SERENA-2: A Randomised, Open-Label, Parallel-Group, Multicentre Phase 2 Study Comparing the Efficacy and Safety of Oral AZD9833 Versus Fulvestrant in Women With Advanced ER-Positive HER2-Negative Breast Cancer
Phase: PHASE2
Conditions: Advanced ER-Positive HER2-Negative Breast Cancer
Sponsor: AstraZeneca

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Clinical Study Protocol
Drug Substance
AZD9833
Study Code
D8530C00002
Version
5.0
Date
15 September 2021 
SERENA-2: A Randomised, Open-Label, Parallel-Group, Multicentre Phase 
2 Study Comparing the Efficacy and Safety of Oral AZD9833 versus 
Fulvestrant in Women with Advanced ER-Positive HER2-Negative Breast 
Cancer
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s):
IND: 138 396
EudraCT: 2019-003706-27

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disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
TABLE OF CONTENTS...................................................................................................... 7
1
PROTOCOL SUMMARY................................................................................ 12
1.1
Schedule of Activities (SoA)............................................................................. 12
1.2
Synopsis ........................................................................................................... 16
1.3
Schema............................................................................................................. 23
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.......................................................................................................... 25
2.2.2.1
Safety and tolerability....................................................................................... 27
2.2.2.2
Pharmacokinetics.............................................................................................. 37
2.2.2.3
Biological activity and clinical efficacy............................................................. 39
2.3
Benefit/risk assessment..................................................................................... 41
2.3.1
Fulvestrant........................................................................................................ 42
2.3.2
AZD9833.......................................................................................................... 42
2.3.2.1
Potential benefits .............................................................................................. 42
2.3.2.2
Potential risks ................................................................................................... 42
2.3.3
Overall benefit-risk and ethical assessment ....................................................... 44
3
OBJECTIVES AND ENDPOINTS................................................................... 46
4
STUDY DESIGN ............................................................................................. 48
4.1
Overall design................................................................................................... 48
4.2
Scientific rationale for study design .................................................................. 49
4.3
Justification for dose......................................................................................... 51
4.4
End of study definition...................................................................................... 51
5
STUDY POPULATION ................................................................................... 52
5.1
Inclusion criteria............................................................................................... 52
5.2
Exclusion criteria.............................................................................................. 54
5.3
Lifestyle restrictions ......................................................................................... 57
5.3.1
Meals and dietary restrictions............................................................................ 57
5.4
Screen failures .................................................................................................. 57
6
STUDY TREATMENTS.................................................................................. 58
6.1
Treatments administered................................................................................... 58
6.1.1
Investigational products.................................................................................... 58
Missed doses of AZD9833.................................................................................................. 58

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8.2.4
Electrocardiograms ........................................................................................... 78
8.2.4.1
Triplicate 12-lead digital ECGs......................................................................... 78
8.2.4.2
Ambulatory ECG.............................................................................................. 79
8.2.4.3
Echocardiogram................................................................................................ 79
8.2.5
Other safety assessments................................................................................... 79
8.3
Collection of adverse events ............................................................................. 80
8.3.1
Method of detecting AEs and SAEs .................................................................. 80
8.3.2
Time period and frequency for collecting AE and SAE information.................. 80
8.3.3
Follow-up of AEs and SAEs ............................................................................. 80
8.3.4
Adverse event data collection............................................................................ 81
8.3.5
Causality collection........................................................................................... 81
8.3.6
Adverse events based on signs and symptoms................................................... 82
8.3.7
Adverse events based on examinations and tests ............................................... 82
8.3.8
Hy’s law ........................................................................................................... 82
8.3.9
Disease progression .......................................................................................... 82
8.4
Safety reporting and medical management........................................................ 83
8.4.1
Reporting of serious adverse events .................................................................. 83
8.4.2
Pregnancy......................................................................................................... 84
8.4.3
Overdose .......................................................................................................... 85
8.4.3.1
AZD9833.......................................................................................................... 85
8.4.3.2
Fulvestrant........................................................................................................ 85
8.4.4
Medication error ............................................................................................... 85
8.5
Pharmacokinetics.............................................................................................. 86
8.5.1
Determination of drug concentration................................................................. 86
8.5.2
Storage and destruction of pharmacokinetic samples......................................... 86
8.6
Pharmacodynamics........................................................................................... 86
8.7
............................................................................................................ 87
8.7.1
Optional exploratory genetic sample ................................................................. 87
8.7.2
Storage and destruction of genetic samples ....................................................... 87
8.8
Biomarkers ....................................................................................................... 87
8.8.1
Blood samples for circulating tumour DNA ...................................................... 88
8.8.2
Blood samples for tumour marker
........................................................ 88
8.8.3
.................................................................................... 88
8.8.4
Archival tumour tissue...................................................................................... 88
8.8.5
Tumour biopsy in selected patients ................................................................... 89
8.8.6
Storage, re-use and destruction of biomarker samples ....................................... 89
8.9
Medical Resource Utilisation and Health Economics ........................................ 90
9
STATISTICAL CONSIDERATIONS............................................................... 91
9.1
Statistical hypotheses........................................................................................ 91
9.2
Sample size determination ................................................................................ 91
9.3
Populations for analyses.................................................................................... 92
9.4
Statistical analyses............................................................................................ 93
9.4.1
Efficacy analyses .............................................................................................. 94
9.4.1.1
Primary endpoint: progression-free survival...................................................... 95
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9.4.1.2
Secondary endpoints......................................................................................... 97
9.4.2
Safety analyses ................................................................................................. 99
9.4.2.1
Adverse events.................................................................................................. 99
9.4.2.2
Other significant adverse events........................................................................ 99
9.4.2.3
Other safety data............................................................................................. 100
9.4.3
Other analyses ................................................................................................ 100
9.4.3.1
Pharmacokinetic data...................................................................................... 100
9.4.3.2
Pharmacodynamic data ................................................................................... 100
9.4.3.3
Health-related quality of life assessments........................................................ 100
9.4.3.4
Exploratory analyses....................................................................................... 101
9.4.4
Methods for multiplicity control ..................................................................... 101
9.5
Interim analyses.............................................................................................. 101
9.5.1
AstraZeneca data monitoring committee ......................................................... 101
9.5.2
Safety Review Committee............................................................................... 101
10
REFERENCES............................................................................................... 103
11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 106
LIST OF TABLES
Table 1
Study assessments.................................................................................... 13
Table 2
Duration of exposure ............................................................................... 27
Table 3
Summary of AEs ..................................................................................... 27
Table 4
Treatment-related AEs by system organ class and preferred term 
reported in 2 or more patients .................................................................. 28
Table 5
Summary of visual disturbances............................................................... 31
Table 6
Summary of bradycardia events............................................................... 31
Table 7
Summary of heart rate data ...................................................................... 32
Table 8
Recovery of bradycardia after treatment discontinuation.......................... 33
Table 9
Summary of AEs potentially related to bradycardia symptoms................. 33
Table 10
 values and change from baseline in 
............ 35
Table 11
Recovery of 
 after treatment discontinuation .............. 36
Table 12
Preliminary plasma PK parameters of AZD9833 in humans..................... 38
Table 13
Mean percent change in ER and PgR H-scores and Ki-67 score ............... 40
Table 14
Objective response rate and clinical benefit rate at 24 weeks.................... 41
Table 15
Study objectives....................................................................................... 46
Table 16
Study treatments ...................................................................................... 58
Table 17
Missed doses of AZD9833....................................................................... 59
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Table 18
AZD9833 dose interruption, reduction and/or discontinuation guidance... 64
Table 19
Blood sample volumes............................................................................. 69
Table 20
Laboratory safety variables...................................................................... 77
Table 21
Study populations .................................................................................... 93
Table 22
Summary of analyses and data cut-off triggers......................................... 94
Table 23
Drugs known to be inhibitors of 
.......................................... 112
Table 24
Drugs known to be inducers of 
............................................ 113
Table 25
Examples of 
 and 
 substrate drugs............................. 114
Table 26
substrates with label advice regarding combination with 
 
inhibitors ............................................................................................... 115
Table 27
Summary of Methods of Assessment ..................................................... 132
Table 28
Evaluation of target lesions.................................................................... 136
Table 29
Evaluation of non-target lesions............................................................. 136
Table 30
Overall Visit Response .......................................................................... 138
LIST OF FIGURES
Figure 1
Study design............................................................................................ 23
Figure 2
Mean plasma AZD9833 PK time course Day 1 versus Day 15 of Cycle 1 38
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations........................... 106
Appendix B
Guidelines regarding potential interactions of AZD9833 with 
concomitant medications........................................................................ 111
Appendix C
Adverse event definitions and additional safety information .................. 116
Appendix D
Handling of human biological samples .................................................. 120
Appendix E
................................................................................................ 122
Appendix F
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s law........................................................................... 126
Appendix G
Guidelines for evaluation of objective tumour response using Response 
Evaluation Criteria in Solid Tumours (RECIST) version 1.1.................. 131
Appendix H
Abbreviations ........................................................................................ 139
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1
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)

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Table 1
Study assessments
Screen
ing
Treatment period (28-day cycles)
Post-treatment 
period
Details in 
CSP 
section 
or 
Appendi
x
Visit
1
2
3
4
5
7
8
9
11
≥12
EO
T
visit
28-
day 
safety 
follow
-up
Surviv
al 
follow-
up
Cycle
C1
C2
C3
C4
C5
C6
C≥7
Cycle day
-
D1
D8 D1
5
D1
D1
D1
D1
D1
D1
Study day
-28 to -
1
1
8
15
29
57
85
113
141
≥169
EO
T
EOT+
28
12-
weekly
Week (Day 1 of)
-4 to -1
1
2
3
5
9
13
17
21
≥25
EO
T
EOT+
4
Visit window (days)
±1 ±1
±3
±3
±3
±3
±3
±3
+7
+7
±14
Informed consent 
X
5.1
Eligibility criteria
X
5.1, 5.2
Routine clinical procedures
Demography, 
medical/surgical history, 
baseline characteristics
X
5.1
Concomitant medication
X
At every visit and may be conducted by phone 
6.5
Survival status, anti-
cancer treatments
X
8.1.3
ECOG/WHO
performance status
X
X
X
X
X
X
X
every 
2 cycles
X
X
8.1.4
Routine safety assessments
Adverse events
X
At every visit and may be conducted by phone
8.3
Physical examination
X
X
X
X
X
X
X
every 
2 cycles
X
X
8.2.2
Weight, height a
X
X
X
X
X
X
X
every 
cycle
X
X
8.2.2
Vital signs (temperature, 
pulse rate, blood 
pressure)
X
X
X
X
X
X
X
X
X
every 
2 cycles
X
X
8.2.3
Triplicate ECGs
X
pre-
dose
X
X
X
X
X
X
X
every 
2 cycles
X
X
8.2.4.1
24-hour ECG
X
Once 
between 
D15 and 
D29
8.2.4.2
Echocardiogramg
X
X
every 
3rd 
cycle 
X
8.2.4.3
Clinical chemistry, 
haematology, urinalysis
X
X
X
X
X
X
X
X
every 
2 cycles
X
8.2.1
Coagulation tests
X
X
X
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Table 1
Study assessments
Screen
ing
Treatment period (28-day cycles)
Post-treatment 
period
Details in 
CSP 
section 
or 
Appendi
x
Visit
1
2
3
4
5
7
8
9
11
≥12
EO
T
visit
28-
day 
safety 
follow
-up
Surviv
al 
follow-
up
Cycle
C1
C2
C3
C4
C5
C6
C≥7
Cycle day
-
D1
D8 D1
5
D1
D1
D1
D1
D1
D1
Study day
-28 to -
1
1
8
15
29
57
85
113
141
≥169
EO
T
EOT+
28
12-
weekly
Week (Day 1 of)
-4 to -1
1
2
3
5
9
13
17
21
≥25
EO
T
EOT+
4
Visit window (days)
±1 ±1
±3
±3
±3
±3
±3
±3
+7
+7
±14
PK sampling for AZD9833 and, if appropriate, 
metabolite(s) b
PK sample pre-dose
X
X
8.5
PK samples post-dose (2, 
4 hours)
X
8.5
Efficacy assessments
Tumour imaging
(RECIST version 1.1)
X
X c
X c
8-
weekly c
8.1.1,
Appendix
G
Bone scan, skeletal 
survey
X d
8.1.2
Biomarker analyses
Blood sample for ctDNA
X
pre-
dose
X
X
X
X
X
8-
weekly e
X
8.8.1
Blood sample for 
X
pre-
dose
X
X
X
X
X
8-
weekly e
X
8.8.2
Blood sample for 
X
pre-
dose
X
X
X
8.8.3
Archival tumour tissue
X
8.8.4
Optional tumour biopsy 
(for selected patients)
X
X
at 
progress
ion
8.8.5
Patient reported 
outcomes
HRQoL questionnaires 
(EORTC QLQ-C30, 
EORTC QLQ-BR23, 
NEI VFQ-25, 
EQ-5D-5L, 
 
)
X
X
X
8-
weekly e
X
X
8.1.4.2
 
X
X
X
8.1.4.3
Optional 
 
sampling
Blood sample
X
8.7
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Table 1
Study assessments
Screen
ing
Treatment period (28-day cycles)
Post-treatment 
period
Details in 
CSP 
section 
or 
Appendi
x
Visit
1
2
3
4
5
7
8
9
11
≥12
EO
T
visit
28-
day 
safety 
follow
-up
Surviv
al 
follow-
up
Cycle
C1
C2
C3
C4
C5
C6
C≥7
Cycle day
-
D1
D8 D1
5
D1
D1
D1
D1
D1
D1
Study day
-28 to -
1
1
8
15
29
57
85
113
141
≥169
EO
T
EOT+
28
12-
weekly
Week (Day 1 of)
-4 to -1
1
2
3
5
9
13
17
21
≥25
EO
T
EOT+
4
Visit window (days)
±1 ±1
±3
±3
±3
±3
±3
±3
+7
+7
±14
Study treatment
Randomisation
X
6.3
Fulvestrant (500 mg IM)
X
X
X
X
X
X
X
every 
cycle
6.1.1
Dispense/collect 
AZD9833
X
X
X
X
X
X
every 
cycle
X
6.4
AZD9833 (PO)
75 mg, 150 mg, or 300 mg once daily
6.1.1
a
Height will be measured at screening only.
b
Pharmacokinetic samples will only be collected for patients treated with AZD9833.
c
The time window for tumour imaging is ±7 days. Assessments will be conducted until disease progression.
d
The bone scan /skeletal survey should be performed within 12 weeks of treatment start (C1D1).
e
Sample collection and completion of HRQoL questionnaires will be done 8-weekly (D1 of every 2nd cycle) 
from Week 25 (C7) to coincide with tumour RECIST assessment.
f
PRO interviews will only be conducted for patients enrolled in the United States, United Kingdom, and 
Spain. The interviews will be conducted by phone. The 1st interview will occur at baseline (prior to 1st dose 
within screening period). Vendor conducting interviews will be notified within a day of identification of an 
eligible patient and the date of scheduled C1D1. Best efforts will be used to schedule all interviews within 
the windows allowed. The 2nd interview will occur 4 weeks (±7 days) from C1D1 and the 3rd interview will 
occur 12 weeks (±21 days) from C1D1.
g
Echocardiograms time window for visits C2D1, C5D1 and every 3rd cycle thereafter, and 28-day follow-up 
echocardiograms is ±7 days
; CSP=Clinical Study Protocol; 
 
; Cx=Cycle x; Dx=Day x; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
EORTC=European Organisation for Research and Treatment of Cancer; EORTC QLQ-BR23=EORTC quality of 
life questionnaire - breast cancer module; EORTC QLQ-C30=EORTC quality of life questionnaire - core 
questionnaire, EOT=end of treatment; EQ-5D-5L=EuroQol 5 Dimension 5 level; HRQoL=health-related quality 
of life; IM=intramuscular; NEI VFQ-25=National Eye Institute 25-Item Visual Function Questionnaire; 
 
 PK=pharmacokinetics; 
PO=oral (per os); 
; RECIST=Response Evaluation Criteria in Solid Tumours; 
WHO=World Health Organisation.
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1.2
Synopsis
International co-ordinating Investigator:
, MD
Vall d’Hebron Institute of Oncology
Barcelona, Catalonia, Spain
Protocol title:
SERENA-2: A Randomised, Open-Label, Parallel-Group, Multicentre Phase 2 Study 
Comparing the Efficacy and Safety of Oral AZD9833 versus Fulvestrant in Women with 
Advanced ER-Positive HER2-Negative Breast Cancer
Short title:
SERENA-2: A Randomised Comparative Phase 2 Study of AZD9833 versus Fulvestrant in 
Women with Advanced ER-Positive HER2-Negative Breast Cancer
Rationale:
The oestrogen receptor (ER) alpha (ERα) is a well-established drug target in breast cancer 
with anti-hormonal endocrine therapies being the mainstay of treatment (Early Breast Cancer 
Trialists’ Collaborative Group 2005). The selective ER degrader (SERD) and antagonist 
fulvestrant is used as a standard-of-care treatment for ER-positive metastatic breast cancer 
(Cardoso et al 2018).
Although fulvestrant has demonstrated superior clinical efficacy to other endocrine therapies 
in this metastatic 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 
women 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 (D8530C00001) evaluating AZD9833 in women with advanced 
ER-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer 
completed its monotherapy dose escalation phase. This study evaluated multiple ascending 
doses of AZD9833 administered once daily to post-menopausal women. Subsequent parts of 
this study will examine AZD9833 as monotherapy in pre-menopausal women, and also in 
combination with the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib in a 
pre- and post-menopausal population. Study D8530C00001 established that AZD9833 doses 
of 75, 150 and 300 mg administered once daily were safe and well tolerated in that population, 
and there are sound indications of clinical efficacy at each of these doses.
PPD

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This open-label Phase 2 study will enrol post-menopausal women with advanced ER-positive 
HER2-negative breast cancer who are suitable for fulvestrant therapy. The study will evaluate 
the efficacy and safety of AZD9833 (75, 150 and 300 mg, oral [PO]) administered once daily 
as a monotherapy in comparison with fulvestrant administered according to its label (ie, slow 
IM injection into the buttocks [1 to 2 minutes per injection] as two 5-mL injections, 1 in each 
buttock, on Day 1, Day 15, Day 29 and 4-weekly thereafter).
This study will be key to determining if AZD9833 should be further investigated in Phase 3 
clinical trials.
Objectives and endpoints
Primary Objective:
Endpoint/Variable:
To determine the clinical efficacy (as assessed by 
PFS) of AZD9833 when compared to fulvestrant in 
women with advanced ER-positive HER2-negative 
breast cancer
PFS assessed by the Investigator as defined by 
RECIST version 1.1
Secondary Objectives:
Endpoints/Variables:
To determine anti-tumour effect of AZD9833 when 
compared to fulvestrant in women with advanced 
ER-positive HER2-negative breast cancer
Based on tumour response assessed by the 
Investigator, as defined by RECIST version 1.1:
•
ORR
•
DoR
•
Best percentage change in tumour size and 
percentage change in tumour size at 16 weeks
To determine the effect of AZD9833 on survival and 
clinical benefit when compared to fulvestrant in 
women with advanced ER-positive HER2-negative 
breast cancer
•
OS
•
CBR24
To evaluate the PK of AZD9833 in this patient 
population at steady state
Plasma concentrations of AZD9833 and, if 
appropriate, metabolite(s) on Day 15 (pre- and post-
dose) and Day 29 (pre-dose)
To evaluate the pharmacodynamics of AZD9833 and 
fulvestrant in a subgroup of patients with advanced 
ER-positive HER2-negative breast cancer
•
Percent change from baseline in ER and PgR 
expression assessed by the manual H-score 
method.
•
Percent change from baseline in Ki67 labelling 
index
To evaluate the effect of AZD9833 and fulvestrant on 
the patients’ HRQoL, as assessed by 
patient-completed HRQoL questionnaires
Changes from baseline in total/subscale scores of the 
EORTC QLQ-C30, EORTC QLQ-BR23, 
NEI VFQ-25, and EQ-5D-5L
Safety Objective:
Endpoints/Variables:
To evaluate the safety and tolerability of AZD9833 
when compared to fulvestrant in women with 
advanced ER-positive HER2-negative breast cancer
•
AEs/SAEs
•
Vital signs, ECGs, clinical chemistry, 
haematology, urinalysis parameters

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cycles until disease progression (assessed by the Investigator as defined by Response 
Evaluation Criteria in Solid Tumours [RECIST] version 1.1):

AZD9833 (75 mg, PO, once daily)

AZD9833 (150 mg, PO, once daily)

AZD9833 (300 mg, PO, once daily)

Fulvestrant (500 mg IM, Day 1, Day 15, Day 29, and 4-weekly thereafter)
As of December 2020, the Sponsor stopped enrolment to the 300 mg treatment arm. Ongoing 
patients in the 300 mg treatment arm may continue treatment as planned.
During the treatment period, patients will attend visits on:

Day 1, Day 8, and Day 15 of Cycle 1

Day 1 of each subsequent cycle until treatment discontinuation
After the treatment period, patients will attend 2 safety follow-up visits (at the time of 
treatment discontinuation and 28 days later) and will continue to be followed for survival.
Throughout the study, patients will be asked to report adverse events (AEs) and the use of 
concomitant medication.
Safety assessments (physical examination, vital signs, electrocardiograms [ECGs], clinical 
safety laboratory assessments) will be performed at screening, on Day 1 of every cycle (up to 
Cycle 6) and every 2 cycles (from Cycle 6) and at the end of treatment (EOT) visit. 
Echocardiograms will be performed at screening, on Day 1 of cycle 2 and 5, every 3 cycles 
thereafter and at the 28 day follow up visit. Safety assessments will also be performed on 
Cycle 1 Day 8 (vital signs and triplicate ECGs), Cycle 1 Day 15 (vital signs, ECGs, clinical 
chemistry, haematology, and urinalysis), at the 28-day safety follow-up (physical exam and 
vital signs).
Tumour imaging will be performed for the assessment tumour response according to RECIST 
version 1.1 at screening and every 8 weeks from Week 9 until disease progression. 
Patients will complete health-related quality of life (HRQoL) questionnaires on Day 1 of 
Cycles 1, 2, and 4, then 8-weekly (Day 1 of every 2nd cycle) from Week 25 (Cycle 7) to 
coincide with tumour imaging, at the EOT and/or disease progression, and at the 28-day safety 
follow-up.
Blood and plasma samples for circulating tumour (ctDNA) and 
 
analyses will be collected at screening, on Day 1 and Day 15 of Cycle 1, on Day 1 of Cycles 2 
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to 5, 8-weekly (Day 1 of every 2nd cycle) from Week 25 (Cycle 7) to coincide with tumour 
imaging, at the EOT and/or disease progression.
Blood samples for 
 will be collected at screening, on Day 1 of 
Cycles 1, 2, and 4, and at the EOT.
For patients receiving AZD9833, blood samples will be collected for pharmacokinetic (PK) 
assessments on Cycle 1 Day 15 and Cycle 2 Day 1.
For patients who provide specific consent, the following optional assessments will be 
performed:

Up to 12 patients per treatment group will be selected such that they are suitable for 
providing 1 pre-treatment and 1 on-treatment paired tumour biopsy sample. If provision 
of paired biopsies becomes clinically unfeasible for a selected patient during the course of 
her care, the patient may be replaced until up to 12 evaluable biopsy pairs are collected 
within each treatment group.

An optional blood sample will be collected at pre-dose on Day 1 of Cycle 1 or later 
during the study for future genetic research.
Study period:
Estimated date of first patient enrolled: Q4 2019
Estimated date of last patient completed (primary analysis): Q2 2022
Number of patients:
This study will screen approximately 360 patients (assuming a screen failure rate of 20%), in 
order to randomise 288 patients into 4 treatment groups in a 1:1:1:1 ratio:

AZD9833 75 mg: 72 patients

AZD9833 150 mg: 72 patients

AZD9833 300 mg: 72 patients (closed to recruitment as of December 2020)

Fulvestrant: 72 patients
As of December 2020, the Sponsor stopped enrolment to the 300 mg treatment arm. Ongoing 
patients in the 300 mg treatment arm may continue treatment as planned.
Treatments and treatment duration:
Patients will receive study treatment until objective disease progression (according to RECIST 
version 1.1) or other discontinuation criteria are met.
AZD9833 will be administered once daily:
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
75 mg: 3×25-mg tablets.

150 mg: 1×100-mg tablet + 2×25-mg tablets.

300 mg: 3×100-mg tablets.
Fulvestrant will be administered on Day 1, Day 15 (±1 day), Day 29 (±3 days), and 4-weekly 
thereafter:

500 mg: 2×5-ml IM injections.
Data Monitoring Committee:
Interim analyses and safety review of the data are planned throughout the study, which may be 
combined or conducted separately.
The review of safety data will be conducted by the Safety Review Committee (SRC) 
approximately every 6 months up to the primary analysis for progression-free survival (PFS), 
and thereafter at the discretion of the SRC.
An independent AstraZeneca data monitoring committee (DMC) will undertake interim 
analyses for this study.
Statistical methods:
All efficacy analyses will be performed on the full analysis set (FAS). As of December 2020, 
the Sponsor stopped enrolment to the 300 mg treatment arm. The primary analysis, which is a 
formal comparison of AZD9833 to fulvestrant, only applies to AZD9833 75 mg and 150 mg 
treatment arms, and pairwise comparisons only refer to AZD9833 doses 75 mg and 150 mg. 
Results of all statistical analyses will be presented using 90% confidence intervals (CIs) and 
2-sided p-values. The treatment comparisons of interest are each dose level of AZD9833 
versus fulvestrant. Data accrued from the AZD9833 300 mg treatment arm will be 
summarised and reported as appropriate, but will not contribute to the event triggers for the 
analysis timepoints below.
For the primary analysis, the null hypothesis to be tested is that there is no treatment effect, 
(ie, there is no difference in PFS between patients treated with any dose of AZD9833 and 
patients treated with fulvestrant).

H0: PFS HRAZD9833/fulvestrant=1

H1: PFS HRAZD9833/fulvestrant≠1
Each dose of AZD9833 of interest will be compared with fulvestrant in a pairwise 
comparison. As this is a Phase 2 study, no adjustments for multiplicity will be made. The 
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RECIST version 1.1. A sensitivity analysis based on the Blinded Independent Central Review 
(BICR) of scans will be conducted. 
The analysis of the primary endpoint of PFS (as assessed by the Investigator) will occur when 
recruitment to the study has completed and at least 108 events have occurred for the pairwise 
comparison of 75 mg and 150 mg AZD9833 doses versus fulvestrant (approximately 75% 
maturity). A further analysis of PFS may also be conducted at a later timepoint based on more 
mature data, particularly in the subgroups of interest. 
A sample size of approximately 288 patients, randomised in equal proportions to the 
4 treatment groups will be required to observe a total of at least 108 PFS events for each 
pairwise comparison against fulvestrant. As of December 2020, and the decision to stop 
enrolment to the AZD9833 300 mg treatment arm, the resulting total sample size across the 
3 enrolling treatment arms is approximately 216, with approximately an additional 20 patients 
from the AZD9833 300 mg arm (now closed to recruitment). A HR of 0.59 for each pairwise 
treatment comparison versus fulvestrant is of interest. Under the assumption that a 5-month 
median PFS will be observed on fulvestrant, this is equivalent to a 3.5-month increase in 
median PFS over fulvestrant. A minimum of 108 events for the pairwise comparison of each 
AZD9833 dose of interest versus fulvestrant will provide 86% power at the 2-sided 10% 
significance level if the assumed true treatment effect is HR = 0.59. 
The objective response rate (ORR) will be compared between AZD9833 (each dose level) and 
fulvestrant using a logistic regression model adjusting for prior use of CDK4/6 inhibitors and 
presence of lung and/or liver metastases.
The change from baseline in tumour size at 16 weeks and best change from baseline in tumour 
size will also be summarised and presented by randomised treatment group. 
The overall survival (OS) data will be analysed at the time of the primary analysis of PFS and 
will use the same methodology and model (provided there are enough events available for a 
meaningful analysis). Further survival analyses may be conducted after 
 and 
 of 
patients have died, or other maturities as may be appropriate.
The CBR24 will be summarised by treatment group and analysed using a logistic regression 
model (similarly to the analysis for the ORR).
All safety analyses will be performed on the safety analysis set. Safety data will not be 
analysed formally. 
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2
INTRODUCTION
2.1
Study rationale
The ERα is a well-established drug target in breast cancer with anti-hormonal endocrine 
therapies being the mainstay of treatment (Early Breast Cancer Trialists’ Collaborative Group 
2005). The SERD and antagonist fulvestrant is used as a standard-of-care treatment for 
ER-positive metastatic breast cancer (Cardoso et al 2018).
Although fulvestrant has demonstrated superior clinical efficacy to other endocrine therapies 
in this metastatic 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 
women 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 (D8530C00001) evaluating AZD9833 in women with advanced 
ER-positive HER2-negative breast cancer completed its monotherapy dose escalation phase. 
This study evaluated multiple ascending doses of AZD9833 administered once daily to post-
menopausal women. Subsequent parts of this study will examine AZD9833 as monotherapy in 
pre-menopausal women, and also in combination with the CDK4/6 inhibitor palbociclib in a 
pre- and post-menopausal population. Study D8530C00001 established that AZD9833 doses 
of 75, 150 and 300 mg administered once daily were safe and well tolerated in that population, 
and there are sound indications of clinical efficacy at each of these doses.
This open-label Phase 2 study will enrol post-menopausal women with advanced ER-positive 
HER2-negative breast cancer who are suitable for fulvestrant therapy. The study will evaluate 
the efficacy and safety of AZD9833 (75, 150 and 300 mg, PO) administered once daily as a 
monotherapy in comparison with fulvestrant administered according to its label (ie, slow IM 
injection into the buttocks [1 to 2 minutes per injection] as two 5-mL injections, 1 in each 
buttock, on Day 1, Day 15, Day 29 and 4-weekly thereafter).
This study will be key to determining if AZD9833 should be further investigated in Phase 3 
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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 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).
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 the risk of recurrence observed 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 preferred first-line endocrine therapy for 
post-menopausal women with advanced disease to be an aromatase inhibitor (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 is a potent, selective non-steroidal ERα antagonist and a potent SERD that can be 
administered orally. The drug has shown anti-proliferative effects in a wide panel of 
ER-positive cell lines and significant anti-tumour activity in both tamoxifen-resistant and 
tamoxifen-sensitive ER-positive wild type models of breast cancer in vivo and in a long-term 
oestrogen deprived model. Additionally, AZD9833 has shown efficacy in a number of 
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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. 
AZD9833 doses of 25, 75, 150, 300 and 450 mg once daily have been examined in a 
multiple-dose escalation Phase 1 design. Patients with metastatic or loco-regionally recurrent 
disease which was refractory or intolerant to existing therapy(ies) known to provide clinical 
benefit were enrolled. Prior chemotherapy and/or endocrine therapy for breast cancer was 
permitted, but no more than 2 lines of chemotherapy for advanced disease were allowed. 
Progression on at least one line of endocrine therapy in the advanced/metastatic disease setting 
was required and there was no limit on the number of lines of prior endocrine therapies. Prior 
treatment with CDK4/6 inhibitors was permitted. Pre-dose and on-treatment paired tumour 
biopsies were obtained from a subset of patients at each dose level.
The primary objective of the study was to investigate the safety and tolerability of AZD9833, 
and to define the doses for further clinical evaluation by assessment of dose-limiting toxicities 
(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 study 
withdrawal if that occurred in advance of disease progression. The DLT evaluation period was 
28 days.
On 
, the study SRC determined the AZD9833 dose of 300 mg once daily to 
most likely be the highest dose that should be taken forward for further clinical development.
Preliminary and un-validated data (data cut-off [DCO] date: 
) from Study 
D8530C00001 on the safety, tolerability, PK and biological activity of AZD9833 administered 
once daily at doses up to 
 mg is detailed in the current Investigator’s Brochure and below. 
Of the 
patients exposed to AZD9833 in Study D8530C00001, 
were continuing on study 
at the DCO date). Durations of exposure at each dose level at the DCO date are shown in 
Table 2.
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Table 2
Duration of exposure
Patient
exposure
AZD9833, assigned starting dose
25 mg
(N=12)
75 mg
(N=12)
150 mg
(N=13)
300 mg
(N=11)
450 mg
(N=4)
Total
(N=52)
Days
N
Mean
Standard deviation
Median
Minimum
Maximum
Months, n (%)
<3 months
3 to 6 months
≥6 months
Source: Study D8530C00001 preliminary data (DCO: 
).
2.2.2.1 Safety and tolerability
Of the 
 patients with ER-positive HER2-negative advanced or metastatic breast cancer who 
received at least 1 dose of AZD9833, 
 patients had at least 1 AE during the study. 
The majority of AEs were Common Terminology Criteria for Adverse Event (CTCAE) 
Grade 1. There were 
 patients with CTCAE Grade ≥3 AEs; including 1 (
) 
patient with Grade ≥3 AEs considered treatment-related by the Investigator.
No patients permanently discontinued AZD9833 due to a treatment-related AE. 
patients reported serious adverse events (SAEs); none of which were 
considered treatment-related by the Investigator. No AEs leading to death were reported. 
Table 3
Summary of AEs
Number (%) patients with
AZD9833, assigned starting dose
25 mg
(N=12)
75 mg
(N=12)
150 mg
(N=13)
300 mg
(N=11)
450 mg
(N=4)
Total
(N=52)
Any AE
Treatment-related AE
Grade ≥3 AE a
Treatment-related Grade ≥3 AE a
AE leading to dose interruption
Treatment-related AE leading to dose 
interruption
C
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Table 3
Summary of AEs
Number (%) patients with
AZD9833, assigned starting dose
25 mg
(N=12)
75 mg
(N=12)
150 mg
(N=13)
300 mg
(N=11)
450 mg
(N=4)
Total
(N=52)
AE leading to dose reduction
Treatment-related AE leading to dose 
reduction
AE leading to discontinuation
Treatment-related AE leading to 
discontinuation
SAE
Treatment-related SAE
Fatal AE 
Treatment-related fatal AE 
a
The severity of AEs was graded according to CTCAE version 4.03.
Source: Study D8530C00001 preliminary data (DCO:
).
The most common AEs (ie, reported in >10% of patients) irrespective of causality were visual 
impairment, bradycardia, nausea, anaemia, sinus bradycardia, dizziness, arthralgia, vomiting, 
headache, asthenia and fatigue. AEs considered to be related to AZD9833 by the Investigator 
are summarised by dose in Table 4. 
Table 4
Treatment-related AEs by system organ class and preferred term 
reported in 2 or more patients
Number (%) of patients
AZD9833, assigned starting dose
MedDRA SOC
Preferred term
25 mg
(N=12)
75 mg
(N=12)
150 mg
(N=13)
300 mg
(N=11)
450 mg
(N=4)
Total
(N=52)
Eye disorders
)
Visual impairment
Photopsia
Vision blurred
Cardiac disorders
Bradycardia
Sinus bradycardia
General disorders and administration site 
conditions
Asthenia
Fatigue
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Table 4
Treatment-related AEs by system organ class and preferred term 
reported in 2 or more patients
Number (%) of patients
AZD9833, assigned starting dose
MedDRA SOC
Preferred term
25 mg
(N=12)
75 mg
(N=12)
150 mg
(N=13)
300 mg
(N=11)
450 mg
(N=4)
Total
(N=52)
Gastrointestinal disorders
Nausea
)
Diarrhoea
Dry mouth
Vomiting
Investigations
Electrocardiogram QT prolonged
Alanine aminotransferase increased
Aspartate aminotransferase increased
Neutrophil count decreased
Nervous system disorders
Dizziness
Headache
Blood and lymphatic system disorders
Anaemia
Thrombocytopenia
Skin and subcutaneous tissue disorders
Pruritus
Vascular disorders
Hot flush
Orthostatic hypotension
Musculoskeletal and connective tissue 
disorders
Arthralgia
Psychiatric disorders
Preferred terms and SOCs are per MedDRA version 21.1.
MedDRA=Medical Dictionary for Regulatory Activities; SOC=system organ class.
Source: Study D8530C00001 preliminary data (DCO: 
).
The most commonly reported AEs that were considered AZD9833-related by the Investigator 
were visual disturbances and bradycardia and both are now considered adverse drug reactions 
by AstraZeneca.
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A dose-dependent prolongation of QT interval corrected for heart rate by Fridericia’s formula 
(QTcF) was also observed. These are described in detail below.
Three patients experienced DLTs, which are listed as follows:

CTCAE Grade 3 QTcF prolongation (300 mg; onset on Cycle 1 Day 8; recovered to 
Grade 1 following dosing interruption from Cycle 1 Day 8 to Cycle 1 Day 16, then 
restarted at 150 mg)

CTCAE Grade 3 vomiting (450 mg; progression from Grade 1 onset on Cycle 1 Day 3 to 
Grade 3 on Cycle 1 Day 21 despite antiemetic therapy. Dosing interrupted from Cycle 1 
Day 21 to Cycle 2 Day 1 then restarted at 300 mg)

CTCAE Grade 2 visual changes (verbatim term) and Grade 2 nausea (450 mg; 
necessitating dose interruption from Cycle 1 Day 8 until Cycle 1 Day 15 when restarted at 
300 mg)
Visual disturbances
Reported AEs considered to represent visual disturbances included the following 
Investigator-reported terms: intermittent flashing lights, visual disturbances, visual alterations, 
blurry vision, photopsia and vision problems. The events were intermittent during AZD9833 
dosing and not continuous throughout the day; but if they occurred, they were generally 
reported throughout the study period with unchanged severity. There was a preliminary 
association with variable lighting conditions (eg, dawn or dusk).
Data pertaining to patients who discontinued from AZD9833 treatment and for whom follow-
up visit data is available included  patients who experienced visual disturbance-related AEs 
while on treatment with AZD9833. 
 of these  patients experienced resolution of visual 
disturbance while still receiving AZD9833 (75 mg), while the other 5 patients confirmed 
resolution of visual disturbances at the 28-day follow-up. In at least cases, visual disturbance 
AEs resolved within 
hours of drug discontinuation.
During study, it was recommended that patients reporting visual disturbances be referred for 
ophthalmological examination; the resultant available information has not revealed any 
physical abnormalities of the eye attributable to trial participation.
Expert ophthalmological opinion indicates that these events most likely represent a 
phenomenon of illusory palinopsia (Gersztenkorn and Lee 2015). The precise mechanism 
whereby AZD9833 caused visual disturbance is not understood. Similar visual disturbances 
are associated with other endocrine therapies, including tamoxifen, exemestane and 
clomiphene. 
 
 
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The number of patients with visual disturbances by dose level is summarised in Table 5.
Table 5
Summary of visual disturbances
Number (%) of patients with
AZD9833, assigned starting dose
25 mg 
(N=12)
75 mg 
(N=12)
150 mg
(N=13)
300 mg
(N=11)
450 mg
(N=4)
Visual disturbances
•
leading to dose reduction
•
leading to dose discontinuation
•
leading to dose interruption
Visual disturbances include the MedDRA (version 21.1) preferred terms of visual impairment, vision blurred, 
and photopsia. 
MedDRA=Medical Dictionary for Regulatory Activities.
Source: Study D8530C00001 preliminary data (DCO:
).
No patients required treatment discontinuation but  patient in the
mg cohort experienced 
a 
 due to a combination of 
 (verbatim term) and Grade 2 
nausea. The patient experienced 
 on Cycle 1 Day 2, which progressed 
to Grade 2 by Cycle 1 Day 8. As it occurred in combination with 
, it required 
dose interruption. The patient restarted AZD9833 treatment with dose reduction to 
mg at 
Cycle 1 Day 15.
Bradycardia
The number of patients reporting bradycardia as an AE is shown by dose level in Table 6. 
Although both ‘bradycardia’ and ‘sinus bradycardia’ were reported by Investigators, the 
preferred terms are clinically interchangeable (as all instances of bradycardia were in sinus 
rhythm) and are thus summed in Table 6. Furthermore, all reported AEs of bradycardia or 
sinus bradycardia were CTCAE Grade 1 (asymptomatic).
Table 6
Summary of bradycardia events
Number (%) of patients with 
preferred term
AZD9833, assigned starting dose
25 mg
(N=12)
75 mg
(N=12)
150 mg
(N=13)
300 mg
(N=11)
450 mg
(N=4)
Total
(N=52)
Bradycardia
)
Sinus bradycardia
Combined bradycardia and 
sinus bradycardia
Source: Study D8530C00001 preliminary data (DCO: 
).
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Heart rate and standard ECG parameters were also measured in Study D8530C00001 by 
centrally read digital ECGs collected in triplicate throughout the study. The ECG-derived 
bradycardia data is shown in Table 7 as an absolute reduction from baseline and as a 
percentage change from baseline, along with the number of patients at each dose level with 
on-study observations of heart rate below
beats per minute (bpm), respectively.
Table 7
Summary of heart rate data
AZD9833, assigned starting dose
25 mg 
(N=12)
75 mg
(N=12)
150 mg
(N=13)
300 mg
(N=11)
450 mg
(N=4)
Subject mean a change from baseline for all timepoints from Day 15
mean absolute change (bpm)
95% CI
mean percent change
95% CI
Number of patients with maximum heart rate value b
 absolute value (pre-dose)
 absolute value (post-dose)
 absolute value (pre-dose)
 absolute value (post-dose)
 absolute value (pre-dose)
 absolute value (post-dose)
a
For each patient, the mean of absolute and percent change from baseline measured for all timepoints from 
Day 15 onwards was calculated.
b
Heart rate threshold values 
) are calculated based on the individual patient maximum 
absolute value. This is defined as the maximum absolute reduction of the mean of the triplicate values at 
any timepoint post first dose.
Source: Study D8530C00001 preliminary data (DCO: 
).
AZD9833-related bradycardia exhibits a time-dependent onset, with a gradual decrease in 
heart rate over a period of approximately 
days, reaching a stable nadir at that time. There 
does not appear to be a 
 of heart rate during dosing beyond 
days, but no further 
reductions in rate are observed from that time onwards. Events of bradycardia were 
 
on cessation of treatment, with
 (to above 
 of the baseline value). The 
 patient 
 was in the 
mg cohort and had a heart rate of 
 
bpm at screening, a pre-dose baseline of 
bpm, a stable nadir of 
bpm, a heart rate of 
bpm at the discontinuation visit and a heart rate of 
bpm at 
days post-discontinuation.
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Table 8
Recovery of bradycardia after treatment discontinuation
AZD9833, assigned starting dose
25 mg
(N=12)
75 mg
(N=12)
150 mg
(N=13)
300 mg
(N=11)
450 mg
(N=4)
Total
(N=52)
Number of discontinued patients
Number of discontinued patients 
with at least 1 post-discontinuation 
follow-up visit
Number (%) of patients with heart 
rate above 
 of baseline
Source: Study D8530C00001 preliminary data (DCO: 
).
AZD9833-related bradycardia was not associated with other changes in ECG variables other 
than QT interval (see below) and 
; nor was it observed 
to be associated with significant changes in either supine diastolic or systolic blood pressure. 
patient required 
 for bradycardia. The 
 in the 
mg cohort 
experienced a reduction in resting heart rate from 
bpm pre-dosing on Cycle 1 Day 1 to 
bpm on Cycle 1 Day 15; due to 
 
the dose was 
 to 
mg on Cycle 2 Day 1. No patients required dose 
interruption or discontinuation for AEs of bradycardia. Investigators have reported that 
patients with bradycardia are able to increase heart rate on exercise, although formal exercise 
tolerance testing has not been performed in this metastatic cancer population. 
To better understand the relationship of dose-dependent bradycardia to general symptomology 
all reported AEs that might relate to bradycardia were considered. They included the 
following preferred terms; dizziness, dyspnoea, dyspnoea exertional, fall, orthostatic 
hypotension and presyncope. Table 9 details these AEs, expressing collectively and 
individually their relationship to bradycardia for each dose studied. Due to the sustained 
nature of observed heart rate changes, the table is further split to consider the same AEs when 
experienced for 7 days or more.
Table 9
Summary of AEs potentially related to bradycardia symptoms
Number (%) of patients with
AZD9833, assigned starting dose
25 mg 
(N=12)
75 mg 
(N=12)
150 mg 
(N=13)
300 mg 
(N=11)
450 mg 
(N=4)
Bradycardia and sinus bradycardia
Any symptoms a
  Dizziness
  Dyspnoea
  Dyspnoea exertional
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Table 9
Summary of AEs potentially related to bradycardia symptoms
Number (%) of patients with
AZD9833, assigned starting dose
25 mg 
(N=12)
75 mg 
(N=12)
150 mg 
(N=13)
300 mg 
(N=11)
450 mg 
(N=4)
  Fall
  Orthostatic hypotension
  Presyncope
Any symptoms a lasting ≥7 days
  Dizziness
  Dyspnoea
  Dyspnoea exertional
  Orthostatic hypotension
 
Bradycardia/sinus bradycardia including 
any other symptoms a
Bradycardia/sinus bradycardia including 
any other symptoms a lasting ≥7 days
0
a
Any symptoms include the MedDRA (version 21.1) preferred terms of dyspnoea, dyspnoea exertional, 
dizziness, fall, presyncope, orthostatic hypotension. The AE reporting period is any time from 1st dose, 
including the safety follow-up period.
MedDRA=Medical Dictionary for Regulatory Activities.
Source: Study D8530C00001 preliminary data (DCO: 
).
Patients with AEs of bradycardia and who also experienced at least 1 AE of at least 7-day 
duration that might relate to bradycardia across the 25, 75, 150, 300 and 450 mg cohorts 
numbered 
 respectively. Of the patients in the 
mg cohort,
patient 
experienced 2 transient episodes of 
 that resolved on the same day (Cycle 1 
Day 28 and midway through Cycle 5), 
 from Cycle 2 Day 1 
onwards and transient 
 midway through Cycle 6. The 
 patient in the 
150 mg cohort experienced 
 and 
 from 
Cycle 1 Day 8 onwards. The patient in the 300 mg cohort experienced an AE of 
 
from Cycle 1 Day 5 until Cycle 2 Day 1. Two further patients were identified with AEs of 
 and AEs of any duration that might relate to bradycardia. 
 patient assigned to 
the 
mg cohort had 
 prior to Cycle 4 Day 1 dosing while a patient assigned to the 
mg cohort experienced 
 from Cycle 1 Day 1 to Cycle 1 Day 2. 
Taken altogether, it would appear from the data available that AZD9833-induced bradycardia 
is generally asymptomatic with little association between the degree of bradycardia and 
potential bradycardia-related symptoms.
There was report of 
and 
(CTCAE Grade 1) 
 
 possibly related to AZD9833 during Cycle 1 Day 1 in the 
mg cohort; no 
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relevant past medical history or concomitant medications. No similar event was captured 
either before or subsequently for this patient, nor for any other study subject.
AZD9833 appears to be associated with a 
 increase in 
, as summarised in 
Table 10.
Table 10
 values and change from baseline in 
AZD9833, assigned starting dose
25 mg 
(N=12)
75 mg
(N=12)
150 mg
(N=13)
300 mg
(N=11)
450 mg
(N=4)
Maximum increase from baseline in QTcF (msec)
Median
(95% CI)
 
)
Mean
(95% CI)
 
Min, Max
3
Patients with 
 absolute value
 absolute value
 absolute value
 change from baseline
 change from baseline
change from baseline
 change from baseline
QTcF threshold values are calculated based on the individual patient maximum absolute value occurring at any 
time after the 1st dose. 
Source: Study D8530C00001 preliminary data (DCO: 
)
The time course of onset of 
 appears similar to that of 
, raising 
the possibility that the 
 represents an artefact of the 
, rather than 
a true effect on 
 rate per se. Investigation into the 
 is 
ongoing.
One patient in the 
 mg cohort experienced a 
 from 
msec on 
Cycle 1 to 
msec on Cycle 1 Day 8 (central ECG trace; local site ECG trace 502 msec), 
which was regarded as a DLT (mean 
 
) was 
 msec at the same study timepoint). The mean heart rate on Cycle 1 Day 8
was 
 bpm (representing a decrease of 
bpm from pre-dosing ECGs on Cycle 1 Day 1). 
The mean heart rate on Cycle 1 Day 8 was
 bpm (representing a decrease of 
 bpm from 
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Summary
Overall, based on the emerging safety data from D8530C00001, AZD9833 
 
 daily appears to be tolerated in patients with ER-positive advanced breast cancer. 
Dosing with AZD9833 is associated with bradycardia, 
 and visual 
disturbances, with lower doses showing lesser degrees of bradycardia and 
, 
and inducing visual disturbances in a lower proportion of patients exposed.
2.2.2.2 Pharmacokinetics
Pharmacokinetics after the 1st dose 
After a single AZD9833 dose, the time to reach maximum plasma concentration (tmax) was 
achieved approximately 2 to 4 hours post-dose (Figure 2). Following tmax, plasma 
concentrations declined with a median terminal elimination half-life (t1/2) of approximately 
9 to 13 hours across all dose groups (Table 12). Exposure increased more than in proportion to 
dose over the range 25 to 450 mg, with geometric means of the dose-normalised maximum 
plasma drug concentration (Cmax) and area under the plasma concentration-time curve from 
time of dose to 24 hours (AUC0-24h) values for AZD9833 450 mg being 3.7 and 2.6-fold 
higher respectively than the dose-normalised values for AZD9833 25 mg.
Pharmacokinetics after multiple doses
After 15 days of repeat dosing, the tmax was achieved approximately 2 to 6 hours post-dose. 
After multiple dosing, there was evidence of accumulation at the lower dose levels with the 
Cmax Day 15/Day 1 ratios being 1.8 and 1.4 for the 25 and 75 mg cohorts respectively. 
However, at 150, 300 and 450 mg doses, the Cmax Day 15/Day 1 ratios reduced to 1.2, 1.1 and 
0.7, respectively. After 15 days of once daily dosing, exposure in terms of Cmax and area under 
the plasma concentration-time curve from time of dose to 8 hours (AUC0-8h) increased broadly 
in proportion to dose between 75 and 300 mg.
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Figure 2
Mean plasma AZD9833 PK time course
Day 1 versus Day 15 of Cycle 1
Solid dots/vertical bars represent mean concentration/standard deviation (SD) at each timepoint for each dose
Source: Study D8530C00001 preliminary data (DCO: 
).
Table 12
Preliminary plasma PK parameters of AZD9833 in humans
Dose 
(mg)
Day
N
Cmax a
ng/mL
tmax b
hour
AUC0-last a,c
ng.h/mL
AUC0-inf a
ng h/mL
t1/2 b
hour
25
1
12
25
15
11
75
1
12
75
15
12
150
1
14 d
150
15
12
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Table 13
Mean percent change in ER and PgR H-scores and Ki-67 score
AZD9833, assigned starting dose
25 mg
(N=1)
75 mg
(N=3)
150 mg
(N=3)
300 mg
(N=1)
450 mg
(N=0)
Lesion site (n) 
Liver
Subcutaneous skin
1
-
1
2
2
1
1
-
-
-
Mean % change in ER H-score
(range)
-11%
-56%
(-69, -34)
-32%
(-40, -25)
-38%
-
Mean % change in PgR H-score
(range) 
-63%
-68%
(-83, -52)
-74%
(-100, -47)
-91%
-
Mean % change in Ki-67 score
(range)
-0%
-35%
(-98, +50)
-36%
(-76, 0)
-98%
-
a
One patient had a PgR negative status, so not included in the calculation for mean percent change in PgR 
H-score.
Source: Study D8530C00001 preliminary data (DCO: 
).
All patients enrolled in Study D8530C00001 had 
ctDNA and tumour marker 
 
analysed pre and on-treatment, there was evidence of ctDNA suppression across all dose 
levels following AZD9833. Patients with RECIST responses had the largest level of reduction 
of ctDNA levels and 
 levels.
Patients with measurable and non-measurable disease were enrolled to D8530C00001. The 
RECIST objective response rate (ORR) in patients with measurable disease at baseline along 
with clinical benefit rate at 24 weeks (CBR24) is summarised in Table 14.
For patients with measurable disease in advanced breast cancer and treated with fulvestrant 
monotherapy, response rates range from 11 to 14% (Di Leo et al 2010, Turner et al 2015, 
André et al 2019, Jones et al 2019). 
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Table 14
Objective response rate and clinical benefit rate at 24 weeks
n/m (%)
AZD9833, assigned starting dose
25 mg
(N=12)
75 mg
(N=12)
150 mg
(N=13)
300 mg
(N=11)
450 mg
(N=4)
Total
(N=52)
ORR (based upon 
measurable disease at 
baseline only) a
CBR24 (based upon 
measurable or non-
measurable disease at 
baseline) b
a
For the ORR, n=number of responders; m=number of patients who have a DCO date - date of 1st dose 
≥17 weeks or 2nd post-treatment scan ≥15 weeks.
b
For the CBR24, n=number of patients who have confirmed response or SD for ≥23 weeks post-treatment; 
m=number of patients who have a DCO date - date of 1st dose ≥24 weeks or ≥23 weeks post-treatment scan.
SD=stable disease.
Source: Study D8530C00001 preliminary data (DCO: 
).
Overall, the observed modulation of key pharmacodynamic markers along with the durations 
on study, the CBR24 and ORR are considered to be strong indicators of clinical efficacy for 
doses of AZD9833 of 75 mg once daily and above in this Phase 1 setting, and that warrant 
further investigation in a Phase 2 progression-free survival study.
In light of the overall safety and efficacy findings summarised above, further investigation of 
AZD9833 at doses of 75 mg, 150 mg and 300 mg once daily is planned in a randomised 
Phase 2, second-line ER-positive setting versus the standard-of-care SERD fulvestrant.
A detailed and updated description of the chemistry, pharmacology, efficacy, and safety of 
AZD9833 is provided in the Investigator’s Brochure.
2.3
Benefit/risk assessment
Patients enrolled in the study will be randomly assigned in a 1:1:1:1 ratio to receive one of the 
following 4 treatments:

AZD9833 (75 mg, PO, once daily)

AZD9833 (150 mg, PO, once daily)

AZD9833 (300 mg, PO, once daily)

Fulvestrant (500 mg, IM, on Day 1, Day 15, Day 29, and 4-weekly thereafter)
As of December 2020, the Sponsor stopped enrolment to the 300 mg treatment arm. Ongoing 
patients in the 300 mg treatment arm may continue treatment as planned.
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2.3.1
Fulvestrant
Fulvestrant is approved for the treatment of ER-positive, locally advanced or metastatic breast 
cancer in post-menopausal women (not previously treated with endocrine therapy, or with 
disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression on 
anti-oestrogen therapy) and is considered standard-of-care treatment for ER-positive breast 
cancer (Cardoso et al 2018).
Detailed information about the known and expected benefits and risks and reasonably 
expected AEs of fulvestrant may be found in the local product information of fulvestrant.
2.3.2
AZD9833
2.3.2.1 Potential benefits
There is no certainty that AZD9833 will provide clinical benefit to patients, although the 
biological hypothesis, non-clinical data and preliminary clinical efficacy and safety data from 
the Phase 1 study (D8530C00001) support further evaluation of AZD9833 in the proposed 
patient population. 
2.3.2.2 Potential risks
Based on non-clinical toxicology studies, cardiovascular effects, 
 
), neurological 
effects and reproductive system effects were identified as potential risks. The Phase 1 study 
has identified visual disturbances and bradycardia as new important risks, and 
 
as a new risk as described in detail above.
 
 and 
reproductive symptom effects were not observed in the Phase 1 study.
 
 
 Further information 
about non-clinical toxicology data is provided in the Investigator’s Brochure.
Visual disturbances
Patients with uncontrolled central nervous system (CNS) metastatic disease are excluded from 
the study. Patients with spinal cord compression and/or brain metastases may be enrolled if 
definitively treated (eg, surgery or radiotherapy) and stable off steroids for at least 4 weeks 
prior to start of study treatment (see Section 5.2, exclusion criterion 3).
Patients experiencing neurological AEs (including visual disturbances) should be fully 
assessed by the Investigator and appropriately managed as per standard local practice, 
including ophthalmological examination if indicated.
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Patients will be carefully monitored for the development of visual disturbance AEs through 
conventional AE collection and reporting. Specific patient-centric questionnaires and 
interviews in relation to visual disturbances are detailed in Section 8.1.4.3. 
Patients experiencing visual disturbances will be counselled regarding driving and operating 
machinery, particularly under conditions of variable lighting.
See Section 6.6 for patient-level dose reduction and stopping rules in relation to visual 
disturbances.
Bradycardia and 
The study will exclude patients with clinically important cardiac conditions and factors that 
increase the risk of 
 or arrhythmia (see Section 5.2, exclusion criterion 5):
Cardiovascular monitoring will be performed regularly during the study (see SoA, Table 1). 
Vital signs (including blood pressure and pulse rate, see Section 8.2.3) and 12-lead centralised 
ECGs (see Section 8.2.4.1) will be recorded weekly for the first 3 weeks of Cycle 1, on Day 1 
of every cycle up to Cycle 6 and then every 2 cycles. A 24-hour ambulatory ECG will also be 
performed at screening and once during treatment (see Section 8.2.4.2).
Patients will be carefully monitored for the development of potential bradycardia-related 
symptoms through conventional AE collection and reporting. Patients experiencing 
cardiovascular AEs should be fully assessed by the Investigator and appropriately managed as 
per standard local practice.
See Section 6.6 for patient-level dose reduction and stopping rules in relation to bradycardia 
and/or 
.
Drugs that are known to prolong QT and have a known risk of torsade de pointe are not 
permitted, as indicated in Appendix B 1. Advice regarding drugs known to reduce heart rate is 
provided in Appendix B 4. 
 
Minimal to moderate 
 was observed in  female rats dosed at 
 mg/kg/day 
(mid dose) and female rats dosed at
 mg/kg/day (high dose) after six months 
administration of AZD9833. There were no accompanying clinical signs and no evidence of 
effect on 
). There were no histopathological findings in other 
 examined. Patients will have regular monitoring of 
, 
) at the same frequency as the safety laboratory assessments (see section 8.2.1). 
 will also be performed at 
monthly whilst on treatment 
with AZD9833 and upon discontinuation (see section 8.2.4.3). Furthermore, patients with a 
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baseline left ventricular ejection fraction (LVEF) of <50% will be excluded from the study 
(see Section 5.2).
 and 
 in the 
Moderate or marked 
 was observed in the 
 of female rats dosed at 
 mg/kg/day (high dose) (increased severity of a previously identified finding). This was 
accompanied by mild mixed 
 and 
, co-localised with 
 and an increase in 
 (new findings). Patients will be 
carefully monitored for the development of relevant symptoms through conventional AE 
collection and reporting. 
 were observed in rats ( /15 dosed at 
 mg/kg/day 
[high dose]) and dogs ( /4 dosed at  mg/kg/day [low dose] and 1/4 dosed at 
 mg/kg/day 
[high dose]). In rats only, the findings correlated with 
 macroscopically observed in 
the 
at necropsy. Mild or moderate 
 was observed in 5 rats 
dosed at 
 mg/kg/day (high dose) and at a moderate severity in  rat dosed at 
mg/kg/day 
(low dose) and 1 rat dosed at 
 mg/kg/day (mid dose). Moderate severity 
 
 was present in
4 dogs dosed at 
 mg/kg/day (high dose). 
 
) were considered to be a precursor to the 
 
 
Patients will be carefully monitored for the development of relevant symptoms through 
conventional AE collection and reporting.
Drug-drug interactions
Drugs which may be of risk of drug-drug interactions should be avoided as per the guidance 
provided in Appendices B 2 and B 3.
 
2.3.3
Overall benefit-risk and ethical assessment
The patients in this study will have advanced ER-positive breast cancer and have experienced 
disease progression on endocrine therapy for ER-positive breast cancer. There is an unmet 
clinical need for new therapeutic agents for patients in this disease setting. Although there can 
be no certainty of clinical benefit to patients from AZD9833 at the proposed doses, the 
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biological hypothesis, non-clinical data, and preliminary clinical data described above and in 
the Investigator’s Brochure support its potential benefit in the proposed study population.
The dose-ranging aspect of this Phase 2 study permits a detailed evaluation of the overall 
benefit-risk profile at each of the tolerated AZD9833 doses associated with clinical benefit in 
the Phase 1 study.
Provision is made for appropriate safety and futility interim analyses during the study to 
enable modification of the study if required. Rolling 6-monthly interim safety analyses will be 
performed by a SRC throughout the study and which will permit re-evaluation of potential 
risks during study conduct. The SRC remit will make provision for modification of the study 
(eg, modification of assessment schedule, closure of experimental study arms, or the study 
overall) if required. Interim futility analyses described in Section 9.5.1 and conducted by a 
DMC will minimise patient exposure to AZD9833 should the anticipated benefits not 
materialise. The remit and conduct of the SRC and DMC will be described in separate charter 
documents which will be finalised prior to the 1st patient’s randomisation.
Detailed patient-level dose de-escalation plans and stopping rules are provided for the key 
AZD9833-related AEs identified in the Phase 1 study (see Section 6.6).
Fulvestrant has been selected as an appropriate comparator in this randomised study and is 
used in accordance with the local product information.
The investigation of AZD9833 versus fulvestrant in this patient population is considered to be 
acceptable based upon the data presented above, the lack or limitations of effective alternative 
monotherapy treatments available, the limited life expectancy of the study population due to 
malignant disease. The overall benefit/risk assessment for this Phase 2 study is considered to 
be favourable.
See Section 9.5.1 and Appendix A for information regarding the DMC and the SRC.

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3
OBJECTIVES AND ENDPOINTS
Table 15
Study objectives
Primary Objective:
Endpoint/Variable:
To determine the clinical efficacy (as assessed by 
PFS) of AZD9833 when compared to fulvestrant in 
women with advanced ER-positive HER2-negative 
breast cancer
PFS assessed by the Investigator as defined by 
RECIST version 1.1
Secondary Objectives:
Endpoints/Variables:
To determine anti-tumour effect of AZD9833 when 
compared to fulvestrant in women with advanced 
ER-positive HER2-negative breast cancer
Based on tumour response assessed by the 
Investigator, as defined by RECIST version 1.1:
•
ORR
•
DoR
•
Best percentage change in tumour size and 
percentage change in tumour size at 16 weeks
To determine the effect of AZD9833 on survival and 
clinical benefit when compared to fulvestrant in 
women with advanced ER-positive HER2-negative 
breast cancer
•
OS
•
CBR24
To evaluate the PK of AZD9833 in this patient 
population at steady state
Plasma concentrations of AZD9833 and, if 
appropriate, metabolite(s) on Day 15 (pre- and post-
dose) and Day 29 (pre-dose)
To evaluate the pharmacodynamics of AZD9833 and 
fulvestrant in a subgroup of patients with advanced 
ER-positive HER2-negative breast cancer
•
Percent change from baseline in ER and PgR 
expression assessed by the manual H-score 
method.
•
Percent change from baseline in Ki67 labelling 
index
To evaluate the effect of AZD9833 and fulvestrant on 
the patients’ HRQoL, as assessed by 
patient-completed HRQoL questionnaires
Changes from baseline in total/subscale scores of the 
EORTC QLQ-C30, EORTC QLQ-BR23, 
NEI VFQ-25, and EQ-5D-5L
Safety Objective:
Endpoints/Variables:
To evaluate the safety and tolerability of AZD9833 
when compared to fulvestrant in women with 
advanced ER-positive HER2-negative breast cancer
•
AEs/SAEs
•
Vital signs, ECGs, clinical chemistry, 
haematology, urinalysis parameters

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4
STUDY DESIGN
4.1
Overall design
This is a randomised, open-label, parallel-group, multicentre Phase 2 study to compare the 
efficacy and safety of daily PO AZD9833 versus IM fulvestrant in women with advanced 
ER-positive HER2-negative breast cancer. Post-menopausal women with histologically or 
cytologically confirmed metastatic or loco-regionally recurrent disease before randomisation 
and fulfilling all of the inclusion criteria and none of the exclusion criteria will be included. 
Randomisation will be stratified according to the prior use of CDK4/6 inhibitors and the 
presence of liver and/or lung metastases.
After the screening visit and confirmation of eligibility, patients will be randomly assigned in 
a 1:1:1:1 ratio to receive 1 of the following 4 treatments, consisting in 4-week treatment 
cycles until disease progression (assessed by the Investigator as defined by RECIST 
version 1.1):

AZD9833 (75 mg, PO, once daily)

AZD9833 (150 mg, PO, once daily)

AZD9833 (300 mg, PO, once daily) closed for recruitment as of December 2020

Fulvestrant (500 mg IM, Day 1, Day 15, Day 29, and 4-weekly thereafter)
As of December 2020, the Sponsor stopped enrolment to the 300 mg treatment arm. Ongoing 
patients in the 300 mg treatment arm may continue treatment as planned.
During the treatment period, patients will attend visits on:

Day 1, Day 8, and Day 15 of Cycle 1

Day 1 of each subsequent cycles until treatment discontinuation
After the treatment period, patients will attend 2 safety follow-up visits (at the time of 
treatment discontinuation and 28 days later) and will continue to be followed for survival.
Throughout the study, patients will be asked to report AEs and the use of concomitant 
medication.
Safety assessments (physical examination, vital signs, ECGs, clinical safety laboratory 
assessments) will be performed at screening, on Day 1 of every cycle (up to Cycle 6) and 
every 2 cycles (from Cycle 6) and at the EOT visit. Safety assessments will also be performed 
on Cycle 1 Day 8 (vital signs and triplicate ECGs), Cycle 1 Day 15 (vital signs, ECGs, clinical 
chemistry, haematology, and urinalysis), at the 28-day safety follow-up (physical exam, vital 
signs, triplicate ECGs and echocardiogram).

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Tumour imaging will be performed for the assessment tumour response according to RECIST 
version 1.1 at screening and every 8 weeks from Week 9 until disease progression. 
Patients will complete HRQoL questionnaires on Day 1 of Cycles 1, 2, and 4, then 8-weekly 
(Day 1 of every 2nd cycle) from Week 25 (Cycle 7) to coincide with tumour imaging, at the 
EOT and/or disease progression, and at the 28-day safety follow-up. 
Blood and plasma samples for ctDNA and 
 analyses will be collected at screening, on 
Day 1 and Day 15 of Cycle 1, on Day 1 of Cycles 2 to 5, 8-weekly (Day 1 of every 2nd cycle) 
from Week 25 (Cycle 7) to coincide with tumour imaging, at the EOT and/or disease 
progression.
Blood samples for 
 will be collected at screening, on Day 1 of Cycles 1, 2, and 4, and at 
the EOT.
For patients receiving AZD9833, blood samples will be collected for PK assessments on 
Cycle 1 Day 15 and Cycle 2 Day 1.
For patients who provide specific consent, the following optional assessments will be 
performed:

Up to 12 patients per treatment group will be selected such that they are suitable for 
providing 1 pre-treatment and 1 on-treatment paired tumour biopsy sample. If provision 
of paired biopsies becomes clinically unfeasible for a selected patient during the course of 
her care, the patient may be replaced until up to 12 evaluable biopsy pairs are collected 
within each treatment group.

An optional blood sample will be collected at pre-dose on Day 1 of Cycle 1 or later 
during the study for future 
 research.
For an overview of the study design see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 6.1 Treatments Administered. 
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives 
and Endpoints.
4.2
Scientific rationale for study design
This Phase 2 study is designed to investigate the efficacy and safety of AZD9833 compared 
with fulvestrant for the treatment of ER-positive HER2-negative advanced breast cancer. The 
study will enrol post-menopausal women with histologically or cytologically confirmed 
metastatic or loco-regionally recurrent disease. Fulvestrant, the active comparator selected for 
the study, is approved in this patient population and considered standard-of-care (Cardoso et 
al 2018). 
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The primary endpoint for this study is PFS (defined by RECIST version 1.1). The anti-tumour 
efficacy will be further evaluated with secondary endpoints (ie, ORR, duration of response 
[DoR], percent change in tumour size). The OS and CBR24 will also be assessed.
Patients will be randomly assigned to 1 of the 4 treatment groups, or from December 2020, to 
1 of the 3 treatment groups via an interactive web response system (IWRS). An open-label 
design is adopted due to the impracticality and patient impact in administering dummy IM 
injections 4-weekly for the 3 groups of patients randomised to AZD9833. The potential 
assessment biases of an open-label design are mitigated by a BICR sensitivity analysis for 
PFS. 
Randomisation will be stratified according to the following:

Prior use of CDK4/6 inhibitors (yes/no), controlled such that between 32 and up to a 
maximum of 40 patients per treatment group are enrolled for each strata

Presence of liver and/or lung metastases at baseline (yes/no)
It is currently unknown how prior use of CDK4/6 inhibitors will affect the overall PFS in this 
patient population, and therefore a capped stratification (as described above) will be 
implemented to allow approximately equal proportions of patients with or without prior use of 
CDK4/6 inhibitors to be recruited. However, given the rapidly evolving treatment landscape 
with accelerating usage of CDK4/6 inhibitors in this disease setting, in the event that the 
availability of patients without prior of CDK4/6 inhibitor use becomes limited, then the 
Sponsor may choose to modify the cap limit.
Presence of lung/liver metastases is known as an important prognostic factor in women with 
advanced breast cancer and therefore it is important to balance this disease characteristic 
across the treatment groups.
Sparse PK samples will be collected on Day 15 (pre-dose, 2 and 4 hours post-dose) and 
Cycle 2 Day 1 (pre-dose only) to measure pre-dose and post-dose plasma concentrations of 
AZD9833 and, if appropriate, metabolite(s). The 2 and 4 hours post-dose reflect timepoints 
around absorption phase and tmax. Pre-dose values at Day 15 and Cycle 2 Day 1 will confirm 
steady state.
For patients who provide specific consent, up to 12 patients per treatment group will be 
selected such that they are suitable for providing 1 pre-treatment and 1 on-treatment paired 
tumour biopsy sample. In the event that a subject has been selected for provision of paired 
biopsies, and this becomes clinically unfeasible during the course of their care, the individual 
treatment groups may be expanded by recruiting additional biopsy-eligible subjects until up to 
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The study will also include exploratory investigations into variations in pharmacodynamics 
and exploratory biomarker profiles and their relationship to drug effect. These biomarkers 
may be derived from
, and may include 
. There 
are many potential benefits of this exploratory research, including the possibility to identify 
patients most likely to benefit from treatment, explain outliers or non-responders, and identify 
adverse reactions related to drug exposure. This research may result in an understanding of the 
impact of variation between individuals and how it can be utilised to bring better drugs to the 
clinic. The ability to acquire appropriate consent to collect biological samples is of utmost 
importance to establish an archive and allow future meta-analysis of data derived from this 
and future studies with AZD9833.
AstraZeneca intends to perform 
research in the broader AZD9833 clinical 
development programme to explore how 
 may affect the clinical parameters 
associated with AZD9833. This may result in improvements in the design and interpretation 
of future clinical studies and, potentially, the development of 
 guided treatment 
strategies.
4.3
Justification for dose
The selected dose of fulvestrant is the dose recommended in its product information for this 
patient population.
The selection of the 3 dose levels of AZD9833 to be tested is supported by the PK and safety 
data collected during the first-in-human study of AZD9833 (Protocol D8530C00001, see 
Section 2.2). Rules for AZD9833 dose modifications in case of toxicity are summarised in 
Section 6.6
4.4
End of study definition
The end of study is defined as the last expected visit/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. After this visit, the patient will 
continue to be followed for survival and may have further tumour assessments until disease 
progression is confirmed.
For the purpose of the primary efficacy analysis, the DCO will be after enrolment is complete 
and when a minimum of 108 events is observed for the pairwise comparison of 75 mg and 
150 mg AZD9833 doses versus fulvestrant (corresponding to approximately 75% PFS 
maturity for the best performing dose level). At the time of this DCO, the database will be 
locked, the data analysis will be performed, and the Clinical Study Report (CSR) written. 
Following the decision to stop enrolment to the 300 mg AZD9833 treatment arm, data from 
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this arm will be reported in the same CSR when the DCO is reached for the remaining 
treatment arms.
After the primary DCO, efficacy and safety data may continue to be collected. Additional 
DCOs may be defined for PFS and OS follow-up analyses. If these additional DCOs are 
reached, the database will be locked, further limited data analysis will be performed and an 
addendum or addenda to the CSR will be written to document the results. The last DCO may 
be when 
 OS maturity is reached (see Section 9.4, Table 22 for the definition of DCOs).
See Appendix A 6 for guidelines for the dissemination of study results.
5
STUDY POPULATION
Prospective approval of protocol deviations to inclusion/exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to assigned/randomised to a study intervention. Patients who are enrolled and 
do not meet the entry requirements are screen failures, refer to Section 5.4.
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.
For procedures for withdrawal of incorrectly enrolled patients see Section 7.3.
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply:
Informed consent
1
Provision of signed and dated, written informed consent prior to any mandatory 
study-specific procedures, sampling, and analyses. Patients are also required to consent to 
the provision of archival tumour biopsies.
2
For patients who consent, provision of signed and dated written 
 informed consent 
prior to collection of sample for 
 analysis.
Age and gender
3
Female patients aged at least 18 years.
Menopausal status
4
Post-menopausal defined as meeting at least 1 of the following criteria:
(a) Have undergone a bilateral oophorectomy.
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(b) Age ≥60 years.
(c) Age ≥50 years and with cessation of regular menses ≥12 months and with an intact 
uterus in the absence of gonadotropin-releasing hormone (GnRH) agonist, oral 
contraception or hormone replacement therapy.
(d) Age <50 years and with cessation of regular menses ≥12 months and follicle 
stimulating hormone (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 gonadotropin-releasing hormone (GnRH) agonist, oral contraception or 
hormone replacement therapy.
Disease characteristics
5
Histologically or cytological confirmation of adenocarcinoma of the breast.
6
Documented ER-positive status of primary or metastatic tumour tissue, according to the 
local laboratory parameters and where those laboratory parameters are in accordance with 
accepted diagnostic guidelines (eg, American Society of Clinical Oncology/College of 
American Pathologists Guideline Recommendations for Immunohistochemical Testing of 
Estrogen and Progesterone Receptors in Breast Cancer, [Hammond et al 2010]). 
7
Documented HER2-negative status defined as an immunohistochemistry (IHC) Score 0 or 
1+ or negative by in situ hybridisation (ISH; FISH/CISH/SISH); if IHC 2+, ISH 
negativity is required. Where available, assessment of ER and HER2 status should be 
based on the most recent tumour biopsy sample. according to the local laboratory 
parameters and where those laboratory parameters are in accordance with accepted 
diagnostic guidelines (eg, American Society of Clinical Oncology/College of American 
Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen 
and Progesterone Receptors in Breast Cancer, [Hammond et al 2010]).
8
Metastatic disease or loco-regionally recurrent disease suitable for treatment with 
fulvestrant.
9
Radiological or other objective evidence of progression on or after the last systemic 
therapy prior to starting study treatment. Tumour marker progression alone is not 
considered objective evidence of progression.
10 Patients must have:
(a) at least 1 lesion, not previously irradiated, that can be measured accurately at baseline 
as ≥10 mm in the longest diameter (except lymph nodes which must have short axis 
≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) 
which is suitable for accurate repeated measurements, or 
in absence of measurable disease as defined above, at least 1 lytic or mixed 
(lytic+sclerotic) bone lesion that is amenable to serial assessment by CT or MRI; 
patients with sclerotic/osteoblastic bone lesions only in the absence of measurable 
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11 Eastern Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) 
performance status 0 to 1, with no deterioration over the previous 2 weeks and a 
minimum life expectancy of 12 weeks.
Prior chemotherapy, endocrine therapy and other anti-cancer therapy
12 Prior endocrine therapy as follows:
(a) Recurrence or progression on at least one line of endocrine therapy.
(b) No more than 1 line of endocrine therapy for advanced disease.
(c) No more than 1 line of chemotherapy for advanced disease. A chemotherapy line in 
advanced disease is an anti-cancer regimen(s) that contains at least one cytotoxic 
chemotherapy agent and given for 21 days or longer. If a cytotoxic chemotherapy 
regimen was discontinued for a reason other than disease progression and lasted less 
than 21 days, then this regimen does not count as a prior line of chemotherapy. 
Repeat administration of the same anti-cancer regimen on a separate occasion does 
not count as a new line of chemotherapy.
(d) Prior treatment with CDK4/6 inhibitors is permitted.
(e) No prior treatment with fulvestrant, oral SERD, or related therapies (eg, ER, 
proteolysis targeting chimeras [PROTACs], selective ER covalent antagonists 
[SERCAs] in the metastatic setting).
Inclusion criteria for the paired tumour biopsy research subgroup
1
Disease suitable for paired baseline and on-treatment tumour biopsies.
2
Washout from prior tamoxifen: 4 months to elapse from last tamoxifen dose to pre-dose 
on-study biopsy.
3
Provision of signed, written, and dated informed consent for tumour biopsies.
5.2
Exclusion criteria
Patients must not enter the study if any of the following exclusion criteria are fulfilled:
Prior/concomitant therapy
1
Intervention with any of the following:
(a) Any cytotoxic chemotherapy, investigational agents or other anti-cancer drugs for the 
treatment of breast cancer from a previous treatment regimen or clinical study within 
14 days of the first dose of study treatment.
(b) Use of systemic oestrogen-containing hormone replacement therapy within 6 months 
prior to the first dose of study treatment.

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(c) Medications or herbal supplements known to be strong inhibitors/inducers of 
cytochrome P450 
 sensitive
 substrates (commonly prescribed 
drugs are listed in Appendix B), and drugs which are substrates of 
and/or 
 which have a narrow therapeutic index ie, 
 and 
or inability to stop use 
within the washout period as specified in Appendix B prior to receiving the first dose 
of study treatment.
(d) Drugs that are known to prolong QT and have a known risk of torsades de pointes, as 
indicated in Appendix B 1.
(e) Radiotherapy with a limited field of radiation for palliation within 1 week of the first 
dose of study treatment, and/or radiation to more than 30% of the bone marrow or a 
wide field of radiation within 4 weeks of the first dose of study treatment.
(f) Major surgical procedure or significant traumatic injury, as judged by the 
Investigator, within 4 weeks of the first dose of study treatment, 
 
Medical conditions
2
Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of 
starting study treatment, with the exception of alopecia and chemotherapy-related 
peripheral neuropathy.
3
Presence of life-threatening metastatic visceral disease or uncontrolled CNS metastatic 
disease as judged by the Investigator. Patients with spinal cord compression and/or brain 
metastases may be enrolled if definitively treated (eg, surgery or radiotherapy) and stable 
off steroids for at least 4 weeks prior to start of study treatment.
4
Any of the following criteria: 
(a) 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,
(b) Immunocompromised patients, eg, patients who are known to be serologically 
positive for human immunodeficiency virus (HIV). 
(c) Patients with known active hepatitis (ie, heapatitis B or C)
5
Any of the following cardiovascular criteria:
(a) Mean resting QTcF >470 msec obtained from screening triplicate ECG.
(b) Resting heart rate <45 bpm
(c) Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG (eg, complete left bundle branch block, second- and third-degree heart 
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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 hyper-magnesaemia, 
hypo- and hyper-calcaemia.
(e) 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 rescreened 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) Absolute neutrophil count (ANC) <1.5×109/L
(b) Platelet count <100×109/L
(c) Haemoglobin (Hb) <90 g/L
(d) Alanine aminotransferase (ALT) >2.5×the upper limit of normal (ULN)
(e) Aspartate aminotransferase (AST) >2.5×ULN
(f) Total bilirubin (TBL) >1.5×ULN or >3×ULN in the presence of documented 
Gilbert’s Syndrome (unconjugated hyperbilirubinaemia)
(g) Estimated glomerular filtration rate (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 
preclude adequate absorption of AZD9833.
Other exclusions
8
History of hypersensitivity to active or inactive excipients of AZD9833 or fulvestrant.
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.

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12 Male patients are excluded from this study.
13 Women of childbearing potential are excluded from this study.
5.3
Lifestyle restrictions
5.3.1
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 
food). There are no food restrictions for fulvestrant.
5.4
Screen failures
Screen failures are defined as patients who are enrolled (ie, signed the informed consent form 
[ICF] to participate in the clinical study) but do not meet entry requirements and therefore 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 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
reasons for screen failure (captured in the screening log), and any 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 have to re-consent to the study and all screening procedures out of screening period 
window must be repeated. Laboratory values re-tested within the 28-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 case 
report form (CRF).

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6
STUDY TREATMENTS
Study treatment is defined as any product(s) (including marketed product comparator) 
intended to be administered to a study participant according to the study protocol. Study 
treatment in this study refers to AZD9833, and to fulvestrant.
6.1
Treatments administered
6.1.1
Investigational products
Table 16
Study treatments
Treatment 1
Treatment 2
Treatment 3
Treatment 4
Treatment name
AZD9833
Fulvestrant
Dosage formulation
25-mg and 100-mg tablets
250 mg/5 ml solution for IM 
injection
Dosage level(s)
75 mg
once daily
150 mg
once daily
300 mg
once daily
500 mg
Day 1, Day 15, Day 29, and 
4-weekly thereafter
Route of 
administration 
PO
IM injection
Dosing instructions
3×25-mg 
tablets
2×25-mg tablets + 
1×100-mg tablet
3×100-mg 
tablets
2 consecutive 250-mg 
injections from 2 prefilled 
syringes (1 in each buttock)
AZD9833 should be taken in the morning, with or 
without food, at approximately the same time.
Packaging and 
labelling
AZD9833 will be provided in bottles. Each bottle 
will be labelled in accordance with country 
regulatory requirements.
Fulvestrant will be packed into 
single-dose cartons containing 
2 labelled prefilled syringes. 
Each carton will be labelled in 
accordance with country 
regulatory requirements.
Provider
AstraZeneca 
Commercial fulvestrant 
(Faslodex) will be provided by 
AstraZeneca.
Missed doses of AZD9833
The patient should make every reasonable effort to take the AZD9833 tablet(s) at the same 
time of day. Table 17 below provides advice in the event of missed AZD9833 doses. If a 
patient needs to take the dose earlier, for whatever reason, the patient can take the dose up to 
2 hours earlier than the scheduled dose time. 
Patients should not attempt to take a replacement dose of AZD9833 should they vomit shortly 
after attempting to swallow the tablet(s). Rather, they should wait and take their next 

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scheduled dose of AZD9833. The patient should make every reasonable effort to take 
AZD9833 on time.
Table 17
Missed doses of AZD9833
Issue
Action
Patient misses dose of AZD9833, but 
remembers within 6 hours of their normal 
scheduled dosing time
Patient should take the missed dose of 
AZD9833
Patient misses dose of AZD9833, but 
remembers more than 6 hours after their 
normal scheduled dosing time
Patient should wait and take their next 
scheduled dose of AZD9833
6.2
Preparation/handling/storage/accountability
Fulvestrant must be stored in a refrigerator (2°C to 8°C) in the original packaging, to protect 
from light. 
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.
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.
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. 
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.
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.
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).

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6.3
Measures to minimise bias: randomisation and blinding
This is an open-label study. All patients will receive active treatment.
As the Investigators will not be blinded to study treatments, a BICR of tumour scans will be 
performed to provide independent tumour response assessment in addition to response 
evaluation by Investigator.
To reduce potential bias during the study, eligible patients will be randomly allocated at a 
1:1:1:1 ratio to receive 1 of the 4 study treatments. As of December 2020, the Sponsor stopped 
enrolment to the 300 mg treatment arm. 
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, with a maximum delay of 
3 days. The randomisation will be stratified based on 2 stratification factors:

prior use of CDK4/6 inhibitors in any setting (yes/no)

presence of lung and/or liver metastases (yes/no)
The 1st factor (ie, prior use of CDK4/6 inhibitors) will be controlled such that between 32 and 
up to a maximum of 40 patients per treatment arm (out of 72 planned patients) are included in 
each stratum, to ensure approximately 50% of patients in each treatment group at the final 
analysis will be naïve to CDK4/6 inhibitors. The cap will allow a maximum number of 
40 patients to be enrolled per stratum, but will not exceed the total planned per treatment 
group. There will be no cap imposed on the 2nd stratification factor (ie, presence of lung 
and/or liver metastases). Given the rapidly evolving treatment landscape with accelerating 
usage of CDK4/6 inhibitors in this disease setting, the Sponsor may choose to modify the cap 
limit if the availability of patients without prior of CDK4/6 inhibitor use becomes limited.
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 treatment.
6.4
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, 
dose interruptions, dose reductions, dose discontinuations should be recorded in the CRF.
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.

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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
Drugs affecting 
 metabolism
Strong inhibitors and strong inducers of 
 should not be combined with AZD9833 
and are not allowed in this study (see Section 5.2 Exclusion criteria).
Strong inhibitors or inducers of 
 should be stopped at least 2 weeks before the first 
dose of AZD9833 (3 weeks for 
).
Moderate inhibitors and inducers of 
 are permitted but, caution should be exercised 
and patients monitored closely for possible drug interactions.
Guidelines regarding potential interactions of AZD9833 with concomitant medications, 
including lists of drugs known to be inhibitors or inducers of 
 are provided in 
Appendix B 2.
For fulvestrant, the current local product information should be followed, as appropriate for 
the study site region.
6.5.2
 substrates
6.5.2.1 Sensitive 
 substrates
Sensitive 
 substrates (eg, 
) should be stopped at least 2 weeks 
before the 1st dose of AZD9833. 
6.5.2.2
 and 
 substrates
Drugs which are substrates of 
 and/or 
 which have a narrow therapeutic 
index ie, 
 
hould not be combined with AZD9833. These drugs should be stopped at least 
2 weeks before the 1st dose of AZD9833 and not used for at least two weeks after the last dose 
of AZD9833.
Guidelines regarding drugs whose exposure may be affected by AZD9833, including lists of 
known drugs which are substrates of 
 and 
 are provided in Appendix B 3
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6.5.3
Substrates
Preliminary PK data from Part 
 
 of SERENA-1 suggest there is a possibility that AZD9833 may effect clinically 
relevant 
. 
Guidelines regarding drugs whose exposure may be affected by AZD9833, including lists of 
known drugs that are substrates of 
are provided in Appendix B 3.
6.5.4
Medications that prolong QT and have a known risk of torsades de 
pointes
Drugs that are known to prolong QT and have a known risk of torsades de pointes should not 
be combined with AZD9833, as indicated in Appendix B 1. 
6.5.5
Medications known to reduce heart rate
Drugs that are known to reduce heart rate are allowed, but new prescriptions or dose 
increments while on study should be discussed with the clinical study team, as indicated in 
Appendix B 4.
6.5.6
Anti-cancer treatments

Patients requiring radiotherapy or surgery for breast cancer to manage worsening of 
disease after randomisation will generally be considered to have progressed. If radiation 
or surgery is performed for breast cancer for reasons other than objective disease 
progression, the patient may continue to receive study medication and be followed for 
objective disease progression.

Bisphosphonate/denosumab therapy for the prevention of skeletal related events in 
patients with bone metastases must be started at least 14 days prior to the first dose of 
study treatment. Patients who have commenced randomised study treatment and are 
considered to require treatment with denosumab or bisphosphonates will need to be 
discussed with the Sponsor.

Patients must not receive any other anti-cancer therapy, including investigational agents, 
while on study.
 
 
6.5.8
Drugs containing sex hormones or affecting sex hormone status
Sex hormone containing drugs such as hormone replacement therapy, progestational agents 
(megestrol acetate), dehydroepiandrosterone, other androgens (eg, oxandrolone) and selective 
ER modulators (eg, raloxifene [Evista®]) are not permitted during the study. In cases where 
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patients suffer severe menopausal symptoms, management with non-hormonal agents (eg, 
clonidine or venlafaxine) is recommended. In cases of atrophic vaginitis the use of non-
hormonal vaginal moisturising or lubricating gels or creams is recommended. Use of 
oestrogen-containing vaginal creams or other topical preparations is not allowed on the study, 
but use of controlled-release vaginal rings (eg, Estring®) may be considered at the 
Investigator’s discretion in severe cases or where all the other treatment possibilities have 
been exhausted.
In addition, other drugs than those mentioned above which may affect sex hormone status or 
disease response, such as systemic ketoconazole, systemic corticosteroids and adrenocortical 
suppressants are not allowed to begin after randomisation into the study. However, the patient 
can continue to receive such drugs if they were taken before randomisation and the 
Investigator is satisfied that the patient’s hormonal status is stable. Hormone antagonists and 
related agents (eg, soyisoflavones) 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.
Details of all subsequent breast cancer therapies received from the time of objective disease 
progression on randomised treatment in this study and, up to the date of DCO for the 
 
survival analysis (or final database closure whichever is the earliest) must be collected.
6.6
Dose modification
6.6.1
AZD9833
For AZD9833, guidance for dose modifications (dose interruption, reduction and/or 
discontinuation) in case of toxicities that are not attributable to the disease or disease-related 
processes and considered to be possibly related to AZD9833 by the investigator is summarised 
in Table 18. 
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Table 18
AZD9833 dose interruption, reduction and/or discontinuation guidance
CTCAE (version 5.0) 
toxicity
Details
Actions
Other AEs considered 
related to AZD9833
 
 
 
 
 
 
a
Permitted dose reduction levels are 
mg and/or 
 mg once daily. In the event that a patient receiving 
mg once daily requires a dose reduction, any further reduced dose level should be discussed with the 
Sponsor.
b
The following (non-exhaustive) list details actions that may aid in the identification of alternative causative 
factors for the QTcF prolongation:

Investigate for electrolyte disturbance; to include hypokalaemia, hyperkalaemia, hypomagnesaemia, 
hypermagnesaemia, hypocalcaemia and hypercalcaemia.

Investigate for thyroid abnormality

Interrogate concomitant medication including new prescriptions and/or dose alterations to existing 
prescriptions
ADL=activities of daily living; CTCAE=Common Terminology Criteria for Adverse Events; QTcF=QT interval 
corrected for heart rate by Fridericia’s formula.
6.6.2
Fulvestrant
Dose reductions for fulvestrant are not permitted.
6.7
Treatment after the end of the study
Subsequent anti-cancer treatment (after study treatment discontinuation) will be at the 
discretion of the patient’s treating physician and should be recorded in the CRF.
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7
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL
7.1
Discontinuation of study treatment
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.

Confirmed disease progression.

Patients incorrectly initiated on study treatment (see Section 7.1.1 Procedures for 
handling patients incorrectly initiated on study treatment).
See the SoA (Table 1) 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 rechallenge
As described in Section 6.6.1, temporary discontinuations of AZD9833 are recommended for 
the management of some toxicities (see Table 18).
7.1.2
Procedures for handling subjects 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.

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7.2
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. 
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 with unknown survival status at end of study.
7.3
Withdrawal from the study
A patient may withdraw from the study (eg, withdraw consent), at any time at her own 
request, without prejudice to further treatment. Patients who are withdrawn from the study 
will not be replaced.
A patient may withdraw from providing biopsy samples at any time, without prejudice to 
further treatment and independent of any decision concerning participation in other aspects of 
the main study. These patients may be replaced until up to 12 evaluable biopsy pairs are 
collected in each treatment group.
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.
AstraZeneca or its delegate will request Investigators to collect information on patients’ 
survival status (dead or alive; date of death when applicable).
See SoA (Table 1) for data to be collected at the time of study discontinuation and 28-day 
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8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (Table 1). 
The Investigator will ensure that data are recorded on the CRFs. The web-based data capture 
(WBDC) system will be used for data collection and query handling.
The Investigator ensures 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 (Table 1), 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 (Table 1).
The total amount of mandatory blood samples collected from each patient up to Week 24 is 
estimated to a maximum of 305 mL. From Week 25 to the EOT and/or disease progression, a 
maximum of 27 mL will be collected 8-weekly (Table 19). Repeat or unscheduled samples 
may be taken for safety reasons or for technical issues with the samples.

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Table 19
Blood sample volumes
Blood volume (mL)
Type of samples
Visit / Cycle /Weeks
Safety c
PK
ctDNA
 d
Total
Screening / Week -4 to -1
15 +2
20
2
10
49
Cycle 1 / Week 1 to 4
2×15+2
3×2
2×10
2×2
10
(6 optional)
72 
(+6 optional)
Cycle 2 / Week 5 to 8
15+2
2
10
2
10
41
Cycle 3 / Week 9 to 12
15
10
2
27
Cycle 4 / Week 13 to 16
15
10
2
10
37
Cycle 5 / Week 17 to 20
15
10
2
27
Cycle 6 / Week 21 to 24
15
15
EOT
15
10
2
10
37
Total up to Week 24 + EOT assessments
•
Mandatory
•
Optional
141
-
8
-
90
-
16
-
50
-
-
6
305
6
From Week 25 onward 
(8-weekly)
15 until 
EOT
-
10 until 
progression
2 until 
progression
-
-
27
c
A volume of 15 mL is estimated for safety, assuming 6 mL clinical chemistry and 9 mL haematology per 
visit with 2 mL added for coagulation tests for a subset of visits. 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.
d
If the 
 sample is not drawn prior to dosing (for any reason), it may be taken at any visit until the last 
study visit.
; ctDNA=circulating tumour DNA.
8.1
Efficacy assessments
8.1.1
Assessment of tumour response
The assessment of tumour response per RECIST version 1.1 will be used to determine the 
clinical activity (assessed by PFS) and anti-tumour activity (assessed by ORR, clinical benefit 
rate [CBR]) of AZD9833 and fulvestrant.
8.1.1.1 Tumour imaging
Tumour imaging should be performed per the SoA (Table 1). The imaging modalities to be 
used for the assessment of tumour response per RECIST version 1.1 are summarised in 
Appendix G 3. 
Baseline tumour assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual patients. Baseline assessments should be 
performed no more than 28 days before the start of study treatment, ideally, as close as 
possible to the start of study treatment.
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If an unscheduled assessment is performed, and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. This schedule 
is to be followed in order to minimise any unintentional bias caused by some patients being 
assessed at a different frequency than other patients.
8.1.1.2 Investigator’s assessment of tumour response per RECIST version 1.1
Tumour response will be assessed by the Investigators per RECIST version 1.1 (Eisenhauer et 
al 2009). Guidelines for the evaluation of measurable, non-measurable, TLs and non-target 
lesions (NTLs) and the objective tumour response per RECIST version 1.1 are presented in
Appendix G.
From the Investigator’s review of the imaging scans, the evaluation of TLs, NTLs and new 
lesions will be used to determine the overall visit response for each patient. Overall visit 
responses for each visit will then be used to determine if and when a patient has progressed in 
accordance with RECIST and their best objective response to study treatment.
8.1.1.3 Blinded Independent Central Review of tumour assessments
Coded copies of all imaging assessments (regardless of modality and including unscheduled 
visit scans) will be sent to an AstraZeneca-appointed Contract Research Organisation (CRO) 
for central analysis. Results of this independent review will not be communicated to 
Investigators, and the management of patients will be based solely upon the results of the 
RECIST assessment conducted by the Investigator.
The imaging scans will be reviewed by 2 independent radiologists using RECIST version 1.1 
and will be adjudicated, if required (ie, 2 reviewers will review the scans and, in case of a 
disagreement, adjudication is performed by a separate reviewer). The independent reviewers 
will be blinded to study treatment.
The BICR will be conducted on an ongoing basis throughout the study. Where possible scans 
will be batched, and an in-patient series of assessments read together.
For each patient, the BICR will define the overall visit response (ie, the response obtained 
overall at each visit by assessing TLs, NTLs, and new lesions) and no programmatic 
derivation of overall visit response is necessary.
Further details of the BICR will be documented in the BICR Charter.
8.1.2
Bone scan or skeletal survey
All patients should have a baseline bone scan or skeletal survey performed no more than 
12 weeks before and as close as possible to the start of study treatments.
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Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray should be recorded as NTLs and followed by the same method (CT, MRI, or X-ray), as 
indicated in the SoA (Table 1).
8.1.3
Survival follow-up
After discontinuation of study treatment, the survival status of the patients will continue to be 
followed every 12 weeks via phone until closure of the clinical study database. Any new 
anti-cancer therapies commenced by the patient during the survival follow-up period will be 
documented in the clinical database.
A survival follow-up phone call will be made in the week following the DCO date for each 
survival analysis.
8.1.3.1 Post Primary Analysis
At the time of final analysis, the clinical study database will close to new data. Patients are, 
however, permitted to continue to receive study treatment beyond the closure of the database 
if, in the opinion of the Investigator, they are continuing to receive benefit from study 
treatment.
8.1.4
Clinical outcome assessments
8.1.4.1 Performance status
Performance status will be assessed at the visits indicated in the SoA (Table 1), 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.
8.1.4.2 Health-related quality of life questionnaires
PRO measures will be used to examine the impact of treatment on symptoms, functioning, and 
HRQoL and aid in understanding the benefit/risk evaluation from the patient’s perspective. 
The following PRO measures will be administered in this study in accordance with the SoA 
(Table 1), and in the following order: 
1
European Organisation for Research and Treatment of Cancer (EORTC) quality of life 
questionnaire - core questionnaire (EORTC QLQ-C30)

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2
EORTC quality of life questionnaire – breast cancer module (EORTC QLQ-BR23)
3
National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25)
4
EuroQol 5-Dimension 5-level (EQ-5D-5L)
5
6
7
8
 
The PRO measures will be self-administered by patients using an electronic device per the 
SoA (Table 1). PRO measures will be provided in the language of the country in which they 
will be administered.
Each centre must allocate the responsibility for the administration of the questionnaires to a 
specific individual (eg, a research nurse, study coordinator) and if possible assign a back-up to 
cover absence. 
Approximately 25 minutes are required for patients to complete the questionnaires.
The below instructions should be followed:

The research nurse or appointed site staff must explain to the patient the value and 
importance of completing PRO questionnaires, so they are motivated to comply with 
questionnaire completion. The patient should be informed that these questions are being 
asked to find out directly from them how they feel, and the information they provide is 
critical to the success of the study.

It is vital that the PRO reporting is initiated at the baseline visit (Cycle 1, Day 1), as 
specified in the study plan to capture the effect of study treatment. The electronic device 
must be charged and fully functional at the beginning of the baseline visit to ensure that 
the PROs can be completed at the start of the visit. 

PRO questionnaires must be completed prior to treatment administration and ideally 
before any discussions of health status, to avoid biasing the patient's responses to the 
questions. As feasible, site staff should also ensure PRO questionnaires are completed 
prior to other study procedures (eg, collection of laboratory samples) to further minimise 
bias. 

PRO questionnaires should be completed by the patient in a quiet and private location. 
The patient should be given the time they need to complete the questionnaires at their 
own speed. 

The research nurse or appointed site staff should stress that the information is not 
routinely shared with study staff. Therefore, if the patient has any medical problems, they 
should discuss them with the doctor or research nurse separately from the PRO 
assessment. 
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
The research nurse or appointed site staff must train the patient on how to use the 
electronic PRO (ePRO) device, using the materials and training provided by the ePRO 
vendor. 

All questionnaires must be completed using the ePRO device; paper questionnaires are 
not allowed in this study. 

The research nurse or appointed site staff must remind the patient that there are no right 
or wrong answers and avoid introducing bias by not clarifying questions for the patient. If 
the patient is uncertain about the meaning of a question, the site staff should ask the 
patient to answer based on what they think the item means.

The patient should not receive help from relatives, friends, or clinic staff in choosing 
answers on the PRO questionnaires. 

If a patient uses visual aids (eg, spectacles or contact lenses) for reading and does not 
have them when attending the clinic, the patient will be exempted from completing the 
PRO questionnaires at that clinic visit. 

Site staff must not read or complete the PRO questionnaires on behalf of the patient. If the 
patient is unable to read the questionnaire (eg, is blind, illiterate or does not speak the 
available language), the patient is exempted from completing PRO questionnaires but 
may still participate in the study. Patients exempted in this regard should be flagged
appropriately by the site staff in the source documents and CRF. 

Site staff must administer questionnaires available in the language that the patient speaks 
and understands. 

If a patient's compliance drops to 85% or below, they will be flagged in the routine 
compliance report generated by the ePRO system. For missed questionnaires, the 
reason(s) for missing the assessment should be documented in the CRF.
A short description of each questionnaire is provided below and sample questionnaires are 
included in a separate Quality of Life Manual.
European Organisation for Research and Treatment of Cancer quality of life 
questionnaire - core questionnaire
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group to assess 
HRQoL, functioning, and symptoms in cancer clinical trials. It has undergone extensive 
testing and validation and has been translated and linguistically and culturally validated in 
numerous languages (Aaronson et al 1993). It is a 30-item self‑administered questionnaire for 
all cancer types. Questions are grouped into 5 multi‑item functional scales (physical, role, 
emotional, cognitive, and social), 3 multi-item symptom scales (fatigue, pain, and 
nausea/vomiting), a 2‑item global health status/quality of life (QoL) scale, 5 single items 
assessing additional symptoms commonly reported by cancer patients (dyspnoea, loss of 
appetite, insomnia, constipation, and diarrhoea), and 1 item on the financial impact of the 
disease. All but 2 questions are rated on a 4-point verbal rating scale: “Not at all,” “A little,” 
“Quite a bit,” and “Very much.”  The 2 questions concerning global health status and QoL 
have 7-point scales with ratings ranging from “Very poor” to “Excellent.”  For each of the 

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15 domains, final scores are transformed such that they range from 0 to 100, where higher 
scores indicate better functioning, better QoL, or worse symptoms (Aaronson et al 1993).
European Organisation for Research and Treatment of Cancer quality of life 
questionnaire - breast cancer module
The EORTC QLQ-BR23 is a validated breast cancer-specific module used in conjunction with 
the core QLQ-C30 to assess breast cancer-specific HRQoL (Sprangers et al 1996). The 
self‑administered instrument includes 23-items and yields 5 multi-item scores (body image, 
sexual functioning, arm symptoms, breast symptoms, and systemic therapy side effects). Items 
are scored on a 4-point verbal rating scale: “Not at All,” “A Little,” “Quite a Bit,” and “Very 
Much”. Scores are transformed to a 0 to 100 scale, where higher scores indicate better 
functioning, better HRQoL, or greater level of symptoms. 
National Eye Institute 25-Item Visual Function Questionnaire
The NEI VFQ-25 is a valid and reliable instrument capturing vision-related health status. It 
consists of 25 vision-targeted questions representing 11 vision-related subscales, plus an 
additional single-item general health rating question (Mangione et al 2001). The subscales 
include: global vision rating (1 item), difficulty with near vision activities (3 items), difficulty 
with distance vision activities (3 items), limitations in social functioning due to vision 
(2 items), role limitations due to vision (2 items), dependency to others due to vision (3 items), 
mental health symptoms due to vision (4 items), driving difficulties (3 items), limitations with 
peripheral (1 item), colour vision (1 item), ocular pain (2 items), and general health rating 
question.
EuroQol 5-dimension 5-level
The EQ-5D-5L will be used to explore the impact of treatment and disease state on health 
state utility for use in economic analyses. The EQ-5D-5L, developed by the EuroQol Group, is 
a generic questionnaire that provides a descriptive profile of health and a single index value 
for health status for economic appraisal (Herdman et al 2011, EuroQol Group 1990). The 
questionnaire comprises 6 questions that cover 5 dimensions of health (mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression). Respondents also assess their health 
today using the EQ-VAS (visual analogue scale), which ranges from 0 (worst imaginable 
health) to 100 (best imaginable health). 
 
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8.2
Safety assessments
Planned timepoints for all safety assessments are provided in the SoA (Table 1).
8.2.1
Clinical safety laboratory assessments
See Table 20 for the list of clinical safety laboratory tests to be performed and to 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 make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at 
centre 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, coagulation tests 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 20
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
S/P-Sodium
Coagulation parameters
S/P-Glucose
activated partial thromboplastin time (aPTT)
S/P-Magnesium
international normalised ratio (INR)
S/P-Phosphate
S/P-Urea nitrogen
Urinalysis
S/P-Protein, total
U-Glucose
S/P-Troponin
U-Protein
S/P-NT-proBNP
U-Blood
NB. In case a patient shows an AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN please refer to 
Appendix F ‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s law’, for further 
instructions.
B=blood; S/P=serum/plasma; U=urine; ULN=upper limit of normal.
8.2.2
Physical examinations
A complete physical examination, including a standard neurological examination, will be 
performed at the visits indicated in the SoA (Table 1), including body weight and height at 
screening and weight on Day 1 of each cycle.
Investigators should pay special attention to clinical signs related to previous serious illnesses, 
new or worsening abnormalities may qualify as AEs, see Section 8.3.7 for details.

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8.2.3
Vital signs
Temperature, pulse rate, and blood pressure will be assessed at the timepoints indicated in the 
SoA (Table 1) as follows:

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 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 1 pulse 
and 3 blood pressure measurements (3 consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute). The average of the 3 blood pressure readings 
will be recorded on the CRF.
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 (Table 1) using 
standardised ECG machines that automatically calculate the heart rate and measure RR, PR, 
QRS, QT, and QTcF intervals:

e-Research Technology (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, before vital signs 
and PK sampling.

At each timepoint, 3 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

RR interval: duration in msec between 2 R peaks of 2 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 (Table 18).
8.2.4.2 Ambulatory ECG
Ambulatory 24-hour ECG recordings will be performed during screening and once while on 
study at any time between Cycle 1 Day 15 and Cycle 2 Day 1. The ambulatory 24-hour ECG 
can be fitted and worn by the patient for 26 hours to allow 24 hours of recorded data to be 
extracted.
Study sites will be provided with the necessary equipment and training for performing 
ambulatory ECGs. Data will be acquired and centrally analysed through a vendor supplying 
ambulatory ECG services.
The SRC may recommend cessation of 24-hour ambulatory ECG assessment at any time 
following their 1st safety review of the study.
8.2.4.3 Echocardiogram  
This will be a focused study to assess left ventricular ejection fraction (LVEF; Biplane 
Modified Simpson’s method) and left ventricular end-systolic (LVES) and end-diastolic 
(LVED) dimensions. 
The echocardiogram will be conducted on all patients at:

Screening  

Cycle 2 Day 1 (+/- 7 days) 

Cycle 5 Day 1 (+/- 7 days)

D1 of every 3rd cycle thereafter (+/- 7 days)

28-day follow-up (+/- 7 days)  
The schedule of echocardiogram assessment may be modified at any time during the study, if 
supported by emerging data and with the agreement of the SRC.
8.2.5
Other safety assessments
Other safety assessments include ECOG/WHO performance status. For details, see 
Section 8.1.4.

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8.3
Collection of 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 C.
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).
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix C. 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 AE or SAE 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 must notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix C.
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. 

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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 serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Causality assessment 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?’
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 C.

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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, ECG and vital signs will be 
summarised in the CSR. Deterioration as compared to baseline in protocol-mandated 
laboratory values, ECG and vital signs should therefore  be reported as AEs if they are
assessed as clinically significant by the investigator, or if they fulfil any of the SAE criteria or 
are the reason for discontinuation of study treatments.
If deterioration in a laboratory value/ECG/vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result/ECG/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 8.310.
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 to 
be reported as SAEs. Please refer to Appendix F 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 patient’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 
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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.
New cancers
The development of a new cancer should be regarded as an AE and will generally meet at 
least 1 of the seriousness criteria. New cancers are those that are not the primary reason for the 
administration of the study treatments and have been identified after the patient’s inclusion in 
this study. They do not include metastases of the original cancer.
Handling of deaths
All deaths that occur during the treatment period including the 28-day safety follow-up period 
should be reported as follows:

Death that is unequivocally due to disease progression should be communicated to the 
study monitor at the next monitoring visit and be documented in the relevant CRF 
module, but it should not be reported as an SAE during the study.

Where death is not clearly due to the progression of the disease under study, 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.
Deaths that occur after the treatment period during the survival follow-up period should be 
reported on the survival log on the CRF.
8.4
Safety reporting and medical management
8.4.1
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 CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel 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 works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 

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1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 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 is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site staff reports 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 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, Institutional Review Boards (IRB)/Independent Ethics Committees 
(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 C.
8.4.2
Pregnancy
As patients participating in the study are post-menopausal women, no pregnancies are 
expected during the study.

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8.4.3
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 inform appropriate AstraZeneca representatives 
immediately, or 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 
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.
8.4.3.1 AZD9833
For this study, any dose of AZD9833 greater than the intended dosage (ie, 75 mg, 150 mg or 
300 mg per day) will be considered an overdose.
AstraZeneca does not recommend specific treatment for an overdose. Any patient who 
receives a dose higher than intended should be monitored closely, managed with appropriate 
supportive care.
8.4.3.2 Fulvestrant
There are only isolated reports of overdose with fulvestrant in humans; if it occurs, 
symptomatic supportive treatment is recommended. 
8.4.4
Medication error
If any medication error occurs in the course of the study, then the Investigator or other site 
personnel informs 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 works 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 8.3.2) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Appendix C.

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8.5
Pharmacokinetics
Venous blood samples of approximately 2 mL will be collected from patients receiving 
AZD9833 for measurement of plasma concentrations of AZD9833 and, if appropriate, 
metabolite(s) as specified in the SoA (Table 1).
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 or efficacy aspects related to 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
Determination of drug concentration
Samples for determination of drug/metabolite 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.
8.5.2
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. 
PK samples may be disposed of or destroyed and anonymised by pooling. Additional analyses 
may be conducted on the anonymised, pooled pharmacokinetic samples to further evaluate 
and validate the analytical method. Any results from such analyses may be reported separately 
from the CSR.
8.6
Pharmacodynamics
Pharmacodynamic measurements are described in Section 8.8.

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8.7.1
Optional exploratory 
 sample
Patients will be offered the possibility to participate in optional 
 exploratory research. 
Collection and storing of 
 will be according to each country’s local and ethical 
procedures for future exploratory research into 
 that may influence 
response to treatment.
After signing a separate consent for optional 
 research, a 6-mL
 sample will be 
collected in accordance with the inclusion criteria and SoA (Table 1). If for any reason the 
 sample is not 
 on Day 1 according to the SoA, it may be taken at any time up until 
the last study visit. Although the genotype is a stable parameter, early sample collection is 
preferred to avoid introducing bias through excluding subjects who may withdraw due to an 
AE, such subjects would be important to include in any 
 analysis. Only 1 sample 
should be collected per subject for 
 research during the study.
A record of the date the subject consented to the 
 research and the date and time of the 
 sample collection will be recorded in the CRF. Samples will be collected, handled, 
labelled, stored and shipped as detailed in the Laboratory Manual.
See Appendix E for information regarding 
 research. Details on processes for 
collection and shipment and destruction of these samples can be found in Appendix E or in the 
Laboratory Manual.
8.7.2
Storage and destruction of 
 samples
The processes adopted for the coding and storage of samples for 
 analysis are 
important to maintain patient confidentiality. Samples may be stored for a maximum of 
15 years or as per local regulations from the date of the last patient’s last visit, after which 
they will be destroyed. DNA is a finite resource that may be used up during analyses. The 
results of any further analyses will be reported either in the CSR itself or as an addendum, or 
separately in a scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organisations working with the DNA
8.8
Biomarkers
Biomarkers will be tested in plasma, blood and tumour samples for the secondary and 
exploratory objectives to investigate predictive markers of response and/or acquired resistance 
to AZD9833 and to assess the impact of tumour mutation status on response to treatment and 
acquired resistance.
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The following samples for biomarker research are required and will be collected from all 
patients in this study as specified in the SoA (Table 1):

Blood and plasma samples for ctDNA

Blood samples for tumour marker 

Blood samples for 

Archival tumour tissue samples
The following samples for biomarker research are optional and will collected from patients in 
the study where possible as specified in the SoA (Table 1):

Paired tumour biopsy samples; pre- and on-treatment. Samples will be collected for 
patients with tumours amenable to biopsies in up to 12 patients per treatment group.

Additional tumour biopsy samples may be collected at time of progression.
8.8.1
Blood samples for circulating tumour DNA
One 20-mL whole blood sample will be taken at screening, for the isolation of plasma and 
buffy coat to enable the assessment, analysis and interpretation of circulating tumour DNA. 
10-mL blood sample will be taken at all of the other timepoints indicated in the SoA (Table 1) 
to provide plasma only. 
The samples will be used for the extraction and analysis of ctDNA for the analysis of 
predictive and pharmacodynamic biomarkers to interrogate changes in frequency, level, 
specific genetic alterations and potential mechanisms of resistance.
8.8.2
Blood samples for 
A blood sample of approximately 2 mL will be taken for 
 assessment at 
each of the timepoints indicated in the SoA (Table 1). The sample will be analysed 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.
8.8.3
One 10-mL blood sample will be taken at each of the timepoints as indicated in the SoA 
(Table 1). These samples will be taken to obtain a preliminary assessment of AZD9833 
activity in the tumour by evaluation of 
, which may 
include but are not limited to total counts, and expression levels of
 
8.8.4
Archival tumour tissue
Formalin-fixed archival tumour tissue embedded in paraffin blocks are to be retrieved for all 
patients, where available. If baseline biopsy samples can also be collected, retrieval of the 
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archival diagnostic tumour material is still required to provide data on how the tumour has 
evolved since diagnosis. The archival samples can be derived from the primary tumour and/or 
metastatic site and, where possible, the most recently acquired archival sample is required.
If this is not possible, a minimum of 20 slides of freshly prepared unstained 5-micron sections 
from the archival tumour block are accepted, if tumour blocks cannot be submitted. From 
submitted archival tumour blocks, cores may be removed to construct tissue microarrays for 
later biomarker analysis. The remaining part of the tumour block may be returned to the 
institution.
8.8.5
Tumour biopsy in selected patients
Optional paired tumour biopsies will be collected from up to 12 eligible patients in each 
treatment group.
The paired tumour biopsies will be obtained from patients with accessible tumours and who 
consent to provide biopsy samples. Accessible lesions are defined as tumour lesions that are 
amenable to repeat biopsy. Paired biopsies of bone tissue are not permitted. 
The pre-treatment biopsy may be taken during screening as close as possible to starting 
treatment, ideally no greater than 6 weeks prior to treatment start. The on-treatment biopsy 
sample may be taken on Day 1 (±7 days) of Cycle 2, but both pre- and on -treatment samples 
can be taken outside this time window, if agreed with AstraZeneca. The pre-dose and on-
treatment biopsies should be taken from the same tumour lesion. Biopsies should be taken 
within 1 to 12 hours of the last AZD9833 dose where possible. A further tumour biopsy may 
also be taken on disease progression or at the end of treatment.
The biomarkers to be investigated using tumour samples may include, but will not necessarily 
be limited to: ER, PgR, Ki67, genomic/genetic alterations, and other ER-regulated gene 
expression. Where feasible, collection of a tumour biopsy at disease progression is 
encouraged. This sample will be used to investigate changes in pathway signalling and 
potential mechanisms of resistance (ie, genetic alterations or evidence of alternative pathway 
activation).
8.8.6
Storage, re-use and destruction of biomarker samples
Samples will be stored for a maximum of 15 years from the date of the last patient’s last visit, 
after which they will be destroyed. 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 to generate hypotheses to be tested in future research.

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8.9
Medical Resource Utilisation and Health Economics
Medical Resource Utilisation and Health Economics parameters are not evaluated in this 
study.

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9
STATISTICAL CONSIDERATIONS 
As of December 2020, the Sponsor stopped enrolment to the 300 mg treatment arm. Ongoing 
patients in the 300 mg treatment arm may continue treatment as planned.
In the following sections, the primary analysis, which is a formal comparison of AZD9833 
versus fulvestrant, only applies to AZD9833 75 mg and 150 mg treatment groups and pairwise 
comparisons only refer to AZD9833 doses 75 mg and 150 mg. Data accrued from the 
AZD9833 300 mg treatment group will be summarised and reported as appropriate, and will 
not contribute to the event triggers for the analysis timepoints in the following sections.
9.1
Statistical hypotheses
For the primary analysis, the null hypothesis to be tested is that there is no treatment effect, 
(ie, there is no difference in PFS between patients treated with any dose of AZD9833 and 
patients treated with fulvestrant).

H0: PFS HR AZD9833/fulvestrant=1

H1: PFS HR AZD9833/fulvestrant≠1
Each dose of AZD9833 of interest will be compared with fulvestrant in a pairwise 
comparison. As this is a Phase 2 study, no adjustments for multiplicity will be made.
9.2
Sample size determination
A sample size of approximately 288 patients, randomised in equal proportions to the 
4 treatment groups will be required to observe a total of at least 108 PFS events for each 
pairwise comparison against fulvestrant. As of December 2020, and the decision to stop 
enrolment to the AZD9833 300 mg arm, the resulting total sample size across the 3 enrolling 
treatment arms is approximately 216, with approximately an additional 20 patients from the 
AZD9833 300 mg arm enrolled up to recruitment closure of this arm. The primary analysis 
will only be triggered when a minimum of 108 events is observed for the pairwise comparison 
of 75 mg and 150 mg AZD9833 doses versus fulvestrant. 
A HR of 0.59 for each pairwise treatment comparison versus fulvestrant is of interest. Under 
the assumption that a 5-month median PFS will be observed on fulvestrant, this is equivalent 
to a 3.5-month increase in median PFS over fulvestrant. A minimum of 108 events for the 
pairwise comparison of each AZD9833 dose of interest versus fulvestrant will provide 86% 
power at the 2-sided 10% significance level if the assumed true treatment effect is HR = 0.59. 
For each treatment arm comparison, PFS events will be tracked by an unblinded team at the 
CRO on an ongoing basis throughout the study and will be used to estimate when the primary 

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analysis for PFS should occur. The Sponsor will have knowledge of the total number of events 
which have accrued but will not know the allocation between treatment groups.
The primary endpoint will be based on the Investigator assessment of progression. A 
sensitivity analysis based on the BICR of scans will be conducted. Due to the different 
methods of declaring progression, it is expected that the number of events declared via the 
2 methods will be different.
Two interim analyses will be conducted at approximately 
 PFS maturity and 
 PFS 
maturity in the best performing dose group. The interim analyses will be triggered when the 
best performing pair hit a minimum of 
 events and 
 events (based on the Investigators 
assessment), respectively. At the interim analyses, each AZD9833 dose level of interest will 
be compared in a pairwise comparison against fulvestrant to assess both futility and efficacy. 
Each dose level (75 mg and 150 mg) will be tested to assess whether the dose passes the 
futility hurdle and then whether the dose meets the pre-defined acceleration criteria. This 
assessment for efficacy will be used for internal future development purposes only. All 
boundaries will be pre-specified in the DMC charter.
Sample size within subgroups of patients with/without prior use of CDK4/6 inhibitors
As per Section 6.3, patients will be stratified for prior use of CDK4/6 inhibitors. Assuming the 
cap limit is maintained, the study will randomise between 32 and up to a maximum of 
40 patients per stratum in each treatment group. Under this scenario, approximately equal 
proportions (ie, 36 patients per stratum in each treatment group) are expected.
Controlling the sample size in this way will allow for approximately 54 events for the pairwise 
comparison at the primary analysis (under the assumption that the event rates are the same in 
the subgroups of patients with or without prior use of CDK4/6 inhibitor). Fifty-four events for 
the pairwise comparison of each AZD9833 dose versus fulvestrant will provide 86% power at 
the 1-sided 20% significance level if the assumed true treatment effects are HR = 0.59.
9.3
Populations for analyses
For purposes of analysis, the following populations are defined in Table 21. Full details of the 
analysis populations and reporting will be provided in the statistical analysis plan (SAP).
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Table 21
Study populations
Population
Description
Enrolled 
All patients who sign the ICF.
Full analysis set (FAS)
All randomised patients, with treatment groups assigned in accordance with 
the randomisation, regardless of the treatment actually received.
Patients who are randomised but do not subsequently receive treatment will 
be included in the FAS. The analysis of data using the FAS therefore 
follows the principles of ITT.
Safety analysis set
All patients who received any amount of study treatment (AZD9833 or 
fulvestrant), regardless of whether that was the randomised therapy intended 
or whether they received therapy without being randomised and for whom 
any post-dose data are available. 
Patients randomised to AZD9833 who received only fulvestrant will be 
accounted for in the fulvestrant treatment group.
Safety data will not be formally analysed but summarised using the safety 
analysis set, according to the treatment/ AZD9833 dose level actually 
received.
Pharmacokinetics (PK) 
analysis set
All patients who receive at least 1 dose of AZD9833 per the protocol, for 
whom there is at least 1 reportable PK concentration.
Pharmacodynamic analysis set
All patients who received at least 1 dose of AZD9833 or fulvestrant per the 
protocol, and who:
•
had evaluable paired tumour samples by central pathology assessment
•
had no major protocol deviations that impacted the biomarkers 
analysis.
ICF=informed consent form; ITT=intention-to-treat.
9.4
Statistical analyses
All Sponsor personnel involved in the the study will remain blinded to the aggregate efficacy 
data until after database lock for the primary analysis. Following database lock for the primary 
analysis, all study team members will become unblinded. 
Analyses will be performed by AstraZeneca or its representatives, including CROs. A 
comprehensive SAP will be developed and finalised prior to the first patient treated and will 
describe the patient populations to be included in the analyses, the analyses including any 
subgroup analyses or sensitivity analyses, and the procedures for accounting for missing, 
unused, and spurious data. This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints. 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 for the primary analysis will be reported in the CSR.
Table 22 details which data will be analysed at each timepoint.

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Table 22
Summary of analyses and data cut-off triggers
Analysis
Trigger
Data type included
Interim analysis 1
At least 
events for each of the 
pairwise treatment comparisons between 
each dose of AZD9833 (75 mg and 
150 mg) and fulvestrant
Efficacy data (including PFS, ORR 
and BoR).
Safety data may be included in this 
analysis, depending on how 
recently the latest SRC has been 
conducted
Interim analysis 2
At least 
events for the each of the 
pairwise treatment comparisons between 
each dose of AZD9833 (75 mg and 
150 mg) and fulvestrant
Efficacy data (including PFS, ORR 
and BoR).
Safety data may be included in this 
analysis, depending on how 
recently the latest SRC has been 
conducted
PFS primary analysis 
(approximately 75% 
maturity in the best 
performing dose group)
At least 108 events for each of the 
pairwise treatment comparisons between 
each dose of AZD9833 (75 mg and 
150 mg) and fulvestrant
All data (including summary OS 
data available at the time of 
primary analysis) b
Survival follow-up analysis 
a (
 and 
 maturity)
Further survival analyses may be 
conducted at approximately 
 and 
 OS maturity, or other maturities as 
may be appropriate
OSb
Safety update
At clinical database closure
Key safety data (including SAEs)
a
The PFS and OS analysis may be combined if there is sufficient maturity in the OS data at the time of the 
primary PFS analysis.
b
The safety update may be combined with the OS follow-up analysis if the decision is made to close the 
study database at this time. A PFS analysis may also be conducted at this timepoint.
BoR = Best objective response; PFS = Progression-free survival; ORR = Objective response rate; OS = Overall 
survival; SAE = Serious adverse event; SRC = Safety review committee.
9.4.1
Efficacy analyses
All efficacy analyses will be performed on the FAS. The primary analysis, which is a formal 
comparison of AZD9833 to fulvestrant, only applies to AZD9833 75 mg and 150 mg 
treatment arms and pairwise comparisons only refer to AZD9833 doses 75 mg and 150 mg. 
Results of all statistical analyses will be presented using 90% CIs and 2-sided p-values. The 
treatment comparison of interest is each dose level of AZD9833 versus fulvestrant. Data 
accrued from the AZD9833 300 mg treatment arm will be summarised and reported as 
appropriate.
Investigator’s assessment of tumour response per RECIST version 1.1
From the Investigators review of the imaging scans, the measurement of TLs (where 
appropriate), assessment of NTLs and new lesions will be used to determine the overall visit 
response of each patient according to RECIST version 1.1: patients will be programmatically 
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assigned an overall visit response of complete response (CR), partial response (PR), stable 
disease (SD), or progressive disease (PD) depending on the status of their disease compared 
with baseline and previous assessments (see Appendix G 4).
The efficacy endpoints of PFS, CBR24, ORR and DoR will be derived programmatically from 
the overall visit responses determined for each visit. 
The endpoint of percentage change in sum of TLs will be derived programmatically from the 
TL tumour measurements.
Blinded independent central review of tumour response
A sensitivity analysis for the primary endpoint for this study will be based on the BICR of the 
radiological scans.
For each patient, the BICR will define the overall visit response (ie, the response obtained 
overall at each visit by assessing TLs, NTLs and new lesions) data and no programmatic 
derivation of visit response is necessary.
PFS will be derived programmatically from the overall visit responses determined for each 
visit. 
A BICR of all patients will be performed for the final database lock for the primary analysis of 
PFS. The BICR will cover all available scans up to the respective DCO.
Further details of the BICR will be documented in the BICR Charter.
9.4.1.1 Primary endpoint: progression-free survival
The analysis of the primary endpoint of PFS (as assessed by the Investigator) will occur when 
recruitment to the study has completed and at least 108 events have occurred for the pairwise 
comparison of each AZD9833 dose versus fulvestrant (approximately 75% maturity). A 
further analysis of PFS may also be conducted at a later timepoint based on more mature data, 
particularly in the subgroups of interest. 
The PFS is defined as the time from date of randomisation to date of objective disease 
progression or death (by any cause in the absence of progression), regardless of whether the 
patient withdraws from randomised therapy or receives another anti-cancer therapy prior to 
progression (ie, date of PFS event or censoring – date of randomisation + 1). 
Patients who have not progressed or died at the time of analysis will be censored at the time of 
the latest date of assessment from their last evaluable assessment (per RECIST version 1.1). 
However, if the patient progresses or dies immediately after 2 or more consecutive missed 
visits, the patient will be censored at the time of the latest evaluable assessment (per RECIST 

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version 1.1) prior to the 2 missed visits. The PFS time will always be derived based on 
scan/assessment dates and not on visit dates.
PFS will be analysed based on the FAS using a Cox proportional hazards model, allowing for 
the effect of treatment and including terms for the stratification factors; prior use of CDK4/6 
inhibitors (yes/no) and presence of lung and/or liver metastases (yes/no). A stratified log-rank 
test adjusting for prior use of CDK4/6 inhibitors and presence of lung and/or liver metastases 
will be used to compare all AZD9833 doses against fulvestrant.
The stratification variables in the statistical modelling will be based on the values entered into 
the IWRS at randomisation, even if it is subsequently discovered that these values were 
incorrect. If considered necessary, a sensitivity analysis may be conducted based on the 
correct assignment.
The HRs for each treatment comparison against fulvestrant will be estimated along with their 
90% CIs and 2-sided p-values.
Kaplan-Meier plots of PFS will be presented by treatment arm. Summaries of the number and 
percentage of patients experiencing a PFS event, and the type of event (progression or death) 
will be provided along with the median PFS, and the proportion of patients progression-free at 
6 months and 1 year for each treatment arm.
The assumption of proportionality will be assessed, should evidence of non-proportionality 
exist a time-dependent covariate will be fitted to assess the extent to which this represents 
random variation. Full details will be provided in the SAP.
As a sensitivity analysis to the primary endpoint, the above analysis methods will be repeated 
based on the BICR.
Collected RECIST version 1.1 data (Investigator determined and BICR) will be listed for all 
randomised patients.
Subgroup analyses
The primary endpoint will also be summarised and analysed for the subgroups of patients with 
prior use of CDK4/6 inhibitors (yes/no), provided there are enough events available for a 
meaningful analysis; if not, descriptive summaries will be provided. Further subgroups of 
interest may be defined based on patient characteristics at baseline, these will be illustrated in 
a forest plot comparing the HR and 90% CIs. The subgroups of interest, along with any 
sensitivity analyses will be fully defined in the SAP.

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9.4.1.2 Secondary endpoints
Objective response rate
The ORR is defined as the percentage of patients with at least 1 Investigator-assessed visit 
response of CR or PR prior to any evidence of progression. The ORR will be based on a 
subset of the FAS with measurable disease at baseline. A response does not need to be 
confirmed to be included in the calculation of ORR. 
The ORR will be compared between AZD9833 (each dose level) and fulvestrant using a 
logistic regression model adjusting for prior use of CDK4/6 inhibitors and presence of lung 
and/or liver metastases. The results of the analysis will be presented in terms of an odds ratio 
for each treatment comparison together with its associated profile likelihood 90% CI and 
2-sided p-values (based on twice the change in log-likelihood resulting from the addition of a 
treatment factor to the model).
Summaries will be produced that present the number and percentage of patients with a tumour 
response (CR/PR), these will include frequencies of confirmed complete responses and partial 
responses, in addition to unconfirmed complete and partial responses, stable disease, 
progressive disease and not evaluable.
Duration of response
The DoR will be defined as the time from the date of first documented response until date of 
documented progression or death in the absence of disease progression. The time of the initial 
response will be defined as the latest of the dates contributing towards the first visit response 
of PR or CR. If a patient does not progress or die following a response, then their DoR will 
use the PFS censoring time.
Descriptive data will be provided for the duration of response in responding patients, 
including the associated Kaplan-Meier curves. 
Change in tumour size
One of the secondary outcome variables for this study is percentage change from baseline in 
the sum of TL diameters at 16 weeks. The percentage change in tumour size at 16 weeks will 
be obtained for each patient, based on RECIST measurements taken at baseline and at 
16 weeks. Tumour size is the sum of the longest diameters of the TLs. TLs are measurable 
tumour lesions. Baseline for RECIST is defined to be the last evaluable assessment prior to 
randomisation.
Best percentage change
The absolute change and percentage change from baseline in the sum of tumour size at each 
visit will be calculated. The best change in tumour size (ie, depth of response) is the largest 
decrease from baseline or the smallest increase from baseline in the absence of a reduction and 

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will include all assessments prior to the earliest of death in the absence of progression, any 
evidence of progression, the start of subsequent anti-cancer therapy or the last evaluable 
RECIST assessment if the patient has not died, progressed or started subsequent anti-cancer 
therapy.
The absolute value, the change in tumour size from baseline and the percentage change in 
tumour size from baseline will be summarised using descriptive statistics and presented at 
each timepoint and by randomised treatment group.
The change from baseline in tumour size at 16 weeks and best change from baseline in tumour 
size will also be summarised and presented by randomised treatment group. 
Normality of the data will be assessed and if appropriate the effect of AZD9833 on percentage 
change in tumour size will be estimated from an analysis of covariance (ANCOVA) model. 
The number of patients, unadjusted mean and least squares means (LSmeans) for each 
treatment group will be presented, together with the difference in LSmeans, 90% CI and 
corresponding 2-sided p-values. If the assumptions do not hold, an appropriate transformation 
of the data will be investigated, full details of which will be provided in the SAP. 
Tumour size will also be presented graphically using waterfall plots and spider plots split by 
treatment as appropriate.
Overall survival
The OS is defined as the time from the date of randomisation until death due to any cause 
regardless of whether the patient withdraws from randomised therapy or receives another 
anti-cancer therapy. Any patient not known to have died at the time of analysis will be 
censored based on the last recorded date on which the patient was known to be alive.
Note: Survival follow-up phone calls will be made in the week following the date of DCO for 
the analysis, and if patients are confirmed to be alive or if the death date is after the DCO date 
these patients will be censored at the date of DCO. 
The OS data will be analysed at the time of the primary analysis of PFS and will use the same 
methodology and model (provided there are enough events available for a meaningful analysis 
[>20% maturity in OS], if not, descriptive summaries will be provided). Further survival 
analyses may be conducted after 
 and 
 of patients have died.
Clinical benefit rate at 24 weeks
The CBR24 is defined as the percentage of patients who have a best objective response (BoR) 
of CR or PR in the first 25 weeks (to allow for a late assessment within the assessment 
window) or who have SD (without subsequent cancer therapy) for at least 23 weeks after start 
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of treatment (to allow for an early assessment within the assessment window). The CBR will 
be defined based on the Investigator’s assessment of RECIST.
The CBR24 will be summarised by treatment group and analysed using a logistic regression 
model (similarly to the analysis for the ORR).
9.4.2
Safety analyses
All safety analyses will be performed on the safety analysis set. Safety data will not be 
analysed formally.
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. Additional subgroup 
analyses of safety data may be performed, as specified in the SAP. 
9.4.2.1 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 1st 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 only treatment-emergent adverse events (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. Any AE occurring after 
initiation of the first subsequent therapy following discontinuation of study treatment will be 
flagged in the data listings.
9.4.2.2 Other significant adverse events
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 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 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.

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9.4.2.3 Other safety data
Duration of exposure will be summarised appropriately. 
Clinical chemistry, haematology, urinalysis, vital signs and echocardiogram data 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) obtained from the central review 
will be summarised over time in terms of absolute values and change from baseline.
Details of any death will be listed for all patients.
Visualisations of the safety data over time may also be produced as appropriate. Full details of 
the analysis of safety data will be provided in the SAP.
9.4.3
Other analyses
The PK, pharmacodynamic, demographic, safety, and tumour response data collected in this 
study may also be combined with similar data from other studies and explored using 
population PK and/or pharmacokinetic-pharmacodynamic methods. The results of any such 
analyses will be presented separately from the main CSR. 
9.4.3.1 Pharmacokinetic data
Pre and post-dose PK concentrations of AZD9833 at steady state will be summarised by 
AZD9833 dose level, and PK concentration data will be listed for each patient in the PK 
analysis set. If applicable, AZD9833 metabolites will be summarised appropriately.
9.4.3.2 Pharmacodynamic data
The secondary endpoints; percentage change from baseline in ER and PgR expression as 
assessed by manual H-score method and percentage change in Ki67 labelling index will be 
listed and summarised appropriately. An ANCOVA model will be fitted to each endpoint, 
with baseline value, day of biopsy and treatment group included in the model. Estimates of the 
treatment effect will be calculated together with confidence intervals. It is expected that the 
distribution of the Ki67 index data will not be normally distributed (Robertson et al 2013), 
hence, Ki67 index data will be naturally log transformed before being analysed.
9.4.3.3 Health-related quality of life assessments
Patient-reported HRQoL data from the EORTC QLQ-C30, EORTC QLQ-BR23, NEI VFQ-25 
and EQ-5D-5L questionnaires will be analysed by descriptive summaries and graphical data 
presentations.
Descriptive summaries and figures may include the following, which will be produced for 
each questionnaire by randomised treatment group:

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
Summary of compliance of subjects to the PRO instruments 

Summary statistics of the change from baseline in total and subscale scores at each visit 

Plots of mean change from baseline in total and subscale scores over time with indicators 
of number of subjects at each visit (eg, n and error bars)
Further analyses using mixed effects model for repeated measures data may be utilised if there 
are sufficient data and further exploratory of the HRQoL data is required, these analyses will 
look at the effect of treatment on the change in total or subscale score of each HRQoL score 
over time. The analysis population will be the subset of the FAS with baseline and at least 
1 follow-up assessment. Full details will be included in the SAP. 
9.4.3.4 Exploratory analyses
All exploratory endpoints will be reported outside of the CSR.
9.4.4
Methods for multiplicity control
As this is a Phase 2 study, there will be no adjustment for multiplicity.
9.5
Interim analyses
Interim analyses and safety review of the data are planned throughout the study, which may be 
combined or conducted separately.
9.5.1
AstraZeneca data monitoring committee
An independent AstraZeneca DMC will undertake interim analyses for this study.
Two interim analyses will be conducted at approximately 
 PFS maturity and 
PFS 
maturity in the best performing dose group. These interim analyses will assess the primary 
endpoint for both futility and efficacy. PFS based on the Investigator assessment will be 
analysed using a Cox proportional hazards model, as described above. The data will be 
reviewed by the DMC, who will make a recommendation based on pre-defined decision 
criteria. The DMC may include a recommendation to continue the study as planned, stop an 
AZD9833 dose level (or dose levels) for futility, or accelerate future planning activities. The 
clinical project team within AstraZeneca will remain blinded to the aggregate efficacy data 
and will only be informed of the final decision of the DMC, should there be a requirement to 
change study conduct. Full details of the DMC remit will be provided in the DMC charter.
Section A 5 provides more details on the rationale for and the remit of the committee.
9.5.2
Safety Review Committee
A review of the safety data will be conducted by the SRC approximately every 6 months up to 
the primary analysis for PFS, and thereafter at the discretion of the SRC. Other safety reviews 
outside of this may be conducted either at the request of the SRC, based on the emerging 
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profile of the drug (either within or outside of this clinical trial) or at the Sponsor’s discretion. 
At each review the SRC will review the accumulated safety data available at that point in 
time. Based on the SRC’s review of the data, the SRC will make a recommendation to the AZ 
study team: this may include to continue study as planned, to modify the study, or to consider 
dropping one or more doses from the study based on the tolerability profile. 
The SRC will consist of:

AstraZeneca physician who will chair the committee

AstraZeneca safety physician

2 external Investigator clinicians who are independent of the study
The full remit, membership and conduct of the SRC will be described in the SRC charter. 

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10
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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, ethical and study oversight considerations
A 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 Council for International Organisations of Medical Sciences 
(CIOMS) International Ethical Guidelines

Applicable International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator 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 21 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.
A 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.

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A 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 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (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. 
If a patient declines to participate in any voluntary exploratory 
 research component of 
the study, there will be no penalty or loss of benefit to the patient and he/she will not be 
excluded from other aspects of the study.
Patients who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorised designee will 
explain to each patient the objectives of the exploratory research. Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. The patient will give a separate agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate 
in this optional research will indicate this in the ICF. 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 already have been analysed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research.
A 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. 
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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.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to Investigators.
An independent AstraZeneca data monitoring committee (DMC, see Section 9.5.1) and a 
Safety Review Committee (SRC, see Section 9.5.2) will be convened.
A 6
Dissemination of clinical study data
A description of this clinical trial 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 trial 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.
A 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 
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. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
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 

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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. 
A 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.
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.
A 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 
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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 intervention development
A 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. In this case, a co-
ordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.

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Appendix B
Guidelines regarding potential interactions of AZD9833 with 
concomitant medications
There are currently no data confirming that there is a PK interaction between any concomitant 
medication and AZD9833. Potential interaction is considered on the basis of preclinical 
data only.
For a complete overview of the preclinical Drug Metabolism and Pharmacokinetics (DMPK) 
work conduct, including the drug-drug interaction liability of AZD9833, please refer to the 
Investigator’s Brochure.
B 1
Guidance for drugs that prolong QT and have a known risk of 
torsades de pointes
Drugs that are known to prolong QT and have a known risk of torsades de pointes (according 
to the CredibleMeds® list [www.crediblemeds.org]) should not be combined with AZD9833.
B 2
Restrictions regarding drugs affecting 
 metabolism
It is probable that AZD9833 is predominantly eliminated via 
Therefore, inhibitors 
or inducers of 
 may increase or decrease exposure to AZD9833, respectively.
Strong inhibitors and strong inducers of 
 should not be combined with AZD9833.
Moderate inhibitors and inducers of 
are permitted, but caution should be exercised and 
patients monitored closely for possible drug interactions.
Strong inhibitors or inducers of 
should be stopped at least 2 weeks before the first dose of 
AZD9833 (3 weeks for 
).
The lists below provide examples of 
 inhibitors and inducers. These lists are not 
intended to be exhaustive, and similar restrictions will apply to other drugs that are known to 
modulate 
 activity. Appropriate medical judgement is required. Please contact 
AstraZeneca with any queries you have on this issue. Please refer to full prescribing 
information for all drugs prior to co-administration with AZD9833.
If the Investigator feels that concomitant administration of medications or herbal supplements 
that strongly modulate 
 is essential (eg, to treat AEs) AZD9833 treatment should be 
discontinued.
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Concomitant medication should be given in accordance with its prescribing information.   
Examples of 
 and 
 substrate drugs are provided in Table 25  This list is not 
exhaustive.
Table 25
Examples of 
 and 
 substrate drugs.
CYP enzymes
Sensitive drug substrate2
Drug with narrow therapeutic 
range1
e
-
1 The University of Washington Drug Interaction Database https://www.druginteractionsolutions.org/
2 Guidance for Industry. Drug Interaction Studies, Study Design, Data Analysis, Implications for Dosing, and 
Labelling Recommendations: Draft Guidance 2012
In vitro, it has been shown that AZD9833 is an inhibitor of 
.
 substrates:
Sensitive 
 substrates should not be combined with AZD9833 (eg, 
).
Sensitive 
 substrates should be stopped at least 2 weeks before the first dose of AZD9833.
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Preliminary PK data from Part 
 
 of SERENA-1 are unable to exclude the possibility that AZD9833 may affect 
drugs that are sensitive to 
 inhibition. Therefore, prescribing advice for drugs that are 
known 
 substrates and which have specific label advice regarding combination with 
 
inhibitors should be consulted. Examples of such drugs in clinical practice are provided in 
Table 26; please note drugs already excluded by other concomitant medication restrictions 
may not be listed below.
Table 26
 substrates with label advice regarding combination with 
 
inhibitors
Drug
USPI
SmPC
 
No label comment 
See label advice 
 
See label advice 
See label advice 
 
See label advice 
See label advice 
  
See label advice 
No label comment 
 
See label advice 
See label advice 
 
See label advice 
See label advice 
 
See label advice 
No label comment 
; SmPC = Summary of product characteristics; USPI = United States prescribing 
information.
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Drugs known to reduce sinus heart rate
Patients already taking drugs known to reduce sinus heart rate can be enrolled onto study 
provided that cardiovascular-related eligibility criteria are satisfied. New prescriptions or dose 
increments of such drugs while on study should be discussed with the clinical study team, 
ideally before the new drug or increment is commenced,
Drugs known to reduce sinus heart rate include, but are not limited to, the following:
Beta blockers, including non-selective and 1-selective beta-adrenoreceptor antagonists 
Non-dyhdropyridine calcium-channel blockers (eg, verapamil, diltiazem)
Cardiac glycosides (eg, digoxin)
Ivabradine
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Appendix C
Adverse event definitions and additional safety information
C 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.
C 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..
This 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 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.
C 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 

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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).
C 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, 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.
C 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 iv 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
C 6
Intensity rating scale
The grading scales found in the revised National Cancer Institute CTCAE latest version will 
be utilised for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used. A copy of the CTCAE 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 C 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 

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several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix C 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 C 2.
C 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.

Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
rechallenge.

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?

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.

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C 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 recognise 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)
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 D
Handling of human biological samples
D 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
patients while in storage at the centre 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 AZ-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.
D 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 and the action 
documented and returned to the study site.

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D 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, 
Human immunodeficiency virus 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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E 1
Use/analysis of 
 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 
 
analysis from consenting patients.
AstraZeneca intends to collect and store 
 for 
 research to explore how 
 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. 
 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 
samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to 
 guided treatment strategies.
 research may consist of the analysis of the structure of the patient´s
 (ie, the 
entire genome). 
The results of
 analyses may be reported in the CSR or in a separate study summary.
The Sponsor will store the 
 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.
E 2
 research plan and procedures
Selection of
 research population
Study selection record
All patients will be asked to participate in this 
 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.
Inclusion criteria
For inclusion in this 
research, patients must fulfil all of the inclusion criteria described 
in the main body of the CSP and: Provide informed consent for the 
 sampling and 
analyses.
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Exclusion criteria
Exclusion from this 
 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 
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 
 research
The blood sample for 
research will be obtained from the patients at Visit 2. Although 
 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
 analysis. If for any reason the sample is not drawn at Visit 1, it may be 
taken at any visit until the last study visit. Only one sample should be collected per patient for 
 during the study. Samples will be collected, labelled, stored, and shipped as detailed 
in the Laboratory Manual.
Coding and storage of
 samples
The processes adopted for the coding and storage of samples for 
 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. 
 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 
 
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 
laboratories, or at the designated 
organisation. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the 
).
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 
 samples for 
analysis, facilitate correlation of 
 results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.
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Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this 
 
research component, are outlined in Appendix C.
Informed consent
The 
 component of this study is optional and the patient may participate in other 
components of the main study without participating in the 
 component. To participate 
in the 
 component of the study the patient must sign and date both the consent form for 
the main study and the 
 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 centre. The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely withdrawal from the 
 aspect of the study at 
any time.
Patient data protection
AstraZeneca will not provide individual 
 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 
 data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the 
 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 
 data. In addition, Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the 
 
files would remain physically separate.
Data management
Any 
data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organisations to analyse the samples.
AstraZeneca and its designated organisations may share summary results (such as 
 
differences from groups of individuals with a disease) from this 
 research with other 
researchers, such as hospitals, academic organisations or health insurance companies. This can 
be done by placing the results in scientific databases, where they can be combined with the 
results of similar studies to learn even more about health and disease. The researchers can 
only use this information for health-related research purposes. Researchers may see summary 
results but they will not be able to see individual patient data or any personal identifiers. 
Some or all of the clinical datasets from the main study may be merged with the 
 data 
in a suitable secure environment separate from the clinical database.
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Statistical methods and determination of sample size
The number of patients that will agree to participate in the 
 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. A SAP may be 
prepared where appropriate.
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Appendix F
Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s law
F 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 drug-induced liver injury (DILI) caused by the IP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting serious AEs (SAEs) and AEs according to the outcome of the review and assessment 
in line with standard safety reporting processes.
F 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× ULN together 
with total bilirubin (TBL) ≥ 2×ULN at any point during the study following the start of study 
medication irrespective of an increase in alkaline phosphatase (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.
F 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 F 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
F 4
Follow-up
F 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.
F 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.
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 total 
bilirubin) in isolation or in combination, or a clinically relevant change in associated 
symptoms. The determination of whether there has been a significant change will be at 

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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.
F 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.

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 AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study treatment:

Send updated SAE (report term ‘Hy’s law’) according to AstraZeneca standard processes. 

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
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.
F 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 F 4.2 for reporting PHL as an SAE.
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 F 4.2 for 
reporting PHL as an SAE.

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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 total 
bilirubin) in isolation or in combination, or a clinically relevant change in associated 
symptoms. The determination of whether there has been a significant change will be at 
the discretion of the Investigator; this may be in consultation with the Study Physician if 
there is any uncertainty.
REFERENCES
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’

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Appendix G
Guidelines for evaluation of objective tumour response using 
Response Evaluation Criteria in Solid Tumours (RECIST) 
version 1.1
G 1
INTRODUCTION
This appendix details the implementation of RECIST version 1.1 Guidelines (Eisenhauer et al 
2009) for study D8530C00002 with regards to Investigator assessment of tumour burden 
including protocol-specific requirements for this study.
G 2
Definition of measurable, non-measurable, target and non-target 
lesions
Measurable disease is defined by the presence of at least one measurable lesion which has not 
been previously irradiated and not chosen for biopsy during the screening period.
Measurable:
A lesion, not previously irradiated and not chosen for biopsy during the screening period, that 
can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph 
nodes which must have short axis ≥15 mm) with CT or MRI and which is suitable for accurate 
repeated measurements. If only one measurable lesion exists, it is acceptable to be used (as a 
TL) as long as it has not been previously irradiated and baseline tumour assessment scans are 
done at least 14 days after the screening biopsy is performed.
Non-measurable:

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 to <15 mm short axis at baseline).
Note: Nodes with <10 mm short axis are considered non-pathological and should not be 
recorded or followed as NTL.

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that is not measurable by CT or MRI.

Previously irradiated lesions
Note: Localised post-radiation changes which affect lesion sizes may occur. Therefore, 
lesions that have been previously irradiated will not be considered measurable and must 
be selected as NTLs at baseline and followed up as part of the NTL assessment.

Skin lesions assessed by clinical examination

Brain metastasis

Lesions biopsied within the screening period
Exception: if only 1 measurable lesion exists, it is acceptable to be used (as a target 
lesion [TL]) as long as it has not been previously irradiated and baseline tumour 
assessment scans are done at least 14 days after the screening biopsy is performed.

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Special cases:

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
can be considered measurable if the soft tissue component meets the definition of 
measurability. Blastic lesions are considered non-measurable.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in the 
same patient, these should be selected as TLs.
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline.
Non-target lesions:
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.
G 3
Methods of assessment
The same method of assessment and the same technique should be used to characterise 
each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST assessment is provided below and those 
excluded from tumour assessments for this study are highlighted, with the rationale provided.
Table 27
Summary of Methods of Assessment
Target Lesions
Non Target Lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI
Clinical examination
X-ray, chest X-ray
CT (preferred)
MRI
Clinical examination 
X-ray, chest X-ray
Ultrasound
Bone scan
FDG-PET
CT=computed tomography; FDG-PET=fluorodeoxyglucose-positron emission tomography; MRI=magnetic 
resonance imaging
G 3.1
CT and MRI
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TLs selected for response assessment and to assess NTLs and 
identification of any new lesions. 

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It is recommended that CT examinations of the chest and abdomen (including liver and 
adrenal glands), will be used to assess tumour burden at baseline and follow-up visits. CT 
examination with intravenous (iv) contrast media administration is the preferred method. MRI 
should be used where CT is not feasible or it is medically contra-indicated. For brain lesion 
assessment, MRI is the preferred method although CT is acceptable.
G 3.2
Clinical examination
Clinical examination will not be used for assessment of TLs. Clinically detected lesions can be 
selected as TLs if they are assessed by CT or MRI scans. Clinical examination can be used to 
assess NTLs and to identify the presence of new lesions.
G 3.3
X-ray
Chest X-ray
Chest X-ray assessment will not be used for assessment of TLs as they will be assessed by CT 
examination or MRI examination. Chest X-ray can, however, be used to assess NTLs and to 
identify the presence of new lesions.
Plain X-ray
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions. 
G 3.4
Ultrasound
Ultrasound examination will not be used for assessment of TLs and NTLs as it is not a 
reproducible method, does not provide an accurate assessment of tumour size and it is 
subjective and operator dependent. Ultrasound examination can, however, be used to identify 
the presence of new lesions. If new clinical symptoms occur and an ultrasound is performed 
then new lesions should be confirmed by CT or MRI examination.
G 3.5
Endoscopy and laparoscopy
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour assessment.
G 3.6
Tumour markers
Tumour markers will not be used for tumour response assessments as per RECIST 
version 1.1.
G 3.7
Cytology and histology
Histology will not be used as part of the tumour response assessment as per RECIST 
version 1.1.

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Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease. In such circumstances, the cytology is necessary to differentiate between 
response / stable disease (an effusion may be a side effect of the treatment) and progressive 
disease (if the neoplastic origin of the fluid is confirmed). Where cytology findings are not 
available, any effusion that significantly worsens (from trace to large) or appearance of 
clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTLs, or disease progression due to new lesions.
G 3.8
Isotopic bone scan
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or 
X-ray at baseline should be recorded as NTLs and followed by the same method as per 
baseline assessment.
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. New lesions will be recorded where a positive hot-spot that 
was not present on the baseline bone scan assessment is identified on a bone scan performed 
at any time during the study. The Investigator should consider the positive hot-spot to be a 
significant new site of malignant disease and represent true disease progression in order to 
record the new lesion. Confirmation by CT, MRI and X-ray is recommended where bone scan 
findings are equivocal.
G 3.9
FDG-PET scan
Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans may be used as a 
method for identifying new lesions, according with the following algorithm:  New lesions will 
be recorded where there is positive FDG uptake not present on baseline FDG-PET scan or in a 
location corresponding to a new lesion on CT/MRI at the same follow-up visit. If there is no 
baseline FDG-PET scan available, and no evidence of new lesions on CT/MRI scans then 
follow-up CT/MRI assessments should be continued, scheduled as per protocol or clinical 
indicated, in order to confirm new lesions.
Note: A positive FDG-PET scan lesion should be reported only when an uptake greater than 
twice that of the surrounding tissue is observed.
G 4
Tumour response evaluation
G 4.1
Schedule of evaluation
Baseline assessments should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based
on signs and symptoms of individual patients and should be performed no more than 28 days 
before the start of study treatment (refer to Table 1 and Section 8.1.1 of the CSP). Follow-up 

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assessments will be performed every 8 weeks (±1 week) after randomisation until objective 
disease progression as defined by RECIST version 1.1 even if a patient discontinues treatment 
prior to progression or receives other anti-cancer treatment. Any other sites at which new 
disease is suspected should also be adequately imaged at follow-up.
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. This schedule 
is to be followed in order to minimise any unintentional bias caused by some patients being 
assessed at a different frequency than other patients.
G 4.2
Target lesions
G 4.2.1
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved should be identified as TLs at baseline. 
The TLs should be selected on the basis of their size (longest diameter for non-nodal lesions 
or short axis for nodal lesions), but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimetres. At baseline, the sum of the diameters for all TLs will be calculated and reported 
as the baseline sum of diameters. At follow-up visits the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.
Special cases:

For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis. 

If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 0 mm.

If a TL splits into 2 or more parts, then record the sum of the diameters of those parts. 

If 2 or more TLs merge then the sum of the diameters of the combined lesion should be 
recorded for one of the lesions and 0 mm recorded for the other lesion(s). 

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. 

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
When a TL has had any intervention (eg, radiotherapy, embolisation, surgery, etc) during 
the study, the size of the TL should still be provided where possible.
G 4.2.2
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumour visit 
response for TL.
Table 28
Evaluation of target lesions
CR
Disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must have a 
reduction in short axis to <10 mm.
PR
At least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of 
diameters.
SD
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
PD
At least a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
NE
Only relevant if any of the TLs were not assessed or not evaluable or had a lesion intervention at this 
visit. Note:  If the sum of diameters meets the progressive disease criteria, progressive disease 
overrides not evaluable as a TL response.
CR=complete response; NE=not evaluable; PD=progressive disease; PR=partial response; SD=stable disease; 
TL=target lesion.
G 4.3
Non-target lesions
G 4.3.1
Evaluation of non target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. At each visit an overall assessment of the NTL response should be 
recorded by the Investigator. This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit.
Table 29
Evaluation of non-target lesions
CR
Disappearance of all NTLs since baseline. All lymph nodes must be non-pathological in size 
(<10 mm short axis).
Non-CR/ 
Non-PD
Persistence of 1 or more NTL.
PD
Unequivocal progression of existing NTLs. Unequivocal progression may be due to an important 
progression in one lesion only or in several lesions. In all cases the progression MUST be clinically 
significant for the physician to consider changing (or stopping) therapy.

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CR
Disappearance of all NTLs since baseline. All lymph nodes must be non-pathological in size 
(<10 mm short axis).
NE
Only relevant when one or some of the NTLs were not assessed and, in the Investigator’s opinion, 
they are not able to provide an evaluable overall NTL assessment at this visit.
Note:  For patients without TLs at baseline, this is relevant if any of the NTLs were not assessed at 
this visit and the progression criteria have not been met.
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; NE=not evaluable; 
NA=not applicable (only relevant if there were no NTLs at baseline); NTL=non-target lesion; TL=target lesion.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.
G 4.4
New lesions
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed. If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
G 4.5
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed.
G 4.6
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 30.

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Table 30
Overall Visit Response
TLs
NTLs
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
Non-CR / Non-PD
No
PR
CR
NE
No
PR
Non-PD or NE
No
SD
Non-PD or NE
No
SD
NE
Non-PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
Any
Any
Yes
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; NE=not evaluable; 
NA=not applicable (only relevant if there were no NTLs at baseline); NTL=non-target lesion; TL=target lesion.
G 5
Central review
The CRO appointed by AstraZeneca to perform the independent central review for this study 
will provide specification for radiological imaging protocols in standard acquisition guidelines 
documentation. 
G 6
References
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47

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Appendix H
Abbreviations
Abbreviation or special 
term
Explanation
AE
adverse event
AI
aromatase inhibitor
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin time
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
BICR
Blinded Independent Central Review
BoR
Best objective response
bpm
beat per minute
CBR
clinical benefit rate
CBR24
clinical benefit rate at 24 weeks
CDK4/6
cyclin-dependent kinase 4 and 6
CI
confidence interval
CIOMS
Council for International Organisations of Medical Sciences
CK
creatine kinase
Cmax 
maximum plasma drug concentration
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRF
case report form (electronic/paper)
CRO
Contract Research Organisation
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
computed tomography
CCI

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Abbreviation or special 
term
Explanation
CTC 
circulating tumour cell
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
circulating tumour deoxyribonucleic acid
DCO
data cut-off
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
data monitoring committee
DMPK
Drug Metabolism and Pharmacokinetics
DNA
deoxyribonucleic acid 
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eGFR
estimated glomerular filtration rate
EORTC
European Organisation for Research and Treatment of Cancer
EORTC QLQ-C30
EORTC quality of life questionnaire – core questionnaire
EORTC QLQ-BR23
EORTC quality of life questionnaire – breast cancer module
EOT
end of treatment
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQol 5-Dimension 5-level
ER
oestrogen receptor
ERα
oestrogen receptor alpha
ERT
E-Research Technology
ESR1
oestrogen receptor 1
FAS
full analysis set
FDG-PET
fluorodeoxyglucose-positron emission tomography
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
Hb
haemoglobin
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
CCI

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Abbreviation or special 
term
Explanation
HRQoL
health-related quality of life
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
INR
international normalised ratio
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. 
ISH
in situ hybridisation
IWRS
interactive web response system
LSmeans
least squares means
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NEI VFQ-25
National Eye Institute 25-Item Visual Function Questionnaire
NTL
non target lesion
OAE
other significant adverse event
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PgR
progesterone receptor
PHL
potential Hy’s law
PK
pharmacokinetic(s)
PR
partial response
CCI
CCI

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Abbreviation or special 
term
Explanation
PRO
patient-reported outcome
QoL
quality of life
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 Tumours
RNA
ribonucleic acid
SAE
serious adverse event 
SAP
statistical analysis plan
SD
stable disease
SERD
selective oestrogen receptor degrader
SmPC
Summary of product characteristics
SoA
Schedule of Activities
SOC
system organ class
SRC
Safety Review Committee
t1/2
terminal elimination half-life
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TL
target lesion
tmax
time to reach maximum plasma concentration 
ULN
upper limit of normal
USPI
United States prescribing information
WBDC
web-based data capture
WHO
World Health Organisation

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Document Name: d8530c00002-csp-v5
Document Title:
D8530C00002 Clinical Study Protocol version 5
Document ID:
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