AEs. AEs will be graded according to the National Cancer Institute of 
Common Terminology Criteria for AEs (CTCAE) version 5.0. 
Events will be defined as treatment-emergent AEs, and reported in the summary tables if they onset 
or worsen (by investigator report of a change in CTCAE grade), during the treatment period as defined 
in the CSP or during the 28-day safety follow-up period. Any events in this period that occur after a 
patient has received further therapy for cancer (following discontinuation of study treatment) will be 
flagged in the data listings.
During the evaluation of the AE data prior to database lock, an AZ medically qualified expert will 
review the list of AEs that were not reported as SAEs and AEs leading to discontinuation of study 
treatment. Based on the expert’s judgment, significant AEs of particular clinical importance may, 
after consultation with the Global Patient Safety Physician, be considered other significant AEs 
(OAEs) and reported as such in the CSR. A similar review of laboratory/vital signs/ECG data will be 
performed for identification of OAEs.
Examples of these could be marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction or 
significant additional treatment.
Some clinical concepts (including some selected individual preferred terms and higher-level terms) 
are considered to be “AEs of special interest” (AESIs). AESIs represent pre-specified risks that are 
considered to be of importance to a clinical development program. These AESIs, if applicable, will 
be identified as a list of categories provided by the patient safety team.
Reviews will take place prior to database lock to determine whether any AE should be classified as 
AESIs. The review will identify which higher-level terms, and which preferred terms should 
contribute to each AESI.
In general, all AE summary tables include only TEAEs. AEs occurring prior to dosing or starting 
more than 28 days after discontinuation of study drug will be flagged in listings and will not be
included in any summaries.
All reported AEs will be listed along with the actual treatment received at the time of onset, date of 
onset, date of resolution (if AE is resolved), investigator’s assessment of CTCAE grade, relationship 
to study treatment, action taken and outcome. Frequencies and percentages of patients reporting each 
preferred term will be presented (i.e., multiple events per patient will not be accounted for, except for 
event level summaries).
Summaries of adverse events (the number and percentage of patients by treatment) by MedDRA 
System Organ Class (SOC) and Preferred Term (PT) will include but are not limited to:

All AEs

All AEs possibly related to study treatment

AEs of CTCAE grade 3 or higher

AEs of CTCAE grade 3 or higher, possibly related to treatment

AEs with outcome of death

All SAEs

All SAEs possibly related to study treatment

AEs leading to discontinuation of treatment


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
AEs leading to discontinuation of treatment, possibly related to treatment

SAEs leading to discontinuation of treatment

SAEs leading to discontinuation of treatment, possibly related to treatment

Other significant AEs (if applicable)

AESIs (if applicable)
An overall summary of the number and percentage of patients in each of the above categories will be 
presented, as well as an overall summary of number of events in each of the above categories. In 
addition, a truncated AE table of most common AEs, showing all events that occur in at least 5% of 
patients overall will be summarised by PT, by decreasing frequency.
Additionally, an event level summary will be presented for all AEs by PT.
Summaries of the number and percentage of patients with AEs will also be produced by maximum 
reported CTCAE grades, SOC and PT.
All AESI PTs, if applicable, searched for in this study will be presented. Summaries of AESIs will 
be presented by maximum reported CTCAE grade, by AE outcome, including time of resolution (on-
treatment, follow-up or post-treatment), whether treatment was received (yes/no) and action taken.
In addition, AEs with outcome death, SAEs, AEs leading to discontinuation of treatment and OAEs 
will be listed separately.
Covid-19 AEs will also be collected and reported by MedDRA System Organ Class.
4.11.3 Deaths
A summary of deaths will be provided with number and percentage of patients, categorised as:

Related to disease under investigation only

AE outcome = death only

Both related to disease under investigation and with AE outcome = death

Other deaths.
A corresponding listing will also be produced.
4.11.4 Clinical Laboratory Evaluation
All laboratory results collected will be listed.
Summaries for safety laboratory will only include the parameters specified in Table 5.
All values will be classified as low (below range), normal (within range), or high (above range) based 
on local laboratory reference ranges. Results will be converted to standard units and graded with 
CTCAE version 5.0.
Table 5: Laboratory safety variables
Haematology (whole blood)
Clinical chemistry (serum or plasma)
B-Haemoglobin
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total (TBL)
B-Haematocrit
S/P-Conjugated bilirubin
B-Red blood cell count
S/P-Unconjugated bilirubin
B-Leukocyte differential count (absolute count)
S/P-Alkaline phosphatase (ALP)
Neutrophils
S/P-Aspartate transaminase (AST)
Lymphocytes
S/P-Alanine transaminase (ALT)
Monocytes
S/P-Creatine kinase (CK)


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If the same parameter is found as measured in serum and in plasma, then the summaries will not 
distinguish between them (e.g., values from plasma albumin and serum albumin will be summarised 
under albumin). If the same parameter is found as measured in serum and in plasma within the same 
patient, which would be a rare case, then the change from baseline will only be calculated for those 
post-baseline values using the same source, i.e., only within plasma or serum. If one patient has 
multiple toxicity grades, because they are derived separately from serum and plasma then the 
maximum value of the two will be considered.
Corrected calcium will be calculated as:
Corrected calcium (mg/dL) = 0.8 × (normal albumin - patients albumin) + total serum calcium
or
Corrected calcium (mmol/L) = 0.02 × (normal albumin - patients albumin) + total serum calcium
depending on the unit used.
For all continuous laboratory assessments, absolute value, change from baseline and percentage 
change from baseline will be summarised using descriptive statistics at each scheduled assessment 
time by actual treatment group.
For clinical chemistry and haematology, shift tables will present movements from baseline to worst 
value on-treatment (defined from start of treatment to biopsy day) according to reference range 
classification. CTCAE grade changes from baseline to on-treatment will also be provided.
Corresponding shift tables (“Negative”, “Trace”, “Positive”, “0”, “+”, “++”, “+++”) will be produced 
for urinalysis. In addition, the number of patients with ≥ 2 CTCAE grade changes and CTCAE grade 
changes to 3 or 4 will be summarised by actual treatment group for clinical chemistry and 
haematology parameters.
Plots for both maximum post-baseline alanine transaminase (ALT) and aspartate transaminase (AST)
versus the maximum post-baseline total bilirubin (expressed as multiples of their upper limit of 
normal [ULN] reference range) will be produced with reference lines at 3 x ULN for ALT and AST 
and 2 x ULN for total bilirubin. Box plots of absolute values and change from baseline values for all 
haematology and clinical chemistry parameters will also be presented.
Liver biochemistry test results over time for patients who show elevated ALT or AST (≥ 3 x ULN) 
and elevated bilirubin (≥ 2 x ULN) (elevated results do not need to be present at the same visit) or 
ALT or AST of ≥ 5 x ULN, will be tabulated and plotted.
4.11.5 Physical Examination findings
A complete physical examination will be performed at screening; all data will be listed.
Basophils
S/P-Albumin
Eosinophils
S/P-Calcium, total
B-Platelet count
S/P-Potassium
Coagulation Parameters
S/P-Sodium
Prothrombin time (PTT)
S/P-Glucose
Activated partial thromboplastin time
S/P-Magnesium
International normalised ratio
S/P-Phosphate
Urinalysis (dipstick)
S/P-Urea or Urea nitrogen
U-Glucose
S/P-Protein, total
U-Protein
S/P-Troponin I
U-Blood
S/P-Troponin T
S/P-NT-proBNP


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4.11.6 Vital Signs
All vital signs data collected will be listed.
Changes from baseline in vital signs to each post-baseline assessment will be calculated. Absolute 
values, changes from baseline and percentage change from baseline will be summarised for all 
patients by Stage 1 and Stage 2 combined, Stage 3 alone and Stages 1, 2 and 3 combined by actual 
treatment group and by visit. Box plots of absolute values and change from baseline values and 
percentage change from baseline for all vital sign variables will also be presented.
There will be no imputation for missing values. Observed values and changes from baseline will be 
compared to the relevant AstraZeneca defined reference ranges for vital signs (see Table 6) and 
clinically important change criteria and all values (observed and change) falling outside the reference 
ranges will be flagged in the listings.
Table 6: AstraZeneca defined reference ranges for vital signs variables 
SBP- systolic blood pressure; DBP-diastolic blood pressure
mmHg-millimeter of mercury; cm-centimeter; kg-kilogram
4.11.7 ECG Variables
All ECG data received will be presented in data listings.
Absolute values, changes from baseline and percentage change from baseline to each scheduled visit 
will be summarised for all patients Stage 1 and Stage 2 combined, Stage 3 alone and Stages 1, 2 and 
3 combined by actual treatment group and by visit for the following ECG variables: heart rate, QT 
interval corrected for heart rate using Fridericia’s formula (QTcF) and Bazett’s formula (QTcB), RR, 
PR, QRS, and QT.The average of the three individual tracings will be used in summaries. However, 
the individual tracing values will be given in the data listings.
Box plots of observed values, changes from baseline and percentage change from baseline by 
treatment group will also be presented for each ECG variable with reference lines indicating the limits 
of the AstraZeneca Cardiac SKG reference ranges (see Table 7), when available. 
Table 7: AstraZeneca defined reference ranges for ECG variables
ECG Parameter
Outside AZ defined 
reference range lower limit 
if
Outside AZ defined 
reference range upper 
limit if
Heart rate (bpm)
< 40
> 100
RR (msec)
< 600
> 1200
PR (msec)
< 120
> 200
QRS (msec)
< 60
> 109
QT, QTcF, and QTcB (msec)
< 300
> 450
Vital sign (unit)
Outside AZ
defined
reference range
lower limit if
Outside AZ
defined
reference range
upper limit if
Treatment
emergent
decrease if
Treatment
emergent
increase if
SBP (mmHg)
<100
>160
<-30
>30
DBP (mmHg)
<60
>100
<-15
>15
Pulse
<40
>100
<-20
>20
Height (cm)
<140
>220
Weight (kg)
<40
>200




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
Number of observations (n)

n > LLoQ (Lower Limit of Quantification)
Plasma concentrations that are below the limit of quantification (BLQ) will be reported as follows:
Individual concentrations below the LLoQ of the bioanalytical assay will be reported as NQ (not 
quantifiable) in the listings with the LLoQ defined in the footnotes of the relevant tables, listings 
and figures (TLFs).
Individual plasma concentrations that are not reportable will be reported as NR and those that are 
missing will be reported as NS (no sample) in the listings. Plasma concentrations that are NQ, NR 
or NS will be handled as follows for the provision of descriptive statistics:

Any values reported as NR or NS will be excluded from the summary tables and figures. At 
a time point where less than or equal to 50% of the concentration values are NQ, all NQ values 
will be substituted with the LLoQ concentration, and all descriptive statistics will be 
calculated accordingly.

At a time point where more than half (but not all) of the values are NQ, the mean, gmean, 
gCV%, +gSD and SD will be set to Not Calculable (NC). The maximum value will be reported 
from the individual data and the minimum and median will be set to NQ.

If all concentrations are NQ at a time point, the mean, gmean, min, median and max will be 
reported as NQ and the +gSD, gCV% and SD will be reported as NC.
The number of values above LLoQ (n >LLoQ) will be reported for each time point together with 
the total number of collected values.
Three observations > LLoQ will be required as a minimum for PK plasma concentrations to be 
summarised. Two values will be presented as minimum and maximum with the other summary 
statistics as NC. For consistency, the same plasma concentration values are used in the mean data 
graphs as those given in the descriptive statistics summary table for each time point.
The plasma PK concentration data for AZD9833 will be displayed graphically by nominal sample 
time.
Displays will include:

Individual patient plasma concentration-time profiles of AZD9833 (on the linear scale).

Gmean plasma concentration-time profiles (with and without gSD error bars) of AZD9833
(on the linear scale).

Mean plasma concentration-time profiles (with and without SD error bars) of AZD9833 (on 
the linear scale).
4.13 Sample Size Considerations
The study is designed as an exploratory estimation of ER knockdown of different AZD9833 doses, 
as assessed by the manual H-score method. The sample size is based on the primary endpoint, percent 
change from baseline in ER expression in each dose group. Assuming a drop-out rate of 15%, 
approximately 14 patients will be recruited per treatment group, to allow 12 evaluable patients per 
treatment group for the analysis of the primary endpoint at the end of Stage 1.
For Stage 1, a total of 12 evaluable patients per treatment group will provide an 80% chance of 
obtaining an 80% CI, where one half of the CI is at most 14 for the mean percent change from baseline 
in ER. This is under the assumption of a true standard deviation of 29 (Robertson et al 2020b
Robertson JF).




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be analysed as specified in Section 4.10 of SAP. The list of tables, listings and figures required for 
the SDMC review will be prepared as described in the SDMC charter and as per AZ standards; and 
they will be flagged in the list of TLFs for the entire study.
Refer to Section 1 for the SDMC recommendations for stage 2, and Section 3 for the detailed 
investigational plan for stage 2.
4.15 Interim Analysis
There will be no formal interim statistical analyses during the conduct of Stage 1. At the end of Stage 
1, the SDMC will review the data emerging from Stage 1 and provide the recommendations for the 
Stage 2 treatment groups (sample size, dose, number of treatment groups, inclusion of a possible pre-
menopausal women group). Please refer to Section 4.14 for more details on SDMC reporting.
In Stage 2, there will be an interim analysis conducted on completion of recruitment and once all 
patients have completed treatment in GE/MX (and with provision to include any patients who have 
been recruited from the UK at the date of data cut off). This analysis will inform internal decision 
making and follow the analysis methods outlined in the main body of this SAP.
No formal interim analysis will be performed during Stage 3.
4.16 Other Analysis
At the end of all stages, data across countries and stages will be combined by treatment groups; and 
summarised following the methodology outlined in the previous sections of this SAP in an unblinded 
fashion.
A selected number of summaries will be produced splitting by country (GE/MX together and the 
UK).
5
REFERENCES
SAS Institute Inc. 2013. SAS® 9.4 Statements: Reference. Cary, NC: SAS Institute Inc.
The SAS System Requirements for SAS® 9.4 Foundation for Microsoft Windows: Copyright 
©2020. SAS Institute Inc. SAS and all other SAS Institute Inc. product or service names are 
registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA.
Nakonezny PA, Shull RD. Hettmansperger and Mckean linear model aligned rank test for the single 
covariate and one-way ANCOVA case (SAS). Journal of Modern Applied Statistical Methods. 
2007; 6:336-340.
Robertson JF, Dixon JM, Sibbering DM, Jahan A, Ellis IO, Channon E, et al. A randomized trial to 
assess the biological activity of short-term (pre-surgical) fulvestrant 500 mg plus anastrozole versus 
fulvestrant 500 mg alone or anastrozole alone on primary breast cancer. Breast Cancer Res 20136; 
15R18.
Robertson S, Acs B, Lippert M, Hartman J. Prognostic potential of automated Ki67 evaluation in 
breast cancer: different hot spot definitions versus true global score. Breast Cancer Res Treat. 
2020;183(1):161-175.
Robertson et al 2020b Robertson JF, Evans A, Henschen S, Kirwan CC, Jahan A, Kenny LM, et al. 
A randomized, window of opportunity study comparing the effects of the novel oral SERD 
AZD9496 with fulvestrant in patients with ER+ HER2- primary breast cancer. Clin Cancer Res 
2020; doi: 10.1158/1078-0432.CCR-19-3387


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Robertson JF, Evans A, Henschen S, Kirwan CC, Jahan A, Kenny LM, et al. A randomized, 
window of opportunity study comparing the effects of the novel oral SERD AZD9496 with 
fulvestrant in patients with ER+ HER2- primary breast cancer. Clin Cancer Res 2020; doi: 
10.1158/1078-0432.CCR-19-3387.


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