A Phase III Double-blind Randomised Study Assessing the Efficacy and Safety of Capivasertib + Fulvestrant Versus Placebo + Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Breast Cancer Following Recurrence or Progression On or After Treatment With an Aromatase Inhibitor
Phase: PHASE3
Conditions: Locally Advanced (Inoperable) or Metastatic Breast Cancer
Sponsor: AstraZeneca

Clinical Study Protocol - 5.0
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Capivasertib (AZD5363) - D3615C00001
CONFIDENTIAL AND PROPRIETARY
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Clinical Study Protocol 
Drug Substance
Capivasertib (AZD5363)
Study Code
D3615C00001
Version
5.0
Date
1 August 2023
A Phase III Double-blind Randomised Study Assessing the Efficacy and 
Safety of Capivasertib + Fulvestrant Versus Placebo + Fulvestrant as 
Treatment for Locally Advanced (Inoperable) or Metastatic Hormone 
Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative 
(HR+/HER2−) Breast Cancer Following Recurrence or Progression On or 
After Treatment with an Aromatase Inhibitor (CAPItello-291)
Sponsor:
AstraZeneca AB, S-151 85 Södertälje, Sweden.  
AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan.  
Regulatory Agency Identifying Number(s):
EudraCT number: 2019-003629-78
EU CT number: 2023-505042-25-00
IND number: 118046

Clinical Study Protocol - 5.0
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Capivasertib (AZD5363) - D3615C00001
CONFIDENTIAL AND PROPRIETARY
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Section 1.1: Added collection of circulating soluble factor, whole blood DNA sample, 
and whole blood RNA samples at discontinuation of IMP if it falls on a different 
visit/time than progression.
Sections 1.1, 1.2, 5.1, and 6.5.1: Updated administration of LHRH agonist in pre- or 
peri-menopausal women must start prior to or on Cycle 1, Day 1.
Section 1.1: Clarified that if fulvestrant and capivasertib/placebo are both discontinued 
at the same time as progression, the discontinuation visits are combined and the 
optional biopsy is completed, if applicable.
Sections 1.2 and 3.2: Clarified secondary objective for PK to evaluate the PK of 
capivasertib (when given in combination with fulvestrant).
Sections 1.2 and 9.3: Clarified FAS to comprise patients randomised into the study 
prior to global cohort LPFV; clarified the Safety Analysis Set will also include patients 
who receive only fulvestrant and these patients will be included in the treatment arm to 
which they were randomised; clarified the Altered Subgroup FAS will include patients 
with a result from a valid biomarker test as pre-specified in the SAP.
Sections 1.2 and 9.6: Clarified the China cohort.
Sections 2.3.3 and 4.5: Added text for impact of COVID-19 on the study conduct.
Section 5.1: Clarified Inclusion criterion for confirmation of breast cancer HER2-
Section 5.1: Clarified Inclusion criterion of metastatic or locally advanced disease with 
radiological or objective evidence of disease progression (the cancer should have 
shown progression during or after most recent therapy).
Section 5.2: Clarified Exclusion criterion for cardiac criteria as QT interval corrected 
by Fridericia’s formula. 
Section 5.2: Clarified Exclusion criterion for severe or uncontrolled systemic diseases 
(as judged by the investigator) to include those with confirmed COVID-19, for 
example.
Section 5.2: Clarified Exclusion criterion for participation in another clinical study and 
to clarify vaccines for COVID-19 are not considered investigational agents.
Sections 1.1, 5.3.3, and 8.2.1: Updated that FSH and oestradiol will be monitored at 
screening, at Day 1 of each cycle, and when clinically indicated in pre- and peri-

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C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 of 1 9 6
T A B L E O F C O N T E N T S
TI T L E P A G E ........................................................................................................................1
V E R SI O N HI S T O R Y ...........................................................................................................2
T A B L E O F C O N T E N T S ......................................................................................................7
1
P R O T O C O L S U M M A R Y ................................................................................1 2
1. 1
Sc he d ule of Act i vities ( S o A).............................................................................1 2
1. 2
S y n o psis ...........................................................................................................2 2
1. 3
Sc he ma .............................................................................................................3 3
2
I N T R O D U C TI O N ............................................................................................3 4
2. 1
St u d y  r atio nale ..................................................................................................3 4
2. 2
Bac k gr o u n d ......................................................................................................3 5
2. 3
Be nefit/ris k assess me nt .....................................................................................3 8
2. 3. 1
Ris ks wit h ca pi vasert i b .....................................................................................3 8
2. 3. 2
O verall be nefit -ris k a n d et hical assess me nt .......................................................3 9
2. 3. 3
I mpact o n Be nefit/ Ris k fr o m St u d y  Disr u pti ons d ue t o C or o na vir us Disease 
2 0 1 9 .................................................................................................................4 0
3
O BJ E C TI V E S A N D E N D P OI N T S ...................................................................4 1
3. 1
Pri mar y o bject i ves ............................................................................................4 1
3. 2
Sec o n dar y  o bjecti ves ........................................................................................4 1
4
S T U D Y D E SI G N .............................................................................................4 5
4. 1
O verall desi g n ...................................................................................................4 5
4. 1. 1
St u d y o versi g ht c o nsi derat i ons ..........................................................................4 9
4. 2
S ci e nt ific rati onale f or st u d y  desi g n..................................................................4 9
4. 3
J ustificati o n f or d ose.........................................................................................5 3
4. 3. 1
Ca pi vasert i b......................................................................................................5 3
4. 3. 2
F ul vestra nt ........................................................................................................5 4
4. 4
E n d of st u d y  defi nitio n ......................................................................................5 4
4. 5
St u d y  C o n d uct Miti gati on D uri n g St u d y  Disr u pti ons D ue t o C O VI D - 1 9 –
T e m p orar y  Meas ures ........................................................................................5 5
5 
S T U D Y P O P U L A TI O N ...................................................................................5 6
5. 1
I ncl usi on cri t eria ...............................................................................................5 7
5. 2
E xcl usi o n cri t eria ..............................................................................................5 9
5. 3
Li festyle restrict i ons .........................................................................................6 3
5. 3. 1
Meals a n d dietar y  restrictio ns............................................................................ 6 3
5. 3. 2
Caffei ne, alc o h o l, a n d t o bacc o ..........................................................................6 3
5. 3. 3
C o ntrace pti o n ...................................................................................................6 3
5. 3. 3. 1
Fe males ............................................................................................................6 3
5. 3. 3. 2
Males ................................................................................................................6 4
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5.3.4
Other restrictions .............................................................................................. 64
5.4
Screen failures .................................................................................................. 65
6
STUDY TREATMENTS.................................................................................. 65
6.1
Treatments administered................................................................................... 65
6.1.1
Capivasertib/placebo......................................................................................... 65
6.1.2
Fulvestrant........................................................................................................ 67
6.1.3
Duration of treatment........................................................................................ 68
6.2
Preparation/handling/storage/accountability...................................................... 68
6.2.1
Dose Preparation............................................................................................... 69
6.3
Measures to minimise bias: randomisation and blinding.................................... 69
6.4
Treatment compliance....................................................................................... 70
6.5
Concomitant therapy......................................................................................... 70
6.5.1
Allowed concomitant therapy ........................................................................... 71
6.5.2
Restricted concomitant therapy......................................................................... 72
6.5.3
Other concomitant treatment............................................................................. 72
6.6
Dose modifications and delay ........................................................................... 73
6.7
Treatment after the end of the study.................................................................. 73
7
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL . 74
7.1
Discontinuation of study treatment.................................................................... 74
7.1.1
Temporary discontinuation ............................................................................... 75
7.1.2
Procedures for discontinuation of study treatment............................................. 75
7.2
Lost to follow-up .............................................................................................. 76
7.3
Withdrawal from the study................................................................................ 76
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 77
8.1
Efficacy assessments......................................................................................... 78
8.1.1
RECIST v1.1 assessments................................................................................. 78
8.1.1.1
Progression-free survival (PFS) ........................................................................ 78
8.1.1.2
Clinical benefit rate (CBR) ............................................................................... 79
8.1.1.3
Duration of response (DoR).............................................................................. 79
8.1.1.4
Objective response rate (ORR).......................................................................... 79
8.1.2
Overall survival (OS)........................................................................................ 79
8.1.3
PFS2................................................................................................................. 80
8.1.4
Time to definitive deterioration of the ECOG performance status ..................... 80
8.1.5
Time to first subsequent chemotherapy or death (TFSC)................................... 81
8.1.6
Bone scan ......................................................................................................... 81
8.1.7
Patient-reported outcomes................................................................................. 81
8.1.7.1
EORTC QLQ-C30............................................................................................ 81
8.1.7.2
EORTC QLQ-BR23 ......................................................................................... 82
8.1.7.3
EQ-5D-5L ........................................................................................................ 82
8.1.7.4
PGIS................................................................................................................. 82
8.1.7.5
PGIC ................................................................................................................ 83
8.1.7.6
PGI-TT............................................................................................................. 83
8.1.7.7
PRO-CTCAE.................................................................................................... 83

Cli nical St u d y Pr ot oc ol - 5. 0
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Ca pi vaserti b ( A Z D 5 3 6 3) - D 3 6 1 5 C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 of 1 9 6
8. 1. 7. 8
A d mi nistrati o n of  patie nt-re p orte d o utc o me q uesti o n naires...............................8 3
8. 2
S af et y assess me nts ............................................................................................8 5
8. 2. 1
Cli nical safet y la b orat or y assess me nts...............................................................8 5
8. 2. 1. 1
Gl uc ose a n d gl yc os ylate d hae m o gl o bi n ( H b A 1c) ..............................................8 7
8. 2. 1. 2
S er u m  creati ni ne...............................................................................................8 7
8. 2. 2
P h ysical e xa mi nat i ons .......................................................................................8 7
8. 2. 3
Vi t al si g ns.........................................................................................................8 7
8. 2. 4
Electr ocar di o gra ms ...........................................................................................8 8
8. 2. 5
M U G A sca n/ Ec h ocar di o gra m ...........................................................................8 8
8. 3
C ollect i on of a d verse e ve nts .............................................................................8 9
8. 3. 1
Met h o d of detecti n g A Es a n d S A Es ..................................................................8 9
8. 3. 2
Ti me peri o d a n d fre q ue nc y  for c ollect i n g A E a n d S A E i nf or mat i on ..................8 9
8. 3. 3
F o ll ow- u p of  A Es a n d S A Es.............................................................................9 0
8. 3. 4
A d verse e ve nt data c ollect i on ............................................................................9 0
8. 3. 5
Ca usalit y c ollecti o n...........................................................................................9 1
8. 3. 6
A d verse e ve nts base d o n si g ns a n d s y m pt o ms ...................................................9 1
8. 3. 7
A d verse e ve nts base d o n e xa mi nat i ons a n d tests ...............................................9 1
8. 3. 8
H y’s la w ...........................................................................................................9 2
8. 3. 9
Di sease pr o gressio n ..........................................................................................9 2
8. 3. 1 0
A d verse E ve nts of S pecial I nterest ....................................................................9 2
8. 4
S af et y re p ortin g a n d me dical ma na ge me nt ........................................................9 3
8. 4. 1
Re p orti n g of seri o us a d verse e ve nts ..................................................................9 3
8. 4. 1. 1
Re g ulat or y  Re p orti n g Re q uire me nts f or S A Es..................................................9 4
8. 4. 2
Pre g na nc y .........................................................................................................9 4
8. 4. 2. 1
Mater nal e x p os ure
............................................................................................9 4
8. 4. 2. 2
Pater nal  e x p os ure..............................................................................................9 5
8. 4. 3
O ver d ose ..........................................................................................................9 5
8. 4. 4
Me dicat i on err or, dr u g a b use, a n d dr u g mis use .................................................9 6
8. 4. 4. 1
Ti meli nes ..........................................................................................................9 6
8. 4. 4. 2
Me dicat i on err or ...............................................................................................9 6
8. 4. 4. 3
Dr u g a b use ........................................................................................................9 6
8. 4. 4. 4
Dr u g mis use ......................................................................................................9 6
8. 4. 5
Ma na ge me nt of ca pi vaserti b -relate d t o xicities ...................................................9 7
8. 4. 5. 1
Ca pi vasert i b/ place b o d ose m o dificati on a n d g ui da nce .......................................9 7
8. 4. 5. 2
D ose m o dificat i ons d ue t o ge neral ca pi vasert i b-relate d t o xicities ......................9 7
8. 4. 5. 3
D ose m o dificat i ons d ue t o s pecific ca pi vaserti b -relate d t o xicities .....................9 7
8. 5
P har mac o ki net ics............................................................................................1 0 3
8. 5. 1
Deter mi nat i on of dr u g c o nce ntrati o n ...............................................................1 0 4
8. 5. 2
St ora ge a n d destr ucti o n of p har mac o ki net ic sa m ples.......................................1 0 4
8. 5. 2. 1
S a m ples c o llecte d i n C hi na .............................................................................1 0 4
8. 5. 2. 2
S a m ples c o llecte d o utsi de of C hi na................................................................. 1 0 4
8. 6
Ge net ics..........................................................................................................1 0 5
8. 6. 2
St ora ge a n d destr ucti o n of ge net ic sa m ples .....................................................1 0 5
8. 7
Bi o m ar kers .....................................................................................................1 0 5
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Ca pi vaserti b ( A Z D 5 3 6 3) - D 3 6 1 5 C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 of 1 9 6
8. 7. 1
T u m o ur tiss ue sa m ple .....................................................................................1 0 5
8. 7. 1. 1
Ma n dat or y  t u mo ur ti ss ue sa m ples f or bi omar ker a nal ysis ................................1 0 5
8. 7. 1. 3
C ollect i on, a nal ysis a n d re p orti n g of t u m o ur sa m ples ......................................1 0 7
8. 7. 3
St ora ge, re -use a n d destr ucti o n of bi o mar ker sa m ples .....................................1 0 8
8. 8
Heal t hcare res o urce use ..................................................................................1 0 8
9
S T A TI S TI C A L C O N SI D E R A TI O N S .............................................................1 0 9
9. 1
Stati stical h y p ot heses ......................................................................................1 0 9
9. 2
S a m ple size deter mi nat i on ..............................................................................1 0 9
9. 3
P o p ul at i ons f or a nal yses..................................................................................1 1 2
9. 4
Stati stical a nal yses..........................................................................................1 1 3
9. 4. 1
Efficac y a nal yses ............................................................................................1 1 3
9. 4. 1. 1
Pri mar y e n d p o i nt: P F S i n t he o verall p o p ulati on .............................................1 1 3
9. 4. 1. 2
Pri mar y e n d p o i nt: P F S i n t he PI K 3 C A/ A K T 1/ P T E N -altere d s u b gr o u p.............1 1 4
9. 4. 1. 3
Sec o n dar y  e n d p oi nt: O S i n t he o verall p o p ulati o n...........................................1 1 4
9. 4. 1. 4
Sec o n dar y  e n d p oi nt: O S i n t he PI K 3 C A/ A K T 1/ P T E N -altere d s u b gr o u p ..........1 1 4
9. 4. 1. 5
Sec o n dar y  e n d p oi nt: P F S 2 i n t he o verall a n d altere d F A S p o p ulati on .............1 1 5
9. 4. 1. 6
Sec o n dar y  e n d p oi nt: O R R i n t he o verall a n d altere d F A S p o p ulati on ..............1 1 5
9. 4. 1. 7
Sec o n dar y  e n d p oi nt: D o R i n t he o verall a n d altere d F A S p o p ulati on ...............1 1 5
9. 4. 1. 8
Sec o n dar y  e n d p oi nt: C B R i n t he o verall a n d altere d F A S p o p ulat i on ..............1 1 5
9. 4. 1. 9
Sec o n dar y  e n d p oi nt: P K..................................................................................1 1 5
9. 4. 1. 1 0
Sec o n dar y  e n d p oi nts: E O R T C Q L Q-C 3 0 a n d E O R T C Q L Q -B R 2 3 .................1 1 6
9. 4. 1. 1 1
Sec o n dar y  e n d p oi nt: ti me t o defi niti ve deteri orati o n of t he E C O G perf or ma nce 
stat us i n t he o verall p o p ulati o n a n d t he PI K 3 C A/ A K T 1/ P T E N -altere d 
p o p ul at i on .......................................................................................................1 1 7
9. 4. 2
S af et y a nal yses ...............................................................................................1 1 7
9. 4. 2. 1
A d verse e ve nts ................................................................................................1 1 8
9. 4. 2. 2
Ot her safet y a nal ysis .......................................................................................1 1 9
9. 4. 3
Ot her a nal yses ................................................................................................1 1 9
9. 4. 4
Met h o ds f or m ult i plicity c o ntr ol .....................................................................1 1 9
9. 5
I nteri m a nal yses..............................................................................................1 2 0
9. 5. 1
I n de pe n de nt data m o nit ori n g c o m mittee (I D M C) ............................................1 2 0
9. 6
C hi na c o h ort ...................................................................................................1 2 1
1 0
R E F E R E N C E S ...............................................................................................1 2 3
1 1
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L
C O N SI D E R A TI O N S ......................................................................................1 3 0
LI S T O F T A B L E S
Ta ble 1
Sc he d ule of assess me nts ( S o A) ................................................................1 3
Ta ble 2
Pri mar y o bject i ves ...................................................................................4 1
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1 1 of 1 9 6
T a ble 3
Sec o n dar y  o bjecti ves ...............................................................................4 1
Ta ble 5
Ca pi vasert i b/ place b o................................................................................6 6
Ta ble 6
F ul vestra nt ...............................................................................................6 7
Ta ble 7
D ose l e vels f or ca pi vasert i b/ place b o a n d f ul vestra nt ................................7 3
Ta ble 8
La b orat or y  safety v ari a bles ......................................................................8 6
Ta ble 9
D ose m o dificat i ons f or ge neral ca pi vaserti b-r elate d t o xicities ..................9 7
Ta ble 1 0
D ose m o dificat i ons f or ca pi vaserti b-relate d h yper gl ycae mia a ...................9 9
Ta ble 1 1
D ose m o dificat i ons f or ca pi vaserti b-relate d mac ul o -pa p ular ras h ...........1 0 1
Ta ble 1 2
D os e mo dificat i ons f or ca pi vaserti b-relate d diarr h oea ............................1 0 3
Ta ble 1 3
Stati stical c o nsi derati ons f or O S e n d p oi nt ..............................................1 1 1
Ta ble 1 4
A nal ysis p o p ulati o ns ..............................................................................1 1 2
Ta ble 1 5
S u m mar y  of ima gi n g m o dalit ies f or t u mo ur assess me nt .........................1 3 1
Ta ble 1 6
R E CI S T v 1. 1 e val uat i on of tar get lesi o ns ...............................................1 3 8
Ta ble 1 7
R E CI S T v 1. 1 e val uat i on of n o n -tar get lesi ons ........................................1 3 9
Ta ble 1 8
R E CI S T v 1. 1 o verall visit res p o nse .......................................................1 3 9
Ta ble 1 9 
E C O G perf or ma nce stat us scale ( O ke n et al 1 9 8 2) ................................. 1 4 2
Ta ble 2 0
C Y P 3 A 4 -i nteract i n g me d icatio n t hat m ust be a v o i de d or use d wit h 
ca utio n ...................................................................................................1 5 1
Ta ble 2 1
C Y P 3 A 4 s u bstrates t hat m ust be a v oi de d or use d wit h ca ut i on ...............1 5 3
Ta ble 2 2
M A T E 1 a n d/ or O C T 2 tra ns p orter s u bstrates t hat s h o ul d be use d wit h 
ca utio n ...................................................................................................1 5 3
LI S T O F FI G U R E S
Fi g ure 1
St u d y  desi g n............................................................................................3 3
Fi g ure 2
St u d y  fl ow c hart ......................................................................................4 8
Fi g ure 3
Treat me nt sc he d ule ..................................................................................6 7
Fi g ure 4
Ill ustratio n of  data c ut-offs a n d ass oci ate d treat me nt c o mparis o ns ..........1 1 9
LI S T O F A P P E N DI C E S
A p pe n di x A
G ui deli nes f or e val uat i on of o bjecti ve t u m o ur res p o nse usi n g 
R E CI S T v 1. 1 Criteria ( Res p o nse E val uat i on Cri teria i n S oli d T u m o urs) 1 3 1
A p pe n di x B
E C O G/ W H O Perf or ma nce Stat us ..........................................................1 4 2
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Appendix C
Regulatory, ethical and study oversight considerations........................... 143
Appendix D
Guidance regarding potential interactions of capivasertib with 
concomitant medications........................................................................ 151
Appendix E
Adverse event definitions and additional safety information .................. 155
Appendix F
Handling of human biological samples .................................................. 161
Appendix G
Genetics................................................................................................. 164
Appendix H
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s law........................................................................... 168
Appendix I
Patient-reported outcomes – questionnaires............................................ 172
Appendix J
Abbreviations ........................................................................................ 183
Appendix K
Changes Related to Mitigation of Study Disruptions Due to COVID-19 
Outbreak - Temporary Measures............................................................ 187
Appendix L
Guidance during the COVID-19 Outbreak ............................................. 190
Appendix M
Country-Specific Requirements ............................................................. 193
1
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
The schedule of study assessments is provided in Table 1.

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Table 1
Schedule of assessments (SoA)
Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-
up 
Details in 
CSP section 
or appendix

Fulvestrant Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Informed consent
X
Section 5.1, 
Appendix C
Inclusion/exclusion criteria
X
Sections
5.1 & 5.2
Prepare ePRO deviced
X
Section 
8.1.7.8
Train patient on ePRO 
devicee
X
Section 
8.1.7.8
Routine clinical proceduresf
Demography/baseline 
characteristics
X
Medical/surgical history
X
Sections
5.1 & 5.2
Smoking history
X
Previous cancer therapy
X
Section 5.2
BRCA1/2 status (local 
testing), if available
X
Concomitant medication
X
At every study visit
Section 6.5
ECOG/WHO performance 
status
X
X
X
X
X
X
X
X
X
Appendix B

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Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-
up 
Details in 
CSP section 
or appendix

Fulvestrant Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Physical examination
X
X
X
X
X
X
X
Section 8.2.2
Vital signs
X
Pre (within 
30m) and
1-2h post 
(±30m)
X
X
X
X
X
X
X
Section 8.2.3
Height
X
Section 8.2.2
Weight
X
X
X
X
X
X
X
Section 8.2.2
12-lead ECG
X
Pre (within 
30m) and 
1h post 
(±30m)
Cycle 2, Week 1, Day 1 
and every 12 weeks 
thereafter
X
Section 8.2.4
MUGA/ECHO (LVEF)g
X
As clinically indicated during study treatment
For the alternative requirement, applicable only for UK, France, Italy, Spain, Belgium, Hungary, Poland, Germany refer 
to Appendix M. 
Section 8.2.5, 
Appendix M
Routine safety measurementsf
Adverse events
X
At every study visit
Section 8.3,  
Appendix E
Pregnancy test (peri-/pre-
menopausal only)
X
X
As clinically indicated and at treatment discontinuation
Section 8.4.2
Oestradiol and FSHh
X
X
X
X
Section 8.2.1
International Normalised 
Ratio (INR)
X
As clinically indicated
Section 8.2.1

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Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-
up 
Details in 
CSP section 
or appendix

Fulvestrant Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Haematologyc
X
Pre
Pre
Pre
Pre
X
X
X
Section 8.2.1
Clinical chemistryc,i
X
Pre
Pre
Pre
Pre
X
X
X
Section 8.2.1
Urinalysisc
X
Pre
Pre
Pre
Pre
X
X
X
Section 8.2.1
Glycosylated haemoglobin 
(fasting)c,j
X
Every 12 weeks from Cycle 1, Week 1, Day 1
X
X
Section 8.2.1
Lipids (fasting)c,j
X
Every 12 weeks from Cycle 1, Week 1, Day 1
X
Section 8.2.1
Glucose (fasting)c,j
X
Pre (within 
3h) and 4h 
post 
(±30m)
Pre
Pre
X
X
Section 8.2.1
Biomarker analysis
FFPE tumour samplek
X
Section 
8.7.1.1
Single biopsy at disease 
progression (optional)l
X
Section 
8.7.1.2
Paired biopsies (optional)l,m
X
X
Section 
8.7.1.2
ctDNA blood samplesc,l
X
Pre
Pre
Pre
Pre
X
X
X
Section 8.7.2

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Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-
up 
Details in 
CSP section 
or appendix

Fulvestrant Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Circulating soluble factors 
blood drawc,l,n
X
Pre
Pre
Pre
Pre, C3 
only
X
X
X
Section 8.7.2
Whole blood DNA sample 
(genomic markers)c,l,n
X
Pre
Pre
Pre
Pre, C3 
only
X
X
X
Section 8.7.2
Whole blood RNA sample 
(genomic markers)c,l,n
X
Pre
Pre
Pre
Pre, C3 
only
X
X
X
Section 8.7.2
Genetic sample (optional)
Blood sample for 
pharmacogenetics DNA 
(optional)l
X
Section 8.6
Pharmacokinetic measurementsc
Capivasertib PK plasma 
samples
1h (±10m) 
and 
4h (±30m) 
post-dose
Pre 
(<30
m)
Pre 
(<30 
m)
Pre 
(<30
m)
Section 8.5

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Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-
up 
Details in 
CSP section 
or appendix

Fulvestrant Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Capivasertib PK plasma 
samples for 12 Japanese 
patients only
Pre (within 
30m) and 
0.5 (±5m), 
1 (±10m), 
2 (±10m), 
4 (±30m), 
6 (±30m), 
8 (±30m), 
12h (±1h) 
post-dose
Pre 
(<30
m)
Pre 
(<30
m)
Pre 
(<30
m)
Section 8.5
Imaging and other assessments
Bone scan
X
As clinically indicated
Section 8.1.6
RECIST v1.1 tumour 
assessmentso
X
Every 8 weeks (±7 days) for the first 18 months and every 12 weeks thereafter, from randomisation to radiological 
progression.  Patients who discontinue treatment prior to progression should continue to be scanned until progression.
Section 8.1.1
& 
Appendix A
Survival statusp
X
X
Section 8.1.2
PFS2q
X
X
Section 8.1.3
Subsequent cancer therapy 
following discontinuation 
of study treatmentq
X
X
Section 6.7

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Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-
up 
Details in 
CSP section 
or appendix

Fulvestrant Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Patient-reported outcomes and healthcare resource utilisation
EORTC QLQ-C30
Cycle 1, Week 1, Day 1 (-3 days) and every 4 weeks (±3 days) until PFS2.  Also at discontinuation of study treatment 
visit (+3 days) and, for those who discontinue for reasons other than progression, also at progression visit (+3 days).  If 
PROs have been completed up to 3 days prior to the discontinuation or progression visit, they do not need to be repeated.
Section 
8.1.7.1
EORTC QLQ-BR23
Section 
8.1.7.2
EQ-5D-5L
Section 
8.1.7.3
PGIS
Section 
8.1.7.4
PGIC
Every 4 weeks (±3 days) after Cycle 1, Week 1, Day 1 until PFS2.  Also at 
discontinuation of study treatment visit (+3 days) and, for those who discontinue for 
reasons other than progression, also at progression visit (+3 days). If PROs have been 
completed up to 3 days prior to discontinuation or progression visit, they do not need to 
be repeated.
Section 
8.1.7.5
PGI-TT
Cycle 1, Week 1, Day 1 (-3 days) and every 2 weeks (±2 days) up to and including Week 12 and 
then every 4 weeks (±3 days) until discontinuation of study treatment, at discontinuation of study 
treatment visit (+3 days) and at 4 weeks (±3 days) post discontinuation of study treatment visit.  If 
PROs have been completed up to 3 days prior to discontinuation visit, they do not need to be 
repeated.
Section 
8.1.7.6
PRO-CTCAE
Section 
8.1.7.7
Healthcare resource use 
(HOSPAD)r
Healthcare resource use module is event driven and should be populated as required at every study visit
Section 8.8
Study treatment administration

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Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-
up 
Details in 
CSP section 
or appendix

Fulvestrant Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Randomisations
X
Section 6.3
Fulvestrant dosing
X
X
X
X
Section 6.1.2
Capivasertib/placebo 
dosingt
Twice daily on days 1 to 4 every week (ie, 4 days on 
and 3 days off).  A minimum interval of 3 days is 
required between the last dose of the previous week of 
treatment and the first dose of the following week of 
treatment
Section 6.1.1
LHRH agonist dosing (for 
pre-/peri-menopausal 
women only; both 
treatment arms)
Xu
Sub-cutaneous administration every 28 days or as per 
manufacturer’s instructions
Sections 5.1, 
5.3.3.1, and 
6.5.1
NOTE: Unscheduled visits may be initiated as needed.  Only required assessments are to be performed as per investigator’s discretion.  
a
Specified times (eg, ‘Pre’, ‘1-2h post’, ‘4h post’, etc) refer to capivasertib/placebo dosing.
b
Study visits are scheduled relative to Week 1, Day 1 of each cycle.  As per protocol, the visit window is -1/+3 days for most visits, however. a -1 day 
window cannot be used for study treatment dosing and should only be used for labs and other assessments. 
c
Screening laboratory assessments taken within 3 days of Cycle 1, Day 1 do not need to be repeated and can be utilised for Cycle 1, Day 1/randomisation.  
Laboratory safety assessments, the collection of blood samples for biomarker analysis (ctDNA sample, circulating soluble factors sample, whole blood 
DNA sample and whole blood RNA sample) and rich PK sampling should be performed on the day of the scheduled study visit.  However, from Cycle 2 
onwards, the laboratory safety assessments and biomarker sampling may be performed 1 day before the scheduled study visit.  These samples must be 
collected pre-dosing.  
d
The handheld 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.
e
The patient should be trained on the use of the device and the importance of completing the PRO questionnaires in accordance with the schedule throughout 
the study.

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f
Routine safety measurements and routine clinical procedures should be performed before dosing of study treatment unless otherwise specified.
g
Bidimensional ECHO is the preferred modality because of the global technetium [Tc-99m] shortage (but MUGA can be used alternatively).  The modality 
of the cardiac function assessments must be consistent within patient ie, if ECHO is used for the screening assessment and a follow-up assessment if 
clinically indicated, then ECHO should also be used for subsequent scans if required.  Patients should also be examined using the same machine and 
operator whenever possible. For the alternative requirement, applicable only for UK, France, Italy, Spain, Belgium, Hungary, Poland, Germany refer to 
Appendix M. 
h
Female pre- and peri-menopausal patients starting an LHRH agonist (either starting or continuing this treatment) must have oestradiol and FSH 
measurements done at screening (before Cycle 1, Day 1) and after at least 4 weeks after commencing LHRH agonist treatment to confirm post-menopausal 
levels; assessments after screening will be at Day 1 of each cycle and when clinically indicated.  Female patients <60 years who are considered 
post-menopausal per wording of inclusion criterion 5, must have oestradiol and FSH levels confirmed as being within the standard laboratory reference 
range for post-menopausal females at screening (before Cycle 1, Day 1) only and if clinically indicated (see Section 8.2.1 for all details when and for whom 
FSH and oestradiol must be checked). 
i
For patients taking concomitant metformin, please refer to Sections 8.2.1.2 and 8.4.5.3.
j
‘Fasting’ is defined as no caloric intake for ≥4 hours before sampling.  Glucose samples should be done under fasting conditions with the exception of the 
4-hour post dose sample on Cycle 1, Week 1, Day 1 which can be fasting or non-fasting.
k
FFPE tumour sample: Tumour tissue will be required at baseline for determination of PIK3CA/AKT1/PTEN status at a central laboratory to allow 
monitoring of the prevalence of the PIK3CA/AKT1/PTEN-altered subgroup.  Tumour tissue samples will be collected as detailed in the Laboratory Manual 
and Diagnostic Testing Manual.  The most recently collected tumour tissue, from primary or recurrent cancer is required.  FFPE blocks are strongly 
preferred.  If not possible, preferably 30 (minimum 20) freshly-cut unstained serial tumour tissue sections are accepted provided they met the specifications 
described in the Diagnostic Testing Manual.  Local pathology QC must be completed prior to randomisation to ensure the sample is suitable for NGS 
analysis, based on the requirements described in the Diagnostic Testing Manual.  
l
These samples will not be collected in China.  Results can be provided to the investigator upon request, if available.
m
Paired biopsies (optional): Baseline sample: at screening OR pre-dose on Cycle 1, Week 1, Day 1.  On-treatment sample: at Cycle 1, Week 3, Day 4 (any 
day between Cycle 1, Week 3, Day 2 and Cycle 1, Week 3, Day 4 is allowed) >4 hours post-dose.  
n
Circulating soluble factor, whole blood DNA sample, and whole blood RNA sample draws: To be taken at screening, pre-dose on Cycle 1, Week 1, Day 1; 
Cycle 1, Week 3, Day 1; Cycle 2, Week 1, Day 1; Cycle 3, Week 1, Day 1, at progression, and at discontinuation of IMP if this falls on a different visit/time 
than progression.
o
Baseline RECIST v1.1 assessments will be performed using CT scans of the chest, abdomen and pelvis (or MRI where CT is contraindicated) and should be
performed as close as possible to the start of treatment.  RECIST v1.1 follow-up assessments will include CT scans of thorax, abdomen and pelvis (or MRI 
where CT is contraindicated) for all patients.  Any other sites at which new disease is suspected should also be appropriately imaged.
p
In addition to regular contacts at ≤8-week intervals, patients will be contacted in the 7 days following a specified date (data cut-off date) for survival 
analysis.  
q
Patients will enter the PFS2 follow-up period once the patient has discontinued study treatment due to progressive disease by RECIST v1.1.  Progression on 
second-line treatment will be documented by site personnel at the 30-day follow-up visit, every 8 weeks (±7 days) for the first 2 years and every 12 weeks 
(±7 days) thereafter until second progression.  Survival status and subsequent cancer therapies will be documented by site personnel, following objective 
disease progression or treatment discontinuation, at the 30-day follow-up, every 8 weeks (±7 days) for the first 2 years and every 12 weeks (±7 days) 
thereafter until end of study, study withdrawal or death.  
r
Assessments include: number of hospitalisations and attendances; primary symptom/reason associated with hospitalisation or attendance; length of stay, 
including time in intensive care; and concomitant medication and procedures undertaken.

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s
Randomisation must occur within 28 days of the start of screening.  Randomisation and Cycle 1, Week 1, Day 1 should ideally occur on the same day.  
t
Day 1 of each cycle is defined by fulvestrant dosing and fulvestrant should not be delayed due to capivasertib/placebo toxicity.  In the case of a 
capivasertib/placebo dosing delay at the beginning of the cycle, the same routine safety measurements and routine clinical procedures must be repeated on 
the next planned date of dosing.  Cycles are 28-day long, dosing outside of the prespecified window will be considered as overdose except for a dose delay 
situation.  
u
Administration of LHRH agonist in pre- or peri-menopausal women must start prior to or on Cycle 1, Day 1.
v
If both drugs are discontinued at the same time as progression, visits are combined and the optional biopsy is completed, if applicable.  
, onwards; BRCA1/2, breast cancer gene 1/2; CT, computed tomography; ctDNA, circulating tumour DNA; DNA, deoxyribonucleic acid; ECG, 
electrocardiogram; ECHO, echocardiography; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research and Treatment of 
Cancer; EORTC QLQ-BR23, EORTC Quality of Life Questionnaire breast cancer specific module; EORTC QLQ-C30, EORTC Quality of Life Questionnaire –
Core 30 items; ePRO, electronic patient-reported outcome; EQ-5D-5L, European Quality of Life 5-Domain 5-Level Scale; FFPE, formalin-fixed 
paraffin-embedded; FSH, follicle stimulating hormone; HOSPAD, Hospital Admission module; LHRH, luteinising-hormone releasing hormone; LVEF, left 
ventricular ejection fraction; MRI, magnetic resonance imaging; MUGA, multiple-gated acquisition scan; PFS2, time from randomisation to second progression 
or death; PGIC, Patient Global Impression–Change; PGIS, Patient Global Impression–Severity; PGI-TT, Patient Global Impression–Treatment Tolerability; PK, 
pharmacokinetics; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; PRO, patient-reported outcome; PRO-CTCAE, 
Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; PTEN, phosphatase and tensin homolog; RECIST v1.1, Response 
Evaluation Criteria in Solid Tumours version 1.1; RNA, ribonucleic acid; WHO, World Health Organisation.

Cli nical St u d y Pr ot oc ol - 5. 0
Astra Ze neca
Ca pi vaserti b ( A Z D 5 3 6 3) - D 3 6 1 5 C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 2 of 1 9 6
1. 2
S y n o psis
I nter n ati o n al c o-o r di n ati n g i n vesti g at or
Breast U nit, T he R o y al Mars de n N H S F o u n dati on Tr ust
Breast Ca ncer N o w Researc h Ce ntre, T he I nst itute of Ca ncer Re searc h
L o n d o n, S W 3 6JJ
U nite d Ki n g d o m
Pr ot oc ol Title: A P hase III D o u ble -bli n d Ra n d o mise d St u d y  Assessi n g t he Efficac y a n d 
S af et y of  Ca pi vaserti b + F ul vestra nt Vers us Place b o + F ul vestra nt as Treat me nt f or L ocall y 
A d va nce d (I n o pera ble) or Metastatic H or m o ne Rece pt or P osi ti ve, H u ma n E pider mal  Gr o wt h 
Fact or Rece pt or 2 Ne gati ve ( H R +/ H E R 2 −) Breast Ca ncer F o ll owi n g Rec urre nce or 
Pr o gressi o n O n or After Treat me nt wit h a n Ar o ma tase I n hi bit or ( C A PItell o- 2 9 1)
S h ort Title: P hase III St u d y  of Ca pi vaserti b + F ul vestra nt vs Place b o + F ul vestra nt as 
Treat me nt f or L ocall y A d va nce d (I n o pera ble) or Metastatic H R +/ H E R 2 − Breast Ca ncer 
( C A PItell o- 2 9 1)
R ati o n ale: 
N u m er o us precli nical st u dies ha ve s h o w n t hat e n d o ge n o us A K T act i vity pr o m otes breast 
ca ncer cell s ur vi val a n d resista nce t o c he m ot hera p y or e n d ocri ne t hera p y (Fr o g ne et al 2 0 0 5 , 
G ha ya d et al 2 0 1 0 , va n der Ha ge et al 2 0 0 4 ).  T his ca n be o verc o me b y d o w n-re g ulat i on or 
i n hi biti on o f t he PI 3 K/ A K T pat h wa y, as has been s h o w n i n se veral i n vitr o a n d i n vi v o breast 
ca ncer mo d el s (Fr o g ne et al 2 0 0 5 , G ha ya d et al 2 0 1 0 , va n der Ha ge et al 2 0 0 4 ).  I n a d diti on, 
l on g -t er m estr o ge n de pri vati on ( L T E D) of h u ma n breast ca ncer c ells i n vitr o (t o mi mic t he 
l ow estr o ge n l e vels o bser ve d i n ar o matase i n hi bit or [ AI] treate d patie nts) has re veale d 
h y peract i vati on of t he PI 3 K/ m T O R si g nalli n g pat h wa y  (Miller et al  2 0 1 0).  C o nsiste ntl y, 
i ncrease d PI 3 K/ A K T si g nalli n g i n cli nical t u m o ur sa m ples is ass ociate d wit h p o or 
a nt i- pr oliferati ve res p o nse t o AI i n breast ca ncer patie nts (T o k u na ga et al 2 0 0 6 , Ga o et al 
2 0 1 4 ).  I n hi biti on of t he PI 3 K pat h wa y  in t he L T E D cells i n d uce d a p o pt osis, i n dicat i n g 
de pe n de nce o n t he PI 3 K pat h wa y u p o n h or m o ne de pri vat i on (Miller et al 2 0 1 0 ).  Recipr o c al  
fee d bac k bet wee n t he estr o ge n rece pt or ( E R) a n d PI 3 K si g nalli n g s u g gests t hat t he 
c o m bi nat i on of e n d ocri ne t hera p y  a n d i n hi bit ors of t he PI 3 K/ A K T pat h wa y ma y ha ve cli nical 
utilit y i n t he treat me nt of H R + breast ca ncer, wit h res p o nses e x pecte d b ot h i n patient s wit h 
t u mo urs har b o uri n g a ge net ic alterati on lea di n g t o a n acti vate d PI 3 K pat h wa y as well as i n 
pati e nts w h ose t u mo urs d o n ot har b o ur s uc h ge net ic alterati o ns, b ut bec ome de pe n de nt o n t he 
PI 3 K pat h wa y  u p o n treat me nt wit h E R d o w nre g ulati n g/ de gra di n g a ge nts, e g, AIs or selecti ve 
E R de gra ders ( S E R Ds).  
A rece nt i n vest i gat or-s p o ns ore d, ra n d o mised, d o u ble -bli n d, place b o -c o ntr olle d P hase I b/II 
st u d y ( N C T 0 1 9 9 2 9 5 2, F A K TI O N) e val uate d t he c o m bi nati on of ca pi vasert i b (a n A K T 
P P D

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inhibitor) + fulvestrant (a selective estrogen down-regulator) compared with placebo + 
fulvestrant in post-menopausal patients with estrogen receptor positive, human epidermal 
growth factor receptor 2 negative (ER+/HER2−) advanced breast cancer (ABC) (140 patients, 
randomised 1:1) after relapse or disease progression on an AI therapy (Jones et al 2019). The 
study met its primary endpoint of progression-free survival (PFS), showing a statistically 
significant improvement in PFS with the addition of capivasertib to fulvestrant.  At the time of 
the PFS analysis, overall survival (OS) data were not mature; however, the data suggest an 
improvement with the addition of capivasertib to fulvestrant.  The combination of capivasertib 
+ fulvestrant was generally well tolerated, with a manageable safety profile.  
This Phase III study (CAPItello-291) is being conducted in response to the positive results 
from the FAKTION study and aims to evaluate the efficacy and safety of capivasertib + 
fulvestrant versus (vs) placebo + fulvestrant in patients with locally advanced (inoperable) or 
metastatic hormone receptor positive (HR+)/HER2− breast cancer following recurrence or 
progression on or after third generation AI therapy in an unselected population (hereafter 
referred to as the “overall population”) and a molecularly defined subgroup with tumours 
harbouring at least one PIK3CA/AKT1/PTEN-qualifying alteration detected in tissue (hereafter 
referred to as the “altered subgroup”).
Objectives and Endpoints:
Primary objective
Endpoint
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
PFS in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.
PFS is defined as the time from randomisation until 
progression per RECIST v1.1, as assessed by the 
investigator at the local site, or death due to any cause.  
PFS, progression-free survival; RECIST v1.1, Response Evaluation Criteria in Solid Tumours version 1.1; 
vs, versus.
Secondary objectives
Endpoint
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of OS 
in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
OS is length of time from randomisation until the date 
of death due to any cause.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
PFS2 in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
PFS2 is defined as the time from randomisation until 
second progression on next-line treatment, as assessed 
by the investigator at the local site, or death due to any 
cause.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
ORR in the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup.  
ORR is defined as the percentage of patients with at 
least one CR or PR per RECIST v1.1, as assessed by 
the investigator at the local site.  

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Secondary objectives
Endpoint
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
DoR in the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup.  
DoR is defined as the time from the date of first 
documented response until date of documented 
progression or death in the absence of disease 
progression.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
CBR in the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup.  
CBR is defined as the percentage of patients who have 
a CR, PR or stable disease per RECIST v1.1 (without 
subsequent cancer therapy) maintained ≥24 weeks 
after randomisation.  
To assess the safety and tolerability of capivasertib + 
fulvestrant as compared to placebo + fulvestrant in 
the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup.  
Safety and tolerability will be evaluated in terms of 
AEs/SAEs, vital signs, clinical 
chemistry/haematology/glucose metabolism 
parameters, and ECG parameters.  
Assessments related to AEs cover:

Occurrence/frequency

Relationship to capivasertib and fulvestrant 
as assessed by investigator

CTCAE grade

Seriousness

Death

AEs leading to discontinuation of 
capivasertib/placebo

AEs leading to discontinuation of fulvestrant

AEs leading to dose interruption of 
capivasertib/placebo

AEs leading to dose interruption of 
fulvestrant

AEs leading to dose reduction of 
capivasertib/placebo

AEs of special interest

Other significant AEs
Vital signs parameters include systolic and diastolic 
blood pressure, pulse, respiratory rate, body 
temperature and weight.
Assessments cover:

Observed value

Absolute and change from baseline values 
over time

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Secondary objectives
Endpoint
To evaluate the PK of capivasertib when given in 
combination with fulvestrant.  
Plasma concentration of capivasertib pre-dose (Ctrough) 
and post-dose (C1h and C4h) in the overall population 
(patients randomised to capivasertib + fulvestrant).  
AUC 0-12h, Cmax and tmax in a subpopulation of 
approximately 6 Japanese patients with rich PK 
sampling.  
To assess the impact of capivasertib + fulvestrant vs 
placebo + fulvestrant on patients’ disease-related 
symptoms, function and HRQoL in the overall 
population and in the PIK3CA/AKT/PTEN-altered 
subgroup where applicable.  
Evaluation of EORTC QLQ-C30, EORTC 
QLQ-BR23, scale/item scores including change from 
baseline and time to deterioration.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
time to definitive deterioration of ECOG 
performance status from baseline in the overall 
population and in the PIK3CA/AKT/PTEN-altered 
subgroup.  
Time to definitive deterioration of ECOG performance 
status is defined as time from randomisation to the 
earlier of the date of the first definitive deterioration or 
death due to any cause.  
AE, adverse event; AUC 0-12h, area under the plasma concentration-time curve from zero to 12 hours; C, 
concentration; CBR, clinical benefit rate; Cmax, maximum observed plasma (peak) concentration; CR, complete 
response; CTCAE, Common Terminology Criteria for Adverse Event; ctDNA, circulating tumour DNA; DoR, 
duration of response; 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 specific module; EORTC QLQ-C30, EORTC Quality of Life Questionnaire-Core 30 items; 
HRQoL health-related quality of life; ORR, objective response rate; OS, overall survival; PFS, progression-free 
survival; PFS2, time from randomisation to second progression or death; PIK3CA, 
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; PK, pharmacokinetics; PR, partial 
response; PTEN, phosphatase and tensin homolog; RECIST v1.1, Response Evaluation Criteria in Solid Tumours 
version 1.1; SAE, serious adverse event; tmax, time to reach peak or maximum observed concentration following 
drug administration; vs, versus.

Cli nical St u d y Pr ot oc ol - 5. 0
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A nal y sis of ct D N A a n d/ or t u m o ur tiss ue.  
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Overall design:
This is a Phase III, double-blind, randomised study assessing the efficacy of capivasertib + 
fulvestrant vs placebo + fulvestrant for the treatment of patients with locally advanced 
(inoperable) or metastatic HR+/HER2− breast cancer following recurrence or progression on 
or after AI therapy.  
Enrolment will be open to all eligible patients irrespective of the PIK3CA/AKT1/PTEN status 
of their tumour(s); however, adequate tumour tissue collected before study entry will be 
required for central retrospective analysis to monitor the prevalence of PIK3CA/AKT1/PTEN
mutation status.  The list of eligible alterations is curated on the basis of the currently 
published literature for causal associations between pathogenicity and the alterations, using 
the AstraZeneca strategy for early-stage clinical studies as described by Carr et al 2016.  The 
list of eligible variants will be defined and specified in the statistical analysis plan (SAP) prior 
to analysis.  
The target patient population is adult males and pre-menopausal or post-menopausal adult 
females (aged ≥18 years [≥20 years in Japan]) with histologically confirmed, locally advanced 
(inoperable) or metastatic, HR+/HER2− ABC with recurrence or progression while receiving 
or within 12 months of the end of (neo)adjuvant treatment with an AI, or progression while on 
prior AI for locally advanced or metastatic breast cancer (although this does not need to be the 
most recent therapy).  In accordance with these criteria, the study intends to recruit patients 
with AI resistance.  
HR+/HER2− breast cancer must be histologically determined from the most recent tumour 
sample (primary or metastatic), as per the American Society of Clinical Oncology-College of 
American Pathologists guideline recommendations (Hammond et al 2010, Wolff et al 2018).  
To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without 
co-expression of progesterone receptor (Hammond et al 2010, Wolff et al 2018).  
Patients must be candidates to receive further endocrine-based therapy (ie, fulvestrant 
monotherapy).  Eligible patients may have received up to 2 prior endocrine therapy lines for 
metastatic disease and up to 1 line of chemotherapy in the metastatic setting.  A minimum of 
51% of patients recruited to the study should have been previously treated with a CDK4/6 
inhibitor.
NOTE: CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) are, in certain markets, 
approved treatment options in combination with an aromatase inhibitor or fulvestrant 
(± luteinising-hormone releasing hormone (LHRH) agonist depending on menopausal 
status) for patients with advanced or metastatic HR+HER2- breast cancer who have 
received prior endocrine therapy and/or as initial endocrine-based therapy.  Some of these 
agents have been shown to improve overall survival in this patient population and, where 

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available in the country in which a patient is being enrolled, must be considered and 
excluded as treatment options before the patient can be considered for entering this study.  
Prior CDK4/6 inhibition will be a stratification factor; the actual proportions will be 
monitored during the course of the study (Section 6.3).  Reasons why a patient has not 
received a CDK4/6 inhibitor will be collected.  
Patients with prior exposure to fulvestrant, other SERDs or PI3K/AKT/mTOR inhibitors are 
not permitted to enter the study.  Concomitant treatment with a CDK4/6 inhibitor is not 
permitted.
Pre-menopausal patients with adequate ovarian suppression are eligible for the study.  
Pre-menopausal patients without ovarian suppression could be eligible if concomitant 
treatment with a LHRH agonist is started prior to or on Cycle 1, Day 1.
Patients must have radiological evidence of recurrence or progression, an Eastern Cooperative 
Oncology Group (ECOG) Performance Status of 0 or 1, and measurable lesion(s) according to 
RECIST v1.1 or, in the absence of measurable disease, lytic or mixed bone lesions that can be 
assessed by computerised tomography (CT) or magnetic resonance imaging (MRI). 
Patients with visceral metastases may be eligible unless the visceral involvement is associated 
with organ dysfunction (ie, visceral crisis) in which case, such patients are excluded.  
A recently collected formalin-fixed paraffin embedded (FFPE) tumour tissue block (strongly 
preferred) or 30 (minimum 20) freshly-cut unstained, serial slides from the most recently 
collected tumour tissue (primary or recurrent cancer) will be required from all patients.  If 
tissue is inadequate for testing, the study site may collect a fresh sample before the start of 
treatment.  
Adequate haematology, glucose metabolism, renal and liver function tests are required at 
screening; patients with type 2 diabetes are eligible if HbA1c at screening is less than 8.0% 
(63.9 mmol/mol), and if they do not require insulin treatment.  Patients with type 1 diabetes 
are not eligible.
Approximately 700 patients will be randomised (1:1) with approximately 350 included in each 
arm.  Patients will receive capivasertib (400 mg or placebo, oral, twice daily; 4 days on and 3 
days off, weekly) and fulvestrant (500 mg, intramuscular injection on Day 1 of Weeks 1 and 3 
of Cycle 1, and then on Day 1, Week 1 of each cycle thereafter).  Study treatment will 
continue until objective radiological disease progression as defined by RECIST v1.1.  
Randomisation will occur as soon as possible after commencement of screening and should be 
within 28 days of screening.  The randomisation scheme will be stratified on the following 
factors:

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
Liver metastases (yes vs no)

Prior use of CDK4/6 inhibitors (yes vs no)

Geographic location:

Region 1: United States, Canada, Western Europe, Australia, and Israel

Region 2: Latin America, Eastern Europe and Russia

Region 3: Asia
The study schema is depicted in Figure 1.
Study Period:
Estimated date of first patient enrolled Q1 2020
Estimated date of last patient completed Q2 2024
Number of Patients:
It is expected that an estimated 930 patients will be screened and approximately 700 patients 
will be randomised, with half of the patients included in each treatment arm.  The China 
cohort will consist of approximately 134 randomised patients from National Medical Product 
Administration (NMPA)-certified sites.  In the event that recruitment of China cohort is not 
completed during global recruitment of approximately 700 patients, the recruitment of China 
cohort will continue until approximately 134 patients have been randomised from 
NMPA-certified sites.  
Treatments and treatment duration:
Capivasertib/placebo will be administered orally twice daily on an intermittent dosing 
schedule with treatment on Days 1 to 4 each week of a 28-day treatment cycle.  The starting 
dose is 400 mg twice daily (BD) (4 days on and 3 days off).  Capivasertib/placebo dose 
reductions are permitted: the initial dose reduction can be to 320 mg BD and the second dose 
reduction can be to 200 mg BD.
Fulvestrant will be administered as 2 × 5 mL intramuscular injections (250 mg/5 mL = 500 
mg in total) on Day 1 of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of each cycle 
thereafter.  Dose reductions for fulvestrant are not allowed.  
Study treatment will be continued until disease progression unless there is evidence of 
unacceptable toxicity, or if the patient requests to stop the study treatment.  
If capivasertib/placebo is discontinued for reasons other than disease progression, the patient 
may continue on fulvestrant alone at the investigator’s discretion.  Likewise, if fulvestrant is 
discontinued for reasons other than disease progression, the patient may continue 
capivasertib/placebo alone at the investigator’s discretion.

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Cross-over from placebo to capivasertib is not allowed.
Data Monitoring Committee:
An Independent Data Monitoring Committee (IDMC) will be established to assess the safety 
of capivasertib in an unblinded manner. The IDMC will be responsible for reviewing the 
safety data accruing in the study at regular intervals prior to the primary PFS analysis database 
lock, to provide a recommendation to AstraZeneca whether the study should continue 
unchanged, be stopped, or be modified in any way. The IDMC will consist of at least 2 
physicians with expertise in breast cancer and one biostatistician. Further information on the 
IDMC and schedule of meetings will be defined in the IDMC Charter.
Statistical methods
The Full Analysis Set (FAS) will be used as the primary population for reporting efficacy data 
and to summarise baseline characteristics.  This comprises all patients randomised into the 
study, excluding patients randomised in China after the global cohort last patient first visit 
(LPFV), and will be analysed according to randomised treatment regardless of the treatment 
received (intention-to-treat [ITT] principle).  Any important deviations from randomised 
treatment will be listed and considered when interpreting the efficacy data.  The Safety 
Analysis Set will be used as the primary population for reporting safety data.  This comprises 
all patients included in the FAS, who received at least 1 dose of study drug (fulvestrant, 
capivasertib, placebo) and will be analysed according to the treatment received.  If a patient 
receives at least 1 dose of capivasertib they will be summarised in the capivasertib arm for 
safety summaries.  
The primary objective of this study is to assess the efficacy of capivasertib +fulvestrant vs 
placebo + fulvestrant by assessment of PFS; the dual primary endpoints are PFS in the overall 
population and PFS in the PIK3CA/AKT1/PTEN-altered population.  This will be analysed 
using a stratified log-rank test adjusting for the stratification factors.  From the stratified Cox 
proportional hazards model (ties = Efron), the hazard ratio (HR) (capivasertib + fulvestrant vs 
placebo + fulvestrant) together with its corresponding 95% CI (calculated using a profile 
likelihood approach) will be presented.  An HR <1 will favour capivasertib + fulvestrant.  
The key secondary endpoints are OS and objective response rate (ORR) in the overall and the 
PIK3CA/AKT1/PTEN-altered populations.  OS will be assessed as described above for the 
primary endpoint.  ORR will be presented with two-sided 95% CIs using the Clopper-Pearson 
method (Clopper and Pearson 1934).  
To preserve the overall type 1 error (familywise error rate) in the strong sense, a multiple 
testing procedure (MTP) including the primary and secondary endpoints will be implemented.  
The PFS Analysis (primary) will take place after PFS reaches approximately 77% maturity in 
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expected to occur when approximately 394 OS events have been observed in the overall 
population (80% information fraction) and the PIK3CA/AKT1/PTEN-altered population has 
reached similar maturity.  The OS Final Analysis will take place when the approximately 70% 
maturity has been observed in both the overall and the PIK3CA/AKT1/PTEN-altered 
populations. 
Safety and tolerability data will be summarised using appropriate descriptive statistics.  

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1.3
Schema
The general study design is summarised in Figure 1.
Figure 1
Study design

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a
FFPE (formalin-fixed, paraffin-embedded) blocks are strongly preferred, or if not possible, preferably 
30 [minimal 20]) freshly-cut unstained serial tumour tissue sections are acceptable provided that they meet 
the specifications described in the Diagnostic Testing Manual.
AI, aromatase inhibitor; AKT, serine/threonine specific protein kinase; CBR, clinical benefit rate; CDK, cyclin 
dependent kinase; CT, computerised tomography; FFPE, formalin-fixed paraffin-embedded; HER2, human 
epidermal growth factor receptor 2; HR, Hormone receptor; MRI, magnetic resonance imaging; mTOR, 
mammalian target of rapamycin; ORR, objective response rate; OS, overall survival; PFS, progression-free 
survival; PI3K, phosphatidylinositol-3-kinase; RECIST v1.1, Response Evaluation Criteria in Solid Tumours 
version 1.1; SERD, selective estrogen response degrader; US, United States.
2
INTRODUCTION
Capivasertib, a novel pyrrolopyrimidine-derived compound, is a potent and selective oral, 
intermittently dosed inhibitor of all 3 isoforms of AKT (Davies et al 2012). 
Further details can be found in the current capivasertib (AZD5363) Investigator’s Brochure.
2.1
Study rationale
This Phase III study is designed to provide confirmatory evidence of the findings from the 
previous Phase Ib/II FAKTION study (NCT01992952), which evaluated the combination of 
capivasertib + fulvestrant compared with placebo + fulvestrant in post-menopausal patients 
with estrogen receptor positive, human epidermal growth factor receptor 2 negative 
(ER+/HER2−) advanced breast cancer (ABC) [140 patients, randomised 1:1] after relapse or 
disease progression on an aromatase inhibitor (AI) therapy (Jones et al 2019).  The study met 
its primary endpoint of progression-free survival (PFS), showing a 5.5-month PFS 
improvement with the addition of capivasertib to fulvestrant, regardless of the 
PI3K/AKT/PTEN (phosphatidylinositol-3-kinase/AKT/phosphatase and tensin homolog) 
pathway activation status.  At the time of the PFS analysis, overall survival (OS) data were not 
mature (37% maturity); however, the data suggest an improvement of approximately 6 months 
from the combination treatment (not statistically significant).  The combination of capivasertib 
+ fulvestrant was generally well tolerated, with a manageable safety profile.  Further details 
on the FAKTION study are available in Section 2.2.
This Phase III study (CAPItello-291) aims to evaluate the efficacy and safety of capivasertib + 
fulvestrant versus (vs) placebo + fulvestrant in patients with locally advanced (inoperable) or 
metastatic hormone receptor positive (HR+)/HER2− breast cancer following recurrence or 
progression on or after third-generation AI therapy in an unselected population (hereafter 
referred to as the “overall population”) and a molecularly defined subgroup with tumours 
harbouring at least one PIK3CA/AKT1/PTEN-qualifying alteration (hereafter referred to as the 
“altered subgroup”), as described in Section 4.1. 

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2.2
Background
In women, breast cancer is the most frequently diagnosed malignancy and the leading cause of 
cancer mortality worldwide (GLOBOCAN 2018, NCCN 2019).  ABC comprises both locally 
advanced (inoperable) and metastatic disease.  Although it can be treated, metastatic breast 
cancer remains incurable with a median survival of approximately 3 years and a 5-year 
survival rate of around 25% (Cardoso et al 2018).  Several prognostic indicators for breast 
cancer have been identified including HER2 and the ER (here, also referred to as hormone 
receptor [HR]).  Most of the improvements in survival rates achieved in the last decade have 
been due to advances in the treatment of patients with HER2+ tumours.  Conversely, survival 
rates for patients with HR+/HER2− tumours, which account for approximately 70% of all 
breast cancers (Howlader et al 2014), have not shown much improvement over the same 
period (Gobbini et al 2018).  
In the majority of cases, endocrine-based therapy is the initial treatment for HR+/HER2− 
breast cancer.  The exceptions are patients with visceral crisis or in whom endocrine-based 
alternatives have been exhausted or for whom there is evidence of endocrine resistance; in 
such instances, chemotherapy is required.  In women, endocrine therapy is recommended for 
both post- and pre-menopausal patients where, in the latter setting, it is provided in 
conjunction with the suppression or ablation of ovarian function (Cardoso et al 2018).  In men, 
the treatment approach for ABC is similar to that of women, with some particularities: 
tamoxifen is the preferred treatment in HR+ metastatic disease; in addition, AIs should be 
used in combination with luteinising hormone-releasing hormone (LHRH) agonist or surgical 
orchidectomy due to hypothalamic-pituitary negative feedback and in some case reports, 
fulvestrant has also shown efficacy for the treatment of metastatic disease (Cardoso et al 
2017).  Many patients with HR+/HER2− breast cancer benefit from sequential use of 
endocrine therapies and those who respond to endocrine therapy with either tumour shrinkage 
or long-term stabilisation (ie, clinical benefit) should be offered additional endocrine therapy 
at subsequent disease progression (NCCN 2019).  The optimal sequence and integration of the 
available endocrine agents is not established and is influenced by choice of initial therapy, the 
response obtained, as well as individual patient and disease characteristics (Cardoso et al 
2018).  Several novel, effective agents have become available in recent years for combination 
with endocrine therapies.  These include cyclin-dependent kinase (CDK) 4/6 inhibitors and 
everolimus in combination with exemestane (an inhibitor of the mammalian target of the 
rapamycin receptor [mTOR]).  Available second or further lines of therapies are limited either 
with regard to the population able to gain benefit, or the minimal magnitude of benefit 
(Cardoso et al 2018).  A Phase III study (BOLERO-2) of everolimus plus exemestane in 
patients with HR+/HER2- ABC post-AI progression showed that the combination therapy 
improved PFS compared with exemestane alone from 3.2 to 7.8 months irrespective of 
PIK3CA genotype, albeit without significant OS improvement (Yardley et al 2013).  More 
recently, the Phase III SOLAR-1 study demonstrated an improvement in PFS of 5.7 to 

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11 months with the addition of the alpha-specific PI3K inhibitor alpelisib to fulvestrant in 
patients with HR+/HER2− ABC with tumours harbouring a PIK3CA mutation, who had 
relapsed or progressed on an AI (André et al 2019), based on which the FDA granted 
approval.  Of note, a clinically relevant benefit was not seen in the PIK3CA non-mutant cohort 
and is not included in the approval.  Despite these advances, these tumours eventually develop 
endocrine resistance necessitating the use of chemotherapy and thus, HR+/HER2− ABC 
remains an area of considerable unmet medical need.
The AKT serine/threonine protein kinases (AKT1, AKT2, AKT3) are key downstream 
effectors of the PI3K/AKT/mTOR pathway, mediating cell proliferation and resistance to 
apoptosis, and are activated in a wide range of solid and haematologic malignancies (Brown 
and Banerji 2017, Lindsley 2010, Liu et al 2019).  AKT activation in tumours is largely due to 
input from other signalling pathways upstream of AKT including loss of PTEN function and 
activating mutations in the catalytic subunit of PI3K (PIK3CA) (Yi and Lauring 2016).  
Numerous preclinical studies show that endogenous AKT activity promotes breast cancer cell 
survival and resistance to chemotherapy or endocrine therapy (Frogne et al 2005, Ghayad et al 
2010, van der Hage et al 2004).  This can be overcome by down-regulation or inhibition of the 
PI3K/AKT pathway, as has been shown in several in vitro and in vivo breast cancer models 
(Frogne et al 2005, Ghayad et al 2010, van der Hage et al 2004).
Capivasertib is under investigation by AstraZeneca for a range of therapeutic indications 
(Banerji et al 2018, Tamura et al 2016) including triple-negative breast cancer (TNBC), 
ER+/HER2− breast cancer and prostate cancer.  Capivasertib inhibits the proliferation of 25 
out of 180 tumour cell lines with a concentration causing 50% inhibition of cell growth (GI50) 
of <1 μM.  Breast cancer cell lines show the highest frequency of sensitivity to capivasertib, 
with a significant correlation between the presence of PIK3CA or PTEN mutations and 
sensitivity (Davies et al 2012).  Capivasertib inhibits the growth of several human breast 
cancer xenograft models, including the TNBC xenograft model HCC1187 and the HER2+, 
PIK3CA mutant xenograft models BT474 and HCC1954.
Long-term estrogen deprivation (LTED) of human breast cancer cells in vitro (to mimic the 
low estrogen levels observed in AI-treated patients) revealed hyperactivation of the 
PI3K/mTOR signalling pathway (Miller et al 2010).  Consistently, increased PI3K/AKT 
signalling in clinical tumour samples is associated with poor anti-proliferative response to AI 
in breast cancer patients (Tokunaga et al 2006, Gao et al 2014).  Inhibition of the PI3K 
pathway in the LTED cells induced apoptosis, indicating dependence on the PI3K pathway 
upon hormone deprivation (Miller et al 2010).  Furthermore, modest reduction of PTEN 
expression in cell lines and xenograft models led to endocrine resistance which could be 
overcome by treatment with capivasertib in combination with fulvestrant (Fu et al 2014).  
Capivasertib synergises with fulvestrant in models of breast cancer irrespective of their 
sensitivity to endocrine therapy; compared with either agent alone, the combined treatment 

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with capivasertib and fulvestrant resulted in a greater anti-tumour response in human breast 
cancer HBCx22 OvaR xenografts growing in ovariectomised mice (Ribas et al 2015).
A recent investigator-sponsored Phase Ib/II randomised, double-blind, placebo-controlled 
study (FAKTION) evaluated the combination of capivasertib (400 mg BD, 4 days on 3 days 
off) with fulvestrant compared with fulvestrant alone in post-menopausal women with locally 
advanced (inoperable) or metastatic breast cancer previously treated with a third-generation 
AI therapy (Jones et al 2019).  Eligible patients were post-menopausal with locally advanced 
or metastatic ER+/HER2- breast cancer that was not amenable to surgical resection.  Patients 
had to be suitable for endocrine treatment but were to have received no more than 3 previous 
lines of endocrine treatment for ABC and up to 1 line of chemotherapy for ABC.  Patients 
were also to have experienced disease progression during treatment with a third-generation AI 
for metastatic disease (although this did not need to be the most recent therapy) or have 
relapsed on an AI in the adjuvant setting.  Previous treatment with fulvestrant or 
PI3K/mTOR/AKT inhibitors was not allowed.  PI3K/AKT/PTEN pathway activation status 
was determined prior to randomisation; the protocol-specified definition of activated 
PI3K/AKT/PTEN pathway was: an activating PIK3CA mutation detected in either tissue 
and/or circulating tumour DNA, or low/absent PTEN by immunohistochemistry (primary or 
metastatic tumour).  Patients (N=140) were randomised 1:1; of these, 69 received capivasertib 
+ fulvestrant and 71 received placebo + fulvestrant.  Baseline patient and disease 
characteristics were largely balanced between treatment arms.  The analysis at the time of the 
primary endpoint data cut-off (DCO) [after 112 events; 80% maturity] showed that the study 
met its primary endpoint (Jones et al 2019).  In the intention-to-treat analysis, median PFS was 
10.3 months in the capivasertib + fulvestrant group compared with 4.8 months for the placebo 
+ fulvestrant group (hazard ratio [HR] = 0.58; 95% confidence interval [CI]: 0.39 to 0.84; 
two-sided p=0.004).  The overall survival (OS) data were not mature (52 deaths reported; 37% 
maturity), but the addition of capivasertib to fulvestrant resulted in an observed OS 
improvement of approximately 6 months (26 vs 20 months, respectively), though this was not 
statistically significant (HR 0.59; 95% CI: 0.34 to 1.05; two-sided p=0.071).  Of note, the PFS 
benefit appeared to be independent of the PI3K/AKT/PTEN pathway activation status based 
on the available data at the time of primary analysis: in patients with pathway activated 
tumours (N=59) the HR was 0.59 (95% CI 0.34 to 1.03; two-sided p=0.064) and in those with 
pathway non-active tumours (N=81) it was 0.56 (95% CI 0.33 to 0.96, two-sided p=0.035).  In 
addition, and in keeping with other studies in the clinical development program, the 
combination of capivasertib + fulvestrant demonstrated an overall manageable safety profile 
with a low rate of discontinuation of capivasertib due to adverse events (AEs) (11.6% [8 from 
69]).  The most frequent grade ≥3 AEs that occurred in ≥10% of the population, irrespective 
of causality, in the capivasertib vs placebo treatment groups, respectively, were: diarrhoea 
(14.5% vs 4.2%), fatigue (1.4% vs 4.2%), rash (20.3% vs 0%), hyperglycaemia (4.3% vs 0%), 
vomiting (2.9% vs 0%), and infections (5.8% vs 2.8%).  Two patients died during the study, 1 

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in the placebo arm (grade 5 haemorrhage) and 1 death without progression on treatment with 
capivasertib, possibly related to treatment (atypical pulmonary infection).  
The combination of capivasertib (400 mg, 4 days on 3 days off) with fulvestrant in 
ER+ metastatic breast cancer is also being evaluated in the AstraZeneca-sponsored 
Study D3610C00001 (Parts E [AKT1-mutant, completed] and F [PTEN-mutant, ongoing] and 
in 2 ongoing investigator-sponsored studies (plasmaMATCH- and Hyman AKT mutant), 
adopting the recommended combination dose regimen of capivasertib with fulvestrant 
established in the FAKTION study.  Interim efficacy data from Study D3610C00001 Part E 
have shown clinical activity of capivasertib plus fulvestrant in heavily pre-treated patients 
with AKT1-mutant ER+ metastatic breast cancer, including those with prior resistance to 
fulvestrant, with an overall manageable safety profile (Smyth et al 2017).  Pooled AE data 
from Study D3610C00001 Parts E and F (DCO of 4 October 2018) indicate that the most 
common CTCAE grade >3 events (>5% of patients) were diarrhoea (5.4%), hyperglycaemia 
(5.4%), and rash maculo-papular (10.8%).  The discontinuation rate for toxicity was low: 7 
(9.5%) and 3 (4.1%) patients had at least 1 AE that led to discontinuation of capivasertib 
treatment, irrespective of causality and causally-related, respectively. The only AE leading to 
discontinuation that affected more than 1 patient was fatigue (reported in 2 patients).
Taken together, the overall benefit/risk of capivasertib + fulvestrant appears to be favourable 
for patients with HR+/HER2− locally advanced/metastatic breast cancer but requires 
confirmation in this pivotal Phase III study.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of capivasertib is 
provided in the Investigator’s Brochure.  
2.3
Benefit/risk assessment
2.3.1
Risks with capivasertib
Based on non-clinical and clinical data available to date, the risks associated with capivasertib 
are as follows:

Identified Risks: nausea and vomiting, diarrhoea, stomatitis, dry skin, pruritus, decreased 
appetite, dyspepsia, rash, dysgeusia, erythema multiforme, drug eruption, dermatitis, 
dermatitis exfoliative generalised, toxic skin eruption, fatigue, mucosal inflammation, 
blood creatinine increased, glycosylated haemoglobin increased, anaemia, 
hypersensitivity and urinary tract infection.

Important Identified Risks: hyperglycaemia.

Important Potential Risk: acute complications of hyperglycaemia.
Based on non-clinical data available (dog telemetry study), QT prolongation has been noted as 
a potential risk.  However, in AstraZeneca-sponsored clinical studies of capivasertib to date, 

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there were no reports of sudden death, torsades de pointes, or seizures, and from a recent 
concentration-QT model analysis, capivasertib is not predicted to pose a clinically significant 
safety risk for QT prolongation at the therapeutic dosing regimen.  However, it is 
recommended to avoid drugs known to prolong QT interval (see Section 6.5.3).  Further 
details on the risks are available in ‘Section 6: Summary of data and guidance for the 
investigators’ of the Investigator’s Brochure.  
Overall in the monotherapy intermittent dosage pool (N=229), 42.4% patients had serious 
adverse events (SAEs), 17% were causally related and 3.1% patients were reported with SAEs 
leading to death.  There were no capivasertib treatment-related deaths in this pool.  A total of 
17.5% patients were discontinued due to SAEs, and 11.4% were discontinued due to SAEs 
related to capivasertib treatment.
Based on data from the D3610C00001 and FAKTION studies (Section 2.2), the combination 
of capivasertib with fulvestrant has a tolerability profile that is manageable with dose 
modifications and supportive care.  
There are 16 externally sponsored research studies which are planned, have recently 
commenced recruitment or are ongoing.  Of these 16, 10 are investigating capivasertib 
specifically and 6 are “umbrella/basket” studies in which capivasertib is an option in a panel 
of potential investigational drugs.  AstraZeneca is not aware of any new and significant safety 
information from externally sponsored research.  
2.3.2 Overall benefit-risk and ethical assessment
Although endocrine therapy administered with or without either a CDK4/6 inhibitor, 
everolimus or alpelisib (in PIK3CA mutant tumours) are effective options for at least some 
patients with HR+/HER2− ABC, all tumours eventually develop endocrine resistance, and 
from that point will require sequential chemotherapies given until disease progression or 
unacceptable toxicity, with the intent of reducing disease burden and symptoms, and delaying 
disease progression.  Thus, HR+/HER2− ABC still represents an area of considerable unmet 
medical need for new therapies and/or combinations that can delay or overcome resistance.
Clinical and non-clinical data with capivasertib (see Section 2.2) support the hypothesis that 
AKT inhibition in combination with an endocrine therapy such as fulvestrant may be a valid 
treatment strategy for HR+/HER2− ABC.  Capivasertib has also demonstrated clinical activity 
in several settings including patients with metastatic TNBC in combination with first-line 
paclitaxel (Schmid et al 2018), patients with advanced AKT1 mutant solid tumours in 
monotherapy or combination with fulvestrant (ER+ breast cancer) (Hyman et al 2017, Smyth 
et al 2017) and patients with ER+/HER2- ABC in combination with fulvestrant after AI 
therapy (Jones et al 2019).  

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The non-clinical profile and emerging clinical safety profile from the early clinical studies 
with capivasertib have not identified risks that would preclude investigation in this setting.  
The study design of this randomised clinical trial aims to minimise potential risks in several 
ways.  First, appropriate inclusion and exclusion criteria will be included in the study protocol 
to protect patient safety.  For example, in order to be enrolled, patients must be eligible for 
fulvestrant treatment (as per local investigator assessment) which is administered in both arms 
of the study, and patients with symptomatic visceral disease or any disease burden that makes 
the patient ineligible for endocrine therapy per the investigator’s best judgement will be 
excluded.  Of note, patients with uncontrolled and/or insulin dependent diabetes are also 
excluded from the study.  Second, the protocol includes safety monitoring in excess of 
standard of care monitoring, with the intent of protecting patients involved in the study.  
Furthermore, a dose modification strategy for the management of toxicity and monitoring is in 
place for those risks deemed to be most likely or serious.  Thus, based upon the clinical and 
non-clinical safety profile, the limited life expectancy of patients due to malignant disease, 
and the strength of the scientific hypothesis under evaluation, the benefit/risk assessment for 
this study supports the treatment of capivasertib and fulvestrant in patients with HR+/HER2− 
ABC.  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of capivasertib may be found in the Investigator’s Brochure.  
See Section 9.5.1 and Appendix C for information regarding the Data Monitoring Committee.
2.3.3
Impact on Benefit/Risk from Study Disruptions due to Coronavirus 
Disease 2019
The emergence of the novel coronavirus disease 2019 (SARS-CoV-2/COVID-19) pandemic 
presents a potential safety risk for patients and therefore several risk mitigation factors have 
been implemented in this study (see Section 4.5, Appendix K, and Appendix L).  

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3
OBJECTIVES AND ENDPOINTS
3.1
Primary objectives
The primary objectives for the study and associated outcome measures are summarised in 
Table 2.
Table 2
Primary objectives
Primary objective
Endpoint
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
PFS in the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup..  
PFS is defined as the time from randomisation until 
progression per RECIST v1.1, as assessed by the 
investigator at the local site, or death due to any cause.  
PFS, progression-free survival; RECIST v1.1, Response Evaluation Criteria in Solid Tumours version 1.1; 
vs, versus.
3.2
Secondary objectives
The secondary objectives of the study and associated outcome measures are summarised in 
Table 3.  
Table 3
Secondary objectives
Secondary objectives
Endpoint
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of OS 
in the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup. 
OS is length of time from randomisation until the date 
of death due to any cause.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
PFS2 in the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup.  
PFS2 is defined as the time from randomisation until 
second progression on next-line treatment, as assessed 
by the investigator at the local site, or death due to any 
cause.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
ORR in the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup.  
ORR is defined as the percentage of patients with at 
least one CR or PR per RECIST v1.1, as assessed by 
the investigator at the local site.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
DoR in the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup.  
DoR is defined as the time from the date of first 
documented response until date of documented 
progression or death in the absence of disease 
progression.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
CBR in the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup.  
CBR is defined as the percentage of patients who have 
a CR, PR or stable disease per RECIST v1.1 (without 
subsequent cancer therapy) maintained ≥24 weeks 
after randomisation.  
To assess the safety and tolerability of capivasertib + 
fulvestrant as compared to placebo + fulvestrant in 
Safety and tolerability will be evaluated in terms of 
AEs/SAEs, vital signs, clinical 

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Secondary objectives
Endpoint
the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup.  
chemistry/haematology/glucose metabolism 
parameters, and ECG parameters.  
Assessments related to AEs cover:

Occurrence/frequency

Relationship to capivasertib and fulvestrant 
as assessed by investigator

CTCAE grade

Seriousness

Death

AEs leading to discontinuation of 
capivasertib/placebo

AEs leading to discontinuation of fulvestrant

AEs leading to dose interruption of 
capivasertib/placebo

AEs leading to dose interruption of 
fulvestrant

AEs leading to dose reduction of 
capivasertib/placebo

AEs of special interest

Other significant AEs
Vital signs parameters include systolic and diastolic 
blood pressure, pulse, respiratory rate, body 
temperature and weight.  
Assessments cover:

Observed value

Absolute and change from baseline values 
over time
To evaluate the PK of capivasertib when given in 
combination with fulvestrant.  
Plasma concentration of capivasertib pre-dose (Ctrough) 
and post-dose (C1h and C4h) in the overall population 
(patients randomised to capivasertib + fulvestrant).  
AUC 0-12h, Cmax and tmax in a subpopulation of 
approximately 6 Japanese patients with rich PK 
sampling.  
To assess the impact of capivasertib + fulvestrant vs 
placebo + fulvestrant on patients’ disease-related 
symptoms, function and HRQoL in the overall 
population and in the PIK3CA/AKT/PTEN-altered 
subgroup where applicable.  
Evaluation of EORTC QLQ-C30, EORTC 
QLQ-BR23, scale/item scores including change from 
baseline and time to deterioration.  

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Sec o n d ar y o bjecti ves
E n d p oi nt
T o c o m pare t he effect of ca pi vaserti b + f ul vestra nt 
relati ve t o placeb o + f ul vestra nt b y assess me nt of 
ti me t o defi niti ve deteri orati o n of E C O G 
perf or ma nce stat us fr o m baseli ne i n t he o verall 
p o p ulati o n a n d i n t he PI K 3 C A/ A K T/ P T E N -altere d 
s u b gr o u p.  
Ti me t o defi niti ve deteri orati o n of E C O G perf or ma nce 
stat us is defi ne d as ti me fr o m ra n d o misati o n t o t he 
earlier of t he date of t he first defi niti ve deteri orati o n or 
deat h d ue t o a n y ca use.  
A E, a d verse e ve nt; A U C 0- 1 2 h, area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m zer o t o 1 2 h o urs; C, 
c o nce ntrati o n; C B R, cli nical benefit rate; C ma x , ma xi m u m o bser ve d plas ma ( pea k) c o nce ntrati o n; C R, c o m plete 
res p o nse; C T C A E, C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nt; ct D N A, circ ulati n g t u m o ur D N A; D o R, 
d urati o n of res p o nse; E C G, electr ocar di o gra m; E C O G, Easter n C o o perati ve O nc ol o g y Gr o u p ; E O R T C, E ur o pea n 
Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer; E O R T C Q L Q -B R 2 3, E O R T C Q ualit y of Life Q uesti o n naire
br east ca ncer s pecific m o d ule; E O R T C Q L Q -C 3 0, E O R T C Q ualit y of Life Q uesti o n naire -C or e 3 0 ite ms; 
H R Q o L healt h -relate d q ualit y of life; O R R, o bjecti ve res p o nse rate; O S, o verall s ur vi val; P F S, pr o gr essi o n -free 
s ur vi val; P F S 2, ti me fr o m ra n d o misati o n t o sec o n d pr o gressi o n or deat h; PI K 3 C A , p h os p hati d yli n osit ol-4, 5 -
bis p h os p hate 3 -ki nase catal ytic s u b u nit al p ha ge ne; P K, p har mac o ki neti cs; P R, partial res p o nse; P T E N, 
p h os p hatase a n d te nsi n h o m ol o g; R E CI S T v 1. 1, Res p o nse E val uati o n Criteria i n S oli d T u m o urs versi o n 1. 1; 
S A E, seri o us a d verse e ve nt; tma x , ti me t o reac h pea k or ma xi m u m o bser ve d c o nce ntrati o n f oll o wi n g dr u g 
a d mi nistrati o n ; vs, vers us.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
C CI
C CI

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C ollecti o n a n d st ora ge of D N A f or f ut ure a nal ysis.  
C CI

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700 randomised patients, based on a prevalence of 40% to 45% for PIK3CA/AKT1/PTEN
alterations (Cristofanilli et al 2016, Curtis et al 2012, Di Leo et al 2018, Hortobagyi et al 2016, 
Pereira et al 2016, Spoerke et al 2016), and a test failure rate of 20%, it is expected that a 
minimum of approximately 224 patients will test positive for tumours with these alterations 
and will be assigned to the PIK3CA/AKT1/PTEN-altered subgroup.  The prevalence of 
PIK3CA/AKT1/PTEN mutation status will be monitored post-randomisation by central testing 
of formalin-fixed paraffin-embedded (FFPE) tumour samples collected before study entry.  
Given the proposed sample size (approximately 700 patients overall), it is expected that 
randomisation will be sufficient to ensure a balance between treatment arms with respect to 
mutational status.  Enrolment will be open to all eligible patients irrespective of the 
PIK3CA/AKT1/PTEN status of their tumour(s); however adequate tumour tissue collected 
before study entry will be required for a central retrospective analysis.  
In China, recruitment will continue until approximately 134 Chinese patients have been 
randomised, irrespective of whether or not the overall study enrolment has been reached.  This 
is to ensure adequate participation of Chinese patients to satisfy China Regulatory Authority 
requirements.  
Patients will receive weekly capivasertib (400 mg or placebo, oral, twice daily; 4 days on and 
3 days off) and fulvestrant (at the approved dose regimen [500 mg intramuscular injections on 
Day 1 of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of each cycle thereafter]).  
All patients will attend a screening visit a maximum of 28 days prior to the start of study 
treatment.  
Day 1 is defined as the randomisation date; study treatment should begin as soon as possible 
after randomisation, ideally the same day.  Randomised patients will continue study treatment 
until objective radiological disease progression as defined by Response Evaluation Criteria in 
Solid Tumours version 1.1 (RECIST v1.1), unacceptable toxicity occurs, the patient 
withdraws consent or death.  Following objective disease progression, further treatment 
options will be at the discretion of the investigator.  If a patient discontinues treatment (and/or 
receives a subsequent cancer therapy) prior to progression, the patient should still continue to 
be followed until objective disease progression as defined by RECIST v1.1.  Cross-over from
placebo to capivasertib is not allowed.  
The randomisation scheme will be stratified on the following factors:

Liver metastases (yes vs no)

Prior use of CDK4/6 inhibitors (yes vs no)

Patients may have received prior treatment with CDK4/6 inhibitors as part of 
standard treatment or within clinical trials (in the latter scenario, written confirmation 

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of exposure to the investigational agent rather than placebo is required to allow 
stratification at randomisation)

Geographic location:

Region 1: United States, Canada, Western Europe, Australia, and Israel

Region 2: Latin America, Eastern Europe and Russia

Region 3: Asia
The dual primary endpoints, PFS in overall and PIK3CA/AKT1/PTEN-altered subgroup, are 
defined as the time from randomisation until disease progression based on the investigator’s 
assessment according to RECIST v1.1, or death due to any cause regardless of whether the 
patient withdraws from therapy or receives another anticancer therapy prior to progression.  
The key secondary endpoint of OS is defined as the time from the date of randomisation until 
death due to any cause.  A sensitivity analysis will be conducted using PFS assessed by 
blinded, independent central review (BICR) and defined using RECIST v1.1 criteria.  
A study flow chart is illustrated in Figure 2 and the study design is summarised in Figure 1.  
For details on what is included in the efficacy and safety endpoints, see Section 3.  For details 
on treatments given during the study, see Section 6.1.  

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Figure 2
Study flow chart
BD, twice daily; PFS2, time from randomisation to second progression or death; PRO, patient-reported outcome; 
RECIST v1.1, Response Evaluation Criteria in Solid Tumours version 1.1.  
a
If the patient discontinues due to progression, PROs (not including PGI-ITT and PRO-CTCAE) should be 
assessed at progression and every 4 weeks (±3 days) post discontinuation until PFS2.  
b
Patients who discontinue treatment prior to progression should continue to be scanned by RECIST v1.1 
every 8 weeks (± 7 days) for the first 18 months and every 12 weeks (±7 days) thereafter until progression, 
regardless of reason for treatment discontinuation.  If the patient discontinues due to toxicity but does not 
progress, PROs (not including PGI-ITT and PRO-CTCAE) should be assessed every 4 weeks (±3 days) 
until progression, at progression and every 4 weeks (±3 days) post progression until PFS2.  

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4.1.1
Study oversight considerations
The study will use a Trial Steering Committee (TSC) and an external independent data 
monitoring committee (IDMC).  Please see Section 9.5.1 and Appendix C for additional 
information.  
4.2
Scientific rationale for study design
This randomised, double-blind, placebo-controlled, Phase III study will serve as confirmatory 
evidence of the clinical benefit, safety and tolerability of capivasertib + fulvestrant vs placebo 
+ fulvestrant for the treatment of patients with locally advanced or metastatic HR+/HER2− 
breast cancer.  Mandatory tissues samples collected from patients at screening will be used to 
retrospectively identify patients with qualifying PIK3CA/AKT1/PTEN alterations to 
investigate treatment with capivasertib + fulvestrant in this subgroup.  The randomised, 
double-blind design of this study reduces potential for bias when assessing whether the 
combination of capivasertib + fulvestrant shows improved efficacy compared with fulvestrant 
monotherapy.  
This is a Phase III study in adults (pre-menopausal women and post-menopausal women, and 
men) with HR+/HER2− locally advanced or metastatic breast cancer, after recurrence or 
progression on or after treatment with an AI.  This represents a population that may have 
received up to 2 prior lines of endocrine therapy for metastatic disease, including combination 
therapy with a CDK4/6 inhibitor, and up to 1 line of chemotherapy in the metastatic setting; 
all patients will have received hormone (endocrine)-based therapy with an AI. 
This study has been designed to also include pre- or peri-menopausal women, and men as per 
recent international guidelines (Cardoso et al 2018).  These state that all treatment 
recommendations for post-menopausal patients should be extended to the pre-menopausal 
setting (with associated ovarian function suppression or ablation), encouraging the inclusion 
of patients who are initially pre- or peri-menopausal in clinical studies to avoid separate and 
duplicate trials.  Studies evaluating new endocrine-based strategies should be designed to 
allow enrolment of both pre- and post-menopausal women, and men.
Hormone (or endocrine)-based therapy is the preferred initial treatment for ER+/HER2- or 
luminal ABC (Cardoso et al 2018) in the majority of cases, excluding only those with visceral 
crisis or concern for (or proof of) endocrine resistance, for whom chemotherapy is required.  
Current international treatment guidelines state that the preferred first-line endocrine therapy 
depends on the type and duration of adjuvant endocrine therapy as well as the disease-free 
interval.  Available endocrine agents include but are not limited to AIs, tamoxifen, or 
fulvestrant, for pre- and peri-menopausal women (with ovarian function suppression/ablation), 
men (preferably with a LHRH agonist), and post-menopausal women.  Of note, CDK4/6 
inhibitors in combination with an AI or fulvestrant (±LHRH agonist depending on 
menopausal status) have substantially improved PFS compared with endocrine therapy alone.  

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These agents are, in certain markets, approved for advanced or metastatic HR+/HER2- breast 
cancer as initial endocrine-based therapy and/or after disease progression following endocrine 
therapy.  As this class of agents has started to show a survival benefit (Im et al 2019, Slamon 
2019, Sledge 2019), it is expected that their already wide use will continue to increase, 
especially in the first-line setting.  Therefore, if they are available in the country in which a 
patient is being enrolled, they must be considered and excluded as treatment options before 
the patient can be considered for entering the study.  For the above reasons and to make sure 
the enrolled population is representative of the general AI resistant HR+/HER2- advanced or 
metastatic breast cancer population, the study intends to enrol a minimum of 51% of patients 
previously treated with CDK4/6 inhibitor.  Regarding additional endocrine-based options, the 
mTOR inhibitor everolimus is also approved in combination with the AI exemestane in 
patients with previous failure of treatment with letrozole or anastrozole, but the European 
Society for Medical Oncology (ESMO) guidelines state that the decision to treat must take 
into account the toxicities associated with this combination, lack of statistically significant OS 
benefit, cost and availability.
There is no single standard of care following endocrine therapy with or without a CDK4/6 
inhibitor (as first- or second-line treatment).  When patients progress, the choice of therapy 
depends on several factors: prior treatments (and response), disease burden, patient 
preference, and treatment availability, which varies in different countries around the world.  
Regardless of first- or second-line CDK4/6 inhibitor treatment, and despite multiple treatment 
options (eg, fulvestrant, everolimus plus exemestane), median post-progression treatment 
duration is limited, ranging from 4 to 8 months (Lupichuk et al 2019, Turner et al 2017).  
Patients eventually experience disease progression (endocrine resistance) and require 
chemotherapy.  Thus, regardless of prior CDK4/6 inhibitor use, a considerable unmet medical 
need remains in this population for improved second- and additional-line treatment.
Available second or further lines of therapies are limited either with regard to the population 
able to gain benefit, or the magnitude of benefit.  A Phase III study (BOLERO-2) of 
everolimus plus exemestane in patients with HR+/HER2- ABC post-AI progression, showed 
that the combination therapy improved PFS compared with exemestane alone from 3.2 to 
7.8 months irrespective of PIK3CA genotype, albeit without significant OS improvement 
(Yardley et al 2013).  More recently, the Phase III SOLAR-1 study demonstrated an 
improvement in PFS of 5.7 to 11 months with the addition of the alpha-specific PI3K inhibitor 
alpelisib to fulvestrant in patients with HR+/HER2− ABC with tumours harbouring a PIK3CA
mutation, who had relapsed or progressed on an AI (André et al 2019), based on which the 
FDA granted approval.  Of note, a clinically relevant benefit was not seen in the PIK3CA
non-mutant cohort and is not included in the approval.
The purpose of this Phase III study is to further characterise and confirm the efficacy and 
safety of capivasertib + fulvestrant observed in the Phase II randomised FAKTION study 

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where the addition of capivasertib to fulvestrant resulted in a 5.5-month improvement in 
median PFS from 4.8 months on fulvestrant alone to 10.3 months (HR 0.57 [95% CI: 0.393, 
0.841]) regardless of PI3K/AKT/PTEN pathway activation status.  At the time of the PFS 
analysis, OS data were not mature (37%; 52 deaths reported); however, the data suggest an 
improvement of approximately 6 months on the combination treatment.  The positive efficacy 
data are supported by the finding that the addition of capivasertib to fulvestrant appears 
overall well tolerated with no marked impact on the dose intensity of fulvestrant (see 
Section 2.1 and Section 2.2 for further information on the FAKTION study and the study 
rationale).  
In this Phase III study, patients qualifying for the altered subgroup will be identified by 
post-randomisation central testing of tumour tissue collected prior to enrolment based on a 
prespecified list of molecular alterations, using a validated assay as described in Section 8.7.1.  
By enrolment of both the overall population and a minimum number of patients in the altered 
subgroup, the study design (including the sample size and planned statistical analysis 
approach described in Section 9) will allow for further investigation of outcomes in the 2 
populations tested. 
In light of the demonstrated activity of the combination of capivasertib + fulvestrant in the 
Phase II FAKTION study and the common usage of single agent fulvestrant in the 
management of advanced/metastatic HR+/HER2- breast cancer, fulvestrant is considered an 
appropriate comparator for this Phase III study.  In addition, deploying fulvestrant as the 
control agent will enable a robust assessment of the contribution of components in the doublet 
regimen under study.  
The rationale for the choice of stratification factors in this study is as follows:

Liver metastases (yes vs no): The pattern and extent of metastatic disease are considered 
to be important factors with prognostic impact in HR+/HER2− (Solomayer et al 2000).  
Patients with HR+ ABC with non-visceral metastases and visceral non-liver metastases 
have significantly better outcomes from endocrine therapy than patients with liver 
metastases (Robertson et al 2019). 

Prior use of CDK4/6 inhibitors (yes vs no): Recent changes in the treatment landscape for 
HR+/HER2- ABC include the addition of CDK4/6 inhibitors to endocrine agents in the 
first- and second-line settings.  Although limited and retrospective, currently available 
data suggest that patients who have received prior CDK4/6 inhibitors do not appear to 
have a different outcome obtained from subsequent standard of care therapies (Lupichuk 
et al 2019, Turner et al 2017).  However, as the FAKTION study recruited at a time when 
CDK4/6 inhibitors were not available in the enrolling sites, it remains unclear whether 
prior treatment with a CDK4/6 inhibitor would influence the magnitude of benefit from 
treatment with capivasertib plus fulvestrant.  The total number of CDK4/6 naïve patients 
will be limited to 49% of the total number of patients (Section 6.3).

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
Geographic location (Region 1: US, Canada, Western Europe, Australia, Israel; Region 2: 
Latin America, Eastern Europe and Russia; Region 3: Asia): Considering there is no 
single standard of care for the intended population, geographic region has been included 
to account for possible differences in treatment paradigms and patient demographics in 
different territories. 
Despite the documented benefits of endocrine-based therapy in HR+/HER2- ABC, intrinsic 
and acquired resistance remains a common feature that limits the success of this strategy, and 
lack of sensitivity (or primary resistance) to endocrine therapy appears associated with worst 
survival (Cristofanilli et al 2018).  For the purpose of this study, the following definitions for 
endocrine resistance (Cardoso et al 2018) will be used for data collection:

Primary endocrine resistance is defined as relapse while on the first 2 years of adjuvant 
endocrine therapy, or progressive disease within the first 6 months of first-line endocrine 
therapy for ABC, while on endocrine therapy

Secondary endocrine resistance is defined as relapse while on adjuvant endocrine therapy 
but after the first 2 years, or relapse within 12 months of completing adjuvant endocrine 
therapy, or progressive disease ≥6 months after initiating endocrine therapy for ABC, 
while on endocrine therapy
NOTE: Patients who meet any criteria of secondary endocrine resistance are classified as 
such, regardless of whether they meet any aspect of the definition of primary resistance; 
patients who do not meet any of the criteria of secondary endocrine resistance are defined as 
having primary resistance.  
In recent studies with novel therapies in the HR+/HER2- ABC setting, estimation of the effect 
on OS has been jeopardised by limited statistical power, and therefore, suboptimal assessment 
of their benefit.  The proposed study is intended to address this issue by providing adequate 
power to show a statistically significant difference between capivasertib + fulvestrant and 
placebo + fulvestrant in both PFS and OS.  The dual primary endpoints of this study are PFS 
in the overall population and PFS in the PIK3CA/AKT1/PTEN-altered population, as described 
in Section 3.1 and Section 9.  Key secondary efficacy endpoints (see Section 3.2 and 
Section 9) are OS and objective response rate (ORR) in the overall and the 
PIK3CA/AKT1/PTEN -altered populations.  Other secondary endpoints of this study that are 
appropriate include clinical benefit rate (CBR), duration of response (DoR), time to definitive 
deterioration of ECOG performance status from baseline, time from randomisation to second 
progression or death (PFS2), EORTC Quality of Life Questionnaire-Core 30 items (EORTC 
QLQ-C30) and EORTC Quality of Life Questionnaire-breast cancer specific module 
(EORTC QLQ-BR23) and will be assessed in both the overall and the PIK3CA/AKT1/PTEN-
altered populations.  The EORTC QLQ-C30 and EORTC QLQ-BR23 capture relevant 
symptoms and functional impacts for patients with cancer and breast cancer, respectively.  
Examination of change from baseline and time to deterioration in these concepts will allow for 
an assessment of the ability of the investigational treatment to preserve overall health-related 

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q ualit y of  life ( H R Q o L) a n d dela y w orse ni n g of disease s y m pt o ms a n d f u ncti o nal li mitatio ns 
i n t he tar get p o p ulati on.  P har mac o ki netic ( P K) c haracterisat i on of ca pi vaserti b as well as t he 
safety a n d t olera bilit y of  ca pi vaserti b + f ul vestra nt a n d place b o + f ul vestra nt will als o be 
assesse d as sec o n dar y e n d p oi nts.  
 
 
 
 
 
4. 3
J u stific ati o n f or d ose
4. 3. 1
C a pi v aserti b
Se veral d oses a n d sc he d ules of ca pi vaserti b ha ve bee n st u die d cli nicall y  ( all t wice dail y 
[ B D]).  M o n othera p y has bee n gi ve n as c o nti n u o us ( 8 0 m g t o 6 0 0 m g), i nter mitte nt 4 da y s o n, 
3 da y s off ( 4 8 0 m g t o 6 4 0 m g) a n d i nter mitte nt 2 da ys o n, 5 da ys off ( 6 4 0 mg t o 8 0 0 m g) 
sc he d ules.  D ose- a n d/ or c o nce ntrati o n-res p o nse relati ons hi ps ha ve bee n de m o nstrate d f or 
p har mac o d y na mic bi o mar kers of A K T i n hi bit i on i n t u m o ur tiss ue a n d f or t he m ost i m p orta nt 
A Es ( di arr h oea, ras h, a n d h y per gl ycae mia of C T C A E gra de 3 -4) i n cli nical st u dies.  
T he rec o m me n de d re gi me n f or m o n ot hera p y  ( 4 8 0 m g B D, 4 da ys o n 3 da ys off) was selecte d 
base d o n p har mac o d y na mic para meters fr o m t u m o ur bi o psies, P K data, a n d cli nical safet y.   
T he rec o m me n de d P hase II d ose of ca pi vasert i b i n c o m bi nati o n with f ul vestra nt was 
deter mi ne d b y t he r u n -i n part (I b) of t he P hase I b/II F A K TI O N st u d y.  T he ai m of P hase I b o f 
t he st u d y was t o deter mi ne t he ma xi m u m t olerate d d ose ( M T D) f or ca pi vaserti b gi ve n i n 
c o m bi nat i on wi t h t he lice nse d d ose of f ul vestra nt ( 5 0 0 m g i ntra m usc ular o n Da ys 1, 1 5, 2 9 
a n d o nce m o nt hl y t hereafter).  T he t o xicit y pr ofile i n patie nts w h o recei ve d ca pi vaserti b 4 0 0 
m g B D, 4 da ys o n 3 da y s off was c o nsiste nt wit h pri or ca pi vaserti b st u dies.  Alt h o u g h n o 
d ose -li miti n g t o xicities were o bser ve d, t he Safety Re vie w C o m mittee c o ncl u de d t hat 4 8 0 m g 
B D was u nli kel y t o be t olerate d f or l o n g -t er m d osi ng i n c o m bi nat i on wi t h ful vestra nt, a n d t he 
4 da y s o n, 3 da ys off 4 0 0 m g B D sc he d ule was selecte d as t he c o m bi nat i on d ose wit h 
f ul vestra nt.  T his d ose re gi me n was als o s u p p orte d b y s afet y data fr o m St u d y D 3 6 1 0 C 0 0 0 0 1 
a n d precli nical P K- p har mac o d y na mic effica c y mat he mat ical m o delli n g (Yates et al 2 0 1 5 ).  
Res ults fr o m t he ra n d o mise d part of t he F A K TI O N st u d y ( P hase II) pr o vi de e vi de nce t hat t he 
selecte d d ose a n d sc he d ule are efficaci o us wit h acce pta ble safet y a n d t olera bilit y in pat ient s 
wi t h E R + A B C.  T heref ore, t he d ose re gi me n f or t his P hase III st u d y is ca pi vaserti b 
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400 mg BD, 4 days on 3 days off in combination with fulvestrant at the approved dose 
regimen.  
4.3.2
Fulvestrant
Fulvestrant will be used within its marketing authorisation at a monthly dose regimen of 
500 mg (2 × 5 mL intramuscular injections), with an additional loading dose in Cycle 1.  This 
regimen is commonly used in clinical practice and considered as standard of care for the 
treatment of HR+/HER2– metastatic breast cancer in participating countries.  Monthly 
fulvestrant at the approved dose regimen showed an expected and manageable safety profile 
when combined with capivasertib in the FAKTION study (Jones et al 2019) and in 
Study D3610C00001 (Sections 2.2 and 2.3.1).
4.4
End of study definition  
For the purpose of Clinical Trial Transparency the definition of the end of the study differs 
under FDA and EU regulatory requirements:

European Union requirements define study completion as the last visit of the last subject 
for any protocol related activity.

Food and Drug Administration requirements defines 2 completion dates:

Primary Completion Date – the date that the final participant is examined or receives 
an intervention for the purposes of final collection of data for the primary outcome 
measure, whether the clinical study concluded according to the pre-specified protocol 
or was terminated. In the case of clinical studies with more than one primary outcome 
measure with different completion dates, this term refers to the date on which data 
collection is completed for all of the primary outcomes.

Study Completion Date – is defined as the date the final participant is examined or 
receives an intervention for purposes of final collection of data for the primary and 
secondary outcome measures and AEs (for example, last participant’s last visit), 
whether the clinical study concludes according to the pre-specified protocol or is 
terminated.
A participant is considered to have completed the study when they have completed their last 
scheduled visit or their last scheduled procedure in the SoA (Section 1.1) including OS 
determination.  
As the study is event driven, the accrual of the predetermined number of events included in 
the study endpoints will determine the duration of the data collection phase of the study. There 
will be a final DCO, defined by the time of the OS Final Analysis, which will take place after 
OS reaches approximately 70% maturity of events in the overall population and the 
PIK3CA/AKT1/PTEN-altered population (see details in Section 9.2). At this time the clinical 
database will close to new data with the exception of China or Japan if the number of patients 

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is judged insufficient and an additional DCO is required to address regulatory requirements in 
China or Japan.
Should the study meet the primary endpoint at any of the prescribed interim analyses, 
additional data cuts may be needed per local health authority requirements.  
Patients are permitted to continue to receive treatment beyond the closure of the database if, in 
the opinion of the investigator, they are continuing to receive benefit. For patients who 
continue to receive treatment beyond the time of the final DCO, investigators will continue to 
report all SAEs only (no other data will be captured) to AstraZeneca Patient Safety until 
30 days after study treatment is discontinued, in accordance with Section 8.3. It is 
recommended to continue observing ongoing patients at the frequency indicated within the 
study plans as described in the SoA (Table 1). Restrictions regarding concomitant medications 
(Section 6.5) will be followed while the patient is receiving capivasertib/placebo ± fulvestrant. 
A change in capivasertib/placebo ± fulvestrant dose should only occur for safety reasons, 
based on the investigator’s judgement, and should generally follow the approach for dose 
reduction and discontinuation as described in this protocol. If an investigator learns of any 
SAEs, including death, at any time after a patient has completed the study, and he/she 
considers there is reasonable possibility that the event is causally related to the investigational 
product, the investigator should notify AstraZeneca Patient Safety. Additionally, as stated in 
Section 8.3.3, any SAE or non-serious AE that is ongoing at this DCO must be followed up to 
resolution unless the event is considered by the investigator to be unlikely to be resolved, or 
the patient is lost to follow-up.
See Section 6.7 for details on participant management following the final DCO, as well as 
following study completion.  
The study may be terminated at individual centres if the study procedures are not being 
performed to Good Clinical Practice (GCP) or if recruitment is slow.  AstraZeneca may also 
terminate the entire study prematurely for operational reasons or if concerns for safety arise 
within this study, or in any other study, with capivasertib.  
See Appendix C for guidelines for the dissemination of study results.
4.5
Study Conduct Mitigation During Study Disruptions Due to 
COVID-19 – Temporary Measures
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented temporarily only during the COVID-19 outbreak (eg, during quarantines and 
resulting site closures, regional travel restrictions, and considerations if site personnel or study 
patients become infected with COVID-19) which would prevent the conduct of study-related 
activities at study sites, thereby compromising the study site staff or the patient’s ability to 

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conduct the study.  The investigator or designee should contact the study Sponsor to discuss 
whether the mitigation plans below should be implemented.
To ensure continuity of the clinical study during the COVID-19 outbreak, temporary changes 
may be implemented to ensure the safety of study patients, maintain compliance with GCP, 
and minimize risks to study integrity.  Where allowable by local health authorities, ethics 
committees, healthcare provider guidelines (eg, hospital policies) or local government, these 
temporary changes may include the following options:

Obtaining reconsent for the mitigation procedures (note, in the case of verbal reconsent, 
the ICF should be signed at the patient’s next contact with the study site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. The 
investigator should confirm this with the designated study physician.

Home or Remote visit: Performed by a site qualified Health Care Professional or Health 
Care Professional provided by a third party vendor. 

Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 

At-home study treatment administration: Performed by a site qualified Health Care 
Professional, or a Health Care Professional provided by a third party vendor, or by the 
patients or the patient’s caregiver, if possible. Additional information related to the visit 
can be obtained via telemedicine.

At-home or Remote Delivery of oral study treatment (capivasertib/placebo). 
For further details on study conduct during COVID-19, refer to Appendix K.  For further 
guidance during the COVID-19 pandemic, refer to Appendix L.  
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment 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 be assigned/randomised to a study intervention.  Under no circumstances can 
there be exceptions to this rule.  Patients who 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.

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5. 1
I ncl usi o n criteri a
P ati e nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g i ncl usi o n criteria 
a n d n o ne of t he e xcl usi o n cri t eria a p pl y:
I nf or me d c o nse nt
1
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt, w hic h i ncl u des c o m plia nce wit h t he 
re q uire me nts a n d restricti ons liste d i n t he i nf or me d c o nse nt f or m (I C F) a n d i n t he cli nical 
st u d y pr ot o c ol ( C S P)
2
Pr o visi o n of si g ne d a n d date d, writte n I C F pri or t o a n y ma n dat or y st u d y s pecific 
pr oce d ures, sa m pli n g, a n d a nal yses
3
F or i ncl usi o n i n t he 
 pr o visi on of 
sig ne d a n d date d wri tte n 
 c o nse nts, res pecti vel y, pri or 
t o c ollecti on of sa m ple(s)
If a patie nt decli nes t o partici pate i n t he 
 
 t here will be n o pe nalt y or loss of be nefit t o t he patie nt.  T he 
pati e nt will n ot be e xcl u de d fr o m ot her as pects of t he st u d y .  
T he I C F pr ocess is descri be d i n A p pe n di x C 3 .
A ge
4
P ati e nts must be a ge d ≥1 8 y ears (a ge d ≥2 0 years i n Ja pa n ) at t he ti me of sig ni n g t he I C F
T y pe of p atie nt a n d dise ase c h ar acteristics
5
A d ult fe males, pre - a n d/ or p ost -me n o pa usal, a n d a d ult males

Pre -me n o pa usal (a n d peri - me n o pa usal, ie, t h ose t hat d o n ot meet t he criteria f or 
p ost -me n o pa usal defi ne d bel o w) w o me n c a n be e nr olle d if a me na ble t o treat me nt 
wi t h a n L H R H a g o nist.  Patie nts are t o ha ve c o m me nce d c o nc o mita nt treat me nt wit h 
L H R H a g o nist pri or t o or o n C y cle 1, Da y 1 a n d m ust be willi n g t o c o nti n ue o n it f or 
t he d urati o n of t he st u d y

P os t-me n o pa usal w o me n ar e defi ne d as:
o
a ge d ≥6 0 y ears of a ge, O R
o
a ge d < 6 0 years of a ge a n d a me n orr h oeic f or at least 1 2 m o nt hs f o ll owi n g 
cessat i on of all e x o ge n o us h or m o nal treat me nts/c he m ot hera p y/ o varia n 
s u p pressi on/ta m o xife n or si milar.  T hese patie nts s h o ul d als o ha ve ser u m 
o es tra di ol a n d f o llicle sti m ulati n g h or m o ne ( F S H) le vels c o nfir me d as bei n g 
wi t hi n t he sta n dar d la b orat or y r efere nce ra n ge f or p ost -me n o pa usal fe males, O R
o
d oc u m e nte d bilateral o o p h orect o m y
C CI
C CI
C CI

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6
Histologically confirmed HR+/HER2− breast cancer determined from the most recent 
tumour sample (primary or metastatic), as per the American Society of Clinical Oncology 
and College of American Pathologists guideline recommendations (Hammond et al 2010, 
Wolff et al 2018).  To fulfil the requirement of HR+ disease, a breast cancer must express 
ER with or without co-expression of progesterone receptor.  Therefore, tumours must be:

ER+ defined as ≥1% of tumour cells stain positive for ER on immunohistochemistry 
(IHC) or, if no percentage is available, then an Allred IHC score of ≥3/8,

Progesterone receptor positive defined as ≥1% of tumour cells stain positive for 
progesterone receptor on IHC or, if no percentage is available, then an Allred IHC 
score of ≥3/8; or progesterone receptor negative defined as <1% of tumour cells stain 
positive for progesterone receptor on IHC or, if no percentage is available, then an 
Allred IHC score of ≤2/8; or progesterone receptor unknown, and

HER2− defined as 0 or 1+ intensity on IHC, or 2+ intensity on IHC and no evidence 
of amplification on in situ hybridisation (ISH), or if IHC not done, no evidence of 
amplification on ISH.
7
Metastatic or locally advanced disease with radiological or objective evidence of 
recurrence or progression (the cancer should have shown progression during or after most 
recent therapy); locally advanced disease must not be amenable to resection with curative 
intent (patients who are considered suitable for surgical or ablative techniques following 
potential down-staging with study treatment are not eligible)
8
Patients are to have received treatment with an AI (aromatase inhibitor) containing 
regimen (single agent or in combination) and have:
(a) Radiological evidence of breast cancer recurrence or progression while on, or within 
12 months of the end of (neo)adjuvant treatment with an AI, OR
(b) Radiological evidence of progression while on prior AI administered as a treatment 
line for locally advanced or metastatic breast cancer (this does not need to be the 
most recent therapy)
9
Patients must have: 

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 CT or 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 can be assessed by CT or MRI; patients with 
sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not 
eligible 
10 Patients must be eligible for fulvestrant therapy as per local investigator assessment
11 Consent to submit and provide a mandatory FFPE tumour sample for central testing.  A 
FFPE tissue block from the most recently collected pre-randomisation tumour sample 

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(primary or recurrent cancer) is preferred.  If it is not possible to provide a tissue block, 
30 (minimum 20) freshly-cut unstained serial tumour slides are to be provided.  Local 
pathology QC must be completed prior to randomisation to ensure the sample is suitable 
for next-generation sequencing (NGS) analysis, based on the requirements described in 
the Diagnostic Testing Manual 
12 Patients must be able to swallow and retain oral medication
13 Eastern Cooperative Oncology Group (ECOG)/ World Health Organisation (WHO) 
performance status 0 or 1 with no deterioration over the previous 2 weeks and life 
expectancy of ≥12 weeks
Reproduction
14 Pre-menopausal patients with ovarian suppression induced by LHRH agonist should 
agree to use 2 forms of highly effective methods of accepted contraception (see 
Section 5.3.3.1) to prevent pregnancy during the study and for 2 years after the last dose 
of fulvestrant, or until 16 weeks after discontinuing capivasertib/placebo whichever 
occurs later
15 Male patients should use barrier contraception (ie, condoms) from the time of screening 
until 2 years after the last dose of fulvestrant or until 16 weeks after discontinuation of 
capivasertib/placebo, whichever occurs later.  Male patients wishing to father children in 
the future should be advised to arrange for the freezing of sperm prior to the start of study 
treatment
NOTE: Female partners should be advised to use accepted contraception during their 
partner’s participation in the study and for 2 years after the last dose of fulvestrant or until 
16 weeks after discontinuing capivasertib/placebo, whichever occurs later.
For the alternative requirement, applicable only for UK, France, Italy, Spain, Belgium, 
Hungary, Poland, Germany refer to Appendix M. 
5.2
Exclusion criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
Medical conditions
1
A disease burden that makes the patient ineligible for endocrine therapy per the 
investigator’s best judgement (eg, symptomatic visceral disease that is potentially 
life-threatening in the short-term)
2
Malignancies other than breast cancer within 5 years prior to study treatment initiation 
(except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma or Stage I endometrioid uterine cancer)

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3
Radiotherapy with a wide field of radiation within 4 weeks prior to study treatment 
initiation (capivasertib/placebo) and/or radiotherapy with a limited field of radiation for 
palliation within 2 weeks prior to study treatment initiation (capivasertib/placebo)
4
Major surgery (excluding placement of vascular access) within 4 weeks prior to study 
treatment initiation
5
With the exception of alopecia, any unresolved toxicities from prior therapy greater than 
CTCAE grade 1 at the time of starting study treatment 
6
Spinal cord compression or brain metastases unless asymptomatic, treated and stable and 
not requiring steroids within 4 weeks prior to study treatment initiation
7
Leptomeningeal metastases
8
Past medical history of interstitial lung disease, drug-induced interstitial lung disease, 
radiation pneumonitis which required steroid treatment, or any evidence of clinically 
active interstitial lung disease
9
Any of the following cardiac criteria:

Mean resting QT interval corrected by Fridericia’s formula (QTcF) >470 msec 
obtained from 3 consecutive ECGs

Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG (eg, complete left bundle branch block, third degree heart block)

Any factors that increase the risk of corrected QT interval (QTc) prolongation or risk 
of arrhythmic events such as heart failure, hypokalaemia, potential for torsades de 
pointes, congenital long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age or any concomitant medication 
known to prolong the QT interval

Experience of any of the following procedures or conditions in the preceding 
6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial 
infarction, angina pectoris, congestive heart failure New York Heart Association 
(NYHA) grade ≥2

Uncontrolled hypotension – systolic blood pressure <90 mmHg and/or diastolic 
blood pressure <50 mmHg

Cardiac ejection fraction outside institutional range of normal or <50% (whichever is 
higher) as measured by echocardiogram (or multiple-gated acquisition [MUGA] scan 
if an echocardiogram cannot be performed or is inconclusive)
10 Clinically significant abnormalities of glucose metabolism as defined by any of the 
following:

Patients with diabetes mellitus type 1 or diabetes mellitus type 2 requiring insulin 
treatment

HbA1c ≥8.0% (63.9 mmol/mol)

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11 Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following laboratory values:

Absolute neutrophil count <1.5 × 109/L

Platelet count <100 × 109/L

Haemoglobin <9 g/dL (<5.59 mmol/L). [NOTE: any blood transfusion must be 
>14 days prior to the determination of a haemoglobin ≥9 g/dL (≥5.59 mmol/L)]

Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) >2.5 times 
upper limit of normal (ULN) if no demonstrable liver metastases or >5 × ULN in the 
presence of liver metastases

Total bilirubin >1.5 × ULN (Patients with confirmed Gilbert’s syndrome may be 
included in the study)

Creatinine >1.5 × ULN concurrent with creatinine clearance <50 mL/min (measured 
or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance 
is only required when creatinine is >1.5 × ULN
12 As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, 
including uncontrolled hypertension, or active infection including hepatitis B, hepatitis C 
and human immunodeficiency virus (HIV), including those who have confirmed 
COVID-19. Screening for chronic conditions is not required
13 Known abnormalities in coagulation such as bleeding diathesis, or treatment with 
anticoagulants precluding intramuscular injections of fulvestrant or LHRH agonist (if 
applicable)
14 Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal 
diseases, inability to swallow the formulated product or previous significant bowel 
resection, or other condition that would preclude adequate absorption of capivasertib
15 Previous allogenic bone marrow or solid organ transplant
16 Known immunodeficiency syndrome
17 History of hypersensitivity to active or inactive excipients of capivasertib, fulvestrant and 
LHRH agonists (if applicable, ie, concomitant LHRH agonist required in this study) or 
drugs with a similar chemical structure or class to capivasertib, fulvestrant or LHRH 
agonists (if applicable, ie, concomitant LHRH agonist required in this study)
18 Evidence of dementia altered mental status or any psychiatric condition that would 
prohibit understanding or rendering of informed consent
19 Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, render the patient at high risk from treatment complications 
or interferes with obtaining informed consent 

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Prior/concomitant therapy
20 More than 2 lines of endocrine therapy for inoperable locally advanced or metastatic 
disease 
NOTE: If an attempt to downstage a locally advanced tumour with endocrine therapy 
was made in the absence of metastatic breast cancer (neoadjuvant), and the tumour 
operated upon, then this does not count as a line of therapy for ABC.  In contrast, if the 
tumour remained inoperable, this treatment should be included as a line of therapy for 
ABC.  Adjuvant endocrine therapy is not considered a line of therapy for ABC. 
In addition, switching drugs within a line of therapy to manage toxicities in the absence 
of progressive disease does NOT count as a new line of therapy.
21 More than 1 line of chemotherapy for inoperable locally advanced or metastatic disease. 
Adjuvant and neoadjuvant chemotherapy are not classed as lines of chemotherapy for 
ABC
22 Prior treatment with any of the following:

AKT, PI3K and mTOR inhibitors

Fulvestrant, and other SERDs

Nitrosourea or mitomycin C within 6 weeks prior to study treatment initiation

Any other chemotherapy, immunotherapy, immunosuppressant medication (other 
than corticosteroids) or anticancer agents within 3 weeks prior to study treatment 
initiation.  A longer washout period may be required for drugs with a long half-life 
(eg, biologics) as agreed by the sponsor 

Potent inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of 
study treatment (3 weeks for St John’s wort) or drugs that are sensitive to CYP3A4 
inhibition within 1 week prior to study treatment initiation.  For details, see 
Appendix D

Any concomitant medication that may interfere with fulvestrant safety and efficacy 
based on the prescribing information of fulvestrant and local clinical guidelines 
Prior/concurrent clinical study experience
23 Previous randomisation in this study
24 Participation in another clinical study with a non-marketed investigational medicinal 
product (IMP) administered in the last 30 days or 5 half-lives, whichever is longer (for 
IMPs which are a previously marketed drug, regardless of indication, only Exclusion 
Criterion 22 applies).  Vaccines for COVID-19 with emergency use authorization are not 
considered investigational agents.

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Other exclusions
25 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site)
26 Judgment 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
27 Pregnant women (confirmed with positive pregnancy test) or breast-feeding women
5.3
Lifestyle restrictions
5.3.1
Meals and dietary restrictions
There is a potential for delayed and reduced absorption of capivasertib if it is administered 
with food.  The clinical relevance of this is unknown.  Until further information is available, it 
is recommended that patients fast from 2 hours before dosing to 1 hour after dosing, where 
possible.  Additional fasting restrictions also apply on days where glucose is to be tested 
(Section 8.2.1.1).  
In addition, patients should avoid herbal supplements (eg, St John’s wort) and ingestion of 
large amounts of foods and beverages known to potently modulate CYP3A4 enzyme activity 
during study treatment.  For example, no more than half a grapefruit, a small glass of 
grapefruit juice (approximately 125 mL) or 2 teaspoons of Seville orange marmalade should 
be consumed daily. 
5.3.2
Caffeine, alcohol, and tobacco
No interactions with caffeine, alcohol or tobacco have been identified.  
5.3.3
Contraception
5.3.3.1
Females
Females of childbearing potential should use two forms of highly reliable methods of 
contraception from the time of screening until 2 years after the last dose of fulvestrant or until 
16 weeks after discontinuing capivasertib/placebo, whichever occurs later.  A permitted 
combination of acceptable and highly effective contraception methods includes the use of a 
barrier method of contraception with spermicidal combined with one of the highly effective 
methods of contraception described below.  
The choice of contraception should be in line with international guidelines for ABC.  Current 
guidelines advise against the use of hormonal contraception in patients with breast cancer 
(NCCN 2019).  
Highly effective methods of contraception include:

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
Intrauterine device

Bilateral tubal occlusion

Male partner sterilisation (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate)

True abstinence (ie, not engaging in sexual activity; however, periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of birth 
control)
Acceptable methods of contraception include:

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
The investigator should discuss fertility preservation options for women of childbearing 
potential prior to the start of study treatment, in line with recommendations from international 
breast cancer guidelines for advanced disease.  
Pre-menopausal and peri-menopausal women are required to have treatment for ovarian 
suppression with LHRH agonist in order to participate in the study.  FSH and oestradiol will 
be monitored at screening, at Day 1 of each cycle, and when clinically indicated; due to the 
structural similarity of fulvestrant and oestradiol, fulvestrant may interfere with antibody-
based oestradiol assays and may result in falsely increased levels of oestradiol 
(Fulvestrant SmPC 2018, Folkerd et al 2014).  If deemed appropriate by the investigator, ad 
hoc monthly pregnancy tests can be performed.  
5.3.3.2
Males
Male patients should use barrier contraception (condoms) from the time of screening until 
2 years after the last dose of fulvestrant or until 16 weeks after discontinuation of 
capivasertib/placebo, whichever occurs later.  Male patients should refrain from donating 
sperm from the start of dosing until 2 years after the last dose of fulvestrant or until 16 weeks 
after discontinuation of capivasertib/placebo, whichever occurs later. 
For the alternative requirement, applicable only for UK, France, Italy, Spain, Belgium, 
Hungary, Poland, Germany refer to Appendix M.
Female partners should be advised to use accepted contraception during their partners 
participation on the trial and for 2 years after the last dose of fulvestrant or until 16 weeks 
after discontinuation of capivasertib/placebo, whichever occurs later. 
5.3.4
Other restrictions
Patients who are blood donors should not donate blood during the study.  For blood donation 
after study participation, refer to WHO guidelines (WHO 2012).  

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5.4
Screen failures
Screen failures are defined as patients who signed the ICF to participate in the clinical study 
but are not subsequently randomised.  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, screen failure details, 
eligibility criteria, and any SAEs.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, upon the study physician’s approval and agreement.  However, rescreening 
should be documented so that its effect on study results, if any, can be assessed.  
These patients should have the reason for study withdrawal, including failed 
inclusion/exclusion criteria, recorded in the electronic case report form (eCRF).
6
STUDY TREATMENTS
Study treatment is defined as any IMPs including marketed product comparator and placebo 
or medical device(s) intended to be administered to a study participant according to the CSP.  
Study treatment in this study refers to capivasertib, placebo and fulvestrant.  
LHRH agonist is not an IMP and this should be prescribed in accordance with local 
guidelines, where applicable.  
6.1
Treatments administered
6.1.1
Capivasertib/placebo
Capivasertib/placebo is considered an IMP and will be supplied by AstraZeneca.  Details of 
capivasertib are shown in Table 5.  Placebo tablets match the appearance of capivasertib. 
A schematic presentation of the treatment schedule is presented in Figure 3.  

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Table 5
Capivasertib/placebo
Study treatment name:
Capivasertib/placebo
Dosage formulation:
160 mg and 200 mg film-coated tablets
Route of administration:
Oral
Dosing instructions:
400 mg BD (2 tablets of 200 mg taken twice a day = total 
daily dose 800 mg) given on an intermittent weekly dosing 
schedule.  Patients will be dosed on Days 1 to 4 in each week 
of a 28-day treatment cycle
Packaging and labelling:
Study treatment will be provided in white high-density 
polythene bottles.  Each bottle will be labelled in accordance 
with Good Manufacturing Practice Annex 13 and per country 
regulatory requirement
Where possible, all doses of capivasertib/placebo should be taken:

At approximately the same time each day

12 hours apart

In a fasted state (water to drink only) from at least 2 hours prior to the dose to at least 
1-hour post-dose.  
If vomiting occurs, a replacement dose should not be taken.
Should a patient miss a scheduled dose, the patient will be allowed to take the dose up to a 
maximum of 2 hours after the scheduled dose time, with a fasting state being maintained.  If 
greater than 2 hours after the scheduled dose time, the missed dose should not be taken and 
the patient should take their allotted dose at the next scheduled time.  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.  The patient should make every reasonable effort to take the 
capivasertib/placebo tablet(s) on time.  
Capivasertib/placebo dose reductions are permitted (see Section 6.6).
Cross-over from placebo to capivasertib is not allowed.  

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Figure 3
Treatment schedule
6.1.2
Fulvestrant
Fulvestrant is considered an IMP and commercial fulvestrant will be obtained centrally.  
Available stock will be used in keeping with the standard local practice.  Details are shown in 
Table 6.  Please refer to local prescribing information for information on formulation, 
preparation, and administration.  
A schematic presentation of the treatment schedule is presented in Figure 3.  
Table 6
Fulvestrant
Study treatment name:
Fulvestrant
Dosage formulation:
250 mg/ 5 mL solution for injection
Route of administration:
Intramuscular injection
Dosing instructions:
Patients will be administered 500 mg (2 injections) on Day 1 
of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of 
each cycle thereafter 
Packaging and labelling:
Study treatment will be provided in a pre-filled syringe.  
Each syringe will be labelled in accordance with Good 
Manufacturing Practice Annex 13 and per local practice
If injection-related symptoms occur, patients should be treated according to best medical 
practice and patients will be monitored until adequate resolution of signs and symptoms.  

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Dose reductions for fulvestrant are not permitted.
6.1.3
Duration of treatment
Study treatment will be continued until disease progression unless there is evidence of 
unacceptable toxicity, or if the patient requests to stop the study treatment.  
If capivasertib/placebo is discontinued for reasons other than disease progression, the patient 
may continue on fulvestrant alone at the investigator’s discretion.  The patient must continue 
being scanned for RECIST v1.1 assessment every 8 weeks (±7 days) for the first 18 months 
and every 12 weeks (±7 days) thereafter, until objective disease progression (RECIST v1.1), 
administration of further anticancer therapy, withdrawal of consent or death whichever occurs 
first. 
If fulvestrant is discontinued for reasons other than disease progression, the patient may 
continue on capivasertib/placebo alone at the investigator’s discretion.  The patient must 
continue being scanned for RECIST v1.1 assessment every 8 weeks (±7 days) for the first 
18 months and every 12 weeks (±7 days) thereafter, until objective disease progression (even 
if further anticancer therapy is administered).  
Patients with locally advanced disease who are considered suitable/planned for surgical or 
ablative techniques following potential down-staging with study treatment are not eligible. 
Cases in which a patient become amenable to surgery or ablative therapy must be 
communicated to the sponsor.  Study drug must be discontinued prior to surgery.  However, if, 
in the opinion of the investigator, the patient is continuing to receive benefit, they may be 
permitted to continue to restart treatment after surgery after discussion and agreement with the 
Sponsor.  Patients should continue RECIST v1.1 assessment until progression.  
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.  Capivasertib must 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.  

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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).  
Any study drug remaining at the end of the trial must be destroyed or returned according to 
the sites local standard operating procedures following authorisation by the sponsor.  
6.2.1
Dose Preparation
The dose of fulvestrant and capivasertib/placebo for administration must be prepared by the 
pharmacy staff members (or an appropriate designee trained in study drug preparation), in 
compliance with local regulations and site requirements.
Fulvestrant and capivasertib/placebo should be handled in accordance with practices required 
for hazardous drugs (i.e., chemotherapy).
6.3
Measures to minimise bias: randomisation and blinding
Capivasertib and placebo film-coated tablets will be identical in appearance and presented in 
the same packaging to ensure blinding of the capivasertib.  
Capivasertib and placebo will be labelled using a unique kit identification (kit ID) number, 
which is linked to the randomisation scheme.  
Fulvestrant will be allocated to be dispensed to each patient using the interactive web response 
system (IWRS) system (if centrally sourced) or via the local pharmacy (if locally sourced) at 
each patient dispensing visit.  Routines for this will be described in the interactive voice 
response system (IVRS)/IWRS user manual that will be provided to each centre.  
Eligible patients will be randomised in a 1:1 ratio (capivasertib + fulvestrant: placebo + 
fulvestrant).  The planned treatment given to individual patients will be determined by a 
randomisation scheme that will be loaded into the IWRS database.  The randomisation scheme 
will be produced by a process called AZRand (AZ Global Randomisation process) that 
incorporates a standard procedure for generating random numbers.  
A blocked randomisation will be generated, and all centres will use the same list in order to 
minimise any imbalance in the number of patients assigned to each treatment group.  
Eligibility will be established before treatment randomisation.  It is recommended that patients 
commence study treatment as soon as possible after randomisation and ideally on the same 
day of randomisation.  
In order to meet the required minimum of 51% of recruited patients pre-treated with CDK4/6 
inhibitors, the actual proportions will be monitored during the course of the study.  Selective 

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recruitment of patients with prior CDK4/6 inhibitor treatment may be implemented in the 
event that approximately 343 CDK4/6 inhibitors naïve patients are randomised. This would be 
achieved via the IWRS system as prior CDK4/6 inhibition is a stratification factor.
If a patient withdraws from the study, then his enrolment/randomisation code cannot be 
reused.  Withdrawn patients will not be replaced.  
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the patient requires knowledge of the treatment randomisation.  
The investigator must document and report the action to AstraZeneca, without revealing to the 
AstraZeneca staff the treatment given to the patient.  
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IMP and that potentially require expedited reporting to 
regulatory authorities.  Randomisation codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual patient have been 
made and documented.
In the event that the treatment allocation for a patient becomes known to the Investigator or 
other study staff involved in the management of study patients, or needs to be known to treat 
an individual patient for an AE, the Sponsor must be notified promptly by the Investigator and 
if possible, before unblinding.
6.4
Treatment compliance
Data regarding capivasertib/placebo dosing will be collected and entered into the eCRF along 
with reasons for missed dose(s) if applicable.
In addition, patients will be required to return all bottles of study medication.  The number of 
tablets remaining will be counted by the research nurse/pharmacist/investigator, documented 
in the eCRF and returned to pharmacy.  Site personnel are responsible for managing the IMP 
from receipt by the study site until the destruction or return of all unused IMP.  The 
investigator is responsible for ensuring that the patient has returned all unused IMP.  
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

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Guidance regarding potential interactions of capivasertib with concomitant medications is 
provided in Appendix D.  
6.5.1
Allowed concomitant therapy
The following therapies are allowed during study participation, as applicable:

No prophylactic anti-emetic therapy is planned for capivasertib/placebo but standard 
anti-emetic therapy including a 5-HT3-antagonist can be given as needed on a 
prophylactic and treatment basis in compliance with the standards of the centre’s local 
policy

Anti-diarrhoeal therapy for symptomatic treatment of diarrhoea, as indicated in the 
toxicity management guideline (Section 8.4.5)

Erythropoietin: patients already receiving erythropoietin at the time of screening for the 
study may continue it providing they have been receiving it for more than 1 month at the 
time study treatment is started.  Prophylactic erythropoietin should not be started during 
Cycle 1 of the study but may be started during or after Cycle 2

Blood transfusions are allowed at any time during the study
NOTE: any blood transfusion before screening must be >14 days prior to the 
determination of a haemoglobin at screening; see Section 5.2].  

Patients may receive bisphosphonate or denosumab therapy for the treatment of bone 
metastases; however, these agents must be started prior to randomisation.  Modification 
of the pre-study bisphosphonate or denosumab treatment regimen for bone metastasis 
requires the approval of the sponsor or study physician

Patients may take corticosteroids; however, electrolyte and/or glucose levels should be 
monitored carefully due to the potential for corticosteroid-related metabolic disturbance

Patients who need to begin anti-coagulant therapy while receiving study treatment may be 
treated, at the discretion of the investigator, with low molecular weight heparin (LMWH). 
The LMWH should be temporarily discontinued 12 to 24 hours prior to each injection of 
fulvestrant and then resumed 12 to 24 hours later (depending on the particular LMWH 
used).  There is an increased risk of haemorrhage in these patients and the investigator 
should decide whether that risk is outweighed by the possible benefits of continued 
treatment.  It is advised to apply direct pressure to the injection site in these patients

Patients receiving antiplatelet therapy (acetylsalicylic acid, ticlopidine, clopidogrel, etc) 
may be at increased risk of bleeding from intramuscular injection.  The investigator 
should decide whether that risk is outweighed by the possible benefits of continued 
treatment.  It is advised to apply direct pressure to the injection site in these patients

Supportive care and other medication, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the investigator and recorded in 
the appropriate sections of the eCRF

LHRH agonist: Pre- or peri-menopausal patients are to have commenced concomitant 
treatment with LHRH agonist prior to or on Cycle 1, Day 1 and must be willing to 

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continue LHRH agonist treatment for the duration of the study.  Male patients can receive 
concomitant LHRH agonist if deemed appropriate by the investigator

Authorised/approved COVID-19 vaccines can be given to patients enrolled in 
CAPItello-291, following local prescribing information, and policies when considering if 
vaccination against COVID-19 is appropriate for the patients participating in the study.  
Investigators should apply their discretion assessing the risk benefit of COVID-19 
vaccines for participants in clinical trials.  The administration of any vaccine and any 
potential adverse events must be documented in the eCRF
Other concomitant medication may be given as medically indicated.  Details (including doses, 
frequency, route and start and stop dates) of the concomitant medication given must be 
recorded in the patient’s medical records and the eCRF.  
6.5.2
Restricted concomitant therapy
The following concomitant therapies are restricted during study treatment:

Other anticancer agents, other investigational agents and radiotherapy, although radiation 
for palliation at focal sites is permitted (as long as the radiation field covers less than 30% 
of the marrow and does not include whole pelvis or spine; disease progression in the 
bones has to be excluded by appropriate imaging investigations)

Drugs or herbal supplements that are known to be potent inhibitors/inducers of CYP3A4 
must be avoided, but moderate inhibitors/inducers may be used with caution.  Drugs 
known to be sensitive to inhibition of CYP3A4 metabolism and/or MATE1 or OCT2 
transport must be avoided or used with caution, depending on their therapeutic window.  
If co-administration is necessary, then additional monitoring for signs of toxicity related 
to increased exposure to the substrates is required

Patients must not receive other investigational drugs while on study
Please refer to Appendix D for further guidance on potential PK interactions with 
capivasertib.  For guidance regarding potential PK interactions with fulvestrant, please refer to 
the current local prescribing information (package insert).
Patients must be instructed not to take any medications, including herbal and dietary 
supplements, without first consulting with the investigator.  
6.5.3
Other concomitant treatment
Medication other than that described in Section 6.5.2, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the investigator and recorded 
in the appropriate sections of the eCRF.  The concomitant administration of drugs known to 
prolong QT interval is restricted unless considered essential due to patient management, in 
which case, patients should be closely monitored.  Information regarding drugs known to 
prolong the QT interval can be found on the CredibleMeds® website 
(URL: https://crediblemeds.org).  

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6.6
Dose modifications and delay
For capivasertib/placebo, dose reductions or holds are allowed as clinically indicated by the 
treating physician and in line with Table 7.  For each patient, a maximum of 2 dose reductions 
will be allowed (Table 7).  Dose re-escalations are not allowed for capivasertib/placebo.  For 
guidance on capivasertib dose reductions for management of AEs, refer to Section 8.4.5.  
Dose reductions for fulvestrant are not allowed.  
Refer to locally approved prescribing information for guidance on fulvestrant monitoring and 
management of toxicities.  
Table 7
Dose levels for capivasertib/placebo and fulvestrant
Study treatment
Starting dose
Dose reduction levels
Capivasertib/placebo 
400 mg BD
Reduction level 1: 320 mg BD 
Reduction level 2: 200 mg BD 
Fulvestrant
500 mg
Dose reductions not allowed
In the event of an AE which the investigator considers to be related to the administration of 
study treatment, supportive therapy should be given at the discretion of the investigator.  In 
addition, the investigator may decide that dosing of study treatment should be temporarily 
interrupted, a subsequent treatment cycle delayed, or study treatment permanently 
discontinued as per the guidelines outlined in Section 7.1.  
Substantial acute toxicities should be managed as medically indicated and with temporary 
suspension of study drug, as appropriate.  
A maximum break of 28 consecutive days for capivasertib/placebo dosing is allowed within 
each treatment cycle or between two consecutive cycles.  A maximum delay of 35 days since 
a planned injection of fulvestrant is allowed.   
Any further delays in capivasertib/placebo and/or fulvestrant treatment must be approved by 
the sponsor or study physician.  Following a treatment break, the patient may resume 
treatment at the Day/Week in the cycle that they stopped.
6.7
Treatment after the end of the study
After the clinical study database closes, patients who continue to derive clinical benefit from 
study treatments in the opinion of the investigator may continue to receive study treatment 
until progression.  These treatments will continue to be provided by AstraZeneca until the 
availability of either a local commercial supplier and reimbursement program or an early 
access program; at which point a change in supply will be requested.  Treatment of patients 
beyond progression is not allowed. 

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As described in Section 4.4, the study will remain open until all participants have discontinued 
study intervention and completed their last expected visit/contact.
After the final DCO for this study, AstraZeneca will continue to supply capivasertib to 
participants who were randomised to receive capivasertib treatment until progression as 
judged by the investigator or until meeting any other discontinuation criteria, as defined in 
Section 7.1.
Participants should be followed according to the institution’s standard of care assessments. No 
further data collection is required, except for reporting of SAEs.
Participants who were randomised to receive other study interventions (ie, placebo + 
fulvestrant), or who discontinue from the study, should continue appropriate treatment at the 
discretion of the investigator.
AstraZeneca will continue to supply capivasertib in the continued access phase of this study 
and after completion of this study while, in the opinion of the investigator, the patient is 
benefiting.
In the event that product development reaches a point where alternative product supply 
options become available, then these alternative product supply options will be discussed by 
AstraZeneca with the investigator. AstraZeneca will work with the investigator to transition 
the patient(s) to alternative supply, where possible.  
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, participant(s) currently receiving treatment with capivasertib may then 
be transitioned to such a study, and the current study may reach its end. The roll-over or 
extension study would ensure treatment continuation with visit assessments per its protocol, as 
applicable. Any participant who would be eligible to move to such a study would be given a 
new informed consent, as applicable.
Please refer to Section 4.4 for End of Study definition.  
7
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
Patients will be discontinued from IMP in the following situations.  Note that discontinuation 
from study treatment is NOT the same as a complete withdrawal from the study.  Patients who 
discontinue study treatment should continue the study and be followed-up as outlined in the 
CSP.  

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
Objective disease progression assessed by RECIST v1.1

Clinical disease progression/worsening of disease under investigation

Patients incorrectly initiated on IMP 

Patient becomes pregnant 

Intercurrent illness that, in the judgment of the investigator, will affect assessments of 
clinical status to a significant degree or contraindicate further dosing

AE or unacceptable toxicity 

Determination by the investigator that it is no longer safe for the patient or in the patient’s 
best interest to continue therapy 

Patient request 

Severe non-compliance with study protocol in the judgement of the investigator and/or 
the sponsor 

Clinical need for concomitant or ancillary therapy (ie, non–protocol-specified anticancer 
therapy) that is not permitted in the study 

General or specific changes in the patient’s condition that are unacceptable for further 
treatment in the judgment of the investigator
Patients found to be deriving benefit from treatment and tolerating treatment may continue 
therapy, subject to agreement between the treating and Sponsor physicians.  The patients will 
be followed according to protocol-defined procedures and assessments.  All protocol 
deviations will be reviewed and important protocol deviations will be identified prior to the 
unblinding of the study.
See the schedule of activities (SoA; Section 1.1) for data to be collected at the time of 
treatment discontinuation and follow-up and for any further evaluations that need to be 
completed.  
All reasons for discontinuation of study treatment must be documented in the eCRF (see 
Section 7.1.2).  
7.1.1
Temporary discontinuation 
If study treatment will be interrupted for a period longer than permitted in the dose 
modification guidelines (Section 6.6), the investigator will need approval from the sponsor to 
restart the patient on study treatment. 
7.1.2
Procedures for discontinuation of study treatment
The investigator should instruct the patient to contact the site before or at the time the patient 
decides to stop the study treatment.  A patient who decides to discontinue study treatment 
must 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 eCRF.  All study treatment should be returned 
by the patient at their next on-site study visit or unscheduled visit.  Patients permanently 

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discontinuing study treatment should be given locally available standard of care therapy, at the 
discretion of the investigator.  
Discontinuation of study treatment, for any reason, does not impact on the patient´s 
participation in the study.  The patient should continue attending subsequent study visits and 
data collection should continue according to the study protocol.  If the patient does not agree 
to continue in-person study visits, a modified follow-up must be arranged to ensure the 
collection of endpoints and safety information.  This could be a telephone contact with the 
patient, a contact with a relative or treating physician, or information from medical records.  
The approach taken should be recorded in the medical records.  A patient that agrees to 
modified follow-up is not considered to have withdrawn consent or to have withdrawn from 
the study.  
7.2
Lost to follow-up
A patient may be considered lost to follow-up if he or 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 by for example, 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

Efforts to reach the patient should continue until the end of the study.  Should the patient 
be unreachable at the end of the study the patient will be considered lost to follow-up, 
with unknown vital status at end of study and censored at the last follow-up contact
7.3
Withdrawal from the study
A patient may withdraw from the study (eg, withdraw consent) at any time at his/her own 
request, without prejudice to further treatment.  If a patient withdraws consent, they will be 
specifically asked if they are withdrawing consent to all further participation in the study 
(treatment, assessments and follow-up) or withdrawing from treatment/assessments only and 
will allow further follow-up.
A patient who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records).  

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If the patient also 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, he/she may request destruction of any samples taken, 
and the investigator must document this in the site study records and inform the study monitor 
and study team.  
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs.  The investigator will follow-up patients as medically indicated. The patient will 
return electronic patient-reported outcomes (ePRO) devices.  
AstraZeneca or its delegate will request investigators to make every effort to collect 
information on patients’ survival status (dead or alive; date of death when applicable) at the 
end of the study, including patients that withdrew consent or are classified as "lost to 
follow-up".  Survival status can be obtained by site personnel from publicly available 
resources where it is possible, in accordance with local regulations.  Knowledge of the 
survival status at study end in all patients is crucial for the integrity of the study.  
See SoA (Section 1.1), for data to be collected at the time of study discontinuation and 
follow-up, and for any further evaluations that need to be completed.  All study treatment 
should be returned by the patient.  
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (see Section 1.1).  
The investigator will ensure that data are recorded on the eCRFs.  A Web Based Data Capture 
system will be used for data collection and query handling.  
The investigator must ensure the accuracy and completeness for eCRFs which includes: 
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 eCRFs.  
A copy of the completed eCRFs will be archived at the study site.  
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study treatment.  
Adherence to the study design requirements, including those specified in the SoA, 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 

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all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
Procedures conducted as part of the patient’s routine clinical management (eg, blood count)
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.  
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.  
8.1
Efficacy assessments
8.1.1
RECIST v1.1 assessments
RECIST v1.1 tumour assessments will be performed using CT or MRI scans of the chest, 
abdomen and pelvis (with additional anatomy as clinically indicated by extent of disease) at 
baseline (no more than 28 days before the date of randomisation, as close as possible to the 
start of study treatment).  Afterward, CT or MRI scans of the chest, abdomen and pelvis (with 
additional anatomy as clinically indicated by extent of disease) will be repeated every 8 weeks 
(±7 days) for the first 18 months and every 12 weeks (±7 days) thereafter, after start of 
treatment (Cycle 1, Week 1, Day 1) until objective radiological disease progression as defined 
by RECIST v1.1 (regardless of reason for treatment discontinuation).  If an unscheduled 
assessment is performed (eg, to investigate clinical signs/symptoms of progression) and the 
patient has not progressed, every attempt should be made to perform the subsequent image 
acquisition at the next scheduled imaging visit.  Patients who discontinue treatment prior to 
RECIST v1.1 progression (eg, discontinuation due to toxicity or clinical progression) should 
continue to be scanned until confirmed RECIST v1.1 progression.  The same imaging 
modality and the same assessment (eg, the same contrast protocol for CT scans) should be 
performed at baseline and at all follow-up time-points.  Guidelines on the valid methods of 
assessment and the evaluation of objective tumour response using RECIST v1.1 are provided 
in Appendix A.  
8.1.1.1
Progression-free survival (PFS)
PFS is defined as the time from the date of randomisation until the date of disease progression, 
as defined by RECIST v1.1, or death (by any cause in the absence of progression) regardless 
of whether the patient withdraws from randomised therapy or receives another anticancer 
therapy prior to progression. 
PFS will be assessed by investigator assessment.  A supplementary analysis of PFS by BICR 
will be reported.  

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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 RECIST v1.1 assessment.  However, if 
the patient progresses or dies immediately after two or more consecutive missed visits, the 
patient will be censored at the time of the latest evaluable RECIST v1.1 assessment prior to 
the two missed visits.  
8.1.1.2
Clinical benefit rate (CBR)
CBR is defined as number of patients with complete or partial response or with stable disease 
maintained ≥24 weeks (as assessed by the investigator, using RECIST v1.1) divided by the 
number of patients in the analysis.  Patients without a post-baseline tumour assessment will be 
considered to have no clinical benefit.  
8.1.1.3
Duration of response (DoR)
For patients who achieve complete or partial response per RECIST v1.1, DoR is defined as the 
time from the date of first documented response until date of documented progression (as 
assessed by the investigator, using RECIST v1.1) or death in the absence of disease 
progression.  The end of response should coincide with the date of progression or death from 
any cause used for the PFS endpoint.  The time of the initial response will be defined as the 
latest of the dates contributing towards the first visit response of complete or partial response.
If a patient does not progress following a response, then their DoR will use the PFS censoring 
time.
8.1.1.4
Objective response rate (ORR)
ORR is defined as the percentage of patients with at least one investigator-assessed visit 
response of complete or partial response (as assessed by the investigator, using RECIST v1.1) 
and will be based on a subset of patients with measurable disease at baseline per the site 
investigator.
Data obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR.  Patients who discontinue randomised treatment 
without progression, receive a subsequent anticancer therapy (note that for this analysis 
radiotherapy is not considered a subsequent anticancer therapy) and then respond will not be 
included as responders in the ORR.
8.1.2
Overall survival (OS)
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 
anticancer therapy.  

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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.  
Assessments for survival will be conducted every 8 weeks for the first 2 years following 
objective disease progression or treatment discontinuation and then every 12 weeks.  
Survival information may be obtained via telephone contact with the patient, patient’s family, 
by contact with the patient’s current physician, or local death registries as described in 
Section 7.3.  
Survival calls will be made in the week following the date of DCO for each of the PFS or OS 
analyses, and if patients are confirmed to be alive or if the death date is post the DCO date, 
these patients will be censored at the date of DCO.
8.1.3
PFS2
Time from randomisation to second progression or death (PFS2) will be defined as the time 
from the date of randomisation to the earliest of the progression events subsequent to the first 
subsequent therapy, or death.
Patients alive and for whom a second disease progression has not been observed should be 
censored at date last known alive and without a second disease progression (ie, censored at the 
latest of the PFS or PFS2 assessment date if the patient has not had a second progression or 
death).
Following discontinuation of study treatment due to disease progression, as determined by 
investigator-based by RECIST v1.1 assessment, patients who started on subsequent cancer 
therapy post progression will continue to be followed at the 30-day follow-up visit, every 
8 weeks (±7 days) for the first 2 years, and every 12 weeks (±7 days) thereafter for 
documentation of progression on second-line therapy.  Determination of progressive disease 
for PFS2 will be by institutional call.  
8.1.4
Time to definitive deterioration of the ECOG performance status
ECOG performance status will be used to assess physical health of patients.  Time to 
definitive deterioration of ECOG performance status is defined as time from randomisation to 
the earlier of the date of the first definitive deterioration or death due to any cause.  
Deterioration is defined as a 1-point increase in ECOG score from baseline, and the 
deterioration is considered definitive if no improvements in the ECOG performance status are 
observed at a subsequent time of measurement during the treatment period, or at no further 
assessments following the time point where the deterioration is observed. 
Patients who have not had definitive deterioration or have not died at the time of analysis will 
be censored at the time of the latest date of assessment from their last evaluable ECOG 

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assessment.  However, if the patient has definitive deterioration or dies immediately after two 
or more consecutive missed visits, the patient will be censored at the time of the latest 
evaluable ECOG assessment prior to the two missed visits.  
8.1.5
Time to first subsequent chemotherapy or death (TFSC)
Time to first subsequent chemotherapy or death (TFSC) is defined as time from randomisation 
to the earlier of start date of the first subsequent chemotherapy after discontinuation of 
randomised treatment or death due to any cause.
Patients alive and not known to have had a first subsequent chemotherapy will be censored at 
the earliest of: date of study termination, date last known alive, DCO or, the last date that the 
patient was known not to have received a first subsequent chemotherapy.
8.1.6
Bone scan
An initial bone scan should be performed within 4 weeks prior to randomisation and repeated 
as necessary (see Appendix A [Isotopic bone scan]).  
8.1.7
Patient-reported outcomes
PRO assessments will be used to examine the impact of treatment on disease-related 
symptoms, function, HRQoL, patient-perceived treatment tolerability, and overall health 
status.  PROs have become increasingly important in evaluating the efficacy and tolerability 
of study treatments in clinical studies as part of the overall benefit/risk evaluation (Kluetz et al 
2018).  The PROs included in this study are as follows and will be administered in this order:

EORTC QLQ-C30

EORTC QLQ-BR23

EuroQol 5-dimension, 5-level health state utility index (EQ-5D-5L)

Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE)

Patient Global Impression–Severity (PGIS)

Patient Global Impression–Change (PGIC)

Patient Global Impression–Treatment Tolerability (PGI-TT)
The PROs will be assessed in accordance with the SoA (see Section 1.1) and Section 8.1.7.8.  
The individual questionnaires are provided in Appendix I.  
8.1.7.1
EORTC QLQ-C30
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 as well as detailed cross-cultural testing and validation (Aaronson et al 

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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 QoL scale, 
5 single items assessing additional symptoms commonly reported by cancer patients (dyspnea, 
loss of appetite, insomnia, constipation, and diarrhoea), and 1 item on the financial impact of 
the disease.  All but 2 questions have 4-point scales: “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 15 domains, 
final scores are transformed such that they range from 0 to 100, where higher scores indicate 
better functioning, better HRQoL, or greater level of symptoms (Aaronson et al 1993).  
8.1.7.2
EORTC QLQ-BR23
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.  
8.1.7.3
EQ-5D-5L
The EQ-5D-5L will be used to explore the impact of treatment and disease state on health 
state utility. 
The EQ-5D-5L, developed by the EuroQol Group, is a generic questionnaire that provides a 
simple descriptive profile of health and a single index value for health status for economic 
appraisal (van Reenen and Janssen 2015).  The questionnaire comprises six questions that 
cover five 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).  
8.1.7.4
PGIS
The PGIS item is included to assess how a patient perceives the overall severity of cancer 
symptoms over the past week.  Patients will be asked to choose the response that best 
describes the severity of their overall cancer symptoms with options ranging from “No 
Symptoms” to “Very Severe”.  

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8.1.7.5
PGIC
The PGIC item is included to assess how a patient perceives their overall change in health 
status since the start of study treatment.  This is a single-item questionnaire, and patients will 
choose from response options ranging from “Much Better” to “Much Worse”.  
8.1.7.6
PGI-TT
The PGI-TT item is included to assess how a patient perceives the overall tolerability of the 
study treatment.  This is a single-item questionnaire, and patients will rate the bother 
associated with any treatment-related symptoms using response options ranging from “Not at 
all” to “Very much”.  
8.1.7.7
PRO-CTCAE
The PRO-CTCAE, developed by the National Cancer Institute (NCI) is included to address 
tolerability from the patients’ perspective.  The PRO-CTCAE will only be administered in 
those countries where a linguistically validated version is available.  All applicable 
translations available during the study will be used.  PRO-CTCAE is an item library of 
symptoms experienced by patients while undergoing treatment of their cancer.  The items 
pre-selected for this study are based on a review of the treatment-related symptoms of 
capivasertib and fulvestrant and in consideration of symptoms that are already captured in the 
other PRO instruments with a view to minimise burden.  The free text item in the 
PRO-CTCAE instrument is not included in the study, as the utility of this information and the 
analysis method have not been established.  
8.1.7.8
Administration of patient-reported outcome questionnaires
The PRO instruments will be self-administered by patients using a handheld electronic device 
in accordance with the SoA (see Section 1.1).  PROs will be provided in the language of the 
country in which it will be administered, except for the PRO-CTCAE, which will only be 
administered in the languages where a linguistically validated version is available.  
Patients will complete PRO assessments at home or at the study sites if the assessment 
timepoint coincides with a scheduled site visit.  Similarly, during the post-progression period, 
patients will complete PROs at home or at the study site if a scheduled visit coincides with the 
timepoint.  If patients have had scans or other tests at an outside facility or missed a scheduled 
data collection site visit, PRO questionnaires should still be completed by patients at home 
according to the PRO completion schedule.  
While PROs may be completed at home or site visits, patients should always bring the 
handheld electronic device to all site visits.  It will take approximately 20 to 30 minutes for 
patients to complete the questionnaires.  

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If screening and randomisation are on the same day, ePRO questionnaire do not need to be 
repeated. 
The following instructions should be followed when collecting PRO data via an electronic 
device:

Following informed consent, PRO questionnaires completed at site visits 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, 
such as collection of laboratory samples, to further minimise bias.

For PROs collected at site visits, PRO questionnaires must be completed by the patient in 
a quiet and private location and the patient given enough time to complete the PRO 
questionnaires at their own speed.  

The research nurse or appointed site staff must explain to patients the value and relevance 
of study participation and inform them that these questions are being asked to find out, 
directly from them, how they feel.  The research nurse or appointed site staff should also 
stress that the information is not routinely shared with study staff.  Therefore, if patients 
have any medical problems, they should discuss them with the doctor or research nurse 
separately from the PRO assessment.  

The research nurse or appointed site staff must train the patient on how to use the PRO 
device, using the materials and training provided by the PRO vendor, and provide 
guidance on whom to call if there are problems with the device if the patient is 
completing the PRO at home.  All PRO questionnaires are to be completed using an 
ePRO device.  If technical or other issues prohibit completion on the device, an 
appropriate back-up option may be considered with prior approval from AstraZeneca.

The research nurse or appointed site staff must remind patients that there are no right or 
wrong answers and avoid introducing bias by not interpreting or clarifying items.  

The patient must not receive help from relatives, friends, or clinic staff deciding on 
answers to the PRO questionnaires.  The responses are the patient’s alone.  If a patient 
uses visual aids (eg, glasses or contact lenses) for reading and does not have them when 
he or she visits the site, the patient will be exempted from completing the PROs at the 
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 not fluent in the 
available language), that patient is exempted from completing PRO questionnaires but 
may still participate in the study.  If the patient cannot complete the PRO questionnaires 
due to reasons other than being blind, illiterate, or fluent in language, the AstraZeneca 
study team must be contacted to determine if they can be exempted.  Patients exempted in 
this regard should be flagged appropriately by the site staff in the source documents and 
the Review of PRO/Questionnaire/Diary eCRF.  

Site staff must administer questionnaires available in the language that the patient speaks 
and understands.  Questions should not be read in an available language and translated 
into another language for the patient.  

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
It is vital that the PRO reporting is initiated at the baseline visit (Cycle 1, Week 1, Day 1), 
as specified in the study plan to capture the effect of study treatment.  The handheld 
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. 

Finally, the research nurse or appointed site staff will review the completion status of 
questionnaires during site visits and document the reason(s) why a patient could not 
complete assessments in the eCRF.  The research nurse or appointed site staff must 
monitor compliance since minimising missing data is a key aspect of study success.  It is 
important that the PRO device is charged and fully functional at the baseline visit.  
Compliance must be checked at each study visit and should be checked more frequently 
to identify problems early.  If compliance drops to 85% or below, the patient will be 
flagged in the routine compliance report generated by the ePRO system, and a check-in
call from the study site to ask the patient if he or she has any difficulties is highly 
recommended.  A solution to enhance/resolve compliance should be discussed with the 
patient.  Discussions and compliance review should be reflected in source documents.  
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the SoA (see Section 1.1).
8.2.1
Clinical safety laboratory assessments
See Table 8 for the list of clinical safety laboratory tests to be performed and the SoA 
(Section 1.1) for the timing, frequency and additional information.  
The date and time of each collection will be recorded in the appropriate eCRF.  
Laboratory values that meet the criteria for CTCAE grade 3 or have changed significantly 
from baseline and are considered to be of clinical concern will be repeated/confirmed within 
7 days and followed up as appropriate.  
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 eCRF.  
The clinical chemistry, haematology 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 8
Laboratory safety variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin
S/P-Albumin
B-Leukocyte (white blood cells [WBC])
S/P-ALT
B-Leukocyte (WBC) % differential or absolute 
count:a
S/P-AST
B-Neutrophils
S/P-Alkaline phosphatase
B-Lymphocytes
S/P-Bilirubin, total
B-Eosinophils
S/P-Calcium, total
B-Platelet count
S/P-Creatinine
Coagulation
S/P-FSH (females only)d
INRb
S/P-Glucose
Urinalysis
S/P-Glycosylated haemoglobin (HbA1c)
U-Glucose
S/P-Magnesium
U-Protein
S/P-Oestradiol (females only)d
U-Blood
S/P-Potassium
U-Ketones
S/P-Total Protein
U-Microscopyc (red blood cells and white blood cells, 
bacteria, casts and crystals)
S/P Free T4b
S/P TSHb
S/P Troponine I or T
S/P-Sodium
S/P-Urea nitrogen and/or Urea
S/P-Lipids (total cholesterol, HDL, LDL, and 
triglycerides)
a
For Exclusion Criterion 11 (Section 5.2), if sites only collected % differential of neutrophils, the absolute 
neutrophil count will need to be calculated for eligibility, based on leukocytes (WBC) and % of neutrophils.
b
Only at screening and as clinically indicated.
c
Only perform if urinalysis is abnormal.
d
FSH and oestradiol will be performed only in: 
-
Pre- and peri-menopausal women (ie, all women <60 years of age unless considered 
post-menopausal per Inclusion Criterion 5 [Section 5.1]) – at screening, at Day 1 Week 1 of each 
cycle, and when clinically indicated. 
-
Post-menopausal women <60 years of age – only at screening to confirm post-menopausal status 
and when clinically indicated.
All other women (ie, ≥60 years of age or with documented bilateral oophorectomy) do not need to have a 
check of FSH and oestradiol (refer to Inclusion Criterion 5 in Section 5.1).
e
Test will only be performed when clinically indicated.
NOTE: In case a patient shows an AST or ALT ≥3 × ULN or total bilirubin ≥2 x ULN please refer to 
Appendix H ‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law’, for 
further instructions.  

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ALT, alanine aminotransferase; AST, aspartate aminotransferase; B, blood; FSH, follicle-stimulating hormone; 
INR, International Normalised Ratio; P, plasma; S, serum; TSH, thyroid-stimulating hormone; U, urine.  
8.2.1.1
Glucose and glycosylated haemoglobin (HbA1c)
Blood glucose and HbA1c will be assessed according to the SoA (see Section 1.1).  On blood 
glucose assessment days (incorporating clinical chemistry and glucose) it is requested that 
patients fast and refrain from caloric intake for ≥4 hours prior to the morning dose of study 
treatment. 

Glucose pre-dose (fasting) and 4 hours post dose (fasting or non-fasting) in Cycle 1, 
Week 1, Day 1

Glucose (fasting) in Cycle 1, Week 3, Day 1; Cycle 2, Week 1, Day 1; and in Cycle 3 
onwards on Day 1 (Week 1)

Further glucose monitoring may be performed at the investigator’s discretion as clinically 
indicated

HbA1c to be measured at screening, pre-dose every 12 weeks, and at discontinuation
8.2.1.2
Serum creatinine
Patients taking capivasertib/placebo and metformin in combination should have creatinine 
assessments conducted as part of the routine clinical chemistry with additional monitoring of 
creatinine at the discretion of the investigator (see Section 8.4.5.3).
8.2.2
Physical examinations
The physical examination will be performed at timelines as specified in the SoA (Section 1.1) 
and will include an assessment of the following: general appearance, respiratory, 
cardiovascular, abdomen skin, head and neck (including ears, eyes, nose and throat), lymph 
nodes, thyroid, musculoskeletal (including spine and extremities) and neurological systems.
Weight and height will be assessed at timelines as specified in the SoA (Section 1.1).  
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.  
8.2.3
Vital signs
Vital signs (including blood pressure, pulse rate, respiratory rate, and body temperature) will 
be assessed at timelines as specified in the SoA (Section 1.1).  
Blood pressure and pulse measurements will be assessed with a completely automated device.  
Manual techniques will be used only if an automated device is not available.  

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Blood pressure, pulse, and respiratory rate measurements should be preceded by at least 
5 minutes of rest for the patient in a quiet setting without distractions (eg, television, cell 
phones).  
Vital signs will be measured in a supine, semi-supine, or sitting position after 5 minutes rest 
and will include temperature, systolic and diastolic blood pressure, pulse, and respiratory rate.  
Three readings of blood pressure and pulse will be taken with a ≥1-minute interval in between 
and should be reported in the patient notes.  The first reading should be rejected.  The second 
and third readings should be averaged to give the measurement to be recorded in the eCRF.  
Respiratory rate will be counted only once.
8.2.4
Electrocardiograms
Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.1).  
All ECGs to be conducted as triplicate measurements, within approximately 5 minutes of 
starting (the 3 ECGs separated by approximately 2 minutes).  Assessments should be 
performed as close as possible to, but within 30 minutes of the nominal time point.  
The timing and number of ECGs may be altered depending on emerging safety information.  
Additional ECGs may be taken at the discretion of the investigator.
Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 
10 minutes prior to times indicated.  All ECGs should be recorded with the patient in the same 
physical position.  A standardised ECG machine should be used and the patient should be 
examined using the same machine throughout the study if possible. 
After paper ECGs have been recorded, the investigator or designated physician will review 
each of the ECGs and may refer to a local cardiologist if appropriate.  A paper copy should be 
filed in the patient’s medical records.  
If an abnormal ECG finding at screening or baseline is considered to be clinically significant 
by the investigator, it should be reported as a concurrent condition.  For all ECGs details of 
intervals PR, R-R, QRS, QT, and QTcF and an overall evaluation will be recorded (normal; 
abnormal and non-clinically significant; or abnormal and clinically significant).  
8.2.5
MUGA scan/Echocardiogram 
Assessments will be performed as outlined in the SoA (see Section 1.1). For the alternative 
requirement, applicable only for UK, France, Italy, Spain, Belgium, Hungary, Poland, 
Germany refer to Appendix M. Bidimensional echocardiography (ECHO) is the preferred 
modality because of the global technetium [Tc-99m] shortage (but MUGA can be used 
alternatively).  

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The modality of the cardiac function assessments must be consistent within patient ie, if 
echocardiogram is used for the screening assessment and a follow-up assessment if clinically 
indicated, then echocardiogram should also be used for subsequent scans if required.  The 
patients should also be examined using the same machine and operator whenever possible.  
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 E.  
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.
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF.  
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 and SAEs will be collected from time of signature of the ICF, throughout the treatment 
period and including the 30-day follow-up period after discontinuation of study drug.  
For patients who continue to receive treatment beyond the time of the final DCO, investigators 
will continue to report all SAEs to AstraZeneca Patient Safety until 30 days after study 
treatment is discontinued (see Section 4.4).  
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix E.  The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.  
Investigators are not obligated to actively seek AEs or SAEs in patients who have already 
completed follow-up.  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 may notify the sponsor.  

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The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix E.  
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 SAEs/non-serious AEs/AEs of special interest (as defined in 
Appendix E), will be followed until resolution, stabilisation, the event is otherwise explained, 
or the patient is lost to follow-up.  
A post-study assessment will be performed preferably within 7 days of the time that the IMP 
is permanently discontinued.  
Safety follow-up should be carried out with the patient 30 days (± 7 days) after the 
discontinuation of study treatment to follow-up any SAEs/AEs and concomitant medications 
(including any subsequent cancer therapy).  
Any AE/SAE/abnormal laboratory findings that are ongoing at the time of study treatment 
discontinuation or any new treatment related events within 30 days of study treatment, must 
be followed up to resolution or until the event becomes stable (or returns to baseline) or is 
unlikely to resolve further in the opinion of the investigator.  Any AEs that are unresolved at 
the patient’s last AE assessment or other assessment/visit as appropriate in the study are 
followed up by the investigator for as long as medically indicated, but without further 
recording in the eCRF.  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 and changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the IMP(s) (yes or no)

Action taken with regard to IMP(s)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

AE is serious due to

Date of hospitalisation

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
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 IMP 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 IMP?’.  
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 E to the CSP.  
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff (eg, “Have you had any health problems since the previous visit/you 
were last asked?”) or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred (when possible) to 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 CSP mandated laboratory tests and vital signs will be summarised in the 
CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values, vital 
signs and ECG abnormalities should therefore only be reported as AEs if they fulfil any of the 
SAE criteria or are the reason for discontinuation of treatment with the IMP or if they are 
considered to be clinically relevant as judged by the investigator (which may include but is not 
limited to consideration as to whether treatment or non-planned visits were required or other 
action was taken with the study treatment, eg, dose adjustment or drug interruption).  
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia vs low haemoglobin value).  In 

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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 Section 8.3.9).  
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, without 
any findings of cholestasis (as indicated by elevated serum alkaline phosphatase [ALP]), may 
need to be reported as SAEs.  Please refer to Appendix H 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 IMP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease.  The development of new 
or progression of existing metastasis to the primary cancer under study should be considered 
as disease progression and not an AE.  Events, which are unequivocally due to disease 
progression, should not be reported as an AE during the study.
8.3.10
Adverse Events of Special Interest
Adverse Events of Special Interest (AESIs) are events of scientific and medical interest 
specific to the further understanding of capivasertib safety profile and require close 
monitoring and rapid communication by the investigators to AstraZeneca.  An AESI can be 
serious or non-serious.  All AESIs will be recorded in the eCRF.  Serious AESIs will be 
recorded and reported as per Section 8.4.1.
The AESIs for this study are:

Urinary tract infection 

Hyperglycaemia

Non-infectious diarrhoea

Infective pneumonia

Rash

Stomatitis

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
QT Prolongation  
8.4
Safety reporting and medical management
Investigators should refer to locally approved prescribing information for guidance on 
fulvestrant monitoring and the management of fulvestrant-related toxicities.  
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IMP, or to the 
study procedure(s).  All SAEs will be recorded in the eCRF.  
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.  
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.  
For fatal or life-threatening 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 electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative.  
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone, email or fax.  
The AstraZeneca representative will advise the investigator/study site staff how to proceed OR
investigators or other site personnel send relevant eCRF modules by fax to the designated 
AstraZeneca representative.  
For further guidance on the definition of a SAE, see Appendix E of the Clinical Study 
Protocol.  
The reference document for definition of expectedness/listedness is the IB for the capivasertib 
and fulvestrant.

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8.4.1.1
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 utilizing 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.
8.4.2
Pregnancy
A pregnancy test will be locally administered to female patients at screening, on Day 1 of the 
study (Cycle 1, Week 1, Day 1), at discontinuation of capivasertib, and as clinically indicated.  
Confirmation of absence of pregnancy is strongly recommended in case of delayed menstrual 
period (including infrequent or irregular menstrual cycles).
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca (see 
Section 8.4.2.1) except where the pregnancy is discovered before the study patient has 
received any study treatment.  
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.  
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, study treatment should be 
discontinued immediately.  
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 

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birth or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.  
If any pregnancy 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 provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs and within 30 days for all other pregnancies.  
The same timelines apply when outcome information is available.  
8.4.2.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
2 years after the last dose of fulvestrant or until 16 weeks after discontinuing 
capivasertib/placebo, whichever occurs later.  Patients wishing to father children should be 
advised to arrange for freezing of sperm samples prior to the start of study treatment.  
Pregnancy of a patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality), occurring from the date of the first dose until 2 years after the last 
dose of fulvestrant or until 16 weeks after discontinuing capivasertib/placebo whichever 
occurs later, should, if possible, be followed up and documented.  
8.4.3
Overdose
There is currently no specific treatment in the event of an overdose with capivasertib and 
possible symptoms of overdose are not established.  Capivasertib must only be used in 
accordance with the relevant CSP.  AEs associated with overdose should be treated in 
response to symptoms.  Any dose, or frequency of dosing, that exceeds the dose regimen 
specified in the CSP should be reported as an overdose.  The MTD for capivasertib is 
400 mg BD in combination with fulvestrant and 480 mg BD as monotherapy.  Fulvestrant 
must be used according to local prescribing information.  
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately.  

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module

An overdose without associated symptoms is only reported on the Overdose eCRF 
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If an overdose on an AstraZeneca study drug 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
8.4.4
Medication error, drug abuse, and drug misuse
8.4.4.1
Timelines
If an event of medication error, drug abuse or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one day ie, immediately but no later than 24 hours of when they become aware of it.  
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within one (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 event of medication error, drug abuse, or misuse (see Section 8.3.2) 
and within 30 days for all other events.
8.4.4.2
Medication error  
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP that either causes harm to the participant or has the 
potential to cause harm to the participant.
The full definition and examples of a medication error can be found in Appendix E.
8.4.4.3
Drug abuse  
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP for 
a perceived reward or desired non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix E.
8.4.4.4
Drug misuse  
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP for 
medicinal purposes outside of the authorised product information, or for unauthorised IMPs, 
outside the intended use as specified in the protocol and includes deliberate administration of 
the product by the wrong route. 
The full definition and examples of drug misuse can be found in Appendix E.

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8.4.5
Management of capivasertib-related toxicities
8.4.5.1
Capivasertib/placebo dose modification and guidance
Please refer to Section 6.6 for guidance on dose modifications.  
8.4.5.2
Dose modifications due to general capivasertib-related toxicities
Treatment with capivasertib/placebo should be temporarily interrupted for any intolerable AE 
regardless of grade or for any AE grade ≥3, that is not attributable to the disease under
investigation, where the investigator considers the AE of concern to be specifically associated 
with capivasertib.  Dose modification guidelines for capivasertib-related toxicities are shown 
in Table 9.  Appropriate and optimal treatment of the toxicity is assumed prior to considering 
dose modifications.  The study physician may be consulted prior to discontinuation of study 
drug due to toxicities.  Please see Section 8.4.5.3 for the management of capivasertib specific 
toxicities including hyperglycaemia, maculo-papular rash and other skin reactions, and 
diarrhoea.  
Table 9
Dose modifications for general capivasertib-related toxicities
NCI CTCAE v5 Toxicity Grade:
Actions:
Grade 1 or 2 clinically significant or intolerable
Hold dosing and follow guidance below, 
depending on outcome

Resolves to baseline or clinically tolerable within 
21 days of onset

Resume dosing at same dose or one reduced 
dose level as clinically appropriate

Does not resolve or remains intolerable within 
21 days of onset

Discontinue study drug and observe patient 
until resolution
Grade ≥3
Hold dosing and follow guidance below, 
depending on outcome

Grade ≥3 toxicity for ≤21 days and resolves to 
≤grade 2 or baseline within 21 days of onset 

Resume dosing at one reduced dose or same 
dose level as clinically appropriate

Grade ≥3 toxicity for >21 days

Discontinue study drug and observe patient 
until resolution
NCI CTCAE v5, National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0.  
8.4.5.3
Dose modifications due to specific capivasertib-related toxicities 
Hyperglycaemia
These are general recommendations therefore due consideration should be given to baseline 
values and fasting condition (and time since food if applicable) when interpreting glucose 
results.  In diabetic patients, it may be beneficial to rule out concomitant aetiologies that could 
be associated with hyperglycaemia (eg, infections, dehydration, vascular events, 
glucocorticoids).  
Patients should be made aware of symptoms of hyperglycaemia (eg, polydipsia and polyuria). 

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Dose modification guidelines for capivasertib-related hyperglycaemia are shown in Table 10.  
In addition, for all grades, patients should receive education on lifestyle changes (eg, a 
diabetic diet) and consider beginning home glucose monitoring (eg, fasting self-blood glucose 
monitoring [SBGM] once-daily) at the discretion of the investigator.  If glucose home 
monitoring is instituted, the capivasertib/placebo treatment decision should be based on the 
morning fasting glucose value obtained prior to the dose of capivasertib/placebo.  
It is recommended that approaches to the management of capivasertib-induced 
hyperglycaemia include advice from a diabetologist where appropriate (eg, diabetic patients).  
Metformin is currently the preferred oral antidiabetic recommended for the management of 
hyperglycaemia occurring in patients participating in studies of capivasertib (see below for 
further guidance).  If a second agent is required, consideration should be given to the 
intermittent schedule of capivasertib and the pattern of glucose changes (eg, sulphonylureas 
should be avoided due to their risk of hypoglycaemia secondary to their mechanism of action).

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Table 10
Dose modifications for capivasertib-related hyperglycaemiaa
NCI CTCAE v5 Toxicity Grade:
Actions
Grade 1
(Abnormal glucose above baseline with no 
medical intervention)
Maintain same capivasertib/placebo dose level
Grade 2 
(Change in daily management from baseline 
for a diabetic; oral anti-glycaemic agent 
initiated; workup for diabetes)
Asymptomatic: 

Maintain same capivasertib/placebo dose level

Treatment as per local guidelines, consider the use of oral 
antidiabetic (eg, metformin) on capivasertib/placebo 
dosing days only (see further guidance on choice of 
antidiabetic agents on text above and below the table)
Symptomatic: Appropriate clinical management as per local 
guidelines

Interrupt capivasertib/placebo until resolution of 
symptoms and fasting blood glucose ≤160 mg/dL or 
≤8.9 mmol/L (treatment can be interrupted up to 21 days)

Restart at same dose level maintaining appropriate 
antidiabetic treatment (eg addition of/higher dose of oral 
metformin)

Consider consult with the diabetologist
Grade 3 
(Insulin therapy initiated; hospitalisation 
indicated)
Hold capivasertib/placebo up to 21 days until resolution of 
symptoms.  Consult with diabetologist

If fasting blood glucose decreases ≤160 mg/dL or 
≤8.9 mmol/L within 21 days following appropriate 
antidiabetic treatment, resume capivasertib/placebo at 1 
lower dose level

If fasting blood glucose does not decrease to ≤160 mg/dL 
or ≤8.9 mmol/L within 21 days following appropriate 
antidiabetic treatment, permanently discontinue 
Capivasertib/placebo
Grade 4
(Life-threatening consequences; urgent 
intervention indicated)

Appropriate clinical management as per local guidelines

Consider consult with the diabetologist

Consider permanent cessation of capivasertib/placebo
a
Patients may receive education on lifestyle changes (eg, a diabetic diet) and consider beginning home 
glucose monitoring (eg, fasting self-blood glucose monitoring [SBGM] once-daily) at the discretion of the 
investigator.  If glucose home monitoring is instituted, the capivasertib/placebo treatment decision should 
be based on the morning fasting glucose value obtained prior to the dose of capivasertib/placebo.
NCI CTCAE v5, National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0; 
SBGM, self-blood glucose monitoring

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Use of metformin
Metformin is currently the preferred oral antidiabetic recommended for the management of 
hyperglycaemia occurring in patients participating in studies of capivasertib.  Investigators 
should exercise caution in the dosing and management of patients receiving the metformin and 
capivasertib/placebo combination and must be vigilant for signs of renal impairment and 
metformin toxicity, such as lactic acidosis and hypoglycaemia, namely: lethargy, hypotension, 
poor urine output, drowsiness, irritation, tachypnoea, sweating, diarrhoea, and vomiting.  
Due to the potential interaction of metformin and capivasertib (caused by the inhibition of 
renal transporters [eg, OCT2] involved in the excretion of metformin), when taking both 
capivasertib and metformin concurrently, it is recommended weekly monitoring of creatinine 
after initiation of metformin, for up to 3 weeks and then on Day 1 of each cycle thereafter. 
Metformin should only be given on the days when capivasertib/placebo is also administered 
(the half-life of capivasertib is approximately 7-15 hours) and should be withdrawn when 
treatment with capivasertib/placebo is withdrawn, unless otherwise clinically indicated.  
Consider withholding of metformin on the days patients are due to have imaging with contrast 
(in order to reduce the already low risk of lactic acidosis) as per local guidelines.

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Maculo-papular rash
Dose modifications for capivasertib-related maculo-papular rash, which is the most frequent 
skin toxicity observed in patients treated with capivasertib, are provided in Table 11.  
However, these management guidelines can be used for other skin toxicities at the discretion 
of the investigator and/or following consultation with the dermatologist.  
Table 11
Dose modifications for capivasertib-related maculo-papular rash 
NCI CTCAE v5 Toxicity Grade:
Actions:
Grade 1 or 2
Continue dosing at current dose and initiate dermatological 
treatment:

Topical steroid of moderate strength twice-daily

Non-sedating oral antihistamines
Grade ≥3 or any grade clinically intolerable
Withhold dosing for up to 28 days and initiate 
dermatological treatment (topical steroid of moderate 
strength and non-sedating oral antihistamines) with oral 
steroid for a short course (eg, up to 2 weeks).  Consultation 
with dermatologist is advised

Improves to grade ≤1 and tolerable within 
28 days from onset

Continue dermatological treatmenta and restart dosing 
at same dose

Improves to grade 2 and tolerable within 
28 days from onset

Continue dermatological treatmenta and restart dosing 
at reduced dose (1 dose level reduction)

Does not improve to grade 2 and tolerable 
within 28 days from onset

Continue dermatological treatmenta and discontinue 
capivasertib/placebo
Recurrence of Grade 3, or Grade 4 (eg, 
severe bullous, blistering or exfoliating skin 
conditions), or any % BSA associated with 
extensive superinfection, with IV antibiotics 
indicated; life-threatening consequences
Discontinue capivasertib/placebo
a
In patients with persistent rash or previous occurrence of grade 3 rash, consider secondary prophylaxis by 
continuing topical steroids and/or non-sedating oral antihistamines.
BSA, body surface area; NCI CTCAE v5, National Cancer Institute Common Terminology Criteria for Adverse 
Events Version 5.0.
Hypersensitivity
In the case of hypersensitivity reactions, capivasertib/placebo should be discontinued and 
symptomatic/supportive therapy should be initiated (including with antihistamines and/or 
steroids) as considered appropriate by the investigator/treating physician.  Drug re-challenge 
is not recommended; any subsequent consideration on re-challenge with capivasertib at the 
same or a lower dose, with its potential for recurrence of such or more severe events should be 
carefully considered against the potential benefits to the individual patient from continuation 

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of capivasertib therapy and agreed with the sponsor.  Further management should follow local 
guidelines on management of hypersensitivity reactions.  
Diarrhoea
Patients should be instructed to promptly contact investigators if they develop diarrhoea.  
Alternative aetiologies should be ruled out prior to initiating the dose modifications.  
Investigators are recommended to prescribe anti-diarrhoeal treatment at the first visit so that 
patients can start treatment at the first sign of diarrhoea, should it occur.  
Loperamide is the preferred anti-diarrhoea agent for the management of diarrhoea occurring in 
patients participating in studies of capivasertib.  Dose modifications for capivasertib-related 
diarrhoea are provided in Table 12.  
If diarrhoea is reported, additional details regarding this AE will be collected in the eCRF.

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Table 12
Dose modifications for capivasertib-related diarrhoea
NCI CTCAE v5 Toxicity Grade:
Actions:
Grade 1
Maintain same capivasertib/placebo dose.  Anti-diarrhoeal 
treatment (eg, loperamide) should be initiated at first report of 
diarrhoea.  Maximise the supportive care (eg, dietary 
modifications, appropriate hydration therapy and electrolyte 
supplements as clinically indicated).  
Grade 2
Interrupt capivasertib/placebo dose (up to 21 days) until 
recovery to grade ≤1 and resume dosing at same dose level.  
Anti-diarrhoeal (eg, loperamide) treatment should be initiated 
at first report of diarrhoea.  Maximise the supportive care (eg, 
dietary modifications, appropriate hydration therapy and 
electrolyte supplements as clinically indicated).  
Consider starting secondary prophylaxisa.  
Grade ≥3
Interrupt capivasertib/placebo dose (up to 21 days) and 
institute appropriate anti-diarrhoeal treatment

Improves to grade ≤1 within 21 days

Resume dosing at same dose level or 1 reduced dose level 
as clinically appropriate, maintaining treatment for 
toxicity as necessary and/or start secondary prophylaxisa

Does not improve to grade ≤1 after 
21 days 

Discontinue capivasertib/placebo
Recurrence of grade ≥2 or clinically 
significant or intolerable toxicity despite 
secondary prophylaxis
Interrupt capivasertib/placebo dose (up to 21 days) 
maintaining appropriate anti-diarrhoeal treatment

Improves to grade ≤1 or becomes 
clinically tolerable within 21 days

Resume dosing up to 2 reduced dose levels maintaining 
treatment for toxicity as necessary and/or maintaining 
secondary prophylaxisa

Does not improve to grade ≤1 or 
remains clinically 
significant/intolerable after 21 days

Discontinue capivasertib/placebo
a
In patients with persistent grade 1 diarrhoea (eg, loperamide 2 mg, 2 to 4 times daily).  
NCI CTCAE v5, National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0.  
8.5
Pharmacokinetics
Blood samples of approximately 2 mL will be collected from each patient for measurement of 
plasma concentration of capivasertib as per the SoA (Section 1.1).  Samples from patients 
dosed with placebo will not be analysed (for exceptions, see Section 8.5.1).  The 
randomisation list will be supplied to the bioanalytics team before sample analysis.  
Results will only be reported for samples shipped within a timeframe for which the stability of 
capivasertib in the samples has been validated and shown to be acceptable.  

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Samples may be collected at additional time points 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 will be used to evaluate the PK of capivasertib.  Samples collected for analyses of 
capivasertib plasma concentration may also be used to evaluate safety or efficacy aspects
related to concerns arising during or after the study.  
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.  
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but 
separately in a bioanalytical report.  
8.5.1
Determination of drug concentration
Samples for determination of capivasertib concentrations in plasma will be analysed by 
Covance on behalf of Clinical Bioanalysis Alliance, AstraZeneca R&D, using an appropriate 
bioanalytical method.  Full details of the analytical method used will be described in a 
separate bioanalytical report.  
For each placebo patient, samples will only be analysed on a 'for cause' basis, eg, if no 
quantifiable concentrations were observed in a patient's samples when the drug was expected 
to be present.  
8.5.2
Storage and destruction of pharmacokinetic samples
8.5.2.1
Samples collected in China
PK samples will be disposed of after the bioanalytical report finalisation or 6 months after 
issuance of the draft bioanalytical report (whichever is earlier).  
8.5.2.2
Samples collected outside of China
PK samples will be disposed of after the bioanalytical report finalisation or six 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.  

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8. 6
Ge netics
 
 
 
  
 
 
  
 
 
  
8. 6. 2
St or a ge a n d destr ucti o n of ge netic s a m ples
T he pr ocesses a d o pte d f or t he c o di n g a n d st ora ge of sa m ples f or ge net ic a nal ysis are 
i m p orta nt t o mai ntai n patient  c o nfi de ntiality.   Sa m ples ma y be st ore d f or a ma xi m u m of 
1 5 years or as per l ocal re g ulati o ns fr o m t he date of t he Last Patie nt’s Last Visit, after w hic h 
t he y will be destr o ye d.  D N A is a fi nite res o urce t hat ma y be use d u p d uri n g a nal yses.  T he 
res ults of a n y f urt her a nal yses will be re p orte d eit her i n t he C S R itself or as a n a d de n d u m, or 
se paratel y in a scie nt ific re p ort or p u blicati on.  
N o pers o nal details i de ntif yi n g t he i n di vi d ual will be a vaila ble t o Astra Ze neca or desi g nate d 
or ga ni sati ons w or ki n g wit h t he D N A.  
8. 7
Bi o m ar kers
Ma n dat or y  c ollecti on of t u m o ur tiss ue a n d bl o o d sa m ples f or bi o mar ker researc h is re q ui re d 
as a part of t his st u d y.  O ptio nal  t u mo ur ti ss ue sa m ples s h o uld be c ollecte d fr o m  c o nse nti n g 
pati e nts o nl y.  T he f ollo wi n g sa m ples will  be c ollecte d fr o m all patient s i n t his st u d y as 
s pecifie d i n t he S o A ( Secti o n 1. 1 ).  See A p pe n di x F f or a d ditio nal i nf or mat i on o n t he ha n dli n g 
of  biol o gical s a m ples.  
8. 7. 1
T u m o ur tiss ue s a m ple
8. 7. 1. 1
M a n d at or y t u m o ur tiss ue s a m ples f or bi o m ar ker a n al ysis
All ra n d o mise d patie nts m ust pr o vi de a n arc hi val or ne wl y c o llecte d F F P E t u m o ur sa m ple 
(see Secti o n 1. 1 ) c ollecte d as part of r o uti ne cli nical practice, f or ce ntral testi n g.  T his s h o ul d 
prefera bl y be a tiss ue bl oc k t o e na ble t he a nal yses descri be d bel o w. If a bl oc k is n ot p ossi ble, 
C CI

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8. 7. 1. 3
C ollecti o n, a n al ysis a n d re p orti n g of t u m o ur s a m ples
Ma n dat or y  t u mo ur sa m ples will be c ollecte d as detaile d i n t he La b orat or y  Ma n ual a n d t he 
Di a g n ostic Testi n g Ma n ual.  Patie nts m ust c o nse nt t o pr o vi de a n arc hi val or ne wl y  F F P E 
t u mo ur sa m ple, c ollecte d as part of r o uti ne cli nical practice, f or a nal ysis.  
Ma n dat or y  t u mo ur sa m pl es meeti n g t he mi ni m u m t u m o ur c o nte nt a n d tiss ue v ol u me, as 
s pecifie d i n t he La b orat or y Ma n ual a n d Dia g n ostic Testi n g Ma n ual, will be teste d wit h t he 
pri mar y  int e nt t o detect t u m o ur D N A alterati o ns i n t he f oll o wi n g ge nes; A K T 1 , PI K 3 C A , a n d 
P T E N .  If t he first s a mple s u b mitte d f or testi n g is i nc o ncl usi ve d ue t o tec h nical test fail ure, a 
f urt her sa m ple ma y be s u b mitt e d for testi n g.  S u b missi o n a n d testi n g of a d dit i onal sa m ples 
ca n o nl y be perf or me d if t he origi nal  testi n g faile d d ue t o tec h nical reas o ns (ie, faile d test 
res ult).  Please refer t o t he La b orat or y Ma n ual a n d t he Dia g n ostic Test i n g Ma n ual f or f urt her 
details re gar di n g retesti n g pr oce d ures.  Ce ntral testi n g ma y ge nerate res ults o n ge nes ot her 
t ha n A K T 1, PI K 3 C A, a n d P T E N , a n d t he res ults ma y be pr o vide d at t he ti me of treat me nt 
di sc o nti n uati on u p o n i n di vi d ual re q uest b y  t he i n vestigat or i n or der t o a v oi d bias d uri n g t he 
treat me nt perio d.  
O pti o nal  t u mo ur bi o ps y  sa m ples will be c ollecte d fr o m c o nse nti n g patie nts o nl y.  T he o pti o nal 
t u mo ur bi o psi es c ollecte d at disease pr o gressio n meeti n g t he mi ni m u m t u m o ur c o nte nt a n d 
tiss ue v ol ume, as s pecifie d i n t he La b orat or y  M a n u al a n d Pat h olo g y  a n d Ge n omic Test i n g 
Ma n ual, will be teste d ce ntrall y  b y N G S usi n g t he sa me ce ntral test as descri be d a b o ve f or t he 
ma n da t or y t u mo ur s a m ples.  T he pri mar y i nte nt is t o detect c ha n ges i n t he t u m o ur D N A 
alt er atio ns t hat m a y be ass ociate d wit h tr e at me nt resista nce.  T he res ults of t his ce ntral testi n g 
of  t he o ptio nal  t u mo ur bi o ps y  o btai ne d at disease pr o gressio n will  be pr o vide d t o t he 
i n vesti gat or.
Test res ul ts will be re p orte d t o Astra Ze neca.  
 
 
 
 
C CI
C CI

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8. 7. 3
St or a ge, re -use a n d destr ucti o n of bi o m ar ker s a m ples
Bi ol o gi cal sa m ples will be st ore d f or a ma xi m u m of 1 5 years fr o m t he date of t he Last 
P ati e nt’s Last Visit, after w hic h t he y will be destr o ye d.  T he res ults of t his bi o mar ker researc h
will be re p orte d eit her i n t he C S R itself or as a n a d de n d u m, or se paratel y i n a scie nt ific re p ort 
or p u blicat i on.  T he res ults of t his bi o mar ker researc h ma y be p o ole d wit h bi o mar ker data 
fr om ot h er st u dies t o ge nerate h y p ot heses t o be teste d i n f ut ure re searc h. 
A n y u n use d or partiall y use d t u m o ur sa m ples c o llecte d i n C hi na f or t he p ur p ose of 
PI K 3 C A/ A K T 1/ P T E N -alter nati on assess me nt will be destr o y e d or re patriat e d ma xi mall y 
1 year after t he st u d y  dr u g is a p pr o ve d f or mar keti n g i n C hi na.  
8. 8
He alt hc are res o u rce use
T he i m pact of treat me nt a n d disease o n healt hcare res o urce use will be ca pt ure d i n t his st u d y  
o n a n e ve nt -dri ve n basis.  
T he H os pi t al A d missi on ( H O S P A D) m o d ule will be use d t o c ollect i nf or mat i on o n ke y  healt h 
care res o urce use be yo n d st u d y  ma n dat e d visit s.  T he site s h o ul d c om p lete t he H O S P A D f or m 
at t he site at e ver y sc he d ule d cli nic visit u p t o a n d i ncl u di n g t he p ost-stu d y treat me nt 
di sc o nti n uati on f oll ow- u p visi t.  If a patie nt disc o nti n ues st u d y tr e at me nt for reas o ns ot her 
t ha n R E CI S T v 1. 1 pr o gressi o n, t he H O S P A D f or m s h o ul d c o nti n ue t o be a d mi nistere d u ntil 
pr o gressi o n has bee n c o nfir me d.  St u d y  ma n date d visit s s h o ul d n ot be i ncl u de d as a h os pital 
a d missi o n.  
C CI
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The data may be used as input to cost analyses for example cost utility analysis or cost 
effectiveness analysis.  
9
STATISTICAL CONSIDERATIONS 
9.1
Statistical hypotheses
The null hypotheses for the primary time to event endpoint (PFS) are that there is no 
difference between capivasertib + fulvestrant and placebo + fulvestrant in the probability of a 
progression event in the overall population and the PIK3CA/AKT1/PTEN-altered population.   
The intention of the study is to demonstrate the superiority of capivasertib + fulvestrant over 
placebo + fulvestrant in either or both of the overall and PIK3CA/AKT1/PTEN-altered 
populations.  
9.2
Sample size determination
Assuming a significance level of 5%, a total of 492 OS events will be required to achieve 90% 
power to detect a treatment effect of an average HR 0.74 in the overall population, assuming a 
12-month delay to a treatment effect and an HR of 0.64 after the delay.  Assuming 70% 
maturity at the time of the final analysis, approximately 700 patients will need to be 
randomised.  Of these 700 randomised patients, it is expected that a minimum of 280 patients 
will have a tumour harbouring an eligible PIK3CA/AKT1/PTEN alteration based on a 
prevalence of ~40-45% (Cristofanilli et al 2016, Curtis et al 2012, Di Leo et al 2018, 
Hortobagyi et al 2016, Pereira et al 2016, Spoerke et al 2016), and a minimum of 
approximately 224 patients will be in the PIK3CA/AKT1/PTEN-altered subgroup assuming a 
test failure rate of 20%.  
The primary objective of this study is to assess the efficacy of capivasertib + fulvestrant vs 
placebo + fulvestrant by assessment of PFS in the overall and the 
PIK3CA/AKT1/PTEN-altered populations.  The PFS Primary Analysis will take place after 
PFS reaches approximately 77% maturity (542 events) in the overall population, and 
approximately 77% of PFS events have occurred in patients whose tumours harbour an 
eligible PIK3CA/AKT1/PTEN alteration, based on a prevalence of ~40-45% (and 174 events 
will have been observed if a test failure rate is 20%). 
After all the pre-defined PFS endpoints have been tested, the remaining alpha will be used for 
testing OS in the PIK3CA/AKT1/PTEN-altered population and subsequently for OS in the in 
overall population. ORR in the PIK3CA/AKT1/PTEN-altered population and the overall 
population will be tested sequentially only if OS in the overall population is statistically 
significant. 
The OS Interim Analysis is expected to occur when approximately 394 OS events have been 
observed in the overall population  and similar maturity has been reach in the altered 

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population (56% maturity, 80% information fraction).  If the time between the PFS analysis 
and the OS interim analysis is approximately 3 months or less, then the PFS DCO may be 
delayed and the analyses combined. The OS Final Analysis will take place when 
approximately 70% maturity has been observed in both the overall and the 
PIK3CA/AKT1/PTEN-altered populations.  The exact significance level will be determined 
according to the O’Brien & Fleming method (Lan and DeMets 1983) based on the actual 
number of events observed at the OS Interim Analysis. 
Table 13 and Table 14 show the critical values at various significance levels for PFS and OS 
testing.  
Table 13
Statistical considerations for dual primary PFS endpoints
Analysis
Significance 
level
Number of 
events 
(assuming 
20% test 
failure 
rate)
Critical value in HR 
[corresponding median 
PFSa]
Power 
(Assuming HR=0.64)
PFS Analysis (altered 
subgroup, assuming 
77% maturity)
0.021b
217 (174)
0.73 (7.5 months) 
[0.71 (7.7 months)]
83.7% (73.9%) 
0.05c
217 (174)
0.77 (7.2 months)
[0.74 (7.4 months)]
90.8% (83.7%)
PFS Analysis (overall 
population, assuming 
77% maturity)
0.035
542
0.83 (6.6 months)
>99% 
HR, hazard ratio; PFS, progression-free survival.
a
Assuming median PFS for placebo + fulvestrant arm is 5.5 months and PFS is exponentially distributed.  
b
Assuming the null hypothesis for the PFS Analysis in the overall population is not rejected at α=0.035 level 
and the observed ratio of the number of events between the altered subgroup and overall population is 0.4.  
c
Assuming the null hypothesis for the PFS Analysis in the overall population is rejected at α=0.035 level.  

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Table 13
Statistical considerations for OS endpoint
Analysis
Significance 
level
Number 
of events 
(assuming 
20% test 
failure 
rate)
Critical value in HR 
[corresponding median 
OSa]
Power 
(Assuming HR=0.74)
OS Interim Analysis 
(altered subgroup, 
assuming 80% 
information fraction)
0.0056b
158 (127)
0.642 (33.7 months) 
[0.610 (40.9 months)]
13% (6%) 
0.0244c
158 (127)
0.698 (30.8 months)
[0.670 (35.2 months)]
28% (16%)
OS Final Analysis 
(altered subgroup)
0.0133b
197 (158)
0.702 (29.3 months)
[0.673 (32.0 months)]
36% (21%)
0.0429c
197 (158)
0.749 (27.9 months)
[0.724 (29.7 months)]
53% (36%)
OS Interim Analysis 
(overall population, 
assuming 80% 
information fraction)
0.0056b
394
0.756 (28.5 months)
44%
0.0244c
394
0.796 (27.2 months)
64%
OS Final Analysis 
(overall population)
0.0133b
492
0.799 (26.5 months)
80%
0.0429c
492
0.833 (25.8 months)
90%
HR, hazard ratio; OS, overall survival.
a
Assuming median OS for placebo + fulvestrant arm is 23 months and OS follows a Weibull distribution 
with β=1.5.  
b
Assuming the null hypothesis for the PFS Analysis in the overall population is not rejected at α = 0.035 
level.
c            Assuming the null hypothesis for the PFS Analysis in the overall population is rejected at α = 0.035 level.

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9.3
Populations for analyses
For purposes of analyses, the populations described in Table 14 are defined.  
Table 14
Analysis populations
Population
Description
Full Analysis Set (FAS)
The FAS will be used as the primary population for 
reporting efficacy data and to summarise baseline 
characteristics.  
This comprises all patients randomised into the study, 
excluding patients randomised in China after the 
global cohort last patient first visit (LPFV), and will 
be analysed according to randomised treatment 
regardless of the treatment received (intention-to-treat 
[ITT] principle).  Any important deviations from 
randomised treatment will be listed and considered 
when interpreting the efficacy data.  
Safety Analysis Set
The safety analysis set comprises all patients included 
in the FAS, who received at least 1 dose of study drug 
(fulvestrant, capivasertib, placebo) and will be 
analysed according to the treatment received.  If a 
patient receives at least 1 dose of capivasertib, they 
will be summarised in the capivasertib arm for safety 
summaries (eg, capivasertib arm will include patients 
randomised to capivasertib who receive at least 
1 dose of capivasertib, or placebo patients who 
receive at least 1 dose of capivasertib in error at any 
time).  If a patient randomised to capivasertib 
receives only placebo treatment, then they will be 
summarised as part of the placebo arm.  Patients who 
receive only fulvestrant will also be included in the
safety analysis set and will be included in the 
treatment arm to which they were randomised.
Altered Subgroup FAS
This comprises all patients included in the FAS with 
a PIK3CA/AKT1/PTEN-altered result from a valida
biomarker test as determined by central testing.  
Altered Subgroup Safety Analysis Set
This comprises all patients included in the Safety 
Analysis Set with a PIK3CA/AKT1/PTEN-altered 
tumour as determined by central testing.  
Pharmacokinetic (PK) Analysis Set
This comprises all patients included in the FAS who 
received at least 1 dose of capivasertib with at least 
one reportable concentration.
a
The definition of a valid biomarker test will be pre-specified in the SAP prior to any efficacy analysis.

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9.4
Statistical analyses
Analyses will be performed by AstraZeneca or its representative.  A comprehensive SAP will 
be developed and finalised before the primary PFS analysis database lock and will describe 
the patient populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.  This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.  Any deviations from this plan will be 
reported in the CSR.  
9.4.1
Efficacy analyses
Efficacy analyses will be performed based on the Full Analysis Set (FAS) (intention-to-treat 
[ITT]) for the overall population and on the Altered Subgroup FAS for the 
PIK3CA/AKT1/PTEN-altered subgroup. 
Depending on the extent of any impact, summaries of data relating to patients diagnosed with 
COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, delayed or 
discontinued IP, and other protocol deviations) may be generated.  More details will be 
provided in the SAP.  
9.4.1.1
Primary endpoint: PFS in the overall population
PFS is defined in Section 8.1.1.1 together with the details of censoring.
PFS in the overall population will be analysed using a stratified log-rank test adjusting for the 
stratification factors (Section 4.1).  
The stratification variables in the statistical modelling will be based on the values entered into 
IVRS at randomisation.  If there are insufficient events per strata, the strata will be pooled 
following a pooling strategy that will be prespecified in the SAP.  
From the stratified Cox proportional hazards model (ties = Efron) the HR (capivasertib + 
fulvestrant vs placebo + fulvestrant) together with its corresponding 95% CI (calculated using 
a profile likelihood approach) will be presented.  An HR less than 1 will favour capivasertib + 
fulvestrant.
Subgroup analyses will be conducted to assess PFS by the stratification factors (see 
Section 4.1) and the following (but not limited to) subgroups of the FAS:

Age at randomisation (<65 vs ≥65 years of age)

PIK3CA/AKT1/PTEN mutation status in tissue (PIK3CA/AKT1/PTEN-altered vs 
confirmed PIK3CA/AKT1/PTEN-non-altered + unknown)
Additional subgroup analyses (eg, menopausal status, type of endocrine resistance) may be 
conducted and the details outlined in the SAP.  

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Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment arms.  The purpose of the subgroup analyses is to assess the 
consistency of treatment effect across expected prognostic and/or predictive factors. Forest 
plots will be presented.  
No adjustment to the significance level for testing of the subgroup and sensitivity analyses 
will be made, since all these analyses will be considered supportive of the analysis of PFS.
For each subgroup level of a factor, the HRs and associated CIs will be calculated from a Cox 
proportional hazards model (ties = Efron) that only contains a term for treatment.  The Cox 
models will be fitted using SAS® PROC PHREG with the Efron method to control for ties and 
using a BY statement for the subgroup factor.  The HRs and 95% CIs will be presented on a 
forest plot.  
Further sensitivity analyses will be described in the SAP.
Supplementary analysis
PFS defined by BICR in the overall population will be analysed as described for the 
investigator-assessed PFS endpoint (see above).  
9.4.1.2
Primary endpoint: PFS in the PIK3CA/AKT1/PTEN-altered subgroup
PFS in the PIK3CA/AKT1/PTEN-altered subgroup will be analysed as described for the 
investigator-assessed PFS endpoint (Section 9.4.1.1) and stratified by the stratification factors 
(Section 4.1).  
Additional sensitivity and subgroup analyses may be performed (including outcomes based on 
BICR).
9.4.1.3
Secondary endpoint: OS in the overall population
OS is defined in Section 8.1.2 together with details of censoring.
OS will be analysed as described for the investigator-assessed PFS endpoint (Section 9.4.1.1), 
including subgroup analyses, and stratified by the stratification factors (Section 4.1).  
9.4.1.4
Secondary endpoint: OS in the PIK3CA/AKT1/PTEN-altered subgroup
OS in the PIK3CA/AKT1/PTEN-altered subgroup will be analysed as described for the 
investigator-assessed PFS endpoint (Section 9.4.1.1) and stratified by the stratification factors 
(Section 4.1).  
Additional sensitivity and subgroup analyses may be performed.

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9.4.1.5
Secondary endpoint: PFS2 in the overall and altered FAS population
PFS2 is defined in Section 8.1.3 together with details of censoring.
PFS2 in the overall and in the PIK3CA/AKT/PTEN-altered populations will be analysed as 
described for the investigator-assessed PFS endpoint (Section 9.4.1.1) and stratified by the 
stratification factors (Section 4.1).  
9.4.1.6
Secondary endpoint: ORR in the overall and altered FAS population
The ORR will be compared between capivasertib + fulvestrant vs placebo + fulvestrant, for 
both the overall and the PIK3CA/AKT/PTEN-altered populations, using logistic regression 
models adjusting for the stratification factors (Section 4.1).  The results of the analysis will be 
presented in terms of an odds ratio (an odds ratio greater than 1 will favour capivasertib + 
fulvestrant) together with its associated profile likelihood 95% CI and p-value.  If there are not 
enough responses for a meaningful analysis using logistic regression, then a Cochran-Mantel 
Haenszel (CMH) test will be presented.  The CMH test will be stratified using the same 
stratification factors as the dual primary endpoints.  
ORR will be presented with a two-sided 95% CIs using the Clopper-Pearson method (Clopper 
and Pearson 1934).  
9.4.1.7
Secondary endpoint: DoR in the overall and altered FAS population
DoR is defined in Section 8.1.1.3 together with details of censoring.
Descriptive data will be provided for the DoR in responding patients, including the associated 
Kaplan-Meier (KM) plots for both the overall and the PIK3CA/AKT1/PTEN-altered 
populations.  
9.4.1.8
Secondary endpoint: CBR in the overall and altered FAS population
CBR is defined in Section 8.1.1.2.  
CBR in the overall and the PIK3CA/AKT1/PTEN-altered population will be analysed as 
described for the ORR analysis (Section 9.4.1.6).  
9.4.1.9
Secondary endpoint: PK
The plasma concentration-time data will be analysed by population PK methods using 
non-linear mixed-effects modelling.  PK parameters, including variability parameters, will be 
estimated as data permits.  The influence of intrinsic (eg, ethnicity, gender, age, weight, renal 
function and hepatic function) and extrinsic (eg, concomitant medication) factors will be 
evaluated and exposure-response relationships will be explored.  Details will be outlined in a 
separate modelling analysis plan and results may be reported separately.  

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In the subgroup of approximately 6 Japanese patients with rich capivasertib PK data, the area 
under the plasma concentration-time curve from zero to 12 hours (AUC0-12h), the maximum 
observed plasma (peak) concentration (Cmax), and the time to reach peak or maximum 
observed concentration following drug administration (tmax) will be derived.  
PK analyses will be performed based on the PK Analysis Set and any exclusion of data will be 
documented and justified.  
Data from this study may be pooled with data from other studies.
9.4.1.10
Secondary endpoints: EORTC QLQ-C30 and EORTC QLQ-BR23
The EORTC QLQ-C30 and EORTC QLQ-BR23 will be scored according to the EORTC 
Scoring Manual (Fayers et al 2011).  An outcome variable consisting of a score from 0 to 100 
will be derived for each of the symptom scales, each of the functional scales, and the global 
measure of health status scale according to the EORTC Scoring Manual.  Higher scores on the 
global measure of health status and functional scales indicate better health status/function, but 
higher scores on symptom scales represent greater symptom severity.  For each subscale, if 
<50% of the subscale items are missing, then the subscale score will be divided by the number 
of non-missing items and multiplied by the total number of items on the subscales (Fayers et 
al 2011).  If at least 50% of the items are missing, then that subscale will be treated as 
missing.  Missing single items are treated as missing.  The reason for any missing 
questionnaire will be identified and recorded.  
The main PRO measures identified in the secondary objectives are global health status/QoL, 
physical function, role function, fatigue, pain and appetite loss subscales of the 
EORTC QLQ-C30.  However, separate analysis will be conducted for each EORTC 
QLQ-C30 and EORTC QLQ-BR23 scale/symptom score.  
The primary assessment of global health status/QoL, physical function, role function, or 
symptoms will focus on comparing mean change from baseline between treatment arms.  To 
examine the change from baseline and time to deterioration, the analysis population will be a 
modified FAS (ITT) which includes all randomised patients with an evaluable baseline 
assessment and at least one evaluable post-baseline assessment. Similarly, analyses may be 
repeated in a modified PIK3CA/AKT1/PTEN-altered population, which includes patients 
whose tumours harbour a qualifying PIK3CA/AKT1/PTEN-alteration and have an evaluable 
baseline assessment and at least one evaluable post-baseline assessment, where appropriate. 
Change from baseline will be analysed using a mixed model repeated measurements analysis 
of all the post-baseline scores.  The model will include treatment arm, visit, and treatment by 
visit interaction and stratification factors as explanatory variables, and the baseline score and 
baseline score by visit as covariates.  Adjusted mean change from baseline estimates per 

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treatment arm and corresponding 95% CIs will be presented, along with an overall estimate of 
the treatment difference, 95% CI, and p-value.  
Time to deterioration will be analysed using the same approach as described for the PFS and 
OS endpoints (Section 9.4.1.1).  Separate analyses will be conducted for global health 
status/QoL, physical function, role function, fatigue, pain and appetite loss.  The effect of 
treatment arms will be estimated by the HR together with its corresponding 95% CI and 
p-value.  KM plots will be presented by treatment arm.  Summaries of the number and 
percentage of patients who have an event as well as who were censored will be provided along 
with the median time to deterioration for each treatment arm.  The HR, p-value, and 95% CI 
estimates will be presented.  
Summary tables of responses for each EORTC QLQ-C30 and EORTC QLQ-BR23 scale/item 
score (global health status/QoL, 5 functions, symptom scales) for each assessment 
(improvement, deterioration, and no change) will be presented by treatment arm.
Finally, summaries of absolute and unadjusted change from baseline values of each 
EORTC QLQ-C30 and EORTC QLQ-BR23 scale/item score will be reported by assessment 
timepoint for each treatment arm.  Graphical presentations may also be produced as 
appropriate.  
Full details of the statistical analyses and appropriate sensitivity analyses will be described in 
full in the SAP.  
9.4.1.11
Secondary endpoint: time to definitive deterioration of the ECOG 
performance status in the overall population and the PIK3CA/AKT1/PTEN-
altered population
Time to definitive deterioration of the ECOG performance status is defined in Section 8.1.4
together with details of censoring.
Time to definitive deterioration of the ECOG performance status in the overall and the 
PIK3CA/AKT1/PTEN-altered populations will be analysed as described for the investigator-
assessed PFS endpoint (Section 9.4.1.1) and stratified by the stratification factors 
(Section 4.1).  
9.4.2
Safety analyses
Safety analyses will be performed based on the Safety Analysis Set for the overall population 
and key safety results will be presented for the Altered Subgroup Safety Analysis Set for the 
PIK3CA/AKT1/PTEN-altered subgroup. 
Depending on the extent of any impact, summaries of data relating to patients diagnosed with 
COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, delayed or 

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discontinued IP, and other protocol deviations) may be generated.  More details will be 
provided in the SAP. 
9.4.2.1
Adverse events
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) that will have been released for execution at AZ/designee.
Safety data will be presented using descriptive statistics unless otherwise specified.
AEs will be presented for each treatment group by SOC and PT covering number and 
percentage of patients reporting at least one event and number of events where appropriate.  
AEs occurring prior to start of IMP, treatment emergent AEs and post-treatment AEs will be 
presented separately.  
An overview of AEs will present for each treatment group the number and percentage of 
patients with any AE, AEs with outcome of death, serious AEs, and AEs leading to 
discontinuation of IMP, as well as AEs leading to IMP dose interruptions and AEs leading to 
IMP dose reductions. 
Separate AE tables will be provided taken into consideration relationship as assessed by the 
investigator, CTCAE grade, seriousness, death and events leading to discontinuation of IMP 
as well as other action taken related to IMP, events of special interest and other significant 
adverse events.
An additional table will present number and percentage of patients with most common AEs.  
In accordance with the requirements of the FDA, a separate table will present non-serious AEs 
occurring in more than 5% of patients in any treatment group.
Key patient information will be presented for patients with AEs with outcome of death, 
serious AEs, and AEs leading to discontinuation of IMP.  
An AE listing for the safety analysis set will cover details for each individual AE.  
Full details of AE analyses will be provided in the SAP.
Treatment emergent
The following events are considered treatment emergent:

Adverse events with an onset date on or after first dose of IMP

Worsening of pre-existing events on or after first dose of IMP

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Ot her s afet y a n al ysis
Ot her safet y data i ncl u di n g p h ysical e xa mi nati o ns, cli nical hae mat ol o g y , c he mistr y, 
uri nal ysis, vital si g ns a n d E C Gs will be s u m marize d usi n g descri pti ve statist ics.  T he a nal ysis 
will be perf or me d base d o n t he Safet y A nal ysis Set f or t he o verall p o p ulat i on a n d o n t he 
Alt ere d S u b gr o u p Safet y A nal ysis Set f or t he PI K 3 C A/ A K T 1/ P T E N -alt ere d s u b gr o u p, as 
defi ne d i n t he S A P.
9. 4. 3
Ot her a n al yses
  
9. 4. 4
Met h o ds f or m ulti plicit y c o ntr ol
T o c o ntr ol  t he fa mil y-wise err or rate i n t he str o n g se nse at 5 % f or t he treat me nt c o m paris o ns 
i n O S a n d P F S, a pre defi ne d M T P wit h an al p ha -e x ha usti ve rec ycli n g strate g y (B ur m a n et al 
2 0 0 9 ) ta ki n g i nt o acc o u nt i ntri nsic c orrelati on bet wee n test statistics ( S pi esse ns a n d De b o is 
2 0 1 0 ), will be a p plie d.  T he M T P is o utli ne d i n Fi g ure 4 . Acc or di n g t o al p ha (test mass) 
s plitti n g a n d al p ha rec ycli n g, if t he hi g her-le vel h y p ot hesis i n t he M T P is rejecte d f or 
s u periori t y, t he n t he ne xt l o wer le vel h y p ot hesis will be teste d.  T he test mass t hat bec o mes 
a vaila ble after eac h rejecte d h y p ot hesis is rec ycle d t o l o wer le vel h y p ot heses n ot yet rejecte d. 
Tests will be gr o u pe d i nt o 2 mai n fa milies: o ne f or t he c o m paris o ns i n P F S, t he ot her f or t he 
c o mparis o ns i n O S.  Wit hi n t he P F S a n d O S fa milies, t here are 2 sets of tests, o ne i n t he 
o verall p o p ulat i on, t he ot her i n t he altere d s u b gr o u p.  T he P F S fa mil y will be teste d first, t he 
O S fa mil y  will be teste d later (Fi g ure 4 ).  T his testi n g pr oce d ure st o ps w he n t he e ntire test 
mass is all ocate d t o n o n -rejecte d h y p ot heses.  I m ple me ntati o n of t his pre defi ne d testi n g 
pr oce d ure, i ncl u di n g rec y cli n g, will c o ntr ol t h e fa mil y wise t ype I err or i n t he str o n g se nse at 
5 % ( 2 -side d), a m o n g all ke y  h y p ot heses.  
Fi g ure 4
Ill ustr ati o n of d at a c ut-offs a n d ass oci ate d tre at me nt c o m p aris o ns
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The significance level of α1 at PFS primary analysis in the altered subgroup will be determined as follows:

If the p-value for PFS in the overall population is significant at 3.5% level, then the α level of 0.035 tested for the 
overall population will be recycled, making α1=0.05.

If the p-value for PFS in the overall population is not significant at 3.5% level, then the α1 is determined by the 
observed ratio of #events in the altered subgroup and overall population using Spiessens and Debois method.
The significance level of α2 at OS interim analysis and α4 at OS final analysis for the altered subgroup will be determined by 
the observed information fraction (O’Brien & Fleming approach [Lan and DeMets 1983]) based on the remaining α available: 

If the p-value for PFS in the overall population is significant at 3.5% level, then the remaining α=0.05

If the p-value for PFS in the overall population is not significant at 3.5% level, then the remaining α=0.015.
Similarly, if the p-value for OS in the altered subgroup is significant at α2 level at the OS interim analysis, OS in the overall 
population will be tested using the O’Brien & Fleming approach [Lan and DeMets 1983] based on the remaining α available. 
If the p-value for OS in the altered subgroup is significant at α4 level at the OS final analysis, all remaining α available after 
PFS primary analysis will be used to test OS in the overall population, i.e. either 1.5% or 5% based on the outcome of PFS 
hypothesis testing in the overall population.
If the OS endpoint is successful at either interim or final analysis in both the overall 
population and PIK3CA/AKT1/PTEN-altered subgroup, the remaining alpha will be recycled 
to test ORR in the PIK3CA/AKT1/PTEN-altered subgroup. If significant, the remaining alpha 
will be recycled to test ORR in the overall population. Data at PFS primary analysis DCO will 
be used to test ORR.
9.5
Interim analyses 
The OS Interim Analysis is expected to occur when approximately 394 OS events have been 
observed in the overall population and similar maturity has been reached in the 
PIK3CA/AKT1/PTEN-altered population (56% maturity, 80% information fraction).  The 
significance level for OS will be based on the significance level available after the PFS 
primary analysis and will be determined according to the O’Brien and Fleming method (Lan 
and DeMets 1983).  
The Statistical Analysis Plan will describe the planned interim analysis in greater detail.  
9.5.1
Independent data monitoring committee (IDMC)
An IDMC will be established to assess the safety of capivasertib in an unblinded manner. The 
IDMC will be responsible for reviewing the safety data accruing in the study at regular 
intervals prior to the primary PFS analysis database lock, to provide a recommendation to 
AstraZeneca whether the study should continue unchanged, be stopped, or be modified in any 
way. The IDMC will consist of at least 2 physicians with expertise in breast cancer and one 
biostatistician. Further information on the IDMC and schedule of meetings will be defined in 
the IDMC Charter.
Appendix C provides more details on the rationale for and the remit of the committee.  

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9. 6
C h i na c o h ort
T he gl o bal c o h ort will e nr ol a p pr o xi matel y 9 3 0 patie nts t o ra n d o mise a p pr o xi matel y  
7 0 0 pati e nts.  T he C hi na co h ort will  c o nsist of a p pr o xi matel y 1 3 4 ra n d o mise d patie nts fr o m 
Nati o nal Me dical  Pr o d uct A d mi nistratio n ( N M P A) -certifie d sites.  T he gl o bal c o h ort will 
c o nsist of patie nts recr uite d b y t he d oc u me nte d date of L P F V of t he gl o bal c o h ort.  I n t he 
e ve nt t hat r ecr uit me nt  of C hi na c o h ort is n ot c o m plete d d uri n g gl obal recr uit me nt of 
a p pr o xi matel y 7 0 0 p atie nts, t he recr uit me nt  of C hi na c o h ort will c o nti n ue u ntil a p pr o xi matel y 
1 3 4 C hi nese patie nts ha ve bee n ra n d o mise d fr o m N M P A -cert ifie d sites.  Patie nts ra n d omise d
i n t he C hi na c o h ort pri or t o t he L P F V of t he gl o bal c o h ort e nr ol me nt will be i ncl u de d i n b ot h 
t he F A S a n d t he C hi na F A S.  A patie nt ra n d o mise d i n t he C hi na c o h ort after t he L P F V of t he 
gl o bal  c o h ort e nr ol me nt will be i ncl u de d o nl y i n t he C hi na F A S. 
Per N M P A g ui da nce, i n a d dit i on t o t he e val uati o n of t he gl o bal c o h ort data f or pri mar y , 
sec o n dar y a n d safety o bject i ves, e val uati on of c o nsiste nc y i n efficac y a n d safet y i n C hi nese 
p o p ul at i ons is re q uire d t o facilitate t he be nefit-ris k assess me nt f or C hi nese patie nts.  He nce, 
t he safet y a n d efficac y data i n t he C hi na c o h ort will be a nal yse d se paratel y w here t he sa me 
e n d p o i nt defi niti ons (as descri be d i n Sect i on  8. 1 ) a n d t he sa me a nal ysis met h o ds (as detaile d 
i n Secti o n 9. 4 ) are a p plie d.  
T he C hi na F A S will i ncl u de all pat ient s ra n d o mise d i n t he C hi na c o h ort i ncl u di n g t h ose w h o 
were recr uite d pri or t o t he cl os ure of t he gl o bal c o h ort a n d are t heref ore i ncl u de d i n t he 
a nal yses o f efficac y a nd safet y  for t he m ai n st u d y. T he C hi na altere d s u b gr o u p F A S will 
i ncl u de all patient s i n t he C hi na F A S wit h a PI K 3 C A/ A K T 1/ P T E N -alt ered res ul t fr o m a vali d 
bi o mar ker test as deter mi ne d b y ce ntral testi n g. B ot h C hi na F A S a n d C hi na altere d s u b gr o u p 
F A S will be use d f or C hi na -o nl y efficac y a nal yses.
T he C hi na safet y  a nal ysis set will c o nsist of all patie nts i ncl u de d i n t he C hi na F A S w h o 
recei ve d at least 1 d ose of st u d y treat me nt. T he C hi na altere d s u b gr o u p safet y a nal ysis set will 
c o nsist of all pat ient s i ncl u de d i n t he C hi na safet y a nal ysis set wit h a PI K 3 C A/ A K T 1/ P T E N -
altere d res ult fr o m a vali d bio m ar ker test as deter mi ne d b y ce ntral testi n g. 
Efficac y a nal yses f or t he C hi na c o h ort will be perf or me d w he n t he P F S a n d/ or O S data fr o m 
t he patie nts fr o m t he C hi na c o h ort are of si milar mat urit y at w hic h si g nifica nt cli nical efficac y 
is esta blis he d i n t he gl o bal c o h ort, e g, if O S efficac y is esta blis he d at t he O S I nteri m A nal ysis, 
a si milar mat urit y will be use d f or t he c o nsiste nc y e val uati on.
 
 
N o a dj ust me nt  for m ul tiplici t y will b e 
ma de a n d t he pr oce d ure f or hierarc hical testi n g detaile d i n Sect i on 9. 4 will n ot be f o ll owe d.
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Details of the China cohort analyses will be specified in the China SAP, which is to be 
finalised before the global cohort database lock for the PFS primary analysis.

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10
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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
Guidelines for evaluation of objective tumour response using 
RECIST v1.1 Criteria (Response Evaluation Criteria in Solid 
Tumours)
Introduction
This appendix details the implementation of Response Evaluation Criteria in Solid Tumours 
version 1.1 (RECIST v1.1) guidelines (Eisenhauer et al 2009).  Investigator assessments will 
use the RECIST v1.1 guidelines described in this appendix. 
Imaging modalities and acquisition specifications for RECIST v1.1
A summary of the imaging modalities that can be used for tumour assessment of target lesions 
(TLs), non-target lesions (NTLs), and new lesions (NLs) is provided in Table 15.
Table 15
Summary of imaging modalities for tumour assessment
Target lesions 
Non-target lesions
New lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
FDG-PET/CT
CT Computed tomography; MRI Magnetic resonance imaging; FDG-PET/CT 18F-Fluoro-deoxyglucose 
positron emission tomography/CT 
CT and MRI
Computed tomography (CT) with intravenous (IV) contrast, is the preferred imaging modality, 
and magnetic resonance imaging (MRI) with IV contrast being acceptable should CT be 
contraindicated, to generate reproducible anatomical images for tumour assessments, ie, for 
measurement of TLs, assessment of NTLs, and identification of NLs.  It is essential that the 
same correct imaging modality, image acquisition parameters (eg, anatomic coverage, 
imaging sequences, etc.), imaging facility, tumour assessor (eg, radiologist), and method of 
tumour assessment (eg, RECIST v1.1) are used consistently for each patient throughout the 
study.  The use of the same scanner for serial scans is recommended, if possible.  It is 
important to follow the image collection/tumour assessment schedule as closely as possible 
(refer to the clinical study protocol Schedule of Activities [Section 1.1], and this on-study 
imaging schedule MUST be followed regardless of any delays in dosing or missed imaging 
visits.  If an unscheduled assessment is performed (eg, to investigate clinical signs/symptoms 
of progression), and the patient has not progressed, every attempt should be made to perform 
the subsequent scan acquisitions at the next scheduled imaging visit.

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Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice.  Body 
scans should be performed with breath-hold scanning techniques if possible.  Therefore, CT of 
the chest is recommended over MRI due to significant motion artefacts (heart, major blood 
vessels, breathing) associated with MRI.  MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity and measurement.  Furthermore, the 
availability of MRI is variable globally.  The modality used at follow-up should be the same 
as was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence.  In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition.  It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. 
The most critical CT and MRI image acquisition parameters for optimal tumour evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the chest, 
abdomen and pelvis.  Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that 
may be involved based on signs and symptoms of individual patients.  Because a lesion 
later identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up timepoints.  This will enable 
better consistency not only of tumour measurements but also identification of a new 
disease.
Required anatomical regions to be imaged for assessment of tumour burden (TLs and/or 
NTLs) at baseline and follow-up visits vary according to the study, and these are specified in 
the main clinical study protocol (eg, Schedule of Activities [Section 1.1]).  Examples include 
the following:

IV contrast enhanced CT of chest-abdomen (including the entire liver and both 
adrenal glands) and pelvis

Non-contrast CT of chest and IV contrast enhanced abdomen (including the entire 
liver and both adrenal glands) and pelvis

IV contrast enhanced CT or MRI of the head and neck

IV contrast enhanced MRI (preferred) or CT of the brain
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumours require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning.  An adequate volume of a suitable contrast agent should be given so that the tumour 
lesions are demonstrated to best effect and a consistent method is used on subsequent 

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examinations for any given patient.  Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen and pelvis. 
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) with ≤5 mm slice thickness throughout the 
entire anatomic region of interest for optimal lesion measurements.  Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses greater than 5 mm.  If 
this occurs, the minimum size of measurable lesions at baseline should be twice the slice 
thickness of the baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered.  When measuring lesions, 
the TL should be measured on the same window setting for repeated examinations throughout 
the study.
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL.  Chest X-ray can, however, be 
used to assess NTL and to identify the presence of NLs.  However, there is preference that a 
higher resolution modality such as CT be used to confirm the presence of NLs.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence 
of new bone lesions. 
Isotopic bone scan 
A bone scan should be performed at screening; thereafter, a bone scan should only be 
performed in the event of clinical suspicion of progression of existing bone lesions that cannot 
be visualised on CT or MRI, the development of new bone lesions or in the assessment of a 
complete response (CR), if any disease was evident at screening.  
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits.  NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 
equivocal hot-spot on a bone scan which cannot be verified with correlative imaging (CT, 
MRI, X-ray) of the same anatomical region shall not be the only trigger for a progressive 
disease (PD) assessment at that timepoint. 
FDG-PET/CT
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography/CT 
(FDG-PET/CT) scans may be used as a method for identifying new extrahepatic lesions (but 
not intrahepatic lesions) for RECIST v1.1 assessments, according to the following algorithm: 

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NLs will be recorded where there is positive 18F-Fluoro-deoxyglucose uptake1 not present on 
baseline or a prior FDG-PET scan or in a location corresponding to an NL on a companion 
CT/MRI collected close in time to the FDG-PET scan.  The PET portion of the PET/CT 
introduces additional data that may bias an investigator if it is not routinely or serially 
performed.  Therefore, if there is no baseline or prior FDG-PET scan available for 
comparison, and no evidence of NLs on companion CT/MRI scans, then follow-up CT/MRI 
assessments should continue as per the regular imaging schedule in order to verify the 
unequivocal presence of NLs.
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT scan 
are of limited use in anatomically-based efficacy assessments, and it is therefore suggested 
that they should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumour 
measurements by RECIST v1.1.  In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with 
intravenous contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT 
can be used for RECIST v1.1 tumour assessments.  Caution that this is not recommended 
because the PET portion of the CT introduces additional (PET) data that may bias an 
investigator if it is not routinely or serially performed.
Ultrasound 
Ultrasound examination will not be used for RECIST v1.1 assessment of tumours as it is not a 
reproducible acquisition method (operator dependent), is patientive in interpretation and may 
not provide an accurate assessment of true tumour size.  Tumours identified by ultrasound will 
need to be assessed by correlative CT or MRI anatomical scan.
Other tumour assessments 
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST v1.1 assessments.  Tumours identified by clinical examination will 
need to be assessed by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour assessment.
Histology and cytology
                                               
1 A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of 
the surrounding tissue or liver is observed.

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Histology or tumour markers on tumour biopsy samples will not be used as part of the tumour 
response assessment as per RECIST v1.1. 
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, pleural effusion) that appears or worsens during the study will not be 
used as part of the tumour response assessment as per RECIST v1.1. 
Furthermore, an overall assessment of complete response (all other disease disappears/reverts 
to normal) would be changed to partial response if an effusion remains present radiologically.
Measurability of tumour lesions at baseline
RECIST v1.1 measurable lesions at baseline:
A tumour lesion that can be accurately measured at baseline as ≥10 mm in the longest 
diameter for non-nodal lesions or ≥15 mm in short axis2 diameter for lymph node lesions with 
IV contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements.  
Please see additional RECIST v1.1 guidance below on measurability of intrahepatic 
hepatocellular carcinoma (HCC) lesions and porta hepatis lymph nodes.
Non-measurable lesions at baseline:

Truly non-measurable lesions include the following: 

Bone lesions (see exception below for soft tissue component)

Leptomeningeal disease

Ascites, pleural, or pericardial effusion

Inflammatory breast disease

Lymphangitic involvement of skin or lung

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline3)

Previously irradiated lesions4

Brain metastasis
                                               
2 The short axis is defined as the longest in-plane axis perpendicular to long axis.
3 Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs.
4 Localised post-radiation changes which affect lesion sizes may occur.  Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of 
the NTL assessment.

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Special considerations regarding lesion measurability at baseline:

Bone lesions

Bone scan, PET scan or plain X-ray are not considered adequate imaging techniques 
to measure bone lesions; however, these techniques can be used to confirm the 
presence or disappearance of bone lesions

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability

Blastic bone lesions are considered non-measurable

Cystic lesions thought to represent 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 over cystic 
lesions as TLs
RECIST v1.1 target lesion selection at baseline:
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TLs at baseline.  TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis diameter 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.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph node locations as TLs.  A bilateral organ (eg, 
adrenal glands), a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each 
considered as a single organ.
The site and location of each TL should be documented as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes).  All measurements should be 
recorded in millimetres.  At baseline the sum of the diameters for all TL will be calculated and 
reported as the baseline sum of diameters.  At follow-up visits the sum of diameters for all TL 
will be calculated and reported as the follow-up sum of diameters.
Special cases for target lesion assessment at baseline:

For TL measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter

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
When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass.  Non-nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter

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

Tumour lesions selected for fresh screening biopsy should not be selected as TLs, unless 
imaging occurred at least ~2 weeks after biopsy, allowing time for healing
RECIST v1.1 non-target lesion selection at baseline:
All other lesions, including non-measurable lesions and surplus measurable lesions not 
recorded as TLs should be identified as NTLs at baseline.  Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up.
Evaluation of tumour response and progression 
RECIST v1.1 target lesion assessment at follow-up
This section defines the criteria used to determine objective tumour visit response for 
RECIST v1.1-defined TLs.  The imaging modality, location, and scan date of each TL 
identified previously at baseline should be documented at follow-up visits with the long axis 
diameter for non-nodal lesions or short axis diameter for lymph node lesions.  All 
measurements should be recorded in millimetres.  The sum of the diameters for all TL at each 
follow-up visit will be compared to the baseline sum of diameters (for response or stable 
disease) or to the smallest prior (nadir) sum of diameters (for progression) (Table 16). 
Special cases for target lesion assessment at follow-up:

If a lesion has completely disappeared, the diameter should be recorded as 0 mm.  If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL

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 1 of the lesions and 0 mm recorded for the other lesion(s).  If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion.  If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the vector of the longest diameter of the coalesced mass should be used to 
determine the perpendicular vector for the maximal short axis diameter

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.  The choice of ‘Too large to measure’ in the case report form will 
trigger an overall visit response of PD

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
When a TL has had any intervention e.g., definitive radiotherapy, embolisation, surgery, 
transcatheter arterial chemoembolization (TACE), etc., during the study, the size of the 
TL should still be provided where possible and the intervention recorded in the RECIST 
v1.1 case report form for the current imaging visit and all subsequent visits.  If a TL has 
been completely removed (surgery) or disappears, the longest diameter should be 
recorded as 0 mm
Table 16
RECIST v1.1 evaluation of target lesions
Complete response (CR)
Disappearance of all TLs since baseline.  Any pathological lymph 
nodes selected as TLs must have a reduction in short axis diameter 
to <10 mm.
Partial response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters
Stable disease (SD)
Neither sufficient decrease in sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir) – 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 from nadir
Not evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or not 
evaluable (e.g., missing anatomy) 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
Not applicable (NA)
Only relevant if no TLs present at baseline
CR  complete response; PR  partial response; PD  progression of disease; NE  not evaluable; SD  stable disease; 
TL  target lesion.
RECIST v1.1 non-target lesion assessment at follow-up
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.
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 stable disease or 
partial response in TLs, the overall tumour burden has increased sufficiently to merit 
unequivocal progression by NTLs.  A modest ‘increase’ in the size of one or more NTLs is 
usually not sufficient to qualify for unequivocal progression status.  The designation of overall 
progression solely on the basis of change in non-target disease in the face of stable disease 
(SD) or progressive disease (PD) of target disease will therefore be extremely rare (Table 17).

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Table 17
RECIST v1.1 evaluation of non-target lesions
Complete response (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 one or more NTL
Progression (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
Not evaluable (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
Not applicable (NA)
Only relevant if no NTLs present at baseline
CR  complete response; PR  partial response; PD  progression of disease; NE  not evaluable; NTL  non-target 
lesion; TL target lesion.
RECIST v1.1 new lesion identification at follow-up
Details including the imaging modality, the date of scan, and the location of any NLs will be 
recorded in the case report form.  The presence of 1 or more NLs is assessed as progression.  
The finding of an NL 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 an NL is equivocal, for example because of its small size, the treatment and 
tumour assessments should be continued until the previously (pre-existing) new lesion has 
been assessed as unequivocal at a follow-up visit, and then the progression date should be 
declared using the date of the initial scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression.
RECIST v1.1 evaluation of overall visit response at follow-up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs is identical between RECIST v1.1 and RECIST v1.1 using the algorithm shown in 
Table 18.
Table 18
RECIST v1.1 overall visit response
Target lesions
Non-target lesions
New lesions
Overall visit response
CR
CR
No
CR
CR
NA
No
CR

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Target lesions
Non-target lesions
New lesions
Overall visit response
NA
CR
No
CR
CR
Non-CR/Non-PD 
No
PR
CR
NE
No 
PR
PR
Non-PD or NE or NA
No
PR
SD 
Non-PD or NE or NA
No
SD
NA
Non-CR/Non-PD
No
SD (Non-CR/Non-PDa)
NE
Non-PD or NE or NA
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
a
Non-CR/Non-PD for overall response if only non-target lesions (no TLs) are present at baseline.
NOTE: An overall assessment of complete response (all other disease disappears/reverts to normal) would be 
changed to partial response if ascites remains present radiologically.
CR complete response; NA not applicable; NE not evaluable; PD progressive disease; PR partial response; 
(only relevant if there were no target lesions at baseline or no non-target lesions at baseline); SD stable disease; 
TL target lesion. 
The following overall visit responses are possible depending on the extent of tumour disease 
at baseline:

For patients with TLs (at baseline): CR, PR, SD, PD, or NE

For patients with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE
Central imaging
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed imaging Contract Research Organisation (iCRO) for QC, storage, and 
for Blinded Independent Central Review (BICR).  Digital copies of all original scans should 
be stored at the investigator site as Source documents.  Electronic image transfer from the 
sites to the iCRO is strongly encouraged.  A BICR of images will be performed at the 
discretion of AstraZeneca.  Results of these independent reviews will not be communicated to 
investigators, and results of investigator tumour assessments will not be shared with the 
central reviewers.  The management of patients will be based in part upon the results of the 
tumour assessments conducted by the investigator.  Further details of the BICR will be 
documented in an Independent Review Charter.

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REFERENCE
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1).  Eur J Cancer 
2009;45(2):228-47.

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Appendix B
ECOG/WHO Performance Status
The Eastern Cooperative Oncology Group (ECOG)/ World Health Organisation (WHO) 
performance scale is presented in Table 19.  
Table 19
ECOG performance status scale (Oken et al 1982)
Grade
0
Fully active and able to carry on all pre-disease performance without restriction 
(Karnofsky 90-100).  
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work (Karnofsky 70-80).  
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up 
and about more than 50% of waking hours (Karnofsky 50-60).  
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
(Karnofsky 30-40).  
4
Completely disabled. Cannot carry out any self-care.  Totally confined to bed or chair 
(Karnofsky 10-20).  
REFERENCE
Oken et al 1982
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.  Toxicity and 
response criteria of the Eastern Cooperative Oncology Group.  Am J Clin 
Oncol.1982;5(6):649-655.

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Appendix C
Regulatory, ethical and study oversight considerations
C 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, informed consent form (ICF), Investigator’s Brochure, 
and other relevant documents (eg, advertisements) must be submitted to an institutional 
review board (IRB)/independent ethics committee (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 (Code of Federal Regulations), ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.

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
A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study.

If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
they become aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authorities and other regulatory agencies about such breaches.

AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trial Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the EMA CTIS. It is important to note that redacted 
versions of serious breach reports will be available to the public via CTIS.

The investigator should have a process in place to ensure that:

The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach.

A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (e-mail address or telephone number) provided by AstraZeneca.

Cli nical St u d y Pr ot oc ol - 5. 0
Astra Ze neca
Ca pi vaserti b ( A Z D 5 3 6 3) - D 3 6 1 5 C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 4 5 of 1 9 6
C 2
Fi n a nci al discl os ure
I n vesti gat ors a n d s u b-i n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mat i on as re q ueste d t o all o w t he s p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or disc l os ure state me nts t o t he a p pr o priate re g ulat or y a ut h orities.  I n vest i gat ors 
are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y 
a n d f or 1 year after c o mpleti o n of  t he st u d y.  
C 3
I nfor me d c o nse nt pr ocess
T he i n vest i gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he patie nt or 
his/ her le gall y  a ut h orise d re prese ntati ve a n d a ns wer all q uest i ons re gar di n g t he st u d y .  
P ati e nts must be i nf or me d t hat t heir partici pat i on is v ol unt ar y.  P atie nts or t heir le gall y 
a ut h orise d re prese ntati ve will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets 
t he re q uire me nts of 2 1 C F R 5 0 , lo c al  re g ulat i ons, I C H g ui deli nes, Heal t h I ns ura nce P orta bility 
a n d Acc o u nta bilit y Act ( HI P A A) re q uire me nts, w here a p plica ble, a n d t he I R B/I E C or st u d y 
ce ntre.  
T he m e dical rec or d must i ncl u de a state m e nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he patie nt was e nr olle d i n t he st u d y  a n d t he date a n d ti me t he writte n c o nse nt was 
o btai ne d.  T he a ut h oris e d pers o n o btai ni n g t he i nf o r me d c o nse nt m ust als o si g n t he I C F.
P ati e nts must be re -c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
parti ci pat i on i n t he st u d y.  
A c o p y  of t he I C F(s) must be pr o vi de d t o t he pati e nt or t he patie nt’s le gall y a ut h orise d 
re prese ntati ve.  
If a patie nt decli nes t o partici pate i n a n y 
 
, t here will be n o pe nalty or l oss of be nefit t o t he patie nt a n d he/s he will n ot be 
e xcl u de d fr o m ot her as pects of t he s t u d y.  
A pat ient  w h o is rescree ne d is n ot re q uire d t o si g n a n ot her I C F if t he rescree ni n g occ urs 
wi t hi n 2 8 da ys fr om t he pre vi o us I C F si g nat ure date.  
 
 
 
 
 
  Patie nts w h o decli ne t o partici pate 
i n t his o pti o nal researc h will i n dicate t his i n t he I C F.  If a patie nt wit hdra ws c o nse nt t o t he use 
C CI
C CI

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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.  
C 4
Data protection
Each patient will be assigned a unique identifier by the sponsor.  Any patient records or data 
sets transferred to the sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred.  
The patient must be informed that his/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 his/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.  
The patient must be informed that data will be collected only for the business needs. We will 
only collect and use the minimum amount of personal data to support our business activities 
and will not make personal data available to anyone (including internal staff) who is not 
authorised or does not have a business need to know the information.
The patient must be informed that in some cases their data may be pseudonymised. The 
General data Protection Regulation (GDPR) defines pseudonymisation as the processing of 
personal data in such a way that the personal data can no longer be attributed to a specific 
individual without the use of additional information, provided that such additional information 
is kept separately and protected by technical and organisational measures to ensure that the 
personal data are not attributed to an identified or identifiable natural person.
C 5
Committees structure
A Trial Steering Committee (TSC) that includes Principal Investigators for this study and that 
may include Principal Investigators from the other pivotal studies will provide:

Advice on any aspect of the study design or conduct based on requests from the 
sponsor

Review relevant research (completed, ongoing, and pending) which may impact upon 
the study, assure consistency across the entire capivasertib pivotal programme, and to 
support the study team with interpretation of study outcomes

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A Steering Committee Charter will define the primary responsibilities of the steering 
committee, its members, and the purpose and timing of meetings.  
An Independent Data Monitoring Committee (IDMC) will be established to assess the safety 
of capivasertib in an unblinded manner. The IDMC will be responsible for reviewing the 
safety data accruing in the study at regular intervals prior to the primary PFS analysis database 
lock, to provide a recommendation to AstraZeneca whether the study should continue 
unchanged, be stopped, or be modified in any way. The IDMC will consist of at least 2 
physicians with expertise in breast cancer and one biostatistician. Further information on the 
IDMC and schedule of meetings will be defined in the IDMC Charter.
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 clinical study protocol and 
letters to investigators.  

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C 6
Dissemination of clinical study data
A description of this clinical trial will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the D3615C00001 study results when they are available.  The clinical trial and/or 
summary of D3615C00001 study results may also be available on other websites according to 
the regulations of the countries in which the D3615C00001 study is conducted.  
C 7
Data quality assurance
All patient data relating to the study will be recorded on an electronic case report form (eCRF) 
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 eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
AstraZeneca or designee is responsible for medical oversight throughout the conduct of the 
study which includes clinical reviews of study data in accordance with the currently approved 
protocol. 
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 eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for a minimum of 25 years after study archiving or as required 
by local regulations, according to the AstraZeneca GRAD Schedule. No records may be 
destroyed during the retention period without the written approval of AstraZeneca. No records 
may be transferred to another location or party without written notification to AstraZeneca.  

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C 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 eCRF 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.  
C 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 
judgment of AstraZeneca, trial subjects 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 drug

Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject 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 subjects’ interests.
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development

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C 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 
coordinating 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 D
Guidance regarding potential interactions of capivasertib 
with concomitant medications
NOTE: Patients are not eligible to enter the study if they have received any of the medications 
specified in the Exclusion Criterion 22 or are unable to meet the cautions and restrictions 
described below.
D 1
Drugs that may influence capivasertib pharmacokinetics
Based on results from in vitro studies, capivasertib is a substrate of CYP3A4, although data 
suggests that glucuronidation may be the major metabolic route.  Co-administration of some 
CYP3A4 inhibitors may increase exposure to capivasertib and hence potentially affect 
toxicity, while CYP3A4 inducers may decrease the exposure to capivasertib and may 
potentially affect efficacy.  
The following lists (Table 20) are not intended to be exhaustive and a similar restriction will 
apply to other agents that are known to modulate CYP3A4 activity.  Appropriate medical 
judgment is required.  Please contact AstraZeneca with any queries you have on this issue.  
Table 20
CYP3A4-interacting medication that must be avoided or used with 
caution
Medication
Recommendation
Rationale
Clarithromycin
Cobicistat
Itraconazole
Ketoconazole
Nefazodonea
Posaconazole 
Protease inhibitors (ritonavir, 
saquinavir, indinavir, tipranavir, 
telaprevir, elvitegravir, lopinavir, 
nelfinavir, boceprevir)
Telithromycin 
Troleandomycin
Voriconazole 
Must be avoided 2 weeks prior to 
capivasertib administration and for 
2 days following discontinuation of 
capivasertib.  
Potent CYP3A4 inhibitors, 
which may increase the 
capivasertib exposure.  

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Medication
Recommendation
Rationale
Carbamazepinea
Enzalutamide 
Phenobarbital 
Phenytoin 
Rifabutin 
Rifampicin
Mitotane
St John’s wort
Must be avoided 2 weeks 
(3 weeks for St John’s Wort and 
4 weeks for enzalutamide) prior to 
capivasertib administration.  
Potent CYP3A4 inducers, which 
may reduce the capivasertib 
exposure.  
Aprepitant
Diltiazem
Erythromycin 
Fluconazole 
Verapamil 
May be used with cautionb.  
Moderate CYP3A4 inhibitors 
which might increase the 
capivasertib exposure.  
a
Carbamazepine and nefazodone must be avoided prior to capivasertib administration and 1 week following 
discontinuation of capivasertib. Carbamazepine is a potent CYP3A4 inducer and a CYP3A4 substrate; 
nefazodone is a potent CYP3A4 inducer.
b
Drugs are permitted but caution should be exercised and patients monitored closely for possible drug 
interactions.  Please refer to full prescribing information for all drugs prior to co-administration with 
capivasertib.  
D 2
Drugs that may be influenced by capivasertib
There are currently no data confirming that there are any pharmacokinetic (PK) interactions 
between capivasertib and CYP3A4.  Likewise, there are no confirmed interactions with 
MATE1 or OCT2 substrates.  The potential interactions detailed below (Table 21 and 
Table 22) are considered on the basis of preclinical data and physiologically based 
pharmacokinetic (PBPK) modelling.  The following list is not intended to be exhaustive, and a 
similar restriction will apply to other agents that are known to be sensitive to inhibition of 
CYP3A4 metabolism and/or MATE1 or OCT2 transport and have a narrow therapeutic 
window.  Appropriate medical judgment is required.  Please contact AstraZeneca with any 
queries you have on this issue.  

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Table 21
CYP3A4 substrates that must be avoided or used with caution
Medication
Usage
Rationale
Alfentanil 
Atorvastatin
Carbamazepinea
Cerivastatin
Cyclosporin
Diergotamine
Ergotamine
Fentanyl
Lovastatin
Simvastatin
Sirolimus 
Tacrolimus
Must be avoided 1 week prior to 
capivasertib administration and for 
1 week following discontinuation of 
capivasertib.  
CYP3A4 substrates, whose 
exposure may be increased by 
capivasertib.  
Alprazolam 
Domperidone
Erythromycin 
Felodipine 
Haloperidol
Isradipine
Midazolam 
Methylprednisolone
Nifedipine 
Pimozide 
Quinidine
Sertraline
Tamoxifen
Trazodone 
Triazolam
May be used with cautionb.  
CYP3A4 substrates, whose 
exposure may be increased by 
capivasertib.  
a
Carbamazepine must be avoided prior to capivasertib administration and 1 week following discontinuation 
of capivasertib. Carbamazepine is a potent CYP3A4 inducer and a CYP3A4 substrate. 
b
Drugs are permitted but caution should be exercised and patients monitored closely for possible drug 
interactions.  Please refer to full prescribing information for all drugs prior to co-administration with 
capivasertib.
Table 22
MATE1 and/or OCT2 transporter substrates that should be used with 
caution
Medication
Recommendation
Rationale
Dofetilide
May be used with cautiona  
MATE1 and OCT2 substrate with a narrow 
therapeutic window whose exposure may be 
increased by capivasertib

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Medication
Recommendation
Rationale
Metformin
See Section 8.4.5.3  
MATE1 and OCT2 substrate whose exposure 
may be increased by capivasertib
Procainamide
May be used with cautiona  
OCT2 substrate with a narrow therapeutic 
window whose exposure may be increased by 
capivasertib
a
Drugs are permitted but caution should be exercised and patients monitored closely for possible drug 
interactions.  Please refer to full prescribing information for all drugs prior to co-administration with 
capivasertib. 
D 3
Guidance for statins
Atorvastatin, cerivastatin, lovastatin, and simvastatin must be avoided due to the potential for 
increased exposure through inhibition of CYP3A4 by capivasertib (Table 21). 
Fluvastatin, pravastatin, and rosuvastatin are minimally influenced by CYP3A4 inhibitors, 
conveying a relatively low potential for clinically significant drug-drug interactions via this 
mechanism.  
Capivasertib also has a potential to inhibit the organic-anion-transporting polypeptide 1B1 
(OATP-1B1) transporter, which is implicated in the distribution and clearance of many of the 
statins.  The predicted increase in the area under the plasma concentration-time curve (AUC) 
is 1.3-fold for pravastatin and 1.5-fold for rosuvastatin.  It is, therefore, recommended that 
doses of pravastatin be capped to 40 mg once daily and rosuvastatin be capped to 10 mg once 
daily when combined with capivasertib, including 1 week prior to capivasertib administration 
and for 1 week following discontinuation of capivasertib.   
In summary, rosuvastatin (up to 10 mg once daily), pravastatin (up to 40 mg once daily) and 
fluvastatin are appropriate agents to be used in patients included in capivasertib studies who 
require statin therapy.  
D 4
Additional resources
For additional inhibitors, inducers and substrates please refer to:
https://drug-interactions.medicine.iu.edu/Clinical-Table.aspx
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm093664.htm

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Appendix E
Adverse event definitions and additional safety information
E 1
Definition of adverse events
An adverse event (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.  
AEs of special interest events will be identified and actively monitored during the study.  
E 2
Definitions of serious adverse event
A serious adverse event 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 abnormality or birth defect

Is an important medical event that may jeopardise the patient or may require medical 
treatment to prevent one of the outcomes listed above
AEs for malignant tumours reported during a study should generally be assessed as Serious 
AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a Non-
Serious AE. For example, if the tumour is included as medical history and progression occurs 
during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as Serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as Non-Serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 
is being treated by the investigational medicinal 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.
E 3
Life-threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).  
E 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE (SAE), although the 
reasons for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or 
surgical operations planned before or during a study are not considered AEs if the illness or 
disease existed before the patient was enrolled in the study, provided that it did not deteriorate 
in an unexpected way during the study.  
E 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.  
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.  

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse

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E 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).  The applicable 
version of CTCAE should be described clearly.  
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 E 2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix E 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 E 2.  
E 7
A guide to interpreting the causality question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.  

Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?  

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?  

De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?  

No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.  

Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped?  AstraZeneca would not normally recommend or support a 
re-challenge.  

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.  
In difficult cases, other factors could be considered such as:

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
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 judgment.  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.  
E 8
Medication error, drug abuse and drug misuse
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP that either causes harm to the participant or has the potential 
to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.  
Medication error includes situations where an error:

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors include:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, eg, wrong route, dose (error greater than ± 10%), 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 refrigerator when it should be at room 
temperature 

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
Wrong participant received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/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
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP for a perceived reward or desired non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded 
to the DES using the Drug Abuse Report Form.  This form should be used both if the drug 
abuse happened in a study participant or if the drug abuse regards a person not enrolled in the 
study (such as a relative of the study participant).
Examples of drug abuse include but are not limited to:

The drug is used with the intent of getting a perceived reward (by the study participant or 
a person not enrolled in the study)

The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high. 
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP for 
medicinal purposes outside of the authorised product information, or for unauthorised IMPs, 
outside the intended use as specified in the protocol, and includes deliberate administration of 
the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form.  This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant).

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Examples of drug misuse include but are not limited to:

The drug is used with the intention to cause an effect in another person

The drug is sold to other people for recreational purposes

The drug is used to facilitate assault in another person

The drug is deliberately administered by the wrong route

The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole

Only half the dose is taken because the study participant feels that they were feeling better 
when not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug.

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Appendix F
Handling of human biological samples
F 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 AstraZeneca-assigned biobanks and will 
be registered by the AstraZeneca Biobank Team during the entire life cycle.  
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.  
F 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.  
As collection of the biological samples is an integral part of the study, then the patient is 
withdrawn from further study participation.  
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

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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.  
F 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.  
The investigator ensures that samples are labelled and shipped in accordance with the 
Laboratory Manual and the Biological Substance, Category B Regulations.
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

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
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used

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

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Inclusion criteria
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol (CSP) and provide informed consent for the 
genetic sampling and analyses.  
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study.  
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 7.3 of the main 
CSP.  
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients at screening.  
Although DNA is stable, early sample collection is preferred to avoid introducing bias through 
excluding patients who may withdraw due to an adverse event (AE), such patients would be 
important to include in any genetic analysis.  If for any reason the sample is not drawn at 
screening, it may be taken at any visit until the last study visit.  Only one sample should be 
collected per patient for genetics during the study.  Samples will be collected, labelled, stored, 
and shipped as detailed in the Laboratory Manual.  
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 
15 years, from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.  
An additional second code will be assigned to the blood sample either before or at the time of 
DNA extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable only by the second, unique number.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).  

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The link between the patient enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations.  The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.  
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix C.  
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study centre.  The 
investigator(s) is responsible for ensuring that consent is given freely and that the patient 
understands that they may freely withdrawal from the genetic aspect of the study at any time.  
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data.  In addition, regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.  
Data management
Any genotype 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 genetic 
differences from groups of individuals with a disease) from this genetic 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 

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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 genetic data 
in a suitable secure environment separate from the clinical database.  
Statistical methods and determination of sample size
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A statistical 
analysis plan may be prepared where appropriate.  

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Appendix H
Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s law
H 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.  Specific guidance 
on managing liver abnormalities can be found in Section 8.3.8.  
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 adverse event (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 investigational 
medicinal product (IMP).  
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.  
H 2
Definitions
Potential Hy’s Law
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × upper limit of 
normal (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).  

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Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
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.  
H 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 H 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
H 4
Follow-up
H 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 clinical study protocol (CSP).  
H 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 

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
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; 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 IMP, the investigator is not required to
submit a PHL SAE unless there is a significant change in the patient’s condition***
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, and complete 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 eCRF modules as information becomes available
***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.
H 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 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from 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.  

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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 eCRF

If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE CRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provide any further update to the previously submitted SAE of PHL (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to IMP 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 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined

T h e c o nt e nt of p a g e s 1 7 2- 1 7 3  w a s r e n d er e d si n c e it pr e s e nt s i nf or m ati o n u n d er c o p yri g ht pr ot e cti o n - q u e sti o n n air e E O R T C Q L Q- C 3 0

T h e c o nt e nt of p a g e s 1 7 4- 1 7 5  w a s r e n d er e d si n c e it pr e s e nt s i nf or m ati o n u n d er c o p yri g ht pr ot e cti o n - q u e sti o n n air e E O R T C Q L Q- B R 2 3

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I 3
PGIS

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I 4
PGIC

T h e c o nt e nt of p a g e 1 7 8 w a s r e n d er e d si n c e it pr e s e nt s i nf or m ati o n u n d er c o p yri g ht pr ot e cti o n - q u e sti o n n air e P R O- C T C A E

T h e c o nt e nt of p a g e s 1 7 9- 1 8 1  w a s r e n d er e d si n c e it pr e s e nt s i nf or m ati o n u n d er c o p yri g ht pr ot e cti o n - q u e sti o n n air e E Q- 5 D- 5 L

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I 7
PGI-TT

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Appendix J
Abbreviations
The following abbreviations and special terms are used in this study Clinical Study Protocol.  
Abbreviation or special 
term
Explanation
ABC
Advanced breast cancer
AE
Adverse event
AESI
Adverse Event of Special Interest
AI
Aromatase inhibitor
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-12h
Area under the plasma concentration-time curve from zero to 12 hours
BD
Twice-daily
BICR
Blinded Independent Central Review
BRCA1/2
Breast cancer gene 1/2
CBR
Clinical benefit rate
CI
Confidence interval
Cmax
Maximum observed plasma (peak) concentration
CMH
Cochran-Mantel Haenszel
COVID-19
Novel coronavirus disease 2019
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computer tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumour DNA
CTIS
Clinical Trials Information System
CYP
Cytochrome P450
DCO
Data cut-off
DNA
Deoxyribonucleic acid
DoR
Duration of response
ECG
Electrocardiogram
ECHO
Echocardiography
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form

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Abbreviation or special 
term
Explanation
EDC
Electronic data capture
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of Cancer
EORTC QLQ-BR23
EORTC Quality of Life Questionnaire-breast cancer specific module
EORTC QLQ-C30
EORTC Quality of Life Questionnaire-Core 30 items
ePRO
Electronic patient-reported outcomes
EQ-5D-5L
European Quality of Life 5-Domain 5-Level Scale
ER
Estrogen receptor 
EU
European Union
FDA
Food and Drug Administration
FAS
Full Analysis Set
FFPE
Formalin-fixed paraffin-embedded
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
HbA1c
Glycosylated haemoglobin
HER2
Human epidermal growth factor receptor 2
HIV
Human immunodeficiency virus
HOSPAD
Hospital Admission
HR
Hazard ratio
HR+
Hormone receptor positive
HRQoL
Health-related quality of life
IA
Interim analysis
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IMP
Investigational medicinal product
IRB
Institutional Review Board
ITT
Intent-to-treat
IV
Intravenous
IVD
In-vitro diagnostic
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KM
Kaplan-Meier

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Abbreviation or special 
term
Explanation
LHRH
Luteinising-hormone releasing hormone
LTED
Long-term estrogen deprivation
LMWH
Low molecular weight heparin
LPFV
Last patient first visit
LVEF
Left ventricular ejection fraction
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
mTOR
Mammalian target of rapamycin
MTP
Multiple testing procedure
MUGA
Multiple-gated acquisition
NCCN
National Comprehensive Cancer Network
NCI 
National Cancer Institute
NGS
Next-Generation Sequencing
NL
New lesion
NMPA
National Medical Product Administration
NTL
Non-target lesion
ORR
Objective response rate
OS
Overall survival
PFS
Progression-free survival
PFS2
Time from randomisation to second progression or death
PGIC
Patient Global Impression–Change
PGIS
Patient Global Impression–Severity
PGI-TT
Patient Global Impression–Treatment Tolerability
PI3K
Phosphatidylinositol-3-kinase
PK
Pharmacokinetics
PR
Partial response
PRO
Patient-reported outcome
PRO-CTCAE
Patient-reported outcomes version of the Common Terminology Criteria for 
Adverse Events
PTEN
Phosphatase and tensin homolog
QoL
Quality of life
QT
ECG interval measured from the onset of the QRS complex to the end of the 
T wave
QTc
Corrected QT interval
QTcF
QT corrected by Fridericia’s formula

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Abbreviation or special 
term
Explanation
RECIST
Response Evaluation Criteria in Solid Tumours.  This study will use RECIST 
version 1.1. 
RNA
Ribonucleic acid
SAE
Serious adverse event 
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBGM
Self-blood glucose monitoring
SERD
Selective estrogen receptor degrader
SoA
Schedule of Activities
TFSC
Time to first subsequent chemotherapy
TL
Target lesion
tmax
Time to reach peak or maximum observed concentration following drug 
administration
TNBC
Triple-negative breast cancer
TSC
Trial Steering Committee
ULN
Upper limit of normal
VHP
Voluntary Harmonisation Procedure
vs
Versus
WHO
World Health Organisation

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Appendix K
Changes Related to Mitigation of Study Disruptions Due to 
COVID-19 Outbreak - Temporary Measures
Note: Changes below should be temporarily implemented only during study disruptions due to 
COVID-19 outbreak (eg, during quarantines and resulting site closures, regional travel 
restrictions and considerations if site personnel or study patients become infected with 
COVID-19) during which patients may not wish to or may be unable to visit the study site for 
study visits.  These changes should only be implemented if allowable by local/regional 
guidelines and following agreement from the Sponsor.
Study sites may continue to recruit new patients into ongoing studies provided the following 
activities to preserve study integrity can be met: 

Upon discussion with the site monitor, the study site has confirmed the ability to enrol 
and manage new subjects effectively and in compliance with the protocol 

Data will continue to be entered into the eCRF and queries resolved in a timely manner. 
K 1
Reconsent of Study Patients During Study Interruptions
During study interruptions, it may not be possible for the patients to complete study visits and 
assessments on site and alternative means for carrying out the visits and assessments may be 
necessary, eg, remote visits.  Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Section 1.1.  Local and regional regulations and/or guidelines regarding reconsent 
of study patients should be checked and followed.  Reconsent may be verbal if allowed by 
local and regional guidelines (note, in the case of verbal reconsent the ICF should be signed at
the patient’s next contact with the study site).  Visiting the study sites for the sole purpose of 
obtaining reconsent should be avoided.
K 2
Rescreening of Study Patients to Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened patients.  The investigator should confirm this with the designated 
AstraZeneca study physician.  In addition, during study disruption there may be a delay 
between confirming eligibility of a patient and either enrolment into the study or commencing 
of dosing with study treatment.  If this delay is outside the screening window specified in 
Section 1.1, the patient will need to be rescreened to reconfirm eligibility before commencing 
study procedures.  This will provide another opportunity to re-screen a patient in addition to 
that detailed in Section 5.4.  The procedures detailed in Section 1.1 must be undertaken to 
confirm eligibility.

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K 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified health care professional from the study site or third party vendor service may visit 
the patient’s home/or other remote location as per local standard operating procedures, as 
applicable.  Supplies will be provided for a safe and efficient visit.  The qualified health care 
professional will be expected to collect information per the CSP.
K 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During the COVID-19 outbreak, visits may be replaced by a telemedicine visit if allowed by 
local/regional guidelines.  Having a telemedicine contact with the patients will allow adverse 
events, concomitant medication and other relevant data to be collected according to study 
requirements to be reported and documented.
K 5
At-home or Remote Location Study Treatment Administration 
Instructions
If a site visit is not possible, at-home or remote location administration of study treatment may 
be performed, where available on a case by case basis by a qualified health care professional, 
provided this is acceptable within local regulation/guidance.  Please contact your monitor.  
The option of at-home or remote location study treatment administration ensures patients 
safety in cases of a pandemic where patients may be at increased risk by traveling to the 
site/clinic.  This will also minimise interruption of study treatment administration during other 
study disruptions, eg, site closures due to COVID-19.
K 5.1
At-home or Remote Location Study Treatment Administration by a 
Qualified Health Care Professional or Third Party Vendor Service
A qualified health care professional from the study site or third party vendor service may 
administer the study treatment at the patient's home or a remote location according to the CSP.  
All necessary supplies and instructions for administration and documentation of study 
treatment administration will be provided.  Additional information related to the visit can be 
obtained via a telemedicine or home visit.
K 6
At-home or Remote Delivery of Capivasertib/Placebo
Alternative secure delivery methods for oral drug supply (capivasertib/placebo) may be 
permitted if the patient is unable to attend the site, but only provided the critical safety 
assessments have been performed and the delivery methods are in line with local regulatory 
requirements.

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K 7
Data Capture During Telemedicine or Remote Visits
Data collected during telemedicine or remote visits will be captured in the source documents 
by the qualified health care professional from the study site or third party vendor service, or 
from the patient themselves.

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Appendix L
Guidance during the COVID-19 Outbreak
L 1
COVID-19 Risk Assessment 
The safety of participants is of primary importance.  Any potential risks of participating in the 
study, particularly with the added challenges due to COVID-19 outbreak, should be weighed 
against the anticipated benefit (see also principle 2.2 of ICH GCP).  Investigators are advised 
to use clinical judgment in determining infection prevention precautions for study participants.
The emergence of SARS-CoV-2 presents a potential safety risk for cancer patients.  
Participants enrolling in this study may require more frequent visits to the site for study 
treatment administration and for study assessments compared to participants receiving 
standard of care.  Therefore, several risk mitigation factors have been implemented related to 
study conduct during the COVID-19 outbreak, for patient management in an event of 
COVID-19, and actions to be taken on study treatment (see Appendix L 4).  With these 
measures in place, it is considered that the anticipated potential benefits for the participants 
enrolled in this study outweigh the potential risks.  All implemented measures prioritise trial 
participant safety and data validity; in case these two conflict with each other, trial participant 
safety should always prevail (see also EMA 2020). 
Notably, participants with active COVID-19 infection confirmed by local laboratory testing 
will not be eligible for study enrolment (see Section 5.2, Exclusion Criterion 12). 
L 2
Potential Risks during COVID-19
Every effort should be made to follow the CSP.  This appendix provides a dose modification 
and management plan for participants with confirmed or suspected COVID-19 who are being 
treated with study intervention capivasertib/placebo.   
The risk-benefit assessment should be carefully considered for each participant enrolling in 
the study based on the known safety risks related to COVID-19, individual needs, and local 
guidelines and restrictions.  Investigators must continue to use their best clinical judgment in 
determining the most optimal care for participants and utmost diligence in determining their 
eligibility for study participation, continued study treatment, and overall assessment of 
benefit/risk of study treatment or participation.
The sponsor must be promptly notified of a site’s inability to perform study activities due to 
COVID-19 outbreak in order to minimise any potential risks.
L 3
New Participant Enrolment
Study sites may continue to recruit new participants into the study provided the following 
activities to preserve study integrity can be met:

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
Upon discussion with the site monitor, the study site has confirmed the ability to enrol 
and manage new participants effectively and in compliance with the protocol.

Data will continue to be entered into the eCRF and queries resolved in a timely manner. 
Per CSP Exclusion Criterion 12 (see Section 5.2), participants with evidence of severe or 
uncontrolled systemic diseases, including but not limited to, ongoing or active infection are 
not eligible for the study participation and hence such participants (including those who have 
confirmed COVID-19) should not be included for study participation. 
Per Exclusion Criterion 26 (see Section 5.2), patients who have circumstances that could limit 
compliance with study requirements should also be excluded.  Please consider this criterion 
carefully considering evolving circumstances, travel restrictions and health care delivery in 
your local area that may impact the continued treatment in the study. 
The Study Physician should be contacted if any additional guidance or clarification is needed 
via the local monitor or directly.
L 4
Study Treatment Administration
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
participants’ treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the CSP.
Adverse events, SAEs, cycle delays and/or treatment suspensions associated with COVID-19 
along with logistical issues should be reported according to the eCRF Completion Guidelines. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should 
be followed, and the End of Treatment Form(s) completed.
L 5
Vaccination against COVID-19
Protocol restrictions applying to live attenuated vaccines are relevant for live attenuated 
COVID-19 vaccines as well.  Investigators should apply their discretion assessing the risk 
benefit of other types of COVID-19 vaccines for participants in clinical trials.  Ideally, 
administration of the vaccine should be done on a different day other than the day of study 
drug administration to differentiate any potential AEs seen from the vaccine and study drug.  
The administration of the vaccine and any potential AEs associated with the vaccine are to be 
documented on the concomitant medication and AE eCRFs, respectively.

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L 6
Capivasertib/Placebo: Product Specific Guidance In Relation To 
The Ongoing And Emerging Novel Coronavirus (COVID-19) 
Pandemic
For Ongoing Patients: 

Patients must continue to have safety blood tests as per protocol schedule.  Alternative 
methods for safety assessments include using local laboratories and follow up by phone 
contact, virtual visits can be used (see Appendix K for mitigation procedures)

If it becomes unfeasible to perform the required safety blood tests for a patient, then study 
treatment should be interrupted until this can resumed and the reason clearly documented, 
with reference to COVID-19. 

If a patient tests positive for the COVID-19 virus, interrupting capivasertib/placebo 
treatment for 14 days or until symptoms resolve should be considered.  Factors that 
should be taken into consideration might include: 
o
Severity of COVID-19 symptoms 
o
Status of safety blood results, particularly haemoglobin, neutrophils, and 
lymphocytes 
o
Benefit risk for the individual patients including curative vs. palliative intent of 
treatment and response to capivasertib/placebo 

If patients present with new or worsening respiratory symptoms such as dyspnoea, cough 
and fever, or an abnormal chest radiologic finding is observed, capivasertib/placebo 
treatment should be interrupted and prompt investigation initiated to determine whether 
symptoms are due to COVID-19 or potentially drug-induced pneumonitis. 

The use of capivasertib/placebo with the concomitant use of some antibiotics and 
antivirals (eg, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or 
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir and telaprevir) is not 
recommended.  Please review Appendix D for details.

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Appendix M Country-Specific Requirements
Alternative requirements affecting following sections are applicable only for UK, France, 
Italy, Spain, Belgium, Hungary, Poland, Germany. These were introduced in response to 
comments received through the EMA Voluntary Harmonisation Procedure (VHP). 
Sections 1.1 and 8.2.5: Addition of ECHO/MUGA every 12 weeks (+4 weeks) and at 
discontinuation of capivasertib/placebo treatment, to monitor cardiac safety and allow 
detection of asymptomatic left ventricular dysfunction. The modification of Schedule of 
assessments (Table 1) is outlined below.

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Screen
Cycle 1a
Cycle 2a, c
Cycle 
3a, c
Discontinuationv
Post-treatment 
follow-up
Progres-
sion
Survival 
follow-up 
Details in 
CSP 
section or 
appendix

Fulvestrant
Capivasertib/
placebo
30 days after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3
-1/+3
-1/+3
+7
+7
+7
+7
±7
Routine clinical proceduresf
MUGA/ECHO 
(LVEF)g
X
Every 12 weeks (+4 weeks)  from Cycle 1, 
Week 1, Day 1
X
Section 
8.2.5
a
Specified times (eg, ‘Pre’, ‘1-2h post’, ‘4h post’, etc) refer to capivasertib/placebo dosing.
b
Study visits are scheduled relative to Week 1, Day 1 of each cycle.  As per protocol, the visit window is -1/+3 days for most visits, however. a -1 day 
window cannot be used for study treatment dosing and should only be used for labs and other assessments.
c
Screening laboratory assessments taken within 3 days of Cycle 1, Day 1 do not need to be repeated and can be utilised for Cycle 1, Day 1/randomisation.  
Laboratory safety assessments, the collection of blood samples for biomarker analysis (ctDNA sample, circulating soluble factors sample, whole blood 
DNA sample and whole blood RNA sample) and rich PK sampling should be performed on the day of the scheduled study visit.  However, from Cycle 2 
onwards, the laboratory safety assessments and biomarker sampling may be performed 1 day before the scheduled study visit.  These samples must be 
collected pre-dosing.  
f
Routine safety measurements and routine clinical procedures should be performed before dosing of study treatment unless otherwise specified.
g
Bidimensional ECHO is the preferred modality because of the global technetium [Tc-99m] shortage (but MUGA can be used alternatively).  The modality 
of the cardiac function assessments must be consistent within patient ie, if ECHO is used for the screening assessment and a follow-up assessment if 
clinically indicated, then ECHO should also be used for subsequent scans if required.  Patients should also be examined using the same machine and 
operator whenever possible. For the alternative requirement, applicable only for UK, France, Italy, Spain, Belgium, Hungary, Poland, Germany refer to 
Appendix M. 
v
If both drugs are discontinued at the same time as progression, visits are combined and the optional biopsy is completed, if applicable.  
, onwards; ECHO, echocardiography; LVEF, left ventricular ejection fraction; MUGA, multiple-gated acquisition scan.

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Section 5.1: Male patients should use barrier contraception (ie, condoms) or truly abstain from 
sexual activity with female partners (see Section 5.3.3.2) from the time of screening until 2 
years after the last dose of fulvestrant or until 16 weeks after discontinuation of 
capivasertib/placebo, whichever occurs later.  Male patients wishing to father children in the 
future should be advised to arrange for the freezing of sperm prior to the start of study 
treatment.
Section 5.3.3.2: Male patients should either truly abstain from sexual activity with female 
partners (periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable) or use barrier contraception (condoms) from the time of screening until 2 years 
after the last dose of fulvestrant or until 16 weeks after discontinuation of 
capivasertib/placebo, whichever occurs later.  Male patients should refrain from donating 
sperm from the start of dosing until 2 years after the last dose of fulvestrant or until 16 weeks 
after discontinuation of capivasertib/placebo, whichever occurs later. 

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REFERENCES
Curigliano et al 2020 
Curigliano G, Banerjee S, Cervantes A, Garassino M, Garrido P, Girard N. Managing cancer 
patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus. Ann 
Oncol 2020;31(10):1320-35.
EMA 2020
EMA, Clinical Trials Facilitation and Coordination Group, European Commission. Guidance 
on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, Version 
2, 27 March 2020. Available from: URL: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. Accessed: 17 December 2020.

SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: d 3 6 1 5c 0 0 0 0 1-cs p- v 5
D oc u me nt Title:
D 3 6 1 5 C 0 0 0 0 1 Cli nical St u d y Pr ot oc ol versi o n 5
D oc u me nt I D:
D oc I D- 0 0 4 5 8 9 3 7 2
Versi o n L a bel:
5. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
0 9- A u g- 2 0 2 3 1 3: 1 7 U T C
A ut h or A p pr o val
0 8- A u g- 2 0 2 3 1 3: 5 8 U T C
C o nte nt A p pr o val
0 9- A u g- 2 0 2 3 1 6: 5 5 U T C
C o nte nt A p pr o val
N otes: ( 1) D oc u me nt details as st ore d i n A N G E L, a n Astra Ze neca d oc u me nt ma na ge me nt s yste m.
P P D
P P D
P P D

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Clinical Study Protocol 
Drug Substance
Capivasertib (AZD5363)
Study Code
D3615C00001
Version
China Local Version 5.0
Date
29 November 2023
A Phase III Double-blind Randomised Study Assessing the Efficacy and 
Safety of Capivasertib + Fulvestrant Versus Placebo + Fulvestrant as 
Treatment for Locally Advanced (Inoperable) or Metastatic Hormone 
Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative 
(HR+/HER2−) Breast Cancer Following Recurrence or Progression On or 
After Treatment with an Aromatase Inhibitor (CAPItello-291)
Sponsor:
AstraZeneca AB, S-151 85 Södertälje  Sweden.  
AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan.  
Regulatory Agency Identifying Number(s):
EudraCT number: 2019-003629-78
EU CT number: 2023-505042-25-00
IND number: 118046
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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Sections 1.2 and 3.2: Clarified secondary objective for PK to evaluate the PK of 
capivasertib (when given in combination with fulvestrant).
Sections 1.2 and 9.3: Clarified FAS to comprise patients randomised into the study, 
excluding patients randomised in China after the global cohort LPFV; clarified the
Safety Analysis Set will also include patients who receive only fulvestrant and these 
patients will be included in the treatment arm to which they were randomised; clarified 
the Altered Subgroup FAS will include patients with a result from a valid biomarker 
test as pre-specified in the SAP.
Sections 1.2 and 9.6: Clarified the China cohort.
Sections 2.3.3 and 4.5: Added text for impact of COVID-19 on the study conduct.
Section 5.1: Clarified Inclusion criterion for confirmation of breast cancer HER2-
Section 5.1: Clarified Inclusion criterion of metastatic or locally advanced disease with
radiological or objective evidence of disease progression (the cancer should have 
shown progression during or after most recent therapy).
Section 5.2: Clarified Exclusion criterion for cardiac criteria as QT interval corrected 
by Fridericia’s formula. 
Section 5.2: Clarified Exclusion criterion for severe or uncontrolled systemic diseases 
(as judged by the investigator) to includ  those with confirmed COVID-19, for 
example.
Section 5.2: Clarified Exclusion criterion for participation in another clinical study and 
to clarify vaccines for COVID-19 are not considered investigational agents.
Sections 1.1, 5.3.3, and 8.2.1: Updated that FSH and oestradiol will be monitored at 
screening, at Day 1 of each cycle, and when clinically indicated in pre- and peri-
menopausal women (per Inclusion criteria) and only at screening and when clinically
indicated in some post-menopausal women.
Section 6.1.1: Clarified the treatment administered to dosing of capivasertib/placebo 
400 mg BD (2 tablets of 200 mg taken twice a day = total daily dose 800 mg)
Sections 5.2 and 6.5.1: Added clarification that authorized/approved COVID-19 
vaccines are allowed concomitant therapy.
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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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 ........................................................................................................... 22
1.3
Schema............................................................................................................. 32
2
INTRODUCTION............................................................................................ 34
2.1
Study rationale.................................................................................................. 34
2.2
Background .................................................. ................................................. 34
2.3
Benefit/risk assessment............................... ........ ........................................... 38
2.3.1
Risks with capivasertib ..........................
...
.............................................. 38
2.3.2
Overall benefit-risk and ethical assessment ....................................................... 39
2.3.3
Impact on Benefit/Risk from Study Disruptions due to Coronavirus Disease 
2019 ................................................
........................................................... 40
3
OBJECTIVES AND ENDPOINTS.. ................................................................ 41
3.1
Primary objectives .....................
.................................................................. 41
3.2
Secondary objectives ...... ..... ........................................................................ 41
4
STUDY DESIGN .. ..... ..... ........................................................................... 45
4.1
Overall design.......... ....................................................................................... 45
4.1.1
Study oversight considerations.......................................................................... 49
4.2
Scientific rationale for study design .................................................................. 49
4.3
Justification for dose......................................................................................... 53
4.3.1
Capivasertib...................................................................................................... 53
4.3.2
Fulvestrant........................................................................................................ 54
4.4
End of study definition...................................................................................... 54
4.5
Study Conduct Mitigation During Study Disruptions Due to COVID-19 –
Temporary Measures ........................................................................................ 55
5
STUDY POPULATION ................................................................................... 56
5.1
Inclusion criteria............................................................................................... 57
5.2
Exclusion criteria.............................................................................................. 59
5.3
Lifestyle restrictions ......................................................................................... 63
5.3.1
Meals and dietary restrictions............................................................................ 63
5.3.2
Caffeine, alcohol, and tobacco .......................................................................... 63
5.3.3
Contraception ................................................................................................... 63
5.3.3.1
Females ............................................................................................................ 63
5.3.3.2
Males................................................................................................................ 64
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5.3.4
Other restrictions .............................................................................................. 64
5.4
Screen failures .................................................................................................. 65
6
STUDY TREATMENTS.................................................................................. 65
6.1
Treatments administered................................................................................... 65
6.1.1
Capivasertib/placebo......................................................................................... 65
6.1.2
Fulvestrant........................................................................................................ 67
6.1.3
Duration of treatment........................................................................................ 68
6.2
Preparation/handling/storage/accountability...................................................... 68
6.3
Measures to minimise bias: randomisation and blinding.................................... 69
6.4
Treatment compliance....................................................................................... 70
6.5
Concomitant therapy......................................................................................... 70
6.5.1
Allowed concomitant therapy ........................................................................... 71
6.5.2
Restricted concomitant therapy.................... .................................................. 72
6.5.3
Other concomitant treatment....................... ...... ............................................ 72
6.6
Dose modifications and delay ................
..
.............................................. 73
6.7
Treatment after the end of the study...... ...... ................................................... 73
7
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL . 74
7.1
Discontinuation of study treatment .................................................................. 74
7.1.1
Temporary discontinuation ..... ......................................................................... 75
7.1.2
Procedures for discontinuation of study treatment............................................. 75
7.2
Lost to follow-up ...........
.....
...................................................................... 76
7.3
Withdrawal from the study.... ........................................................................... 76
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 77
8.1
Efficacy assessments .. ................................................................................... 78
8.1.1
RECIST v1.1 a sessments................................................................................. 78
8.1.1.1
Progression-free survival (PFS) ........................................................................ 78
8.1.1.2
Clinical benefit rate (CBR) ............................................................................... 79
8.1.1.3
Duration of response (DoR) .............................................................................. 79
8.1.1.4
Objective response rate (ORR).......................................................................... 79
8.1.2
Overall survival (OS)........................................................................................ 79
8.1.3
PFS2................................................................................................................. 80
8.1.4
Time to definitive deterioration of the ECOG performance status ..................... 80
8.1.5
Time to first subsequent chemotherapy or death (TFSC)................................... 81
8.1.6
Bone scan ......................................................................................................... 81
8.1.7
Patient-reported outcomes................................................................................. 81
8.1.7.1
EORTC QLQ-C30............................................................................................ 81
8.1.7.2
EORTC QLQ-BR23 ......................................................................................... 82
8.1.7.3
EQ-5D-5L ........................................................................................................ 82
8.1.7.4
PGIS................................................................................................................. 82
8.1.7.5
PGIC ................................................................................................................ 83
8.1.7.6
PGI-TT............................................................................................................. 83
8.1.7.7
PRO-CTCAE.................................................................................................... 83
8.1.7.8
Administration of patient-reported outcome questionnaires............................... 83
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8.2
Safety assessments............................................................................................ 85
8.2.1
Clinical safety laboratory assessments............................................................... 85
8.2.1.1
Glucose and glycosylated haemoglobin (HbA1c).............................................. 87
8.2.1.2
Serum creatinine............................................................................................... 87
8.2.2
Physical examinations....................................................................................... 87
8.2.3
Vital signs......................................................................................................... 87
8.2.4
Electrocardiograms........................................................................................... 88
8.2.5
MUGA scan/Echocardiogram ........................................................................... 88
8.3
Collection of adverse events ............................................................................. 89
8.3.1
Method of detecting AEs and SAEs .................................................................. 89
8.3.2
Time period and frequency for collecting AE and SAE information.................. 89
8.3.3
Follow-up of AEs and SAEs ............................................................................. 90
8.3.4
Adverse event data collection............................................................................ 90
8.3.5
Causality collection.................................... ..................................................... 91
8.3.6
Adverse events based on signs and symptoms. ............................................... 91
8.3.7
Adverse events based on examinations and tests ... ........................................... 91
8.3.8
Hy’s law ............................................... ... ...... ................................................ 92
8.3.9
Disease progression .............................. ...... ................................................... 92
8.3.10
Adverse Events of Special Interest.................................................................... 92
8.4
Safety reporting and medical management........................................................ 93
8.4.1
Reporting of serious adverse events ................................................................ 93
8.4.1.1
Regulatory Reporting Requirements for SAEs .................................................. 94
8.4.2
Pregnancy......................... . ........................................................................... 94
8.4.2.1
Maternal exposure ........ ... .... ....................................................................... 94
8.4.2.2
Paternal exposure......... ...... ........................................................................... 95
8.4.3
Overdose ............... .. ..... ............................................................................. 95
8.4.4
Medication error ... ...... .................................................................................. 96
8.4.5
Management of capivasertib-related toxicities................................................... 96
8.4.5.1
Capivasertib/placeb  dose modification and guidance....................................... 97
8.4.5.2
Dose modifications due to general capivasertib-related toxicities ...................... 97
8.4.5.3
Dose modifications due to specific capivasertib-related toxicities ..................... 97
8.5
Pharmacokinetics............................................................................................ 103
8.5.1
Determination of drug concentration............................................................... 104
8.5.2
Storage and destruction of pharmacokinetic samples....................................... 104
8.5.2.1
Samples collected in China ............................................................................. 104
8.5.2.2
Samples collected outside of China................................................................. 104
8.6
Genetics.......................................................................................................... 105
8.6.2
Storage and destruction of genetic samples ..................................................... 105
8.7
Biomarkers ..................................................................................................... 105
8.7.1
Tumour tissue sample ..................................................................................... 105
8.7.1.1
Mandatory tumour tissue samples for biomarker analysis................................ 105
8.7.1.3
Collection, analysis and reporting of tumour samples...................................... 107
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8.7.3
Storage, re-use and destruction of biomarker samples ..................................... 108
8.8
Healthcare resource use .................................................................................. 108
9
STATISTICAL CONSIDERATIONS............................................................. 109
9.1
Statistical hypotheses...................................................................................... 109
9.2
Sample size determination .............................................................................. 109
9.3
Populations for analyses.................................................................................. 112
9.4
Statistical analyses.......................................................................................... 113
9.4.1
Efficacy analyses ............................................................................................ 113
9.4.1.1
Primary endpoint: PFS in the overall population ............................................. 114
9.4.1.2
Secondary endpoint: PFS in the PIK3CA/AKT1/PTEN-altered subgroup......... 115
9.4.1.3
Secondary endpoint: OS in the overall population........................................... 115
9.4.1.4
Secondary endpoint: PFS2 in the overall population ....................................... 115
9.4.1.5
Secondary endpoint: ORR in the overall population........................................ 115
9.4.1.6
Secondary endpoint: DoR in the overall population......................................... 116
9.4.1.7
Secondary endpoint: CBR in the overall population ........................................ 116
9.4.1.8
Secondary endpoint: PK.................................................................................. 116
9.4.1.9
Secondary endpoints: EORTC QLQ-C30 and EORTC QLQ-BR23................. 116
9.4.1.10
Secondary endpoint: time to definitive deterioration of the ECOG performance 
status in the overall population........................................................................ 118
9.4.2
Safety analyses ....................... ........ .............................................................. 118
9.4.2.1
Adverse events..................... ..
.... .............................................................. 118
9.4.2.2
Other safety analysis......... .. ......................................................................... 119
9.4.3
Other analyses .............. .... .......................................................................... 119
9.4.4
Methods for multiplicity control ..................................................................... 119
9.5
Interim analyses..... ...... .....
....................................................................... 121
9.5.1
Independent data monitoring committee (IDMC)............................................ 121
9.6
China cohort ...
....... ............................................................................... 121
10
REFERENCES............................................................................................... 123
11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 130
LIST OF TABLES
Table 1
Schedule of assessments (SoA)................................................................ 13
Table 2
Primary objectives ................................................................................... 41
Table 3
Secondary objectives ............................................................................... 41
Table 5
Capivasertib/placebo................................................................................ 66
Table 6
Fulvestrant............................................................................................... 67
Table 7
Dose levels for capivasertib/placebo and fulvestrant ................................ 73
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Table 8
Laboratory safety variables...................................................................... 86
Table 9
Dose modifications for general capivasertib-related toxicities.................. 97
Table 10
Dose modifications for capivasertib-related hyperglycaemiaa................... 99
Table 11
Dose modifications for capivasertib-related maculo-papular rash........... 101
Table 12
Dose modifications for capivasertib-related diarrhoea............................ 103
Table 13
Statistical consideration for PFS endpoint.............................................. 111
Table 14
Statistical consideration for OS endpoint ............................................... 111
Table 15
Analysis populations.............................................................................. 112
Table 16
Summary of imaging modalities for tumour assessment......................... 131
Table 17
RECIST v1.1 evaluation of target lesions............................................... 138
Table 18
RECIST v1.1 evaluation of non-target lesions........................................ 139
Table 19
RECIST v1.1 overall visit response ... ........ ......................................... 139
Table 20
ECOG performance status scale (Oken et al 1982)................................. 142
Table 21
CYP3A4-interacting medication that must be avoided or used with 
caution................................ .
. ......................................................... 151
Table 22
CYP3A4 substrates that must be avoided or used with caution............... 153
Table 23
MATE1 and/or OCT2 transporter substrates that should be used with 
caution......................... ....................................................................... 153
LIST OF FIGURES
Figure 1
Study design
.... ................................................................................. 32
Figure 2
Study flow chart ...................................................................................... 48
Figure 3
Treatment schedule.................................................................................. 67
Figure 4
Illustration of data cut-offs and associated treatment comparisons.......... 120
LIST OF APPENDICES
Appendix A
Guidelines for evaluation of objective tumour response using 
RECIST v1.1 Criteria (Response Evaluation Criteria in Solid Tumours) 131
Appendix B
ECOG/WHO Performance Status .......................................................... 142
Appendix C
Regulatory, ethical and study oversight considerations........................... 143
Appendix D
Guidance regarding potential interactions of capivasertib with 
concomitant medications........................................................................ 151
Appendix E
Adverse event definitions and additional safety information .................. 155
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ale (Oken et al 198
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hat must be avoide
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hat must be avoide
OCT2 transporter su
ro
OCT2 transporter su
............. ..........
pr
............. ..........
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A
dy design
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design
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Ap
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Appendix F
Handling of human biological samples .................................................. 161
Appendix G
Genetics................................................................................................. 164
Appendix H
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s law........................................................................... 168
Appendix I
Patient-reported outcomes – questionnaires............................................ 172
Appendix J
Abbreviations ........................................................................................ 183
Appendix K
Changes Related to Mitigation of Study Disruptions Due to COVID-19 
Outbreak - Temporary Measures............................................................ 187
Appendix L
Guidance during the COVID-19 Outbreak ............................................. 190
1
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
The schedule of study assessments is provided in Table 1.
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Table 1
Schedule of assessments (SoA)
Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-up 
Details in 
CSP 
section or 
appendix

Fulvestrant
Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 
0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Informed consent
X
Section 5.1,
Appendix C
Inclusion/exclusion 
criteria
X
Sections
5.1 & 5.2
Prepare ePRO deviced
X
Section 
8.1.7.8
Train patient on ePRO 
devicee
X
Section 
8.1.7.8
Routine clinical proceduresf
Demography/baseline 
characteristics
X
Medical/surgical history
X
Sections
5.1 & 5.2
Smoking history
X
Previous cancer therapy
X
Section 5.2
BRCA1/2 status (local 
testing), if available
X
Concomitant medication
X
At every study visit
Section 6.5
ECOG/WHO 
performance status
X
X
X
X
X
X
X
X
X
Appendix B
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ve
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ov
ov
prov
pr
pr
pro
Appr
Ap
Ap
App
pp
pp
App
Ap
Ap
Ap
Ap
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Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-up 
Details in 
CSP 
section or 
appendix

Fulvestrant
Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 
0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Physical examination
X
X
X
X
X
X
X
Section 
8.2.2
Vital signs
X
Pre (within 
30m) and
1-2h post
(±30m)
X
X
X
X
X
X
X
Section 
8.2.3
Height
X
Section 
8.2.2
Weight
X
X
X
X
X
X
X
Section 
8.2.2
12-lead ECG
X
Pre (within 
30m) and 
1h post
(±30m)
Cycle 2, Week 1, Day 1
and every 12 weeks 
thereafter
X
Section 
8.2.4
MUGA/ECHO (LVEF)g
X
As clinically indicated during study treatment
Section 
8.2.5
Routine safety measurementsf
Adverse events
X
At every study visit
Section 8.3
& 
Appendix E
Pregnancy test (peri-/pre-
menopausal only)
X
X
As clinically indicated and at treatment discontinuation
Section 
8.4.2
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X
ve
X
X
d
X
ed
ed
ed
ved
X
X
X
rov
X
X
X
ve
prove
pr
pr
pr
Appr
X
p
X
Ap
Ap
App
pp
pp
App
Cy
A
Cy
Ap
Ap
Ap
Ap
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Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-up 
Details in 
CSP 
section or 
appendix

Fulvestrant
Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 
0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Oestradiol and FSHh
X
X
X
X
Section 
8.2.1
International Normalised 
Ratio (INR)
X
As clinically indicated
Section 
8.2.1
Haematologyc
X
Pre
Pre
Pre
Pre
X
X
X
Section 
8.2.1
Clinical chemistryc,i
X
Pre
Pre
Pr
Pre
X
X
X
Section 
8.2.1
Urinalysisc
X
Pre
Pre
P e
Pre
X
X
X
Section 
8.2.1
Glycosylated 
haemoglobin (fasting)c,j
X
Every 12 weeks from Cycle 1, Week 1, Day 1
X
X
Section 
8.2.1
Lipids (fasting)c,j
X
Every 12 weeks from Cycle 1, Week 1, Day 1
X
Section 
8.2.1
Glucose (fasting)c,j
X
Pre (within 
3h) and 4h
post
(±30m)
Pre
Pre
X
X
Section 
8.2.1
Biomarker analysis
FFPE tumour samplek
X
Section 
8.7.1.1
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As clinically indicated
ov
As clinically indicated
ve
Pre
Pre
pr
Pre
Pre
X
ro
X
ro
pro
Pr
Pre
pp
Pr
Pre
X
pr
pr
pr
Appr
Pre
A
Pre
P e
Pre
pp
P e
Pre
Ap
Ap
App
pp
pp
App
eks from Cycle
A
eks from Cycle
Ap
Ap
Ap
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Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-up 
Details in 
CSP 
section or 
appendix

Fulvestrant
Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 
0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Single biopsy at disease 
progression (optional)l
X
Section 
8.7.1.2
Paired biopsies 
(optional)l,m
X
X
Section 
8.7.1.2
ctDNA blood samplesc,l
X
Pre
Pre
Pre
Pre
X
X
X
Section 
8.7.2
Circulating soluble 
factors blood drawc,l,n
X
Pre
Pre
Pr
Pre, C3 
only
X
X
X
Section 
8.7.2
Whole blood DNA 
sample (genomic 
markers)c,l,n
X
Pre
Pre
Pr
Pre, C3 
only
X
X
X
Section 
8.7.2
Whole blood RNA 
sample (genomic 
markers)c,l,n
X
Pre
Pre
Pre
Pre, C3 
only
X
X
X
Section 
8.7.2
Genetic sample (optional)
Blood sample for 
pharmacogenetics DNA 
(optional)l
X
Section 8.6
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Pre
p
Pre
Pre
pro
Pre
ro
pro
Pr
p
Pr
Pre, C3 
pr
Pre, C3 
on
p
on
pr
pr
pr
Appr
Pre
A
Pre
Pr
p
Pr
Ap
Ap
App
pp
pp
App
A
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Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-up 
Details in 
CSP 
section or 
appendix

Fulvestrant
Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 
0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Pharmacokinetic measurementsc
Capivasertib PK plasma 
samples
1h (±10m) 
and 
4h (±30m) 
post-dose
Pre
(<30
m)
Pre
(<30
m)
Pre
(<30
m)
Section 8.5
Capivasertib PK plasma 
samples for 12 Japanese 
patients only
Pre (within 
30m) and 
0.5 (±5m), 
1 (±10m), 
2 (±10m), 
4 (±30m), 
6 (±30m), 
8 (±30m), 
12h (±1h)
post-dose
Pre
(<30
m)
Pre
(<30
m)
Pre
(<30
m)
Section 8.5
Imaging and other assessments
Bone scan
X
As clinically indicated
Section 
8.1.6
RECIST v1.1 tumour 
assessmentso
X
Every 8 weeks (±7 days) for the first 18 months and every 12 weeks thereafter, from randomisation to radiological 
progression. Patients who discontinue treatment prior to progression should continue to be scanned until progression.
Section 
8.1.1 & 
Appendix
A
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30
30
m)
r
m)
ve
prove
Pre
pp
Pre
(<30
Ap
(<30
m)
p
m)
Pre
pp
Pre
(<3
p
(<3
pr
Appro
Pre
A
Pre
(<30
A
(<30
m)
A
m)
A pr
pro
Appro
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18 of 192
Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-up 
Details in 
CSP 
section or 
appendix

Fulvestrant
Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 
0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
Survival statusp
X
X
Section 
8.1.2
PFS2q
X
X
Section 
8.1.3
Subsequent cancer 
therapy following 
discontinuation of study 
treatmentq
X
X
Section 6.7
Patient-reported outcomes and healthcare resource u ilisation
EORTC QLQ-C30
Cycle 1, Week 1, Day 1 ( 3 days  and every 4 weeks (±3 days) until PFS2.  Also at discontinuation of study treatment visit
(+3 days) and, for those who discontinue for reasons other than progression, also at progression visit (+3 days).  If PROs 
have been completed up to 3 days prior to the discontinuation or progression visit, they do not need to be repeated.
Section 
8.1.7.1
EORTC QLQ-BR23
Section 
8.1.7.2
EQ-5D-5L
Section 
8.1.7.3
PGIS
Section 
8.1.7.4
PGIC
Every 4 weeks (±3 days) after Cycle 1, Week 1, Day 1 until PFS2.  Also at discontinuation of 
study treatment visit (+3 days) and, for those who discontinue for reasons other than 
progression, also at progression visit (+3 days). If PROs have been completed up to 3 days 
prior to discontinuation or progression visit, they do not need to be repeated.
Section 
8.1.7.5
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ro
Appro
rce u ilisation
Ap
rce u ilisation
Ap
Ap
App
pp
pp
Ap
eek 1, Day 1 (
Ap
eek 1, Day 1 ( 3 days  and e
Ap
3 days  and e
d, for those who disc
Ap
d, for those who disc
ompleted up to
A
ompleted up to
Ap
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Screen
Cycle 1a
Cycle 2a, c
Cycle 3a, c
Discontinuationv
Post-
treatment 
follow-up
Progres-
sion
Survival 
follow-up 
Details in 
CSP 
section or 
appendix

Fulvestrant
Capivasertib/
placebo
30 days 
after last 
dose
Every 8 
weeks
Week
1
3
1
3
1
Day of week
-28 to 
0
1
1
4
1
1
1
Visit window (days)b
0
-1/+3
-1/+3
-1/+3 -1/+3
-1/+3
+7
+7
+7
+7
±7
PGI-TT
Cycle 1, Week 1, Day 1 (-3 days) and every 2 weeks (±2 days) up to and including Week 12 and 
then every 4 weeks (±3 days) until discontinuation of study trea ment, at discontinuation of study 
treatment visit (+3 days) and at 4 weeks (±3 days) post di continuation of study treatment visit.  If 
PROs have been completed up to 3 days prior to di continuation visit, they do not need to be 
ep ated.
Section 
8.1.7.6
PRO-CTCAE
Section 
8.1.7.7
Healthcare resource use 
(HOSPAD)r
Healthcare resource use modul  is vent driven and should be populated as required at every study visit
Section 8.8
Study treatment administration
Randomisations
X
Section 6.3
Fulvestrant dosing
X
X
X
X
Section 
6.1.2
Capivasertib/placebo 
dosingt
Twice daily on days 1 to 4 every week (ie, 4 days on 
and 3 days off).  A minimum interval of 3 days is 
required between the last dose of the previous week of 
treatment and the first dose of the following week of 
treatment
Section 
6.1.1
LHRH agonist dosing (for 
pre-/peri-menopausal 
women only; both 
treatment arms)
Xu
Sub-cutaneous administration every 28 days or as per 
manufacturer’s instructions
Sections 
5.1, 5.3.3.1,
and 6.5.1
NOTE: Unscheduled visits may be initiated as needed.  Only required assessments are to be performed as per investigator’s discretion.  
a
Specified times (eg, ‘Pre’, ‘1-2h post’, ‘4h post’, etc) refer to capivasertib/placebo dosing.
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ks (±2 days) up to and including
ved
ks (±2 days) up to and includi
tion of study trea
ve
tion of study trea ment, at discon
ve
ment, at discon
3 days) post di continuation of s
ove
3 days) post di continuation of s
days prior to di continuation vis
ov
days prior to di continuation vis
ep ated.
rov
ep ated.
ed
ed
ed
rce use modul  is vent driven a
pro
rce use modul  is vent driven a
ro
pp
Ap
Ap
App
pp
pp
App
pp
X
A
X
X
p
X
Ap
Ap
Ap
Ap
1 t
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b
Study visits are scheduled relative to Week 1, Day 1 of each cycle.  As per protocol, the visit window is -1/+3 days for most visits, however, a -1 day 
window cannot be used for study treatment dosing and should only be used for labs and other assessments.
c
Screening laboratory assessments taken within 3 days of Cycle 1, Day 1 do not need to be repeated and can be utilised for Cycle 1, Day 1/randomisation.  
Laboratory safety assessments, the collection of blood samples for biomarker analysis (ctDNA sample, circulating soluble factors sample, whole blood 
DNA sample and whole blood RNA sample) and rich PK sampling should be performed on the day of the scheduled study visit. However, from Cycle 2
onwards, the laboratory safety assessments and biomarker stampling may be performed 1 day before the scheduled study visit. These samples must be 
collected pre-dosing.  
d
The handheld 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.
e
The patient should be trained on the use of the device and the importance of completing the PRO questionnaires in accordance with the schedule throughout 
the study.
f
Routine safety measurements and routine clinical procedures should be performed before dos ng of tudy treatment unless otherwise specified.
g
Bidimensional ECHO is the preferred modality because of the global technetium [Tc-99m] sho tage (but MUGA can be used alternatively).  The modality 
of the cardiac function assessments must be consistent within patient ie, if ECHO is used for the screening assessment and a follow-up assessment if 
clinically indicated, then ECHO should also be used for subsequent scans if required.  Pati nts should also be examined using the same machine and 
operator whenever possible.
h
Female pre- and peri-menopausal patients starting an LHRH agonist (either star ing or continuing this treatment) must have oestradiol and FSH 
measurements done at screening (before Cycle 1, Day 1) and after at least 4 weeks after commencing LHRH agonist treatment to confirm post-menopausal 
levels; assessments after screening will be at Day 1 of each cycle and when clinically indicated. Female patients <60 years who are considered 
post-menopausal per wording of inclusion criterion 5, must have oes radiol and FSH levels confirmed as being within the standard laboratory reference 
range for post-menopausal females at screening (before Cycle 1 Day 1) only and if clinically indicated (see Section 8.2.1 for all details when and for whom 
FSH and oestradiol must be checked).
i
For patients taking concomitant metformin, pl ase refer t  Sections 8.2.1.2 and 8.4.5.3.
j
‘Fasting’ is defined as no caloric intake for ≥4 hour  before sampling. Glucose samples should be done under fasting conditions with the exception of the 
4-hour post dose sample on Cycle 1, Week 1, Day 1 which can be fasting or non-fasting.
k
FFPE tumour sample: Tumour tissue will be required at baseline for determination of PIK3CA/AKT1/PTEN status at a central laboratory to allow 
monitoring of the prevalence of the PIK3CA/AKT1/PTEN-altered subgroup. Tumour tissue samples will be collected as detailed in the Laboratory Manual 
and Diagnostic Testing Manual. The most recently collected tumour tissue, from primary or recurrent cancer is required. FFPE blocks are strongly 
preferred. If not possible, preferably 30 (minimum 20) freshly-cut unstained serial tumour tissue sections are accepted provided they met the specifications 
described in the Diagnostic Testing Manual.  For patients recruited in mainland China, a minimum of 11 freshly-cut unstained serial tumour slides will be 
required. Local pathology QC must be completed prior to randomisation to ensure the sample is suitable for NGS analysis, based on the requirements 
described in the Diagnostic Testing Manual.  
l
These samples will not be collected in China.  Results can be provided to the investigator upon request, if available.
m
Paired biopsies (optional): Baseline sample: at screening OR pre-dose on Cycle 1, Week 1, Day 1.  On-treatment sample: at Cycle 1, Week 3, Day 4 (any 
day between Cycle 1, Week 3, Day 2 and Cycle 1, Week 3, Day 4 is allowed) >4 hours post-dose.  
n
Circulating soluble factor, whole blood DNA sample and whole blood RNA sample draws: To be taken at screening, pre-dose on Cycle 1, Week 1, Day 1; 
Cycle 1, Week 3, Day 1; Cycle 2, Week 1, Day 1; Cycle 3, Week 1, Day 1, at progression, and at discontinuation of IMP if this falls on a different visit/time
than progression.
o
Baseline RECIST v1.1 assessments will be performed using CT scans of the chest, abdomen and pelvis (or MRI where CT is contraindicated) and should be
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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d
he PRO qu
before dos
ed
before dos ng of tud
ed
ng of tud
m [Tc
m [Tc-99m] sho tage (but M
ed
99m] sho tage (bu
ECHO is used for the screenin
ved
ECHO is used for the screeni
ns if re
ns if required.  Pati nts should
ve
quired.  Pati nts should
onist 
r
onist (either star ing or contin
rov
(either star ing or contin
d after at least 4 weeks after c
ro
d after at least 4 weeks after c
ch cycle and when clinically 
pro
ch cycle and when clinically 
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Clinical Study Protocol - China Local Version 5.0
AstraZeneca
Capivasertib (AZD5363) - D3615C00001
CONFIDENTIAL AND PROPRIETARY
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performed as close as possible to the start of treatment. RECIST v1.1 follow-up assessments will include CT scans of thorax, abdomen and pelvis (or MRI 
where CT is contraindicated) for all patients. Any other sites at which new disease is suspected should also be appropriately imaged.
p
In addition to regular contacts at ≤8-week intervals, patients will be contacted in the 7 days following a specified date (data cut-off date) for survival 
analysis.  
q
Patients will enter the PFS2 follow-up period once the patient has discontinued study treatment due to progressive disease by RECIST v1.1. Progression on 
second-line treatment will be documented by site personnel at the 30-day follow-up visit, every 8 weeks (±7 days) for the first 2 years and every 12 weeks 
(±7 days) thereafter until second progression.  Survival status and subsequent cancer therapies will be documented by site personnel, following objective 
disease progression or treatment discontinuation, at the 30-day follow-up, every 8 weeks (±7 days) for the first 2 years and every 12 weeks (±7 days)
thereafter until end of study, study withdrawal or death.  
r
Assessments include: number of hospitalisations and attendances; primary symptom/reason ass ciated with hospitalisation or attendance; length of stay, 
including time in intensive care; and concomitant medication and procedures undertaken.
s
Randomisation must occur within 28 days of the start of screening.  Randomisation and Cycle 1, W ek 1, Day 1 should ideally occur on the same day.  
t
Day 1 of each cycle is defined by fulvestrant dosing and fulvestrant should not be delayed due  capivasertib/placebo toxicity. In the case of a 
capivasertib/placebo dosing delay at the beginning of the cycle, the same routine safety measurements and routine clinical procedures must be repeated on 
the next planned date of dosing. Cycles are 28-day long, dosing outside of the prespecified window will be considered as overdose except for a dose delay 
situation.  
u
Administration of LHRH agonist in pre- or peri-menopausal women must start prior to or on Cycle 1, Day 1.
v
If both drugs are discontinued at the same time as progression, visits are combined and the optional biopsy is completed, if applicable.  
, onwards; BRCA1/2, breast cancer gene 1/2; CT, computed tomography; ctDNA, circulating tumour DNA; DNA, deoxyribonucleic acid; ECG, 
electrocardiogram; ECHO, echocardiography; ECOG, Eastern Coop rativ  Oncology Group; EORTC, European Organisation for Research and Treatment of 
Cancer; EORTC QLQ-BR23, EORTC Quality of Life Questionnaire breast cancer specific module; EORTC QLQ-C30, EORTC Quality of Life Questionnaire –
Core 30 items; ePRO, electronic patient-reported ou come; EQ 5D-5L, E ropean Quality of Life 5-Domain 5-Level Scale; FFPE, formalin-fixed 
paraffin-embedded; FSH, follicle stimulating hormone; HOSPAD  Hospital Admission module; LHRH, luteinising-hormone releasing hormone; LVEF, left 
ventricular ejection fraction; MRI, magnetic resonance imaging; MUGA, multiple-gated acquisition scan; PFS2, time from randomisation to second progression 
or death; PGIC, Patient Global Impression–Change; PGIS, Patient Global Impression–Severity; PGI-TT, Patient Global Impression–Treatment Tolerability; PK, 
pharmacokinetics; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; PRO, patient-reported outcome; PRO-CTCAE,
Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; PTEN, phosphatase and tensin homolog; RECIST v1.1, Response 
Evaluation Criteria in Solid Tumours version 1.1; RNA, ribonucleic acid; WHO, World Health Organisation.
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
proved
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Clinical Study Protocol - China Local Version 5.0
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Capivasertib (AZD5363) - D3615C00001
CONFIDENTIAL AND PROPRIETARY
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1.2
Synopsis
International co-ordinating investigator
Breast Unit, The Royal Marsden NHS Foundation Trust
Breast Cancer Now Research Centre, The Institute of Cancer Research
London, SW3 6JJ
United Kingdom
Protocol Title: A Phase III Double-blind Randomised Study Assessing the Efficacy and 
Safety of Capivasertib + Fulvestrant Versus Placebo + Fulvestrant as Treatment for Locally 
Advanced (Inoperable) or Metastatic Hormone Receptor Positive, Human Epidermal Growth 
Factor Receptor 2 Negative (HR+/HER2−) Breast Cancer Following Recurrence or 
Progression On or After Treatment with an Aromatase Inhibitor (CAPItello-291)
Short Title: Phase III Study of Capivasertib + Fulvestrant vs Placebo + Fulvestrant as 
Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2− Breast Cancer 
(CAPItello-291)
Rationale: 
Numerous preclinical studies have shown that endogenous AKT activity promotes breast 
cancer cell survival and resistance to chemotherapy or endocrine therapy (Frogne et al 2005,
Ghayad et al 2010, van der Hage et al 2004).  This can be overcome by down-regulation or 
inhibition of the PI3K/AKT pathway, a  has been shown in several in vitro and in vivo breast
cancer models (Frogne et al 2005, Ghayad et al 2010, van der Hage et al 2004).  In addition, 
long-term estrogen deprivation (LTED) of human breast cancer cells in vitro (to mimic the 
low estrogen levels observed in aromatase inhibitor [AI] treated patients) has revealed 
hyperactivation of the PI3K/mTOR signalling pathway (Miller et al 2010).  Consistently, 
increased PI3K/AKT signalling in clinical tumour samples is associated with poor 
anti-proliferative response to AI in breast cancer patients (Tokunaga et al 2006, Gao et al 
2014).  Inhibition of the PI3K pathway in the LTED cells induced apoptosis, indicating 
dependence on the PI3K pathway upon hormone deprivation (Miller et al 2010).  Reciprocal 
feedback between the estrogen receptor (ER) and PI3K signalling suggests that the 
combination of endocrine therapy and inhibitors of the PI3K/AKT pathway may have clinical 
utility in the treatment of HR+ breast cancer, with responses expected both in patients with
tumours harbouring a genetic alteration leading to an activated PI3K pathway as well as in 
patients whose tumours do not harbour such genetic alterations, but become dependent on the 
PI3K pathway upon treatment with ER downregulating/degrading agents, eg, AIs or selective 
ER degraders (SERDs).  
A recent investigator-sponsored, randomised, double-blind, placebo-controlled Phase Ib/II
study (NCT01992952, FAKTION) evaluated the combination of capivasertib (an AKT 
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
Approved
or 
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Clinical Study Protocol - China Local Version 5.0
AstraZeneca
Capivasertib (AZD5363) - D3615C00001
CONFIDENTIAL AND PROPRIETARY
23 of 192
inhibitor) + fulvestrant (a selective estrogen down-regulator) compared with placebo + 
fulvestrant in post-menopausal patients with estrogen receptor positive, human epidermal 
growth factor receptor 2 negative (ER+/HER2−) advanced breast cancer (ABC) (140 patients, 
randomised 1:1) after relapse or disease progression on an AI therapy (Jones et al 2019). The 
study met its primary endpoint of progression-free survival (PFS), showing a statistically
significant improvement in PFS with the addition of capivasertib to fulvestrant.  At the time of 
the PFS analysis, overall survival (OS) data were not mature; however, the data suggest an 
improvement with the addition of capivasertib to fulvestrant.  The combination of capivasertib 
+ fulvestrant was generally well tolerated, with a manageable safety profile. 
This Phase III study (CAPItello-291) is being conducted in response to the positive results 
from the FAKTION study and aims to evaluate the efficacy and safety of capivasertib + 
fulvestrant versus (vs) placebo + fulvestrant in patients with locally advanced (inoperable) or 
metastatic hormone receptor positive (HR+)/HER2− breast ancer following recurrence or 
progression on or after third generation AI therapy in an unselected population (hereafter 
referred to as the “overall population”) and a molecularly defined subgroup with tumours 
harbouring at least one PIK3CA/AKT1/PTEN-qualifying alteration detected in tissue (hereafter 
referred to as the “altered subgroup”).
Objectives and Endpoints:
Primary objective
Endpoint
To compare the effect of capivasertib + fulvestr nt 
relative to placebo + fulvestrant by assessm nt of
PFS in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup
PFS is defined as the time from randomisation until 
progression per RECIST v1.1, as assessed by the 
investigator at the local site, or death due to any cause.  
PFS, progression-free survival; RECIST v1.1  Response Evaluation Criteria in Solid Tumours version 1.1; 
vs, versus.
Secondary objectives
Endpoint
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of OS 
in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
OS is length of time from randomisation until the date 
of death due to any cause.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
PFS2 in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
PFS2 is defined as the time from randomisation until 
second progression on next-line treatment, as assessed 
by the investigator at the local site, or death due to any 
cause.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
ORR in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
ORR is defined as the percentage of patients with at 
least one CR or PR per RECIST v1.1, as assessed by 
the investigator at the local site.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
Approved
ts with 
d
ts with 
− breast anc
d
− breast anc
py in an unselected
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A
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Clinical Study Protocol - China Local Version 5.0
AstraZeneca
Capivasertib (AZD5363) - D3615C00001
CONFIDENTIAL AND PROPRIETARY
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Secondary objectives
Endpoint
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
DoR in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
DoR is defined as the time from the date of first 
documented response until date of documented 
progression or death in the absence of disease 
progression.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
CBR in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
CBR is defined as the percentage of patients who have 
a CR, PR or stable disease per RECIST v1.1 (without 
subsequent cancer therapy) maintained ≥24 weeks 
after randomisation.  
To assess the safety and tolerability of capivasertib + 
fulvestrant as compared to placebo + fulvestrant in 
the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup.  
Safety and tolerability will be evaluated in terms of 
AEs/SAEs, vital signs, clinical 
chemistry/haematology/glucose metabolism 
parameters, and ECG parameters.  
Assessmen s related to AEs cover:

Occurr nce/frequency

Relationship to capivasertib and fulvestrant 
as assessed by investigator

CTCAE grade

Seriousness

Death

AEs leading to discontinuation of 
capivasertib/placebo

AEs leading to discontinuation of fulvestrant

AEs leading to dose interruption of 
capivasertib/placebo

AEs leading to dose interruption of
fulvestrant

AEs leading to dose reduction of 
capivasertib/placebo

AEs of special interest

Other significant AEs
Vital signs parameters include systolic and diastolic 
blood pressure, pulse, respiratory rate, body 
temperature and weight.
Assessments cover:

Observed value

Absolute and change from baseline values 
over time
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
oved
smen s rel
d
smen s rel
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
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Clinical Study Protocol - China Local Version 5.0
AstraZeneca
Capivasertib (AZD5363) - D3615C00001
CONFIDENTIAL AND PROPRIETARY
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Secondary objectives
Endpoint
To evaluate the PK of capivasertib when given in 
combination with fulvestrant.  
Plasma concentration of capivasertib pre-dose (Ctrough) 
and post-dose (C1h and C4h) in the overall population 
(patients randomised to capivasertib + fulvestrant).  
AUC 0-12h, Cmax and tmax in a subpopulation of 
approximately 6 Japanese patients with rich PK 
sampling.  
To assess the impact of capivasertib + fulvestrant vs 
placebo + fulvestrant on patients’ disease-related 
symptoms, function and HRQoL in the overall 
population and in the PIK3CA/AKT1/PTEN-altered 
subgroup where applicable.  
Evaluation of EORTC QLQ-C30, EORTC 
QLQ-BR23, scale/item scores including change from 
baseline and time to deterioration.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
time to definitive deterioration of ECOG 
performance status from baseline in the overall 
population and in the PIK3CA/AKT1/PTEN-altered 
subgroup.  
Time to definitive deterioration of ECOG performance 
status is defi ed as time from randomisation to the 
earlier of the dat  of the first definitive deterioration or 
death d e to 
y cause.  
AE, adverse event; AUC 0-12h, area under the plasma concentr ion-time curve from zero to 12 hours; C, 
concentration; CBR, clinical benefit rate; Cmax, maximum observed plasma (peak) concentration; CR, complete 
response; CTCAE, Common Terminology Criteria for Adverse Event; ctDNA, circulating tumour DNA; DoR, 
duration of response; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC, European 
Organisation for Research and Treatment of Can er; EORTC QLQ-BR23, EORTC Quality of Life Questionnaire
breast cancer specific module; EORTC QLQ-C30, EORTC Quality of Life Questionnaire-Core 30 items; 
HRQoL health-related quality of life; ORR  objec ive response rate; OS, overall survival; PFS, progression-free 
survival; PFS2, time from randomisation to se ond progression or death; PIK3CA, 
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; PK, pharmacokinetics; PR, partial 
response; PTEN, phosphatase and tensi  homolog; RECIST v1.1, Response Evaluation Criteria in Solid Tumours
version 1.1; SAE, serious ad
rse event; tm
time to reach peak or maximum observed concentration following 
drug administration; vs, versus
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
oved
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Clinical Study Protocol - China Local Version 5.0
AstraZeneca
Capivasertib (AZD5363) - D3615C00001
CONFIDENTIAL AND PROPRIETARY
26 of 192
  
  
  
  
  
  
  
  
  
  
  
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Analysis of ctDNA and/or tumour tissue.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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Capivasertib (AZD5363) - D3615C00001
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28 of 192
Overall design:
This is a Phase III, double-blind, randomised study assessing the efficacy of capivasertib + 
fulvestrant vs placebo + fulvestrant for the treatment of patients with locally advanced 
(inoperable) or metastatic HR+/HER2− breast cancer following recurrence or progression on 
or after AI therapy.  
Enrolment will be open to all eligible patients irrespective of the PIK3CA/AKT1/PTEN status 
of their tumour(s); however, adequate tumour tissue collected before study entry will be 
required for central retrospective analysis to monitor the prevalence of PIK3CA/AKT1/PTEN
mutation status. The list of eligible alterations is curated on the basis of the currently 
published literature for causal associations between pathogenicity and the alterations, using 
the AstraZeneca strategy for early-stage clinical studies as described by Carr et al 2016.  The 
list of eligible variants will be defined and specified in the statistical analysis plan (SAP) prior 
to analysis.  
The target patient population is adult males and pre-menopausal or post-menopausal adult 
females (aged ≥18 years [≥20 years in Japan]) with histologically confirmed, locally advanced 
(inoperable) or metastatic, HR+/HER2− ABC with recurrence or progression while receiving 
or within 12 months of the end of (neo)adjuvant treatment with an AI, or progression while on 
prior AI for locally advanced or metastatic breast cancer (although this does not need to be the 
most recent therapy).  In accordance with these criteria, the study intends to recruit patients 
with AI resistance.  
HR+/HER2− breast cancer must be histologically determined from the most recent tumour 
sample (primary or metastatic), as per the American Society of Clinical Oncology-College of 
American Pathologists guideli e recommendations (Hammond et al 2010, Wolff et al 2018).  
To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without 
co-expression of progesterone receptor (Hammond et al 2010, Wolff et al 2018).  
Patients must be candidates to receive further endocrine-based therapy (ie, fulvestrant
monotherapy).  Eligible patients may have received up to 2 prior endocrine therapy lines for 
metastatic disease and up to 1 line of chemotherapy in the metastatic setting.  A minimum of 
51% of patients recruited to the study should have been previously treated with a CDK4/6 
inhibitor.
NOTE: CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) are, in certain markets, 
approved treatment options in combination with an aromatase inhibitor or fulvestrant 
(± luteinising-hormone releasing hormone (LHRH) agonist depending on menopausal 
status) for patients with advanced or metastatic HR+HER2- breast cancer who have 
received prior endocrine therapy and/or as initial endocrine-based therapy. Some of these 
agents have been shown to improve overall survival in this patient population and, where 
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
pproved
s a
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Capivasertib (AZD5363) - D3615C00001
CONFIDENTIAL AND PROPRIETARY
29 of 192
available in the country in which a patient is being enrolled, must be considered and 
excluded as treatment options before the patient can be considered for entering this study.  
Prior CDK4/6 inhibition will be a stratification factor; the actual proportions will be 
monitored during the course of the study (Section 6.3). Reasons why a patient has not
received a CDK4/6 inhibitor will be collected.  
Patients with prior exposure to fulvestrant, other SERDs or PI3K/AKT/mTOR inhibitors are 
not permitted to enter the study.  Concomitant treatment with a CDK4/6 inhibitor is not 
permitted.
Pre-menopausal patients with adequate ovarian suppression are eligible for the study.  
Pre-menopausal patients without ovarian suppression could be eligible if concomitant 
treatment with a LHRH agonist is started prior to or on Cycle 1, Day 1.
Patients must have radiological evidence of recurrence or progression, an Eastern Cooperative 
Oncology Group (ECOG) Performance Status of 0 or 1, and measurable lesion(s) according to 
RECIST v1.1 or, in the absence of measurable disease  lytic or mixed bone lesions that can be 
assessed by computerised tomography (CT) or magnetic resonance imaging (MRI). 
Patients with visceral metastases may be eligible unless the visceral involvement is associated 
with organ dysfunction (ie, visceral crisis) in which case, such patients are excluded.  
A recently collected formalin-fixed paraffin embedded (FFPE) tumour tissue block (strongly
preferred) or 30 (minimum 20) freshly cut unstained, serial slides from the most recently 
collected tumour tissue (primary or recurrent cancer) will be required from all patients.  For 
patients recruited in mainland China, a minimum of 11 freshly-cut unstained serial tumour 
slides will be required.  If tissue is inadequate for testing, the study site may collect a fresh 
sample before the start of treatment.
Adequate haematology, glucose metabolism, renal and liver function tests are required at 
screening; patients with type 2 diabetes are eligible if HbA1c at screening is less than 8.0% 
(63.9 mmol/mol), and if they do not require insulin treatment.  Patients with type 1 diabetes 
are not eligible.
Approximately 700 patients will be randomised (1:1) with approximately 350 included in each 
arm.  Patients will receive capivasertib (400 mg or placebo, oral, twice daily; 4 days on and 3 
days off, weekly) and fulvestrant (500 mg, intramuscular injection on Day 1 of Weeks 1 and 3 
of Cycle 1, and then on Day 1, Week 1 of each cycle thereafter).  Study treatment will 
continue until objective radiological disease progression as defined by RECIST v1.1.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
pproved
n Cy
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Randomisation will occur as soon as possible after commencement of screening and should be 
within 28 days of screening.  The randomisation scheme will be stratified on the following 
factors:

Liver metastases (yes vs no)

Prior use of CDK4/6 inhibitors (yes vs no)

Geographic location:

Region 1: United States, Canada, Western Europe, Australia, and Israel

Region 2: Latin America, Eastern Europe and Russia

Region 3: Asia
The study schema is depicted in Figure 1.
Study Period:
Estimated date of first patient enrolled Q1 2020
Estimated date of last patient completed Q2 2024
Number of Patients:
It is expected that an estimated 930 patients will be screened and approximately 700 patients 
will be randomised, with half of the patients included in each treatment arm.  The China 
cohort will consist of approximately 134 randomised patients from National Medical Product 
Administration (NMPA)-certified sites In the event that recruitment of China cohort is not 
completed during global recruitment of approximately 700 patients, the recruitment of China 
cohort will continue until approximately 134 patients have been randomised from 
NMPA-certified sites.  
Treatments and treatment duration:
Capivasertib/placebo will be administered orally twice daily on an intermittent dosing 
schedule with treatment on Days 1 to 4 each week of a 28-day treatment cycle. The starting 
dose is 400 mg twice daily (BD) (4 days on and 3 days off). Capivasertib/placebo dose 
reductions are permitted: the initial dose reduction can be to 320 mg BD and the second dose 
reduction can be to 200 mg BD.
Fulvestrant will be administered as 2 × 5 mL intramuscular injections (250 mg/5 mL = 500 
mg in total) on Day 1 of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of each cycle 
thereafter. Dose reductions for fulvestrant are not allowed.  
Study treatment will be continued until disease progression unless there is evidence of 
unacceptable toxicity, or if the patient requests to stop the study treatment.  
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If capivasertib/placebo is discontinued for reasons other than disease progression, the patient 
may continue on fulvestrant alone at the investigator’s discretion.  Likewise, if fulvestrant is 
discontinued for reasons other than disease progression, the patient may continue 
capivasertib/placebo alone at the investigator’s discretion.
Cross-over from placebo to capivasertib is not allowed.
Data Monitoring Committee:
An Independent Data Monitoring Committee (IDMC) will be established to assess the safety 
of capivasertib in an unblinded manner. The IDMC will be responsible for reviewing the 
safety data accruing in the study at regular intervals prior to the primary PFS analysis database 
lock, to provide a recommendation to AstraZeneca whether the study should continue 
unchanged, be stopped, or be modified in any way. The IDMC will consist of at least 2 
physicians with expertise in breast cancer and one biostatistician. Further information on the 
IDMC and schedule of meetings will be defined in the IDMC Charter.
Statistical methods
The Full Analysis Set (FAS) will be used as the primary population for reporting efficacy data 
and to summarise baseline characteristics.  This comprises all patients randomised into the 
study, excluding patients randomised in China after the global cohort last patient first visit 
(LPFV), and will be analysed according to randomised treatment regardless of the treatment 
received (intention-to-treat [ITT] principle).  Any important deviations from randomised 
treatment will be listed and considered when interpreting the efficacy data.  The Safety 
Analysis Set will be used as the primary population for reporting safety data.  This comprises 
all patients included in the FAS, who received at least 1 dose of study drug (fulvestrant, 
capivasertib, placebo) and will be analysed according to the treatment received.  If a patient 
receives at least 1 dose of capivasertib they will be summarised in the capivasertib arm for 
safety summaries.  
The primary objective of this study is to assess the efficacy of capivasertib +fulvestrant vs 
placebo + fulvestrant by assessment of PFS; the dual primary endpoints are PFS in the overall 
population and PFS in the PIK3CA/AKT1/PTEN-altered population.  This will be analysed 
using a stratified log-rank test adjusting for the stratification factors.  From the stratified Cox 
proportional hazards model (ties = Efron), the hazard ratio (HR) (capivasertib + fulvestrant vs 
placebo + fulvestrant) together with its corresponding 95% CI (calculated using a profile 
likelihood approach) will be presented.  An HR <1 will favour capivasertib + fulvestrant.  
The key secondary endpoints are OS, and objective response rate (ORR), in the overall and 
the PIK3CA/AKT1/PTEN-altered populations. OS will be assessed as described above for the 
primary endpoint. ORR will be presented with two-sided 95% CIs using the Clopper-Pearson 
method (Clopper and Pearson 1934).
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To preserve the overall type 1 error (familywise error rate) in the strong sense, a multiple 
testing procedure (MTP) including the primary and secondary endpoints will be implemented.  
The PFS Analysis (primary) will take place after the PFS reaches approximately 77% maturity
in both the overall and the PIK3CA/AKT1/PTEN-altered populations.  The OS Interim 
Analysis is expected to occur when approximately 394 OS events have been observed in the 
overall population (80% information fraction) and the PIK3CA/AKT1/PTEN-altered 
population has reached similar maturity. The OS Final Analysis will take place when 
approximately 70% maturity has been observed in the overall and the PIK3CA/AKT1/PTEN-
altered population.
Safety and tolerability data will be summarised using appropriate descriptive statistics.  
1.3
Schema
The general study design is summarised in Figure 1.
Figure 1
Study design
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a
FFPE (formalin-fixed, paraffin-embedded) blocks are strongly preferred, or if not possible, preferably
30 [minimal 20]) freshly-cut unstained serial tumour tissue sections are acceptable provided that they meet 
the specifications described in the Diagnostic Testing Manual. For patients recruited in mainland China, a 
minimum of 11 freshly-cut unstained serial tumour slides will be required.
AI, aromatase inhibitor; AKT, serine/threonine specific protein kinase; CBR, clinical benefit rate; CDK, cyclin 
dependent kinase; CT, computerised tomography; FFPE, formalin-fixed paraffin-embedded; HER2, human 
epidermal growth factor receptor 2; HR, Hormone receptor; MRI, magnetic resonance imaging; mTOR, 
mammalian target of rapamycin; ORR, objective response rate; OS, overall survival; PFS, progression-free 
survival; PI3K, phosphatidylinositol-3-kinase; RECIST v1.1, Response Evaluation Criteria in Solid Tumours 
version 1.1; SERD, selective estrogen response degrader; US, United States.
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2
INTRODUCTION
Capivasertib, a novel pyrrolopyrimidine-derived compound, is a potent and selective oral, 
intermittently dosed inhibitor of all 3 isoforms of AKT (Davies et al 2012). 
Further details can be found in the current capivasertib (AZD5363) Investigator’s Brochure.
2.1
Study rationale
This Phase III study is designed to provide confirmatory evidence of the findings from the
previous Phase Ib/II FAKTION study (NCT01992952), which evaluated the combination of 
capivasertib + fulvestrant compared with placebo + fulvestrant in post-menopausal patients 
with estrogen receptor positive, human epidermal growth factor receptor 2 negative 
(ER+/HER2−) advanced breast cancer (ABC) [140 patients, randomised 1:1] after relapse or 
disease progression on an aromatase inhibitor (AI) therapy (Jones et al 2019). The study met 
its primary endpoint of progression-free survival (PFS), showing a 5.5-month PFS
improvement with the addition of capivasertib to fulvestrant, regardless of the 
PI3K/AKT/PTEN (phosphatidylinositol-3-kinase/AKT/phosphatase and tensin homolog)
pathway activation status.  At the time of the PFS analysis, overall survival (OS) data were not 
mature (37% maturity); however, the data sugg st an improvement of approximately 6 months 
from the combination treatment (not statistically significant).  The combination of capivasertib 
+ fulvestrant was generally well tolerated  with a manageable safety profile. Further details
on the FAKTION study are available in Section 2.2.
This Phase III study (CAPItello 291) aims to evaluate the efficacy and safety of capivasertib + 
fulvestrant versus (vs) placebo + fulvestrant in patients with locally advanced (inoperable) or 
metastatic hormone receptor ositive (HR+)/HER2− breast cancer following recurrence or 
progression on or after third-generation AI therapy in an unselected population (hereafter 
referred to as the “overall population”) and a molecularly defined subgroup with tumours 
harbouring at least one PIK3CA/AKT1/PTEN-qualifying alteration (hereafter referred to as the 
“altered subgroup”), as described in Section 4.1.
2.2
Background
In women, breast cancer is the most frequently diagnosed malignancy and the leading cause of 
cancer mortality worldwide (GLOBOCAN 2018, NCCN 2019).  ABC comprises both locally 
advanced (inoperable) and metastatic disease.  Although it can be treated, metastatic breast 
cancer remains incurable with a median survival of approximately 3 years and a 5-year 
survival rate of around 25% (Cardoso et al 2018).  Several prognostic indicators for breast 
cancer have been identified including HER2 and the ER (here, also referred to as hormone 
receptor [HR]).  Most of the improvements in survival rates achieved in the last decade have 
been due to advances in the treatment of patients with HER2+ tumours.  Conversely, survival 
rates for patients with HR+/HER2− tumours, which account for approximately 70% of all
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breast cancers (Howlader et al 2014), have not shown much improvement over the same 
period (Gobbini et al 2018).  
In the majority of cases, endocrine-based therapy is the initial treatment for HR+/HER2− 
breast cancer. The exceptions are patients with visceral crisis or in whom endocrine-based 
alternatives have been exhausted or for whom there is evidence of endocrine resistance; in 
such instances, chemotherapy is required.  In women, endocrine therapy is recommended for 
both post- and pre-menopausal patients where, in the latter setting, it is provided in 
conjunction with the suppression or ablation of ovarian function (Cardoso et al 2018).  In men, 
the treatment approach for ABC is similar to that of women, with some particularities: 
tamoxifen is the preferred treatment in HR+ metastatic disease; in addition, AIs should be 
used in combination with luteinising hormone-releasing hormone (LHRH) agonist or surgical 
orchidectomy due to hypothalamic-pituitary negative feedback and in some case reports, 
fulvestrant has also shown efficacy for the treatment of metastatic disease (Cardoso et al 
2017).  Many patients with HR+/HER2− breast cancer b nefit from sequential use of 
endocrine therapies and those who respond to endocrine therapy with either tumour shrinkage 
or long-term stabilisation (ie, clinical benefit) should be offered additional endocrine therapy 
at subsequent disease progression (NCCN 2019).  The optimal sequence and integration of the 
available endocrine agents is not established and is influenced by choice of initial therapy, the 
response obtained, as well as individual patient and disease characteristics (Cardoso et al 
2018).  Several novel, effective agents have become available in recent years for combination 
with endocrine therapies.  These include cyclin-dependent kinase (CDK) 4/6 inhibitors and 
everolimus in combination with exemestane (an inhibitor of the mammalian target of the 
rapamycin receptor [mTOR]).  Available econd or further lines of therapies are limited either 
with regard to the population able to gain benefit, or the minimal magnitude of benefit
(Cardoso et al 2018). A Phase III study (BOLERO-2) of everolimus plus exemestane in 
patients with HR+/HER2- ABC post-AI progression showed that the combination therapy
improved PFS compared with exemestane alone from 3.2 to 7.8 months irrespective of 
PIK3CA genotype, albeit without significant OS improvement (Yardley et al 2013). More 
recently, the Phase III SOLAR-1 study demonstrated an improvement in PFS of 5.7 to 
11 months with the addition of the alpha-specific PI3K inhibitor alpelisib to fulvestrant in 
patients with HR+/HER2− ABC with tumours harbouring a PIK3CA mutation, who had 
relapsed or progressed on an AI (André et al 2019), based on which the FDA granted 
approval. Of note, a clinically relevant benefit was not seen in the PIK3CA non-mutant cohort 
and is not included in the approval. Despite these advances, these tumours eventually develop 
endocrine resistance necessitating the use of chemotherapy and thus, HR+/HER2− ABC
remains an area of considerable unmet medical need.
The AKT serine/threonine protein kinases (AKT1, AKT2, AKT3) are key downstream
effectors of the PI3K/AKT/mTOR pathway, mediating cell proliferation and resistance to 
apoptosis, and are activated in a wide range of solid and haematologic malignancies (Brown 
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and Banerji 2017, Lindsley 2010, Liu et al 2019).  AKT activation in tumours is largely due to 
input from other signalling pathways upstream of AKT including loss of PTEN function and 
activating mutations in the catalytic subunit of PI3K (PIK3CA) (Yi and Lauring 2016).  
Numerous preclinical studies show that endogenous AKT activity promotes breast cancer cell 
survival and resistance to chemotherapy or endocrine therapy (Frogne et al 2005, Ghayad et al 
2010, van der Hage et al 2004).  This can be overcome by down-regulation or inhibition of the 
PI3K/AKT pathway, as has been shown in several in vitro and in vivo breast cancer models 
(Frogne et al 2005, Ghayad et al 2010, van der Hage et al 2004).
Capivasertib is under investigation by AstraZeneca for a range of therapeutic indications 
(Banerji et al 2018, Tamura et al 2016) including triple-negative breast cancer (TNBC), 
ER+/HER2− breast cancer and prostate cancer.  Capivasertib inhibits the proliferation of 25 
out of 180 tumour cell lines with a concentration causing 50% inhibition of cell growth (GI50) 
of <1 μM. Breast cancer cell lines show the highest frequency of sensitivity to capivasertib, 
with a significant correlation between the presence of PIK3CA or PTEN mutations and 
sensitivity (Davies et al 2012).  Capivasertib inhibits the growth of several human breast 
cancer xenograft models, including the TNBC xenograft model HCC1187 and the HER2+, 
PIK3CA mutant xenograft models BT474 and HCC1954.
Long-term estrogen deprivation (LTED) of human breast cancer cells in vitro (to mimic the 
low estrogen levels observed in AI-treat d patients) revealed hyperactivation of the 
PI3K/mTOR signalling pathway (Miller et al 2010).  Consistently, increased PI3K/AKT 
signalling in clinical tumour samples is associated with poor anti-proliferative response to AI 
in breast cancer patients (Tokunaga et al 2006, Gao et al 2014).  Inhibition of the PI3K 
pathway in the LTED cells induc d apoptosis, indicating dependence on the PI3K pathway
upon hormone deprivation (Miller et al 2010).  Furthermore, modest reduction of PTEN 
expression in cell lines and xenograft models led to endocrine resistance which could be 
overcome by treatment with capivasertib in combination with fulvestrant (Fu et al 2014).  
Capivasertib synergises with fulvestrant in models of breast cancer irrespective of their 
sensitivity to endocrine therapy; compared with either agent alone, the combined treatment 
with capivasertib and fulvestrant resulted in a greater anti-tumour response in human breast 
cancer HBCx22 OvaR xenografts growing in ovariectomised mice (Ribas et al 2015).
A recent investigator-sponsored Phase Ib/II randomised, double-blind, placebo-controlled 
study (FAKTION) evaluated the combination of capivasertib (400 mg BD, 4 days on 3 days 
off) with fulvestrant compared with fulvestrant alone in post-menopausal women with locally 
advanced (inoperable) or metastatic breast cancer previously treated with a third-generation 
AI therapy (Jones et al 2019).  Eligible patients were post-menopausal with locally advanced 
or metastatic ER+/HER2- breast cancer that was not amenable to surgical resection.  Patients 
had to be suitable for endocrine treatment but were to have received no more than 3 previous 
lines of endocrine treatment for ABC and up to 1 line of chemotherapy for ABC.  Patients 
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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were also to have experienced disease progression during treatment with a third-generation AI 
for metastatic disease (although this did not need to be the most recent therapy) or have 
relapsed on an AI in the adjuvant setting.  Previous treatment with fulvestrant or 
PI3K/mTOR/AKT inhibitors was not allowed.  PI3K/AKT/PTEN pathway activation status 
was determined prior to randomisation; the protocol-specified definition of activated 
PI3K/AKT/PTEN pathway was: an activating PIK3CA mutation detected in either tissue 
and/or circulating tumour DNA, or low/absent PTEN by immunohistochemistry (primary or 
metastatic tumour). Patients (N=140) were randomised 1:1; of these, 69 received capivasertib 
+ fulvestrant and 71 received placebo + fulvestrant.  Baseline patient and disease 
characteristics were largely balanced between treatment arms.  The analysis at the time of the 
primary endpoint data cut-off (DCO) [after 112 events; 80% maturity] showed that the study
met its primary endpoint (Jones et al 2019).  In the intention-to-treat analysis, median PFS was 
10.3 months in the capivasertib + fulvestrant group compared with 4.8 months for the placebo 
+ fulvestrant group (hazard ratio [HR] = 0.58; 95% confiden e interval [CI]: 0.39 to 0.84; 
two-sided p=0.004).  The overall survival (OS) data were not mature (52 deaths reported; 37% 
maturity), but the addition of capivasertib to fulvestrant resulted in an observed OS 
improvement of approximately 6 months (26 vs 20 months, respectively), though this was not 
statistically significant (HR 0.59; 95% CI: 0.34 to 1.05; two-sided p=0.071).  Of note, the PFS 
benefit appeared to be independent of the PI3K/AKT/PTEN pathway activation status based 
on the available data at the time of primary analysis: in patients with pathway activated 
tumours (N=59) the HR was 0.59 (95% CI 0.34 to 1.03; two-sided p=0.064) and in those with 
pathway non-active tumours (N=81) it was 0.56 (95% CI 0.33 to 0.96, two-sided p=0.035). In 
addition, and in keeping with oth r studies in the clinical development program, the 
combination of capivasertib + fulvestrant demonstrated an overall manageable safety profile 
with a low rate of discontinuation of capivasertib due to adverse events (AEs) (11.6% [8 from 
69]).  The most frequent grade ≥3 AEs that occurred in ≥10% of the population, irrespective 
of causality, in the capivasertib vs placebo treatment groups, respectively, were: diarrhoea 
(14.5% vs 4.2%), fatigue (1.4% vs 4.2%), rash (20.3% vs 0%), hyperglycaemia (4.3% vs 0%), 
vomiting (2.9% vs 0%), and infections (5.8% vs 2.8%).  Two patients died during the study, 1
in the placebo arm (grade 5 haemorrhage) and 1 death without progression on treatment with
capivasertib, possibly related to treatment (atypical pulmonary infection).  
The combination of capivasertib (400 mg, 4 days on 3 days off) with fulvestrant in
ER+ metastatic breast cancer is also being evaluated in the AstraZeneca-sponsored 
Study D3610C00001 (Parts E [AKT1-mutant, completed] and F [PTEN-mutant, ongoing] and 
in 2 ongoing investigator-sponsored studies (plasmaMATCH- and Hyman AKT mutant), 
adopting the recommended combination dose regimen of capivasertib with fulvestrant 
established in the FAKTION study. Interim efficacy data from Study D3610C00001 Part E 
have shown clinical activity of capivasertib plus fulvestrant in heavily pre-treated patients 
with AKT1-mutant ER+ metastatic breast cancer, including those with prior resistance to 
fulvestrant, with an overall manageable safety profile (Smyth et al 2017). Pooled AE data 
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from Study D3610C00001 Parts E and F (DCO of 4 October 2018) indicate that the most 
common CTCAE grade >3 events (>5% of patients) were diarrhoea (5.4%), hyperglycaemia 
(5.4%), and rash maculo-papular (10.8%). The discontinuation rate for toxicity was low: 7 
(9.5%) and 3 (4.1%) patients had at least 1 AE that led to discontinuation of capivasertib 
treatment, irrespective of causality and causally-related, respectively. The only AE leading to 
discontinuation that affected more than 1 patient was fatigue (reported in 2 patients).
Taken together, the overall benefit/risk of capivasertib + fulvestrant appears to be favourable 
for patients with HR+/HER2− locally advanced/metastatic breast cancer but requires 
confirmation in this pivotal Phase III study.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of capivasertib is 
provided in the Investigator’s Brochure.  
2.3
Benefit/risk assessment
2.3.1
Risks with capivasertib
Based on non-clinical and clinical data available to date, the risks associated with capivasertib 
are as follows:

Identified Risks: nausea and vomiting, diarrhoea, stomatitis, dry skin, pruritus, decreased 
appetite, dyspepsia, rash, dysgeusia, erythema multiforme, drug eruption, dermatitis, 
dermatitis exfoliative generalised, t xic skin eruption, fatigue, mucosal inflammation, 
blood creatinine increased, glycosylated haemoglobin increased, anaemia, 
hypersensitivity and urinary tract infection.

Important Identified Risks: hyperglycaemia.

Important Potential Risk: cute complications of hyperglycaemia.
Based on non-clinical data available (dog telemetry study), QT prolongation has been noted as 
a potential risk. However, in AstraZeneca-sponsored clinical studies of capivasertib to date, 
there were no reports of sudden death, torsades de pointes, or seizures, and from a recent 
concentration-QT model analysis, capivasertib is not predicted to pose a clinically significant 
safety risk for QT prolongation at the therapeutic dosing regimen. However, it is 
recommended to avoid drugs known to prolong QT interval (see Section 6.5.3). Further 
details on the risks are available in ‘Section 6: Summary of data and guidance for the 
investigators’ of the Investigator’s Brochure.  
Overall in the monotherapy intermittent dosage pool (N=229), 42.4% patients had serious 
adverse events (SAEs), 17% were causally related and 3.1% patients were reported with SAEs 
leading to death.  There were no capivasertib treatment-related deaths in this pool. A total of 
17.5% patients were discontinued due to SAEs, and 11.4% were discontinued due to SAEs 
related to capivasertib treatment.
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Based on data from the D3610C00001 and FAKTION studies (Section 2.2), the combination 
of capivasertib with fulvestrant has a tolerability profile that is manageable with dose 
modifications and supportive care.  
There are 16 externally sponsored research studies which are planned, have recently 
commenced recruitment or are ongoing.  Of these 16, 10 are investigating capivasertib 
specifically and 6 are “umbrella/basket” studies in which capivasertib is an option in a panel 
of potential investigational drugs.  AstraZeneca is not aware of any new and significant safety 
information from externally sponsored research.  
2.3.2 Overall benefit-risk and ethical assessment
Although endocrine therapy administered with or without either a CDK4/6 inhibitor, 
everolimus or alpelisib (in PIK3CA mutant tumours) are effective options for at least some 
patients with HR+/HER2− ABC, all tumours eventually develop endocrine resistance, and 
from that point will require sequential chemotherapies given until disease progression or 
unacceptable toxicity, with the intent of reducing disease burden and symptoms, and delaying 
disease progression. Thus, HR+/HER2− ABC still represents an area of considerable unmet 
medical need for new therapies and/or combinations that can delay or overcome resistance.
Clinical and non-clinical data with capivasertib (see Section 2.2) support the hypothesis that 
AKT inhibition in combination with an endocrine therapy such as fulvestrant may be a valid 
treatment strategy for HR+/HER2− ABC   Capivasertib has also demonstrated clinical activity 
in several settings including patients with metastatic TNBC in combination with first-line 
paclitaxel (Schmid et al 2018), patients with advanced AKT1 mutant solid tumours in 
monotherapy or combination with fulvestrant (ER+ breast cancer) (Hyman et al 2017, Smyth 
et al 2017) and patients with ER+/HER2- ABC in combination with fulvestrant after AI 
therapy (Jones et al 2019).  
The non-clinical profile and emerging clinical safety profile from the early clinical studies 
with capivasertib have not identified risks that would preclude investigation in this setting.  
The study design of this randomised clinical trial aims to minimise potential risks in several 
ways.  First, appropriate inclusion and exclusion criteria will be included in the study protocol
to protect patient safety. For example, in order to be enrolled, patients must be eligible for 
fulvestrant treatment (as per local investigator assessment) which is administered in both arms 
of the study, and patients with symptomatic visceral disease or any disease burden that makes 
the patient ineligible for endocrine therapy per the investigator’s best judgement will be
excluded. Of note, patients with uncontrolled and/or insulin dependent diabetes are also
excluded from the study. Second, the protocol includes safety monitoring in excess of 
standard of care monitoring, with the intent of protecting patients involved in the study. 
Furthermore, a dose modification strategy for the management of toxicity and monitoring is in 
place for those risks deemed to be most likely or serious.  Thus, based upon the clinical and 
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non-clinical safety profile, the limited life expectancy of patients due to malignant disease, 
and the strength of the scientific hypothesis under evaluation, the benefit/risk assessment for 
this study supports the treatment of capivasertib and fulvestrant in patients with HR+/HER2− 
ABC.  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of capivasertib may be found in the Investigator’s Brochure.  
See Section 9.5.1 and Appendix C for information regarding the Data Monitoring Committee.
2.3.3
Impact on Benefit/Risk from Study Disruptions due to Coronavirus 
Disease 2019
The emergence of the novel coronavirus disease 2019 (SARS-CoV-2/COVID-19) pandemic 
presents a potential safety risk for patients and therefore several risk mitigation factors have 
been implemented in this study (see Section 4.5, Appendix K  and Appendix L).
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3
OBJECTIVES AND ENDPOINTS
3.1
Primary objectives
The primary objectives for the study and associated outcome measures are summarised in 
Table 2.
Table 2
Primary objectives
Primary objective
Endpoint
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
PFS in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
PFS is defined as the time from randomisation until 
progression per RECIST v1.1, as assessed by the 
investigator at the local site, or death due to any cause.  
PFS, progression-free survival; RECIST v1.1, Response Evaluation Criteria in Solid Tumours version 1.1; 
vs, versus.
3.2
Secondary objectives
The secondary objectives of the study and associated outcome measures are summarised in
Table 3.  
Table 3
Secondary objectives
Secondary objectives
Endpoint
To compare the effect of capivasertib + fulvest ant 
relative to placebo + fulvestrant by assessment of OS 
in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
OS is length of time from randomisation until the date 
of death due to any cause.  
To compare the effect of capiv
ertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
PFS2 in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
PFS2 is defined as the time from randomisation until 
second progression on next-line treatment, as assessed 
by the investigator at the local site, or death due to any 
cause.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
ORR in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
ORR is defined as the percentage of patients with at 
least one CR or PR per RECIST v1.1, as assessed by 
the investigator at the local site.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
DoR in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
DoR is defined as the time from the date of first 
documented response until date of documented 
progression or death in the absence of disease 
progression.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
CBR in the overall population and in the 
PIK3CA/AKT1/PTEN-altered subgroup.  
CBR is defined as the percentage of patients who have 
a CR, PR or stable disease per RECIST v1.1 (without 
subsequent cancer therapy) maintained ≥24 weeks 
after randomisation.  
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Secondary objectives
Endpoint
To assess the safety and tolerability of capivasertib + 
fulvestrant as compared to placebo + fulvestrant in 
the overall population and in the 
PIK3CA/AKT/PTEN-altered subgroup.  
Safety and tolerability will be evaluated in terms of 
AEs/SAEs, vital signs, clinical 
chemistry/haematology/glucose metabolism 
parameters, and ECG parameters.  
Assessments related to AEs cover:

Occurrence/frequency

Relationship to capivasertib and fulvestrant
as assessed by investigator

CTCAE grade

Seriousness

Death

AEs leading to discontinuation of
capi asertib/placebo

AEs leading to discontinuation of fulvestrant

AEs leading to dose interruption of
capivasertib/placebo

AEs leading to dose interruption of
fulvestrant

AEs leading to dose reduction of
capivasertib/placebo

AEs of special interest

Other significant AEs
Vital signs parameters include systolic and diastolic 
blood pressure, pulse, respiratory rate, body 
temperature and weight.  
Assessments cover:

Observed value

Absolute and change from baseline values
over time
To evaluate the PK of capivasertib when given in 
combination with fulvestrant.  
Plasma concentration of capivasertib pre-dose (Ctrough) 
and post-dose (C1h and C4h) in the overall population 
(patients randomised to capivasertib + fulvestrant).  
AUC 0-12h, Cmax and tmax in a subpopulation of 
approximately 6 Japanese patients with rich PK 
sampling.  
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Secondary objectives
Endpoint
To assess the impact of capivasertib + fulvestrant vs 
placebo + fulvestrant on patients’ disease-related 
symptoms, function and HRQoL in the overall 
population and in the PIK3CA/AKT1/PTEN-altered 
subgroup where applicable.  
Evaluation of EORTC QLQ-C30, EORTC 
QLQ-BR23, scale/item scores including change from 
baseline and time to deterioration.  
To compare the effect of capivasertib + fulvestrant 
relative to placebo + fulvestrant by assessment of 
time to definitive deterioration of ECOG 
performance status from baseline in the overall 
population and in the PIK3CA/AKT1/PTEN-altered 
subgroup.  
Time to definitive deterioration of ECOG performance 
status is defined as time from randomisation to the 
earlier of the date of the first definitive deterioration or 
death due to any cause.  
AE, adverse event; AUC 0-12h, area under the plasma concentration-time curve from zero to 12 hours; C, 
concentration; CBR, clinical benefit rate; Cmax, maximum observed plasma (peak) concentration; CR, complete 
response; CTCAE, Common Terminology Criteria for Adverse Event; ctDNA, circulating tumour DNA; DoR, 
duration of response; ECG, electrocardiogram; ECOG, Eastern Cooperati e Oncology Group; EORTC, European 
Organisation for Research and Treatment of Cancer; EORTC QLQ-BR23, EORTC Quality of Life Questionnaire
breast cancer specific module; EORTC QLQ-C30, EORTC Quality of Life Questionnaire-Core 30 items; 
HRQoL health-related quality of life; ORR, objective response rate; OS, overall survival; PFS, progression-free 
survival; PFS2, time from randomisation to second progression or death; PIK3CA, phosphatidylinositol-4,5-
bisphosphate 3-kinase catalytic subunit alpha gene; PK, pharmacokinetics; PR, partial response; PTEN, 
phosphatase and tensin homolog; RECIST v1.1, Response Evaluation Criteria in Solid Tumours version 1.1; 
SAE, serious adverse event; tmax, time to reach peak or maximum observed concentration following drug 
administration; vs, versus.
.
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endpoint) in the overall population and OS in the PIK3CA/AKT1/PTEN-altered sub-population 
will also be assessed.
The reciprocal feedback between the ER and PI3K signalling (see Section 2.2) suggests that 
the combination of endocrine therapy and inhibitors of the PI3K/AKT pathway may have 
clinical utility in the treatment of ER+ breast cancer, and responses would be expected both in 
patients whose tumours become dependent on the PI3K pathway upon treatment with
fulvestrant, as well as patients whose tumours harbour a genetic alteration leading to an 
activated PI3K pathway. Therefore, PFS will be assessed in patients with qualifying 
activating mutations in the PIK3CA or AKT1 genes and/or loss of function mutations or 
deletion of the PTEN gene (referred to as PIK3CA/AKT1/PTEN-altered) as dual primary
endpoints.  The list of eligible alterations is curated on the basis of the currently published 
literature for causal associations between pathogenicity and the alterations, using the
AstraZeneca strategy for early-stage clinical studies as described by Carr et al 2016.  The list 
of eligible variants will be defined and specified in the SAP prior to analysis.   
It is expected that an estimated 930 patients will be screened so that approximately 
700 patients can be randomised 1:1, with approximately 350 included in each arm.  Of these 
700 randomised patients, based on a prevalenc  of 40% to 45% for PIK3CA/AKT1/PTEN
alterations (Cristofanilli et al 2016, Curtis et al 2012, Di Leo et al 2018, Hortobagyi et al 2016,
Pereira et al 2016, Spoerke et al 2016), and a test failure rate of 20%, it is expected that a 
minimum of approximately 224 patients will test positive for tumours with these alterations 
and will be assigned to the PIK3CA/AKT1/PTEN-altered subgroup. The prevalence of 
PIK3CA/AKT1/PTEN mutation status will be monitored post-randomisation by central testing 
of formalin-fixed paraffin-embedded (FFPE) tumour samples collected before study entry. 
Given the proposed sample siz  (approximately 700 patients overall), it is expected that 
randomisation will be sufficient to ensure a balance between treatment arms with respect to 
mutational status. Enrolment will be open to all eligible patients irrespective of the 
PIK3CA/AKT1/PTEN status of their tumour(s); however adequate tumour tissue collected 
before study entry will be required for a central retrospective analysis.  
In China, recruitment will continue until approximately 134 Chinese patients have been 
randomised, irrespective of whether or not the overall study enrolment has been reached. This 
is to ensure adequate participation of Chinese patients to satisfy China Regulatory Authority
requirements.  
Patients will receive weekly capivasertib (400 mg or placebo, oral, twice daily; 4 days on and 
3 days off) and fulvestrant (at the approved dose regimen [500 mg intramuscular injections on 
Day 1 of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of each cycle thereafter]).  
All patients will attend a screening visit a maximum of 28 days prior to the start of study
treatment.  
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Day 1 is defined as the randomisation date; study treatment should begin as soon as possible 
after randomisation, ideally the same day.  Randomised patients will continue study treatment 
until objective radiological disease progression as defined by Response Evaluation Criteria in 
Solid Tumours version 1.1 (RECIST v1.1), unacceptable toxicity occurs, the patient 
withdraws consent or death.  Following objective disease progression, further treatment
options will be at the discretion of the investigator.  If a patient discontinues treatment (and/or 
receives a subsequent cancer therapy) prior to progression, the patient should still continue to 
be followed until objective disease progression as defined by RECIST v1.1.  Cross-over from 
placebo to capivasertib is not allowed.  
The randomisation scheme will be stratified on the following factors:

Liver metastases (yes vs no)

Prior use of CDK4/6 inhibitors (yes vs no)

Patients may have received prior treatment with CDK4/6 inhibitors as part of 
standard treatment or within clinical trials (in the latter scenario, written confirmation 
of exposure to the investigational agent rather than placebo is required to allow 
stratification at randomisation)

Geographic location:

Region 1: United States, Canada, Western Europe, Australia, and Israel

Region 2: Latin America, Eastern Europe and Russia

Region 3: Asia
The dual primary endpoints, PFS in overall and PIK3CA/AKT1/PTEN-altered subgroup, are 
defined as the time from randomisation until disease progression based on the investigator’s 
assessment according to RECIST v1.1, or death due to any cause regardless of whether the 
patient withdraws from therapy or receives another anticancer therapy prior to progression.  
The key secondary endpoint of OS is defined as the time from the date of randomisation until 
death due to any cause.  A sensitivity analysis will be conducted using PFS assessed by 
blinded, independent central review (BICR) and defined using RECIST v1.1 criteria.
A study flow chart is illustrated in Figure 2 and the study design is summarised in Figure 1.  
For details on what is included in the efficacy and safety endpoints, see Section 3.  For details 
on treatments given during the study, see Section 6.1.  
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Figure 2
Study flow chart
BD, twice daily; PFS2, time from randomisation to second progression or death; PRO, patient-reported outcome; 
RECIST v1.1, Response Evaluation Criteria in Solid Tumours version 1.1.  
a
If the patient discontinues due to progression, PROs (not including PGI-ITT and PRO-CTCAE) should be
assessed at progression and every 4 weeks (±3 days) post discontinuation until PFS2.  
b
Patients who discontinue treatment prior to progression should continue to be scanned by RECIST v1.1 
every 8 weeks (± 7 days) for the first 18 months and every 12 weeks (±7 days) thereafter until progression, 
regardless of reason for treatment discontinuation.  If the patient discontinues due to toxicity but does not 
progress, PROs (not including PGI-ITT and PRO-CTCAE) should be assessed every 4 weeks (±3 days) 
until progression, at progression and every 4 weeks (±3 days) post progression until PFS2.  
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4.1.1
Study oversight considerations
The study will use a Trial Steering Committee (TSC) and an external independent data 
monitoring committee (IDMC).  Please see Section 9.5.1 and Appendix C for additional
information.  
4.2
Scientific rationale for study design
This randomised, double-blind, placebo-controlled, Phase III study will serve as confirmatory 
evidence of the clinical benefit, safety and tolerability of capivasertib + fulvestrant vs placebo 
+ fulvestrant for the treatment of patients with locally advanced or metastatic HR+/HER2− 
breast cancer.  Mandatory tissues samples collected from patients at screening will be used to
retrospectively identify patients with qualifying PIK3CA/AKT1/PTEN alterations to 
investigate treatment with capivasertib + fulvestrant in this subgroup.  The randomised, 
double-blind design of this study reduces potential for bias when assessing whether the 
combination of capivasertib + fulvestrant shows improved efficacy compared with fulvestrant
monotherapy.  
This is a Phase III study in adults (pre-menopausal women and post-menopausal women, and 
men) with HR+/HER2− locally advanced or metastatic breast cancer, after recurrence or 
progression on or after treatment with an AI. This represents a population that may have 
received up to 2 prior lines of endocrine therapy for metastatic disease, including combination 
therapy with a CDK4/6 inhibitor, and up to 1 line of chemotherapy in the metastatic setting; 
all patients will have received hormone (endocrine)-based therapy with an AI. 
This study has been designed to also nclude pre- or peri-menopausal women, and men as per 
recent international guidelines (Cardoso et al 2018).  These state that all treatment 
recommendations for post-menopausal patients should be extended to the pre-menopausal 
setting (with associated ovarian function suppression or ablation), encouraging the inclusion 
of patients who are initially pre- or peri-menopausal in clinical studies to avoid separate and 
duplicate trials. Studies evaluating new endocrine-based strategies should be designed to 
allow enrolment of both pre- and post-menopausal women, and men.
Hormone (or endocrine)-based therapy is the preferred initial treatment for ER+/HER2- or 
luminal ABC (Cardoso et al 2018) in the majority of cases, excluding only those with visceral 
crisis or concern for (or proof of) endocrine resistance, for whom chemotherapy is required. 
Current international treatment guidelines state that the preferred first-line endocrine therapy 
depends on the type and duration of adjuvant endocrine therapy as well as the disease-free 
interval. Available endocrine agents include but are not limited to AIs, tamoxifen, or 
fulvestrant, for pre- and peri-menopausal women (with ovarian function suppression/ablation), 
men (preferably with a LHRH agonist), and post-menopausal women. Of note, CDK4/6 
inhibitors in combination with an AI or fulvestrant (±LHRH agonist depending on 
menopausal status) have substantially improved PFS compared with endocrine therapy alone. 
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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These agents are, in certain markets, approved for advanced or metastatic HR+/HER2- breast 
cancer as initial endocrine-based therapy and/or after disease progression following endocrine 
therapy. As this class of agents has started to show a survival benefit (Im et al 2019, Slamon
2019, Sledge 2019), it is expected that their already wide use will continue to increase, 
especially in the first-line setting.  Therefore, if they are available in the country in which a 
patient is being enrolled, they must be considered and excluded as treatment options before 
the patient can be considered for entering the study. For the above reasons and to make sure 
the enrolled population is representative of the general AI resistant HR+/HER2- advanced or 
metastatic breast cancer population, the study intends to enrol a minimum of 51% of patients 
previously treated with CDK4/6 inhibitor.  Regarding additional endocrine-based options, the 
mTOR inhibitor everolimus is also approved in combination with the AI exemestane in 
patients with previous failure of treatment with letrozole or anastrozole, but the European 
Society for Medical Oncology (ESMO) guidelines state that the decision to treat must take 
into account the toxicities associated with this combination, lack of statistically significant OS 
benefit, cost and availability.
There is no single standard of care following endocrine therapy with or without a CDK4/6 
inhibitor (as first- or second-line treatment). When patients progress, the choice of therapy 
depends on several factors: prior treatments (and response), disease burden, patient 
preference, and treatment availability, which varies in different countries around the world.
Regardless of first- or second-line CDK4/6 inhibitor treatment, and despite multiple treatment 
options (e.g., fulvestrant, everolimus plus exemestane), median post-progression treatment 
duration is limited, ranging from 4 to 8 months (Lupichuk et al 2019, Turner et al 2017). 
Patients eventually experience disease progression (endocrine resistance) and require 
chemotherapy. Thus, regardless of prior CDK4/6 inhibitor use, a considerable unmet medical 
need remains in this population for improved second- and additional-line treatment.
Available second or further lines of therapies are limited either with regard to the population 
able to gain benefit, or the magnitude of benefit. A Phase III study (BOLERO-2) of
everolimus plus exemestane in patients with HR+/HER2- ABC post-AI progression, showed 
that the combination therapy improved PFS compared with exemestane alone from 3.2 to 
7.8 months irrespective of PIK3CA genotype, albeit without significant OS improvement 
(Yardley et al 2013).  More recently, the Phase III SOLAR-1 study demonstrated an 
improvement in PFS of 5.7 to 11 months with the addition of the alpha-specific PI3K inhibitor 
alpelisib to fulvestrant in patients with HR+/HER2− ABC with tumours harbouring a PIK3CA
mutation, who had relapsed or progressed on an AI (André et al 2019), based on which the 
FDA granted approval. Of note, a clinically relevant benefit was not seen in the PIK3CA
non-mutant cohort and is not included in the approval.
The purpose of this Phase III study is to further characterise and confirm the efficacy and 
safety of capivasertib + fulvestrant observed in the Phase II randomised FAKTION study 
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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where the addition of capivasertib to fulvestrant resulted in a 5.5-month improvement in 
median PFS from 4.8 months on fulvestrant alone to 10.3 months (HR 0.57 [95% CI: 0.393, 
0.841]) regardless of PI3K/AKT/PTEN pathway activation status. At the time of the PFS 
analysis, OS data were not mature (37%; 52 deaths reported); however, the data suggest an 
improvement of approximately 6 months on the combination treatment. The positive efficacy 
data are supported by the finding that the addition of capivasertib to fulvestrant appears 
overall well tolerated with no marked impact on the dose intensity of fulvestrant (see 
Section 2.1 and Section 2.2 for further information on the FAKTION study and the study
rationale).  
In this Phase III study, patients qualifying for the altered subgroup will be identified by 
post-randomisation central testing of tumour tissue collected prior to enrolment based on a 
prespecified list of molecular alterations, using a validated assay as described in Section 8.7.1.  
By enrolment of both the overall population and a minimum number of patients in the altered 
subgroup, the study design (including the sample size and planned statistical analysis 
approach described in Section 9) will allow for further investigation of outcomes in the 2 
populations tested. 
In light of the demonstrated activity of the combination of capivasertib + fulvestrant in the 
Phase II FAKTION study and the common usage of single agent fulvestrant in the
management of advanced/metastatic HR+/HER2- breast cancer, fulvestrant is considered an 
appropriate comparator for this Phase III study.  In addition, deploying fulvestrant as the 
control agent will enable a robust assessment of the contribution of components in the doublet 
regimen under study.  
The rationale for the choice of stratification factors in this study is as follows:

Liver metastases (yes vs no): The pattern and extent of metastatic disease are considered 
to be important factors with prognostic impact in HR+/HER2−(Solomayer et al 2000). 
Patients with HR+ ABC with non-visceral metastases and visceral non-liver metastases 
have significantly better outcomes from endocrine therapy than patients with liver 
metastases (Robertson et al 2019).

Prior use of CDK4/6 inhibitors (yes vs no): Recent changes in the treatment landscape for 
HR+/HER2- ABC include the addition of CDK4/6 inhibitors to endocrine agents in the 
first- and second-line settings. Although limited and retrospective, currently available 
data suggest that patients who have received prior CDK4/6 inhibitors do not appear to 
have a different outcome obtained from subsequent standard of care therapies (Lupichuk 
et al 2019, Turner et al 2017). However, as the FAKTION study recruited at a time when 
CDK4/6 inhibitors were not available in the enrolling sites, it remains unclear whether 
prior treatment with a CDK4/6 inhibitor would influence the magnitude of benefit from 
treatment with capivasertib plus fulvestrant. The total number of CDK4/6 naïve patients 
will be limited to 49% of the total number of patients (Section 6.3).
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
Geographic location (Region 1: US, Canada, Western Europe, Australia, Israel; Region 2: 
Latin America, Eastern Europe and Russia; Region 3: Asia): Considering there is no 
single standard of care for the intended population, geographic region has been included
to account for possible differences in treatment paradigms and patient demographics in 
different territories.
Despite the documented benefits of endocrine-based therapy in HR+/HER2- ABC, intrinsic 
and acquired resistance remains a common feature that limits the success of this strategy, and 
lack of sensitivity (or primary resistance) to endocrine therapy appears associated with worst 
survival (Cristofanilli et al 2018).  For the purpose of this study, the following definitions for 
endocrine resistance (Cardoso et al 2018) will be used for data collection:

Primary endocrine resistance is defined as relapse while on the first 2 years of adjuvant 
endocrine therapy, or progressive disease within the first 6 months of first-line endocrine 
therapy for ABC, while on endocrine therapy

Secondary endocrine resistance is defined as relapse while on adjuvant endocrine therapy 
but after the first 2 years, or relapse within 12 months of completing adjuvant endocrine 
therapy, or progressive disease ≥6 months after initiating endocrine therapy for ABC, 
while on endocrine therapy
NOTE: Patients who meet any criteria of secondary endocrine resistance are classified as 
such, regardless of whether they meet any aspect of the definition of primary resistance; 
patients who do not meet any of the criteri  of secondary endocrine resistance are defined as 
having primary resistance.  
In recent studies with novel therapies in the HR+/HER2- ABC setting, estimation of the effect 
on OS has been jeopardised by limited statistical power, and therefore, suboptimal assessment 
of their benefit. The proposed study is intended to address this issue by providing adequate 
power to show a statistically significant difference between capivasertib + fulvestrant and 
placebo + fulvestrant in both PFS and OS.  The dual primary endpoint of this study are PFS in 
the overall population and PFS in the PIK3CA/AKT1/PTEN-altered population, as described in 
Section 3.1 and Section 9.  Key secondary efficacy endpoints (see Section 3.2 and Section 9)
are OS and objective response rate (ORR) in the overall and PIK3CA/AKT1/PTEN-altered
populations. Other secondary endpoints of this study that are appropriate include clinical 
benefit rate (CBR), duration of response (DoR), time to definitive deterioration of ECOG 
performance status from baseline, time from randomisation to second progression or death 
(PFS2), EORTC Quality of Life Questionnaire-Core 30 items (EORTC QLQ-C30) and 
EORTC Quality of Life Questionnaire-breast cancer specific module (EORTC QLQ-BR23)
and will be assessed in both the overall and the PIK3CA/AKT1/PTEN-altered populations.  
The EORTC QLQ-C30 and EORTC QLQ-BR23 capture relevant symptoms and functional 
impacts for patients with cancer and breast cancer, respectively.  Examination of change from 
baseline and time to deterioration in these concepts will allow for an assessment of the ability 
of the investigational treatment to preserve overall health-related quality of life (HRQoL) and 
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delay worsening of disease symptoms and functional limitations in the target population.  
Pharmacokinetic (PK) characterisation of capivasertib as well as the safety and tolerability of 
capivasertib + fulvestrant and placebo + fulvestrant will also be assessed as secondary 
endpoints.  
4.3
Justification for dose
4.3.1
Capivasertib
Several doses and schedules of capivasertib have been studied clinically (all twice daily 
[BD]).  Monotherapy has been given as continuous (80 mg to 600 mg), intermittent 4 days on, 
3 days off (480 mg to 640 mg) and intermittent 2 days on, 5 days off (640 mg to 800 mg) 
schedules.  Dose- and/or concentration-response relationships have been demonstrated for 
pharmacodynamic biomarkers of AKT inhibition in tumour tissue and for the most important 
AEs (diarrhoea, rash, and hyperglycaemia of CTCAE grade 3-4) in clinical studies.  
The recommended regimen for monotherapy (480 mg BD, 4 days on 3 days off) was selected 
based on pharmacodynamic parameters from tumour biopsies, PK data, and clinical safety.
The recommended Phase II dose of capivasertib in combination with fulvestrant was 
determined by the run-in part (Ib) of the Phase Ib/II FAKTION study. The aim of Phase Ib of
the study was to determine the maximum tolerated dose (MTD) for capivasertib given in 
combination with the licensed dose of fulvestrant (500 mg intramuscular on Days 1, 15, 29 
and once monthly thereafter). The toxicity profile in patients who received capivasertib 400 
mg BD, 4 days on 3 days off was consistent with prior capivasertib studies. Although no 
dose-limiting toxicities were observed, the Safety Review Committee concluded that 480 mg 
BD was unlikely to be tolerated for long-term dosing in combination with fulvestrant, and the 
4 days on, 3 days off 400 mg BD schedule was selected as the combination dose with 
fulvestrant.  This dose regimen was also supported by safety data from Study D3610C00001 
and preclinical PK-pharmacodynamic efficacy mathematical modelling (Yates et al 2015). 
Results from the randomised part of the FAKTION study (Phase II) provide evidence that the 
selected dose and schedule are efficacious with acceptable safety and tolerability in patients 
with ER+ ABC. Therefore, the dose regimen for this Phase III study is capivasertib 
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400 mg BD, 4 days on 3 days off in combination with fulvestrant at the approved dose 
regimen.  
4.3.2
Fulvestrant
Fulvestrant will be used within its marketing authorisation at a monthly dose regimen of
500 mg (2 × 5 mL intramuscular injections), with an additional loading dose in Cycle 1. This 
regimen is commonly used in clinical practice and considered as standard of care for the 
treatment of HR+/HER2– metastatic breast cancer in participating countries.  Monthly 
fulvestrant at the approved dose regimen showed an expected and manageable safety profile 
when combined with capivasertib in the FAKTION study (Jones et al 2019) and in 
Study D3610C00001 (Sections 2.2 and 2.3.1).
4.4
End of study definition
For the purpose of Clinical Trial Transparency the definition of the end of the study differs 
under FDA and EU regulatory requirements:

European Union requirements define study completion as the last visit of the last subject 
for any protocol related activity.

Food and Drug Administration requirements defines 2 completion dates:

Primary Completion Date – the date that the final participant is examined or receives 
an intervention for the purposes of final collection of data for the primary outcome 
measure, whether the clinical study concluded according to the pre-specified protocol 
or was terminated. In the ase of clinical studies with more than one primary outcome 
measure with different completion dates, this term refers to the date on which data 
collection is completed for all of the primary outcomes.

Study Completion Date – is defined as the date the final participant is examined or 
receives an intervention for purposes of final collection of data for the primary and 
secondary outcome measures and AEs (for example, last participant’s last visit), 
whether the clinical study concludes according to the pre-specified protocol or is 
terminated.
A participant is considered to have completed the study when they have completed their last 
scheduled visit or their last scheduled procedure in the SoA (Section 1.1) including OS 
determination.
As the study is event driven, the accrual of the predetermined number of events included in 
the study endpoints will determine the duration of the data collection phase of the study.  
There will be a final DCO, defined by the time of the OS Final Analysis, which will take place 
after OS reaches approximately 70% maturity of events in the overall population and the 
PIK3CA/AKT1/PTEN-altered population (see details in Section 9.2).  At this time the clinical 
database will close to new data with the exception of China or Japan if the number of patients
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is judged insufficient and an additional DCO is required to address regulatory requirements in 
China or Japan.  
Should the study meet the primary endpoint at any of the prescribed interim analyses, 
additional data cuts may be needed per local health authority requirements.  
Patients are permitted to continue to receive treatment beyond the closure of the database if, in 
the opinion of the investigator, they are continuing to receive benefit.  For patients who 
continue to receive treatment beyond the time of the final DCO, investigators will continue to 
report all SAEs only (no other data will be captured) to AstraZeneca Patient Safety until 
30 days after study treatment is discontinued, in accordance with Section 8.3.  It is 
recommended to continue observing ongoing patients at the frequency indicated within the 
study plans as described in the SoA (Table 1).  Restrictions regarding concomitant 
medications (Section 6.5) will be followed while the patient is receiving capivasertib/placebo 
± fulvestrant.  A change in capivasertib/placebo ± fulvestrant dose should only occur for 
safety reasons, based on the investigator’s judgement, and should generally follow the 
approach for dose reduction and discontinuation as desc ibed in this protocol.  If an 
investigator learns of any SAEs, including death, at any time after a patient has completed the 
study, and he/she considers there is reasonable possibility that the event is causally related to 
the investigational product, the investigator should notify AstraZeneca Patient Safety.  
Additionally, as stated in Section 8.3.3, ny SAE or non-serious AE that is ongoing at this 
DCO must be followed up to resolution unless the event is considered by the investigator to be 
unlikely to be resolved, or the patient is lost to follow-up.  
See Section 6.7 for details on participant management following the final DCO, as well as 
following study completion   
The study may be terminated at individual centres if the study procedures are not being
performed to Good Clinical Practice (GCP) or if recruitment is slow.  AstraZeneca may also 
terminate the entire study prematurely for operational reasons or if concerns for safety arise 
within this study, or in any other study, with capivasertib.  
See Appendix C for guidelines for the dissemination of study results.
4.5
Study Conduct Mitigation During Study Disruptions Due to 
COVID-19 – Temporary Measures
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented temporarily only during the COVID-19 outbreak (e.g., during quarantines and 
resulting site closures, regional travel restrictions, and considerations if site personnel or study
patients become infected with COVID-19) which would prevent the conduct of study-related 
activities at study sites, thereby compromising the study site staff or the patient’s ability to 
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conduct the study.  The investigator or designee should contact the study Sponsor to discuss 
whether the mitigation plans below should be implemented.
To ensure continuity of the clinical study during the COVID-19 outbreak, temporary changes 
may be implemented to ensure the safety of study patients, maintain compliance with GCP, 
and minimize risks to study integrity.  Where allowable by local health authorities, ethics 
committees, healthcare provider guidelines (e.g., hospital policies) or local government, these 
temporary changes may include the following options:

Obtaining reconsent for the mitigation procedures (note, in the case of verbal reconsent, 
the ICF should be signed at the patient’s next contact with the study site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. The 
investigator should confirm this with the designated study physician.

Home or Remote visit: Performed by a site qualified Health Care Professional or Health 
Care Professional provided by a third party vendor. 

Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 

At-home study treatment administration: Performed by a site qualified Health Care 
Professional, or a Health Care Professional provided by a third party vendor, or by the 
patients or the patient’s caregiver, if possible. Additional information related to the visit 
can be obtained via telemedicine

At-home or Remote Delivery of oral study treatment (capivasertib/placebo).
For further details on study conduct during COVID-19, refer to Appendix K.  For further 
guidance during the COVID-19 pandemic, refer to Appendix L.    
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment 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 be assigned/randomised to a study intervention.  Under no circumstances can 
there be exceptions to this rule.  Patients who 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.
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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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
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in the clinical 
study protocol (CSP)
2
Provision of signed and dated, written ICF prior to any mandatory study specific 
procedures, sampling, and analyses
3
For inclusion in the 
 provision of 
signed and dated written 
 consents, respectively, prior 
to collection of sample(s)
If a patient declines to participate in the 
 there will be no penalty or loss of benefit to the patient.  The 
patient will not be excluded from other aspects of the study.  
The ICF process is described in Appendix C 3.
Age
4
Patients must be aged ≥18 years (aged ≥20 years in Japan) at the time of signing the ICF
Type of patient and disease characteristics
5
Adult females, pre- and/or post-menopausal, and adult males

Pre-menopausal (and peri-menopausal i.e., those that do not meet the criteria for 
post-menopausal defined below) women can be enrolled if amenable to treatment 
with an LHRH agonist. Patients are to have commenced concomitant treatment with 
LHRH agonist prior to or on Cycle 1, Day 1 and must be willing to continue on it for 
the duration of the study

Post-menopausal women are defined as:
o
aged ≥60 years of age, OR
o
aged <60 years of age and amenorrhoeic for at least 12 months following 
cessation of all exogenous hormonal treatments/chemotherapy/ovarian 
suppression/tamoxifen or similar.  These patients should also have serum 
oestradiol and follicle stimulating hormone (FSH) levels confirmed as being 
within the standard laboratory reference range for post-menopausal females, OR
o
documented bilateral oophorectomy
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6
Histologically confirmed HR+/HER2− breast cancer determined from the most recent 
tumour sample (primary or metastatic), as per the American Society of Clinical Oncology
and College of American Pathologists guideline recommendations (Hammond et al 2010,
Wolff et al 2018).  To fulfil the requirement of HR+ disease, a breast cancer must express 
ER with or without co-expression of progesterone receptor. Therefore, tumours must be:

ER+ defined as ≥1% of tumour cells stain positive for ER on immunohistochemistry
(IHC) or, if no percentage is available, then an Allred IHC score of ≥3/8,

Progesterone receptor positive defined as ≥1% of tumour cells stain positive for
progesterone receptor on IHC or, if no percentage is available, then an Allred IHC 
score of ≥3/8; or progesterone receptor negative defined as <1% of tumour cells stain 
positive for progesterone receptor on IHC or, if no percentage is available, then an 
Allred IHC score of ≤2/8; or progesterone receptor unknown, and

HER2− defined as 0 or 1+ intensity on IHC, or 2+ intensity on IHC and no evidence 
of amplification on in situ hybridisation (ISH), or if IHC not done, no evidence of 
amplification on ISH.
7
Metastatic or locally advanced disease with radiological or objective evidence of 
recurrence or progression (the cancer should have shown progression during or after most 
recent therapy); locally advanced disease must not be amenable to resection with curative 
intent (patients who are considered suitable for surgical or ablative techniques following 
potential down-staging with study tre tment are not eligible)
8
Patients are to have received treatment with an AI (aromatase inhibitor) containing 
regimen (single agent or in combination) and have:
(a) Radiological evidence of breast cancer recurrence or progression while on, or within 
12 months of the e d of (neo)adjuvant treatment with an AI, OR
(b) Radiological evidence of progression while on prior AI administered as a treatment 
line for locally advanced or metastatic breast cancer (this does not need to be the 
most recent therapy)
9
Patients must have: 

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 CT or 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 can be assessed by CT or MRI; patients with 
sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not 
eligible 
10 Patients must be eligible for fulvestrant therapy as per local investigator assessment
11 Consent to submit and provide a mandatory FFPE tumour sample for central testing. A 
FFPE tissue block from the most recently collected pre-randomisation tumour sample 
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(primary or recurrent cancer) is preferred.  If it is not possible to provide a tissue block, 
30 (minimum 20) freshly-cut unstained serial tumour slides are to be provided. For 
patients recruited in mainland China, a minimum of 11 freshly-cut unstained serial 
tumour slides will be required.  Local pathology QC must be completed prior to 
randomisation to ensure the sample is suitable for next-generation sequencing (NGS)
analysis, based on the requirements described in the Diagnostic Testing Manual.
12 Patients must be able to swallow and retain oral medication
13 Eastern Cooperative Oncology Group (ECOG)/ World Health Organisation (WHO) 
performance status 0 or 1 with no deterioration over the previous 2 weeks and life 
expectancy of ≥12 weeks
Reproduction
14 Pre-menopausal patients with ovarian suppression induced by LHRH agonist should 
agree to use 2 forms of highly effective methods of accepted contraception (see 
Section 5.3.3.1) to prevent pregnancy during the study and for 2 years after the last dose 
of fulvestrant, or until 16 weeks after discontinuing capivasertib/placebo whichever 
occurs later
15 Male patients should use barrier contraception (i.e., condoms) from the time of screening 
until 2 years after the last dose of fulvestrant or until 16 weeks after discontinuation of 
capivasertib/placebo, whichever ccurs later.  Male patients wishing to father children in 
the future should be advised to arrange for the freezing of sperm prior to the start of study
treatment
NOTE: Female partners should be advised to use accepted contraception during their 
partner’s participation in the study and for 2 years after the last dose of fulvestrant or until 
16 weeks after discontinuing capivasertib/placebo, whichever occurs later.  
5.2
Exclusion criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
Medical conditions
1
A disease burden that makes the patient ineligible for endocrine therapy per the 
investigator’s best judgement (e.g., symptomatic visceral disease that is potentially 
life-threatening in the short-term)
2
Malignancies other than breast cancer within 5 years prior to study treatment initiation
(except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma or Stage I endometrioid uterine cancer)
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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3
Radiotherapy with a wide field of radiation within 4 weeks prior to study treatment 
initiation (capivasertib/placebo) and/or radiotherapy with a limited field of radiation for 
palliation within 2 weeks prior to study treatment initiation (capivasertib/placebo)
4
Major surgery (excluding placement of vascular access) within 4 weeks prior to study 
treatment initiation
5
With the exception of alopecia, any unresolved toxicities from prior therapy greater than 
CTCAE grade 1 at the time of starting study treatment
6
Spinal cord compression or brain metastases unless asymptomatic, treated and stable and 
not requiring steroids within 4 weeks prior to study treatment initiation
7
Leptomeningeal metastases
8
Past medical history of interstitial lung disease, drug-induced interstitial lung disease, 
radiation pneumonitis which required steroid treatment, or any evidence of clinically 
active interstitial lung disease
9
Any of the following cardiac criteria:

Mean resting QT interval corrected by Fridericia’s formula (QTcF) >470 msec 
obtained from 3 consecutive ECGs

Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG (e.g., complete left bundl  branch block, third degree heart block)

Any factors that increase the risk of corrected QT interval (QTc) prolongation or risk 
of arrhythmic events such as heart failure, hypokalaemia, potential for Torsades de 
pointes, congenital long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age or any concomitant medication 
known to prolong the QT interval

Experience of a y of the following procedures or conditions in the preceding 
6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial 
infarction, angina pectoris, congestive heart failure New York Heart Association 
(NYHA) grade ≥2

Uncontrolled hypotension – systolic blood pressure <90 mmHg and/or diastolic 
blood pressure <50 mmHg

Cardiac ejection fraction outside institutional range of normal or <50% (whichever is 
higher) as measured by echocardiogram (or multiple-gated acquisition [MUGA] scan 
if an echocardiogram cannot be performed or is inconclusive)
10 Clinically significant abnormalities of glucose metabolism as defined by any of the 
following:

Patients with diabetes mellitus type 1 or diabetes mellitus type 2 requiring insulin 
treatment

HbA1c ≥8.0% (63.9 mmol/mol)
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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11 Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following laboratory values:

Absolute neutrophil count <1.5 × 109/L

Platelet count <100 × 109/L

Haemoglobin <9 g/dL (<5.59 mmol/L). [NOTE: any blood transfusion must be 
>14 days prior to the determination of a haemoglobin ≥9 g/dL (≥5.59 mmol/L)]

Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) >2.5 times 
upper limit of normal (ULN) if no demonstrable liver metastases or >5 × ULN in the 
presence of liver metastases

Total bilirubin >1.5 × ULN (Patients with confirmed Gilbert’s syndrome may be 
included in the study)

Creatinine >1.5 × ULN concurrent with creatinine clearance <50 mL/min (measured 
or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance 
is only required when creatinine is >1.5 × ULN
12 As judged by the investigator, any evidence of sev re or uncontrolled systemic diseases, 
including uncontrolled hypertension, or active infection including hepatitis B, hepatitis C 
and human immunodeficiency virus (HIV), including those who have confirmed 
COVID-19. Screening for chronic conditions is not required
13 Known abnormalities in coagulation such as bleeding diathesis, or treatment with 
anticoagulants precluding intramuscular injections of fulvestrant or LHRH agonist (if 
applicable)
14 Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal 
diseases, inability to swallow the formulated product or previous significant bowel 
resection, or other condition that would preclude adequate absorption of capivasertib
15 Previous allogenic bone marrow or solid organ transplant
16 Known immunodeficiency syndrome
17 History of hypersensitivity to active or inactive excipients of capivasertib, fulvestrant and 
LHRH agonists (if applicable, i.e., concomitant LHRH agonist required in this study) or 
drugs with a similar chemical structure or class to capivasertib, fulvestrant or LHRH 
agonists (if applicable, i.e., concomitant LHRH agonist required in this study)
18 Evidence of dementia altered mental status or any psychiatric condition that would 
prohibit understanding or rendering of informed consent
19 Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, render the patient at high risk from treatment complications 
or interferes with obtaining informed consent 
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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Prior/concomitant therapy
20 More than 2 lines of endocrine therapy for inoperable locally advanced or metastatic 
disease 
NOTE: If an attempt to downstage a locally advanced tumour with endocrine therapy
was made in the absence of metastatic breast cancer (neoadjuvant), and the tumour 
operated upon, then this does not count as a line of therapy for ABC. In contrast, if the 
tumour remained inoperable, this treatment should be included as a line of therapy for 
ABC.  Adjuvant endocrine therapy is not considered a line of therapy for ABC. 
In addition, switching drugs within a line of therapy to manage toxicities in the absence 
of progressive disease does NOT count as a new line of therapy.
21 More than 1 line of chemotherapy for inoperable locally advanced or metastatic disease. 
Adjuvant and neoadjuvant chemotherapy are not clas ed as lines of chemotherapy for 
ABC
22 Prior treatment with any of the following:

AKT, PI3K and mTOR inhibitors

Fulvestrant, and other SERDs

Nitrosourea or mitomycin C within 6 weeks prior to study treatment initiation

Any other chemotherapy, immunotherapy, immunosuppressant medication (other 
than corticosteroids) or anticancer agents within 3 weeks prior to study treatment 
initiation.  A longer washout period may be required for drugs with a long half-life 
(e.g., biologics) as agreed by the sponsor 

Potent inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of 
study treatment (3 weeks for St John’s wort) or drugs that are sensitive to CYP3A4
inhibition within 1 week prior to study treatment initiation. For details, see 
Appendix D

Any concomitant medication that may interfere with fulvestrant safety and efficacy 
based on the prescribing information of fulvestrant and local clinical guidelines 
Prior/concurrent clinical study experience
23 Previous randomisation in this study
24 Participation in another clinical study with a non-marketed investigational medicinal 
product (IMP) administered in the last 30 days or 5 half-lives, whichever is longer (for 
IMPs which are a previously marketed drug, regardless of indication, only Exclusion 
Criterion 22 applies).  Vaccines for COVID-19 with emergency use authorization are not 
considered investigational agents.
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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ocal
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Other exclusions
25 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site)
26 Judgment 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
27 Pregnant women (confirmed with positive pregnancy test) or breast-feeding women
5.3
Lifestyle restrictions
5.3.1
Meals and dietary restrictions
There is a potential for delayed and reduced absorption of capivasertib if it is administered 
with food.  The clinical relevance of this is unknown.  Until further information is available, it
is recommended that patients fast from 2 hours before dosing to 1 hour after dosing, where 
possible.  Additional fasting restrictions also apply on days where glucose is to be tested 
(Section 8.2.1.1).  
In addition, patients should avoid herbal supplements (e.g., St John’s wort) and ingestion of 
large amounts of foods and beverages known to potently modulate CYP3A4 enzyme activity 
during study treatment.  For example, no more than half a grapefruit, a small glass of
grapefruit juice (approximately 125 mL) r 2 teaspoons of Seville orange marmalade should 
be consumed daily.  
5.3.2
Caffeine, alcohol, and tobacco
No interactions with caffeine, alcohol or tobacco have been identified.  
5.3.3
Contraception
5.3.3.1
Females
Females of childbearing potential should use two forms of highly reliable methods of 
contraception from the time of screening until 2 years after the last dose of fulvestrant or until 
16 weeks after discontinuing capivasertib/placebo, whichever occurs later. A permitted 
combination of acceptable and highly effective contraception methods includes the use of a 
barrier method of contraception with spermicidal combined with one of the highly effective 
methods of contraception described below.  
The choice of contraception should be in line with international guidelines for ABC. Current 
guidelines advise against the use of hormonal contraception in patients with breast cancer 
(NCCN 2019). 
Highly effective methods of contraception include:
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
roved
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
Intrauterine device

Bilateral tubal occlusion

Male partner sterilisation (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate)

True abstinence (i.e., not engaging in sexual activity; however, periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of birth 
control)
Acceptable methods of contraception include:

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
The investigator should discuss fertility preservation options for women of childbearing 
potential prior to the start of study treatment, in line with recommendations from international 
breast cancer guidelines for advanced disease.  
Pre-menopausal and peri-menopausal women are required to have treatment for ovarian 
suppression with LHRH agonist in order to participate in the study. FSH and oestradiol will 
be monitored at screening, at Day 1 of each cycle, and when clinically indicated; due to the 
structural similarity of fulvestrant and oestradiol, fulvestrant may interfere with antibody-
based oestradiol assays and may result in falsely increased levels of oestradiol
(Fulvestrant SmPC 2018, Folkerd et al 2014). If deemed appropriate by the investigator, ad 
hoc monthly pregnancy tests can be performed.  
5.3.3.2
Males
Male patients should use barrier contraception (condoms) from the time of screening until 
2 years after the last dose of fulvestrant or until 16 weeks after discontinuation of 
capivasertib/placebo, whichever occurs later. Male patients should refrain from donating 
sperm from the start of dosing until 2 years after the last dose of fulvestrant or until 16 weeks 
after discontinuation of capivasertib/placebo, whichever occurs later.
Female partners should be advised to use accepted contraception during their partners 
participation on the trial and for 2 years after the last dose of fulvestrant or until 16 weeks 
after discontinuation of capivasertib/placebo, whichever occurs later. 
5.3.4
Other restrictions
Patients who are blood donors should not donate blood during the study.  For blood donation 
after study participation, refer to WHO guidelines (WHO 2012).  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
proved
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5.4
Screen failures
Screen failures are defined as patients who signed the ICF to participate in the clinical study
but are not subsequently randomised.  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, screen failure details, 
eligibility criteria, and any SAEs.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, upon the study physician’s approval and agreement.  However, rescreening 
should be documented so that its effect on study results, if any, can be assessed.  
These patients should have the reason for study withdrawal, including failed 
inclusion/exclusion criteria, recorded in the electronic case r port form (eCRF).
6
STUDY TREATMENTS
Study treatment is defined as any IMPs including marketed product comparator and placebo 
or medical device(s) intended to be administered to a study participant according to the CSP.  
Study treatment in this study refers to capivasertib, placebo and fulvestrant.  
LHRH agonist is not an IMP and this should be prescribed in accordance with local
guidelines, where applicable.  
6.1
Treatments administered
6.1.1
Capivasertib/placebo
Capivasertib/placebo is considered an IMP and will be supplied by AstraZeneca.  Details of 
capivasertib are shown in Table 5.  Placebo tablets match the appearance of capivasertib. 
A schematic presentation of the treatment schedule is presented in Figure 3.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
Approved
drawal
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Table 5
Capivasertib/placebo
Study treatment name:
Capivasertib/placebo
Dosage formulation:
160 mg and 200 mg film-coated tablets
Route of administration:
Oral
Dosing instructions:
400 mg BD (2 tablets of 200 mg taken twice a day = total 
daily dose 800 mg) given on an intermittent weekly dosing 
schedule.  Patients will be dosed on Days 1 to 4 in each week 
of a 28-day treatment cycle
Packaging and labelling:
Study treatment will be provided in white high-density 
polythene bottles.  Each bottle will be labelled in accordance 
with Good Manufacturing Practice Annex 13 and per country 
regulatory requirement
Where possible, all doses of capivasertib/placebo should be taken:

At approximately the same time each day

12 hours apart

In a fasted state (water to drink only) from at least 2 hours prior to the dose to at least 
1-hour post-dose.
If vomiting occurs, a replacement dose should not be taken.
Should a patient miss a scheduled dose, the patient will be allowed to take the dose up to a 
maximum of 2 hours after the scheduled dose time, with a fasting state being maintained.  If 
greater than 2 hours after the scheduled dose time, the missed dose should not be taken and 
the patient should take their allotted dose at the next scheduled time.  If a patient needs to take 
the dose earlier for whatever rea on, the patient can take the dose up to 2 hours earlier than the 
scheduled dose time.  The patient should make every reasonable effort to take the 
capivasertib/placebo tablet(s) on time.  
Capivasertib/placebo dose reductions are permitted (see Section 6.6).
Cross-over from placebo to capivasertib is not allowed.  
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Figure 3
Treatment schedule
6.1.2
Fulvestrant
Fulvestrant is considered an IMP and commercial fulvestrant will be obtained centrally.  
Available stock will be used in keeping with the standard local practice. Details are shown in 
Table 6.  Please refer to local prescribing information for information on formulation, 
preparation, and administration.  
A schematic presentation of the treatment schedule is presented in Figure 3.  
Table 6
Fulvestrant
Study treatment name:
Fulvestrant
Dosage formulation:
250 mg/ 5 mL solution for injection
Route of administration:
Intramuscular injection
Dosing instructions:
Patients will be administered 500 mg (2 injections) on Day 1 
of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of 
each cycle thereafter 
Packaging and labelling:
Study treatment will be provided in a pre-filled syringe.  
Each syringe will be labelled in accordance with Good 
Manufacturing Practice Annex 13 and per local practice
If injection-related symptoms occur, patients should be treated according to best medical 
practice and patients will be monitored until adequate resolution of signs and symptoms.  
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Dose reductions for fulvestrant are not permitted.
6.1.3
Duration of treatment
Study treatment will be continued until disease progression unless there is evidence of 
unacceptable toxicity, or if the patient requests to stop the study treatment.  
If capivasertib/placebo is discontinued for reasons other than disease progression, the patient 
may continue on fulvestrant alone at the investigator’s discretion.  The patient must continue 
being scanned for RECIST v1.1 assessment every 8 weeks (±7 days) for the first 18 months
and every 12 weeks (±7 days) thereafter, until objective disease progression (RECIST v1.1), 
administration of further anticancer therapy, withdrawal of consent or death whichever occurs 
first. 
If fulvestrant is discontinued for reasons other than disease progression, the patient may 
continue on capivasertib/placebo alone at the investigator’s discretion.  The patient must 
continue being scanned for RECIST v1.1 assessment every 8 weeks (±7 days) for the first 
18 months and every 12 weeks (±7 days) thereafter, until objective disease progression (even 
if further anticancer therapy is administered).  
Patients with locally advanced disease who are considered suitable/planned for surgical or 
ablative techniques following potential down-staging with study treatment are not eligible. 
Cases in which a patient become amen ble to surgery or ablative therapy must be 
communicated to the sponsor. Study drug must be discontinued prior to surgery. However, if, 
in the opinion of the investigator, the patient is continuing to receive benefit, they may be 
permitted to continue to restart treatment after surgery after discussion and agreement with the 
Sponsor. Patients should co tinue RECIST v1.1 assessment until progression.  
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. Capivasertib must 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.  
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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records).  
Any study drug remaining at the end of the trial must be destroyed or returned according to 
the sites local standard operating procedures following authorisation by the sponsor.  
6.2.1
Dose Preparation
The dose of fulvestrant and capivasertib/placebo for administration must be prepared by the 
pharmacy staff members (or an appropriate designee trained in study drug preparation), in 
compliance with local regulations and site requirements.
Fulvestrant and capivasertib/placebo should be handled in accordance with practices required 
for hazardous drugs (i.e., chemotherapy).
6.3
Measures to minimise bias: randomisation and blinding
Capivasertib and placebo film-coated tablets will be identical in appearance and presented in 
the same packaging to ensure blinding of the capivasertib.  
Capivasertib and placebo will be labelled using a unique kit identification (kit ID) number, 
which is linked to the randomisation scheme.  
Fulvestrant will be allocated to be d spensed to each patient using the interactive web response 
system (IWRS) system (if centrally sourced) or via the local pharmacy (if locally sourced) at 
each patient dispensing visit.  Routines for this will be described in the interactive voice 
response system (IVRS)/IWRS user manual that will be provided to each centre.  
Eligible patients will be randomised in a 1:1 ratio (capivasertib + fulvestrant: placebo + 
fulvestrant).  The planned treatment given to individual patients will be determined by a 
randomisation scheme that will be loaded into the IWRS database.  The randomisation scheme 
will be produced by a process called AZRand (AZ Global Randomisation process) that 
incorporates a standard procedure for generating random numbers.  
A blocked randomisation will be generated, and all centres will use the same list in order to 
minimise any imbalance in the number of patients assigned to each treatment group.  
Eligibility will be established before treatment randomisation.  It is recommended that patients 
commence study treatment as soon as possible after randomisation and ideally on the same 
day of randomisation.  
In order to meet the required minimum of 51% of recruited patients pre-treated with CDK4/6 
inhibitors, the actual proportions will be monitored during the course of the study. Selective 
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recruitment of patients with prior CDK4/6 inhibitor treatment may be implemented in the 
event that approximately 343 CDK4/6 inhibitors naïve patients are randomised. This would be 
achieved via the IWRS system as prior CDK4/6 inhibition is a stratification factor.
If a patient withdraws from the study, then his enrolment/randomisation code cannot be 
reused.  Withdrawn patients will not be replaced. 
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the patient requires knowledge of the treatment randomisation.  
The investigator must document and report the action to AstraZeneca, without revealing to the 
AstraZeneca staff the treatment given to the patient.  
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IMP and that potentially require expedited reporting to 
regulatory authorities.  Randomisation codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual patient have been 
made and documented.
In the event that the treatment allocation for a patient becomes known to the Investigator or 
other study staff involved in the management of study patients, or needs to be known to treat 
an individual patient for an AE, the Sponsor must be notified promptly by the Investigator and 
if possible, before unblinding.
6.4
Treatment compliance
Data regarding capivasertib/placebo dosing will be collected and entered into the eCRF along 
with reasons for missed d se(s) if applicable.
In addition, patients will be required to return all bottles of study medication.  The number of 
tablets remaining will be counted by the research nurse/pharmacist/investigator, documented 
in the eCRF and returned to pharmacy.  Site personnel are responsible for managing the IMP 
from receipt by the study site until the destruction or return of all unused IMP.  The 
investigator is responsible for ensuring that the patient has returned all unused IMP.  
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
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Guidance regarding potential interactions of capivasertib with concomitant medications is 
provided in Appendix D.  
6.5.1
Allowed concomitant therapy
The following therapies are allowed during study participation, as applicable:

No prophylactic anti-emetic therapy is planned for capivasertib/placebo but standard 
anti-emetic therapy including a 5-HT3-antagonist can be given as needed on a 
prophylactic and treatment basis in compliance with the standards of the centre’s local 
policy

Anti-diarrhoeal therapy for symptomatic treatment of diarrhoea, as indicated in the 
toxicity management guideline (Section 8.4.4.1)

Erythropoietin: patients already receiving erythropoietin at the time of screening for the 
study may continue it providing they have been receiving it for more than 1 month at the 
time study treatment is started.  Prophylactic erythropoietin should not be started during 
Cycle 1 of the study but may be started during or after Cycle 2

Blood transfusions are allowed at any time during the study
NOTE: any blood transfusion before screening must be >14 days prior to the 
determination of a haemoglobin at screening; see Section 5.2].  

Patients may receive bisphosphonate or denosumab therapy for the treatment of bone 
metastases; however, these agents must be started prior to randomisation.  Modification 
of the pre-study bisphosphonate or denosumab treatment regimen for bone metastasis 
requires the approval of the sponsor or study physician

Patients may take corticos eroids; however, electrolyte and/or glucose levels should be 
monitored carefully due to the potential for corticosteroid-related metabolic disturbance

Patients who need to begin anti-coagulant therapy while receiving study treatment may be 
treated, at the discretion of the investigator, with low molecular weight heparin (LMWH). 
The LMWH should be temporarily discontinued 12 to 24 hours prior to each injection of 
fulvestrant and then resumed 12 to 24 hours later (depending on the particular LMWH 
used). There is an increased risk of haemorrhage in these patients and the investigator 
should decide whether that risk is outweighed by the possible benefits of continued 
treatment. It is advised to apply direct pressure to the injection site in these patients

Patients receiving antiplatelet therapy (acetylsalicylic acid, ticlopidine, clopidogrel, etc) 
may be at increased risk of bleeding from intramuscular injection. The investigator 
should decide whether that risk is outweighed by the possible benefits of continued 
treatment. It is advised to apply direct pressure to the injection site in these patients

Supportive care and other medication, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the investigator and recorded in 
the appropriate sections of the eCRF

LHRH agonist: Pre-menopausal patients are to have commenced concomitant treatment 
with LHRH agonist prior to or on Cycle 1, Day 1 and must be willing to continue LHRH 
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agonist treatment for the duration of the study. Male patients can receive concomitant 
LHRH agonist if deemed appropriate by the investigator

Authorized/approved COVID-19 vaccines can be given to patients enrolled in CAPItello 
291, following local prescribing information, and policies when considering if 
vaccination against COVID-19 is appropriate for the patients participating in the study.  
Investigators should apply their discretion assessing the risk benefit of COVID-19 
vaccines for participants in clinical trials.  The administration of any vaccine and any
potential adverse events must be documented in the eCRF
Other concomitant medication may be given as medically indicated.  Details (including doses, 
frequency, route and start and stop dates) of the concomitant medication given must be 
recorded in the patient’s medical records and the eCRF.  
6.5.2
Restricted concomitant therapy
The following concomitant therapies are restricted during study treatment:

Other anticancer agents, other investigational agents and radiotherapy, although radiation 
for palliation at focal sites is permitted (as long as the radiation field covers less than 30% 
of the marrow and does not include whole pelvis or spine; disease progression in the 
bones has to be excluded by appropriate imaging investigations)

Drugs or herbal supplements that are known to be potent inhibitors/inducers of CYP3A4
must be avoided, but moderate inhibitors/inducers may be used with caution.  Drugs 
known to be sensitive to inhibition of CYP3A4 metabolism and/or MATE1 or OCT2 
transport must be avoided or used with caution, depending on their therapeutic window.  
If co-administration is necessary, then additional monitoring for signs of toxicity related 
to increased exposure to the substrates is required

Patients must not receive other investigational drugs while on study
Please refer to Appendix D for further guidance on potential PK interactions with 
capivasertib. For guidance regarding potential PK interactions with fulvestrant, please refer to 
the current local prescribing information (package insert).
Patients must be instructed not to take any medications, including herbal and dietary
supplements, without first consulting with the investigator. 
6.5.3
Other concomitant treatment
Medication other than that described in Section 6.5.2, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the investigator and recorded 
in the appropriate sections of the eCRF.  The concomitant administration of drugs known to 
prolong QT interval is restricted unless considered essential due to patient management, in 
which case, patients should be closely monitored. Information regarding drugs known to 
prolong the QT interval can be found on the CredibleMeds® website 
(URL: https://crediblemeds.org).  
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6.6
Dose modifications and delay
For capivasertib/placebo, dose reductions or holds are allowed as clinically indicated by the 
treating physician and in line with Table 7.  For each patient, a maximum of 2 dose reductions 
will be allowed (Table 7). Dose re-escalations are not allowed for capivasertib/placebo.  For 
guidance on capivasertib dose reductions for management of AEs, refer to Section 8.4.4.1.  
Dose reductions for fulvestrant are not allowed.
Refer to locally approved prescribing information for guidance on fulvestrant monitoring and 
management of toxicities.  
Table 7
Dose levels for capivasertib/placebo and fulvestrant
Study treatment
Starting dose
Dose reduction levels
Capivasertib/placebo 
400 mg BD
Reduction level 1: 320 mg BD
Reduction level 2: 200 mg BD
Fulvestrant
500 mg
Dose reductions not allowed
In the event of an AE which the investigator considers to be related to the administration of 
study treatment, supportive therapy should be given at the discretion of the investigator.  In 
addition, the investigator may decide that dosing of study treatment should be temporarily
interrupted, a subsequent treatment cycle delayed, or study treatment permanently 
discontinued as per the guidelines outlined in Section 7.1.  
Substantial acute toxicities should be managed as medically indicated and with temporary
suspension of study drug, as appropriate.  
A maximum break of 28 consecutive days for capivasertib/placebo dosing is allowed within 
each treatment cycle or between two consecutive cycles.  A maximum delay of 35 days since 
a planned injection of fulvestrant is allowed.   
Any further delays in capivasertib/placebo and/or fulvestrant treatment must be approved by 
the sponsor or study physician. Following a treatment break, the patient may resume 
treatment at the Day/Week in the cycle that they stopped.
6.7
Treatment after the end of the study
After the clinical study database closes, patients who continue to derive clinical benefit from 
study treatments in the opinion of the investigator may continue to receive study treatment 
until progression.  These treatments will continue to be provided by AstraZeneca until the 
availability of either a local commercial supplier and reimbursement program or an early 
access program; at which point a change in supply will be requested.  Treatment of patients 
beyond progression is not allowed.  
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As described in Section 4.4, the study will remain open until all participants have discontinued 
study intervention and completed their last expected visit/contact.
After the final DCO for this study, AstraZeneca will continue to supply capivasertib to 
participants who were randomised to receive capivasertib treatment until progression as 
judged by the investigator or until meeting any other discontinuation criteria, as defined in 
Section 7.1.
Participants should be followed according to the institution’s standard of care assessments. No 
further data collection is required, except for reporting of SAEs.
Participants who were randomised to receive other study interventions (ie, placebo + 
fulvestrant), or who discontinue from the study, should continue appropriate treatment at the 
discretion of the investigator.
AstraZeneca will continue to supply capivasertib in the co tinued access phase of this study 
and after completion of this study while, in the opinion of the investigator, the patient is 
benefiting.
In the event that product development reaches a point where alternative product supply 
options become available, then these alte native product supply options will be discussed by 
AstraZeneca with the investigator. AstraZeneca will work with the investigator to transition 
the patient(s) to alternative supply, where possible.  
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, participant(s) currently receiving treatment with capivasertib may then 
be transitioned to such a study, and the current study may reach its end. The roll-over or 
extension study would ensure treatment continuation with visit assessments per its protocol, as 
applicable. Any participant who would be eligible to move to such a study would be given a 
new informed consent, as applicable.
Please refer to Section 4.4 for End of Study definition.  
7
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
Patients will be discontinued from IMP in the following situations.  Note that discontinuation 
from study treatment is NOT the same as a complete withdrawal from the study.  Patients who 
discontinue study treatment should continue the study and be followed-up as outlined in the 
CSP.  
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
Objective disease progression assessed by RECIST v1.1

Clinical disease progression/worsening of disease under investigation

Patients incorrectly initiated on IMP 

Patient becomes pregnant 

Intercurrent illness that, in the judgment of the investigator, will affect assessments of 
clinical status to a significant degree or contraindicate further dosing

AE or unacceptable toxicity 

Determination by the investigator that it is no longer safe for the patient or in the patient’s 
best interest to continue therapy 

Patient request 

Severe non-compliance with study protocol in the judgement of the investigator and/or 
the sponsor 

Clinical need for concomitant or ancillary therapy (i.e., non–protocol-specified anticancer 
therapy) that is not permitted in the study 

General or specific changes in the patient’s condition that are unacceptable for further 
treatment in the judgment of the investigator
Patients found to be deriving benefit from treatment and tolerating treatment may continue 
therapy, subject to agreement between the treating and Sponsor physicians. The patients will 
be followed according to protocol-defined procedures and assessments. All protocol 
deviations will be reviewed and important protocol deviations will be identified prior to the
unblinding of the study.
See the schedule of activities (SoA; Section 1.1) for data to be collected at the time of 
treatment discontinuation and follow-up and for any further evaluations that need to be 
completed.  
All reasons for discontinuation of study treatment must be documented in the eCRF (see 
Section 7.1.2).  
7.1.1
Temporary discontinuation 
If study treatment will be interrupted for a period longer than permitted in the dose 
modification guidelines (Section 6.6), the investigator will need approval from the sponsor to 
restart the patient on study treatment.
7.1.2
Procedures for discontinuation of study treatment
The investigator should instruct the patient to contact the site before or at the time the patient 
decides to stop the study treatment.  A patient who decides to discontinue study treatment 
must 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 eCRF.  All study treatment should be returned 
by the patient at their next on-site study visit or unscheduled visit.  Patients permanently 
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discontinuing study treatment should be given locally available standard of care therapy, at the 
discretion of the investigator.  
Discontinuation of study treatment, for any reason, does not impact on the patient´s 
participation in the study.  The patient should continue attending subsequent study visits and 
data collection should continue according to the study protocol.  If the patient does not agree 
to continue in-person study visits, a modified follow-up must be arranged to ensure the 
collection of endpoints and safety information.  This could be a telephone contact with the 
patient, a contact with a relative or treating physician, or information from medical records.  
The approach taken should be recorded in the medical records.  A patient that agrees to 
modified follow-up is not considered to have withdrawn consent or to have withdrawn from 
the study.  
7.2
Lost to follow-up
A patient may be considered lost to follow-up if he or 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 by for example, 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

Efforts to reach the patient should continue until the end of the study.  Should the patient 
be unreachable at the end of the study the patient will be considered lost to follow-up,
with unknown vital status at end of study and censored at the last follow-up contact
7.3
Withdrawal from the study
A patient may withdraw from the study (e.g., withdraw consent) at any time at his/her own 
request, without prejudice to further treatment.  If a patient withdraws consent, they will be 
specifically asked if they are withdrawing consent to all further participation in the study
(treatment, assessments and follow-up) or withdrawing from treatment/assessments only and 
will allow further follow-up.
A patient who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options (e.g., telephone contact, a contact with a relative or treating 
physician, or information from medical records).  
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If the patient also 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, he/she may request destruction of any samples taken, 
and the investigator must document this in the site study records and inform the study monitor 
and study team.  
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs.  The investigator will follow-up patients as medically indicated. The patient will 
return electronic patient-reported outcomes (ePRO) devices.  
AstraZeneca or its delegate will request investigators to make every effort to collect 
information on patients’ survival status (dead or alive; date of death when applicable) at the 
end of the study, including patients that withdrew consent or are classified as "lost to 
follow-up".  Survival status can be obtained by site personnel from publicly available 
resources where it is possible, in accordance with local regulations.  Knowledge of the 
survival status at study end in all patients is crucial for the integrity of the study.  
See SoA (Section 1.1), for data to be collected at the time of study discontinuation and 
follow-up, and for any further evaluations that need to be completed.  All study treatment 
should be returned by the patient.  
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (see Section 1.1).  
The investigator will ensur  that data are recorded on the eCRFs.  A Web Based Data Capture 
system will be used for data collection and query handling.  
The investigator must ensure the accuracy and completeness for eCRFs which includes: 
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 eCRFs.  
A copy of the completed eCRFs will be archived at the study site.  
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study treatment.  
Adherence to the study design requirements, including those specified in the SoA, 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 
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all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count)
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.  
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.  
8.1
Efficacy assessments
8.1.1
RECIST v1.1 assessments
RECIST v1.1 tumour assessments will be performed using CT or MRI scans of the chest, 
abdomen and pelvis (with additional anatomy as clinically indicated by extent of disease) at 
baseline (no more than 28 days before the date of randomisation, as close as possible to the 
start of study treatment). Afterward, CT or MRI scans of the chest, abdomen and pelvis (with 
additional anatomy as clinically indicated by extent of disease) will be repeated every 8 weeks 
(±7 days) for the first 18 months and every 12 weeks (±7 days) thereafter, after start of 
treatment (Cycle 1, Week 1, Day 1) until obj ctive radiological disease progression as defined 
by RECIST v1.1 (regardless of reason for treatment discontinuation).  If an unscheduled 
assessment is performed (e.g., to investigate clinical signs/symptoms of progression) and the 
patient has not progressed, every attempt should be made to perform the subsequent image 
acquisition at the next scheduled imaging visit.  Patients who discontinue treatment prior to 
RECIST v1.1 progression (e.g., dis ontinuation due to toxicity or clinical progression) should 
continue to be scanned until confirmed RECIST v1.1 progression.  The same imaging 
modality and the same assessment (e.g., the same contrast protocol for CT scans) should be 
performed at baseline and at all follow-up time-points.  Guidelines on the valid methods of 
assessment and the evaluation of objective tumour response using RECIST v1.1 are provided 
in Appendix A.  
8.1.1.1
Progression-free survival (PFS)
PFS is defined as the time from the date of randomisation until the date of disease progression, 
as defined by RECIST v1.1, or death (by any cause in the absence of progression) regardless 
of whether the patient withdraws from randomised therapy or receives another anticancer 
therapy prior to progression. 
PFS will be assessed by investigator assessment.  A supplementary analysis of PFS by BICR 
will be reported.  
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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 RECIST v1.1 assessment.  However, if 
the patient progresses or dies immediately after two or more consecutive missed visits, the 
patient will be censored at the time of the latest evaluable RECIST v1.1 assessment prior to 
the two missed visits.  
8.1.1.2
Clinical benefit rate (CBR)
CBR is defined as number of patients with complete or partial response or with stable disease 
maintained ≥24 weeks (as assessed by the investigator, using RECIST v1.1) divided by the 
number of patients in the analysis.  Patients without a post-baseline tumour assessment will be 
considered to have no clinical benefit.  
8.1.1.3
Duration of response (DoR)
For patients who achieve complete or partial response per RECIST v1.1, DoR is defined as the 
time from the date of first documented response until date of documented progression (as 
assessed by the investigator, using RECIST v1.1) or death in the absence of disease 
progression.  The end of response should coincide with the date of progression or death from 
any cause used for the PFS endpoint.  The time of the initial response will be defined as the 
latest of the dates contributing towards the first visit response of complete or partial response.
If a patient does not progress following a response, then their DoR will use the PFS censoring 
time.
8.1.1.4
Objective response rate (ORR)
ORR is defined as the percentage of patients with at least one investigator-assessed visit 
response of complete or partial response (as assessed by the investigator, using RECIST v1.1) 
and will be based on a subset of patients with measurable disease at baseline per the site 
investigator.
Data obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR.  Patients who discontinue randomised treatment 
without progression, receive a subsequent anticancer therapy (note that for this analysis 
radiotherapy is not considered a subsequent anticancer therapy) and then respond will not be 
included as responders in the ORR.
8.1.2
Overall survival (OS)
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 
anticancer therapy.  
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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.  
Assessments for survival will be conducted every 8 weeks for the first 2 years following 
objective disease progression or treatment discontinuation and then every 12 weeks.  
Survival information may be obtained via telephone contact with the patient, patient’s family, 
by contact with the patient’s current physician, or local death registries as described in 
Section 7.3.  
Survival calls will be made in the week following the date of DCO for each of the PFS or OS 
analyses, and if patients are confirmed to be alive or if the death date is post the DCO date, 
these patients will be censored at the date of DCO.
8.1.3
PFS2
Time from randomisation to second progression or death (PFS2) will be defined as the time 
from the date of randomisation to the earliest of the progression events subsequent to the first 
subsequent therapy, or death.
Patients alive and for whom a second disease progression has not been observed should be 
censored at date last known alive and without a second disease progression (i.e., censored at 
the latest of the PFS or PFS2 assessment d te if the patient has not had a second progression 
or death).
Following discontinuation of study treatment due to disease progression, as determined by 
investigator-based by RECIST v1.1 assessment, patients who started on subsequent cancer 
therapy post progression will continue to be followed at the 30-day follow-up visit, every 
8 weeks (±7 days) for the first 2 years, and every 12 weeks (±7 days) thereafter for 
documentation of progression on second-line therapy.  Determination of progressive disease 
for PFS2 will be by institutional call.  
8.1.4
Time to definitive deterioration of the ECOG performance status
ECOG performance status will be used to assess physical health of patients. Time to 
definitive deterioration of ECOG performance status is defined as time from randomisation to 
the earlier of the date of the first definitive deterioration or death due to any cause.  
Deterioration is defined as a 1-point increase in ECOG score from baseline, and the 
deterioration is considered definitive if no improvements in the ECOG performance status are
observed at a subsequent time of measurement during the treatment period, or at no further 
assessments following the time point where the deterioration is observed. 
Patients who have not had definitive deterioration or have not died at the time of analysis will 
be censored at the time of the latest date of assessment from their last evaluable ECOG 
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assessment.  However, if the patient has definitive deterioration or dies immediately after two 
or more consecutive missed visits, the patient will be censored at the time of the latest 
evaluable ECOG assessment prior to the two missed visits.  
8.1.5
Time to first subsequent chemotherapy or death (TFSC)
Time to first subsequent chemotherapy or death (TFSC) is defined as time from randomisation 
to the earlier of start date of the first subsequent chemotherapy after discontinuation of 
randomised treatment or death due to any cause.
Patients alive and not known to have had a first subsequent chemotherapy will be censored at 
the earliest of: date of study termination, date last known alive, DCO or, the last date that the 
patient was known not to have received a first subsequent chemotherapy.
8.1.6
Bone scan
An initial bone scan should be performed within 4 weeks prior to randomisation and repeated 
as necessary (see Appendix A [Isotopic bone scan])   
8.1.7
Patient-reported outcomes
PRO assessments will be used to examine the impact of treatment on disease-related 
symptoms, function, HRQoL, patient-perceived treatment tolerability, and overall health 
status.  PROs have become increasingly important in evaluating the efficacy and tolerability 
of study treatments in clinical studies as part of the overall benefit/risk evaluation (Kluetz et al
2018).  The PROs included in thi  study are as follows and will be administered in this order:

EORTC QLQ-C30

EORTC QLQ-BR23

EuroQol 5-dimension, 5-level health state utility index (EQ-5D-5L)

Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE)

Patient Global Impression–Severity (PGIS)

Patient Global Impression–Change (PGIC)

Patient Global Impression–Treatment Tolerability (PGI-TT)
The PROs will be assessed in accordance with the SoA (see Section 1.1) and Section 8.1.7.8.  
The individual questionnaires are provided in Appendix I.  
8.1.7.1
EORTC QLQ-C30
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 as well as detailed cross-cultural testing and validation (Aaronson et al 
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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 QoL scale, 
5 single items assessing additional symptoms commonly reported by cancer patients (dyspnea, 
loss of appetite, insomnia, constipation, and diarrhoea), and 1 item on the financial impact of 
the disease.  All but 2 questions have 4-point scales: “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 15 domains, 
final scores are transformed such that they range from 0 to 100, where higher scores indicate 
better functioning, better HRQoL, or greater level of symptoms (Aaronson et al 1993).  
8.1.7.2
EORTC QLQ-BR23
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.  
8.1.7.3
EQ-5D-5L
The EQ-5D-5L will be used to explore the impact of treatment and disease state on health 
state utility.
The EQ-5D-5L, developed by the EuroQol Group, is a generic questionnaire that provides a 
simple descriptive profile of health and a single index value for health status for economic 
appraisal (van Reenen and Janssen 2015).  The questionnaire comprises six questions that 
cover five 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).  
8.1.7.4
PGIS
The PGIS item is included to assess how a patient perceives the overall severity of cancer 
symptoms over the past week.  Patients will be asked to choose the response that best
describes the severity of their overall cancer symptoms with options ranging from “No 
Symptoms” to “Very Severe”.  
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8.1.7.5
PGIC
The PGIC item is included to assess how a patient perceives their overall change in health 
status since the start of study treatment. This is a single-item questionnaire, and patients will 
choose from response options ranging from “Much Better” to “Much Worse”.  
8.1.7.6
PGI-TT
The PGI-TT item is included to assess how a patient perceives the overall tolerability of the 
study treatment.  This is a single-item questionnaire, and patients will rate the bother 
associated with any treatment-related symptoms using response options ranging from “Not at 
all” to “Very much”.  
8.1.7.7
PRO-CTCAE
The PRO-CTCAE, developed by the National Cancer Institute (NCI) is included to address 
tolerability from the patients’ perspective.  The PRO-CTCAE will only be administered in 
those countries where a linguistically validated version is available.  All applicable 
translations available during the study will be used.  PRO-CTCAE is an item library of
symptoms experienced by patients while undergoing treatment of their cancer. The items 
pre-selected for this study are based on a review of the treatment-related symptoms of 
capivasertib and fulvestrant and in consideration of symptoms that are already captured in the 
other PRO instruments with a view to minimise burden.  The free text item in the 
PRO-CTCAE instrument is not included in the study, as the utility of this information and the 
analysis method have not been established.  
8.1.7.8
Administration of patient-reported outcome questionnaires
The PRO instruments will be self-administered by patients using a handheld electronic device 
in accordance with the SoA (see Section 1.1).  PROs will be provided in the language of the 
country in which it will be administered, except for the PRO-CTCAE, which will only be 
administered in the languages where a linguistically validated version is available.  
Patients will complete PRO assessments at home or at the study sites if the assessment 
timepoint coincides with a scheduled site visit.  Similarly, during the post-progression period, 
patients will complete PROs at home or at the study site if a scheduled visit coincides with the 
timepoint.  If patients have had scans or other tests at an outside facility or missed a scheduled 
data collection site visit, PRO questionnaires should still be completed by patients at home 
according to the PRO completion schedule.  
While PROs may be completed at home or site visits, patients should always bring the 
handheld electronic device to all site visits.  It will take approximately 20 to 30 minutes for 
patients to complete the questionnaires.  
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If screening and randomisation are on the same day, ePRO questionnaire do not need to be 
repeated. 
The following instructions should be followed when collecting PRO data via an electronic 
device:

Following informed consent, PRO questionnaires completed at site visits 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, 
such as collection of laboratory samples, to further minimise bias.

For PROs collected at site visits, PRO questionnaires must be completed by the patient in 
a quiet and private location and the patient given enough time to complete the PRO 
questionnaires at their own speed.  

The research nurse or appointed site staff must explain to patients the value and relevance 
of study participation and inform them that these questions are being asked to find out, 
directly from them, how they feel.  The research nurse or appointed site staff should also 
stress that the information is not routinely shared with study staff.  Therefore, if patients
have any medical problems, they should discuss them with the doctor or research nurse 
separately from the PRO assessment.  

The research nurse or appointed site staff must train the patient on how to use the PRO 
device, using the materials and training provided by the PRO vendor, and provide 
guidance on whom to call if there are problems with the device if the patient is 
completing the PRO at home.  All PRO questionnaires are to be completed using an 
ePRO device. If technical or other issues prohibit completion on the device, an 
appropriate back-up option may be considered with prior approval from AstraZeneca.  

The research nurse or appointed site staff must remind patients that there are no right or 
wrong answers and av id introducing bias by not interpreting or clarifying items.  

The patient must not receive help from relatives, friends, or clinic staff deciding on 
answers to the PRO questionnaires.  The responses are the patient’s alone.  If a patient 
uses visual aids (e.g., glasses or contact lenses) for reading and does not have them when 
he or she visits the site, the patient will be exempted from completing the PROs at the 
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 (e.g., is blind, illiterate, or not fluent in the 
available language), that patient is exempted from completing PRO questionnaires but 
may still participate in the study.  If the patient cannot complete the PRO questionnaires 
due to reasons other than being blind, illiterate, or fluent in language, the AstraZeneca 
study team must be contacted to determine if they can be exempted.  Patients exempted in 
this regard should be flagged appropriately by the site staff in the source documents and 
the Review of PRO/Questionnaire/Diary eCRF.  

Site staff must administer questionnaires available in the language that the patient speaks 
and understands.  Questions should not be read in an available language and translated 
into another language for the patient.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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
It is vital that the PRO reporting is initiated at the baseline visit (Cycle 1, Week 1, Day 1), 
as specified in the study plan to capture the effect of study treatment.  The handheld 
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. 

Finally, the research nurse or appointed site staff will review the completion status of 
questionnaires during site visits and document the reason(s) why a patient could not 
complete assessments in the eCRF.  The research nurse or appointed site staff must 
monitor compliance since minimising missing data is a key aspect of study success.  It is 
important that the PRO device is charged and fully functional at the baseline visit.  
Compliance must be checked at each study visit and should be checked more frequently 
to identify problems early.  If compliance drops to 85% or below, the patient will be 
flagged in the routine compliance report generated by the ePRO system, and a check-in 
call from the study site to ask the patient if he or she has any difficulties is highly 
recommended.  A solution to enhance/resolve compliance should be discussed with the 
patient.  Discussions and compliance review should be reflected in source documents.  
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the SoA (see Section 1.1).
8.2.1
Clinical safety laboratory assessments
See Table 8 for the list of clinical safety laboratory tests to be performed and the SoA 
(Section 1.1) for the timing, frequency and additional information.  
The date and time of each collection will be recorded in the appropriate eCRF.  
Laboratory values that meet the criteria for CTCAE grade 3 or have changed significantly 
from baseline and are co sidered to be of clinical concern will be repeated/confirmed within 
7 days and followed up as appropriate.  
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 eCRF.  
The clinical chemistry, haematology 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 8
Laboratory safety variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin
S/P-Albumin
B-Leukocyte (white blood cells [WBC])
S/P-ALT
B-Leukocyte (WBC) % differential or absolute 
count:a
S/P-AST
B-Neutrophils
S/P-Alkaline phosphatase
B-Lymphocytes
S/P-Bilirubin, total
B-Eosinophils
S/P-Calcium, total
B-Platelet count
S/P-Creatinine
Coagulation
S/P-FSH (females only)d
INRb
S/P-Glucos
Urinalysis
S/P-Glycosylated haemoglobin (HbA1c)
U-Glucose
S/P Magnesium
U-Protein
S/P-Oestradiol (females only)d
U-Blood
S/P Potassium
U-Ketones
S/P-Total Protein
U-Microscopyc (red blood cells and white blood cells, 
bacteria, casts and crystals)
S/P Free T4b
S/P TSHb
S/P Troponine I or T
S/P-Sodium
S/P-Urea nitrogen and/or Urea
S/P-Lipids (total cholesterol, HDL, LDL, and 
triglycerides)
a
For Exclusion Criterion 11 (Section 5.2), if sites only collected % differential of neutrophils, the absolute 
neutrophil count will need to be calculated for eligibility, based on leukocytes (WBC) and % of neutrophils.
b
Only at screening and as clinically indicated.
c
Only perform if urinalysis is abnormal.
d
FSH and oestradiol will be performed only in: 
-
Pre- and peri-menopausal women (ie, all women <60 years of age unless considered 
post-menopausal per Inclusion Criterion 5 [Section 5.1]) – at screening, at Day 1 Week 1 of each 
cycle, and when clinically indicated. 
-
Post-menopausal women <60 years of age – only at screening to confirm post-menopausal status 
and when clinically indicated.
All other women (ie, ≥60 years of age or with documented bilateral oophorectomy) do not need to have a 
check of FSH and oestradiol (refer to Inclusion Criterion 5 in Section 5.1).
e
Test will only be performed on screening and when clinically indicated.
f
Test will only be performed when clinically indicated.
NOTE: In case a patient shows an AST or ALT ≥3 × ULN or total bilirubin ≥2 x ULN please refer to 
Appendix H ‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law’, for 
further instructions.  
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ALT, alanine aminotransferase; AST, aspartate aminotransferase; B, blood; FSH, follicle-stimulating hormone; 
INR, International Normalised Ratio; P, plasma; S, serum; TSH, thyroid-stimulating hormone; U, urine.  
8.2.1.1
Glucose and glycosylated haemoglobin (HbA1c)
Blood glucose and HbA1c will be assessed according to the SoA (see Section 1.1).  On blood 
glucose assessment days (incorporating clinical chemistry and glucose) it is requested that 
patients fast and refrain from caloric intake for ≥4 hours prior to the morning dose of study
treatment. 

Glucose pre-dose (fasting) and 4 hours post dose (fasting or non-fasting) in Cycle 1, 
Week 1, Day 1

Glucose (fasting) in Cycle 1, Week 3, Day 1; Cycle 2, Week 1, Day 1; and in Cycle 3 
onwards on Day 1 (Week 1)

Further glucose monitoring may be performed at the investigator’s discretion as clinically 
indicated

HbA1c to be measured at screening, pre-dose every 12 weeks, and at discontinuation
8.2.1.2
Serum creatinine
Patients taking capivasertib/placebo and metformin in combination should have creatinine 
assessments conducted as part of the routine clinical chemistry with additional monitoring of 
creatinine at the discretion of the investigator (see Section 8.4.5.3).
8.2.2
Physical examinations
The physical examination will be performed at timelines as specified in the SoA (Section 1.1)
and will include an assessment of the following: general appearance, respiratory, 
cardiovascular, abdomen kin  head and neck (including ears, eyes, nose and throat), lymph 
nodes, thyroid, musculoskeletal (including spine and extremities) and neurological systems.
Weight and height will be assessed at timelines as specified in the SoA (Section 1.1).  
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.  
8.2.3
Vital signs
Vital signs (including blood pressure, pulse rate, respiratory rate, and body temperature) will 
be assessed at timelines as specified in the SoA (Section 1.1).  
Blood pressure and pulse measurements will be assessed with a completely automated device.  
Manual techniques will be used only if an automated device is not available.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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Blood pressure, pulse, and respiratory rate, measurements should be preceded by at least 5 
minutes of rest for the patient in a quiet setting without distractions (e.g., television, cell 
phones).  
Vital signs will be measured in a supine, semi-supine, or sitting position after 10 minutes rest 
and will include temperature, systolic and diastolic blood pressure, pulse, and respiratory rate.  
Three readings of blood pressure and pulse will be taken with a ≥1-minute interval in between 
and should be reported in the patient notes.  The first reading should be rejected.  The second 
and third readings should be averaged to give the measurement to be recorded in the eCRF.  
Respiratory rate will be counted only once.
8.2.4
Electrocardiograms
Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.1).  
All ECGs to be conducted as triplicate measurements, within approximately 5 minutes of 
starting (the 3 ECGs separated by approximately 2 minutes).  Assessments should be 
performed as close as possible to, but within 30 minut s of the nominal time point.  
The timing and number of ECGs may be altered depending on emerging safety information.  
Additional ECGs may be taken at the discretion of the investigator.
Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 
10 minutes prior to times indicated   All ECGs should be recorded with the patient in the same 
physical position.  A standardised ECG machine should be used and the patient should be 
examined using the same machine throughout the study if possible. 
After paper ECGs have been recorded, the investigator or designated physician will review 
each of the ECGs and may refer to a local cardiologist if appropriate.  A paper copy should be 
filed in the patient’s medical records.  
If an abnormal ECG finding at screening or baseline is considered to be clinically significant 
by the investigator, it should be reported as a concurrent condition.  For all ECGs details of 
intervals PR, R-R, QRS, QT, and QTcF and an overall evaluation will be recorded (normal; 
abnormal and non-clinically significant; or abnormal and clinically significant).  
8.2.5
MUGA scan/Echocardiogram 
Assessments will be performed at screening and thereafter as clinically indicated.  
Bidimensional echocardiography (ECHO) is the preferred modality because of the global
technetium [Tc-99m] shortage (but MUGA can be used alternatively).  
The modality of the cardiac function assessments must be consistent within patient ie, if 
echocardiogram is used for the screening assessment and a follow-up assessment if clinically 
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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indicated, then echocardiogram should also be used for subsequent scans if required.  The 
patients should also be examined using the same machine and operator whenever possible.  
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 E.  
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.  
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF.
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 fr quency for collecting AE and SAE information 
AEs and SAEs will be collected from time of signature of the ICF, throughout the treatment 
period and including the 30 day follow-up period after discontinuation of study drug.  
For patients who continue to receive treatment beyond the time of the final DCO, investigators 
will continue to report all SAEs to AstraZeneca Patient Safety until 30 days after study
treatment is discontinued (see Section 4.4).  
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix E.  The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.  
Investigators are not obligated to actively seek AEs or SAEs in patients who have already 
completed follow-up.  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 may notify the sponsor.  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix E.  
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8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each patient
at subsequent visits/contacts.  All SAEs/non-serious AEs/AEs of special interest (as defined in 
Appendix E), will be followed until resolution, stabilisation, the event is otherwise explained, 
or the patient is lost to follow-up.  
A post-study assessment will be performed preferably within 7 days of the time that the IMP 
is permanently discontinued.  
Safety follow-up should be carried out with the patient 30 days (± 7 days) after the 
discontinuation of study treatment to follow-up any SAEs/AEs and concomitant medications 
(including any subsequent cancer therapy).  
Any AE/SAE/abnormal laboratory findings that are ongoing at the time of study treatment 
discontinuation or any new treatment related events within 30 days of study treatment, must 
be followed up to resolution or until the event becomes stable (or returns to baseline) or is 
unlikely to resolve further in the opinion of the investig tor.  Any AEs that are unresolved at 
the patient’s last AE assessment or other assessment/visit as appropriate in the study are 
followed up by the investigator for as long as medically indicated, but without further 
recording in the eCRF.  AstraZeneca retains the right to request additional information for any
patient with ongoing AE(s)/SAE(s) at th  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 and changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the IMP(s) (yes or no)

Action taken with regard to IMP(s)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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
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 IMP 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 IMP?’.  
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 f und in Appendix E to the CSP.  
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff (e.g., “Have you had any health problems since the previous visit/you 
were last asked?”) or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred (when possible) to 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 CSP mandated laboratory tests and vital signs will be summarised in the 
CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values, vital
signs and ECG abnormalities should therefore only be reported as AEs if they fulfil any of the 
SAE criteria or are the reason for discontinuation of treatment with the IMP or if they are 
considered to be clinically relevant as judged by the investigator (which may include but is not 
limited to consideration as to whether treatment or non-planned visits were required or other 
action was taken with the study treatment, e.g., dose adjustment or drug interruption).  
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (e.g., anaemia vs low haemoglobin value).  In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).  
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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 Section 8.3.9).  
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, without 
any findings of cholestasis (as indicated by elevated serum alkaline phosphatase [ALP]), may 
need to be reported as SAEs.  Please refer to Appendix H 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 IMP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease.  The development of new 
or progression of existing metastasis to the primary cancer under study should be considered 
as disease progression and not an AE.  Even s  which are unequivocally due to disease 
progression, should not be reported as an AE during the study.  
8.3.10
Adverse Events of Special Interest
Adverse Events of Special Interest (AESIs) are events of scientific and medical interest
specific to the further understanding of capivasertib safety profile and require close 
monitoring and rapid communication by the investigators to AstraZeneca.  An AESI can be 
serious or non-serious. All AESIs will be recorded in the eCRF.  Serious AESIs will be 
recorded and reported as per Section 8.4.1.
The AESIs for this study are:

Urinary tract infection 

Hyperglycaemia

Non-infectious diarrhoea

Infective pneumonia

Rash

Stomatitis

QT Prolongation  
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8.4
Safety reporting and medical management
Investigators should refer to locally approved prescribing information for guidance on 
fulvestrant monitoring and the management of fulvestrant-related toxicities.  
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IMP, or to the 
study procedure(s).  All SAEs will be recorded in the eCRF.  
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.  
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.  
For fatal or life-threatening 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 bu 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 electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative.  
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone, email or fax.  
The AstraZeneca representative will advise the investigator/study site staff how to proceed 
investigators or other site personnel send relevant eCRF modules by fax to the designated 
AstraZeneca representative.  
For further guidance on the definition of a SAE, see Appendix E of the Clinical Study
Protocol.  
The reference document for definition of expectedness/listedness is the IB for the capivasertib 
and fulvestrant.
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8.4.1.1
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 utilizing 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 t  investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.4.2
Pregnancy
A pregnancy test will be locally administered to female patients at screening, on Day 1 of the 
study (Cycle 1, Week 1, Day 1), at discontinuation of capivasertib, and as clinically indicated.  
Confirmation of absence of pregnancy is trongly recommended in case of delayed menstrual
period (including infrequent or irregular menstrual cycles).
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca (see 
Section 8.4.2.1) except where the pregnancy is discovered before the study patient has 
received any study treatment.  
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.  
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, study treatment should be 
discontinued immediately.  
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP under study
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
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birth or congenital abnormality) should be followed up and documented even if the patient
was discontinued from the study.  
If any pregnancy 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 provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs and within 30 days for all other pregnancies.  
The same timelines apply when outcome information is available.  
8.4.2.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
2 years after the last dose of fulvestrant or until 16 weeks after discontinuing 
capivasertib/placebo, whichever occurs later. Patients wishing to father children should be 
advised to arrange for freezing of sperm samples prior to the start of study treatment.  
Pregnancy of a patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, electi e termination, ectopic pregnancy, normal birth 
or congenital abnormality), occurring from the date of the first dose until 2 years after the last 
dose of fulvestrant or until 16 weeks after discontinuing capivasertib/placebo whichever 
occurs later, should, if possible, b  foll wed up and documented.  
8.4.3
Overdose
There is currently no specific treatment in the event of an overdose with capivasertib and 
possible symptoms of overdose are not established.  Capivasertib must only be used in 
accordance with the relevant CSP.  AEs associated with overdose should be treated in 
response to symptoms.  Any dose, or frequency of dosing, that exceeds the dose regimen 
specified in the CSP should be reported as an overdose.  The MTD for capivasertib is 
400 mg BD in combination with fulvestrant and 480 mg BD as monotherapy.  Fulvestrant
must be used according to local prescribing information.  
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately.  

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module

An overdose without associated symptoms is only reported on the Overdose eCRF 
module
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If an overdose on an AstraZeneca study drug 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
8.4.4
Medication error, drug abuse, and drug misuse
8.4.4.1
Timelines
If an event of medication error, drug abuse or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one day ie, immediately but no later than 24 hours of when they become aware of it.  
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within one (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 event of medication error, drug abuse, or misuse (see Section 8.3.2)
and within 30 days for all other events
8.4.4.2
Medication error  
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP that either causes harm to the participant or has the 
potential to cause harm to th  participant.
The full definition and examples of a medication error can be found in Appendix E.
8.4.4.3
Drug abuse  
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP for 
a perceived reward or desired non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix E.
8.4.4.4
Drug misuse  
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP for 
medicinal purposes outside of the authorised product information, or for unauthorised IMPs, 
outside the intended use as specified in the protocol and includes deliberate administration of 
the product by the wrong route. 
The full definition and examples of drug misuse can be found in Appendix E.
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8.4.5
Management of capivasertib-related toxicities
8.4.5.1
Capivasertib/placebo dose modification and guidance
Please refer to Section 6.6 for guidance on dose modifications.  
8.4.5.2
Dose modifications due to general capivasertib-related toxicities
Treatment with capivasertib/placebo should be temporarily interrupted for any intolerable AE 
regardless of grade or for any AE grade ≥3, that is not attributable to the disease under 
investigation, where the investigator considers the AE of concern to be specifically associated 
with capivasertib.  Dose modification guidelines for capivasertib-related toxicities are shown 
in Table 9.  Appropriate and optimal treatment of the toxicity is assumed prior to considering 
dose modifications.  The study physician may be consulted prior to discontinuation of study
drug due to toxicities.  Please see Section 8.4.5.3 for the management of capivasertib specific 
toxicities including hyperglycaemia, maculo-papular rash and other skin reactions, and 
diarrhoea.  
Table 9
Dose modifications for general capivasertib-related toxicities
NCI CTCAE v5 Toxicity Grade:
Actions:
Grade 1 or 2 clinically significant or intolerable
Hold dosing and follow guidance below, 
depending on outcome

Resolves to baseline or clinically tolerable within 
21 days of onset

Resume dosing at same dose or one reduced 
dose level as clinically appropriate

Does not resolve or remains intolerable within 
21 days of onset

Discontinue study drug and observe patient 
until resolution
Grade ≥3
Hold dosing and follow guidance below, 
depending on outcome

Grade ≥3 toxicity for ≤21 days and resolves to 
≤grade 2 or baseline within 21 days of onset 

Resume dosing at one reduced dose or same 
dose level as clinically appropriate

Grade ≥3 toxicity for >21 days

Discontinue study drug and observe patient 
until resolution
NCI CTCAE v5, National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0.  
8.4.5.3
Dose modifications due to specific capivasertib-related toxicities 
Hyperglycaemia
These are general recommendations therefore due consideration should be given to baseline 
values and fasting condition (and time since food if applicable) when interpreting glucose 
results.  In diabetic patients, it may be beneficial to rule out concomitant aetiologies that could
be associated with hyperglycaemia (e.g., infections, dehydration, vascular events, 
glucocorticoids).  
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Patients should be made aware of symptoms of hyperglycaemia (e.g., polydipsia and 
polyuria). 
Dose modification guidelines for capivasertib-related hyperglycaemia are shown in Table 10.  
In addition, for all grades, patients should receive education on lifestyle changes (e.g., a 
diabetic diet) and consider beginning home glucose monitoring (e.g., fasting self-blood 
glucose monitoring [SBGM] once-daily) at the discretion of the investigator.  If glucose home 
monitoring is instituted, the capivasertib/placebo treatment decision should be based on the 
morning fasting glucose value obtained prior to the dose of capivasertib/placebo.  
It is recommended that approaches to the management of capivasertib-induced 
hyperglycaemia include advice from a diabetologist where appropriate (e.g., diabetic patients).  
Metformin is currently the preferred oral antidiabetic recommended for the management of 
hyperglycaemia occurring in patients participating in studies of capivasertib (see below for 
further guidance).  If a second agent is required, consideration should be given to the 
intermittent schedule of capivasertib and the pattern of glucose changes (e.g., sulphonylureas 
should be avoided due to their risk of hypoglycaemia se ondary to their mechanism of action).
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Table 10
Dose modifications for capivasertib-related hyperglycaemiaa
NCI CTCAE v5 Toxicity Grade:
Actions
Grade 1
(Abnormal glucose above baseline with no 
medical intervention)
Maintain same capivasertib/placebo dose level
Grade 2 
(Change in daily management from baseline 
for a diabetic; oral anti-glycaemic agent 
initiated; workup for diabetes)
Asymptomatic: 

Maintain same capivasertib/placebo dose level

Treatment as per local guidelines, consider the use of oral 
antidiabetic (e.g., metformin) on capivasertib/placebo 
dosing days only (see further guidance on choice of 
antidiabetic agents on text above and below the table)
Symptomatic: Appropriate clinical management as per local 
guidelines

Interrupt capivasertib/placebo until resolution of 
symptoms and fasting blood glucose ≤160 mg/dL or 
≤8.9 mmol/L (treatment can be interrupted up to 21 days)

Restart at sa e dose level maintaining appropriate 
antidiabetic treatment (e.g. addition of/higher dose of oral 
metformin)

Consider consult with the diabetologist
Grade 3 
(Insulin therapy initiated; hospitalisation 
indicated)
Hold capivasertib/placebo up to 21 days until resolution of 
symptoms.  Consult with diabetologist

If fasting blood glucose decreases ≤160 mg/dL or 
≤8.9 mmol/L within 21 days following appropriate 
antidiabetic treatment, resume capivasertib/placebo at 1 
lower dose level

If fasting blood glucose does not decrease to ≤160 mg/dL 
or ≤8.9 mmol/L within 21 days following appropriate 
antidiabetic treatment, permanently discontinue 
Capivasertib/placebo
Grade 4
(Life-threatening consequences; urgent 
intervention indicated)

Appropriate clinical management as per local guidelines

Consider consult with the diabetologist

Consider permanent cessation of capivasertib/placebo
a
Patients may receive education on lifestyle changes (e.g., a diabetic diet) and consider beginning home 
glucose monitoring (e.g., fasting self-blood glucose monitoring [SBGM] once-daily) at the discretion of the 
investigator.  If glucose home monitoring is instituted, the capivasertib/placebo treatment decision should 
be based on the morning fasting glucose value obtained prior to the dose of capivasertib/placebo.
NCI CTCAE v5, National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0; 
SBGM, self-blood glucose monitoring
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Use of metformin
Metformin is currently the preferred oral antidiabetic recommended for the management of 
hyperglycaemia occurring in patients participating in studies of capivasertib.  Investigators 
should exercise caution in the dosing and management of patients receiving the metformin and 
capivasertib/placebo combination and must be vigilant for signs of renal impairment and 
metformin toxicity, such as lactic acidosis and hypoglycaemia, namely: lethargy, hypotension, 
poor urine output, drowsiness, irritation, tachypnoea, sweating, diarrhoea, and vomiting.  
Due to the potential interaction of metformin and capivasertib (caused by the inhibition of 
renal transporters [e.g., OCT2] involved in the excretion of metformin), when taking both 
capivasertib and metformin concurrently, it is recommended weekly monitoring of creatinine 
after initiation of metformin, for up to 3 weeks and then on Day 1 of each cycle thereafter.
Metformin should only be given on the days when capivasertib/placebo is also administered 
(the half-life of capivasertib is approximately 7-15 hours) and should be withdrawn when 
treatment with capivasertib/placebo is withdrawn, unless otherwise clinically indicated.  
Consider withholding of metformin on the days patients are due to have imaging with contrast 
(in order to reduce the already low risk of lactic acidosis) as per local guidelines.
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Maculo-papular rash
Dose modifications for capivasertib-related maculo-papular rash, which is the most frequent 
skin toxicity observed in patients treated with capivasertib, are provided in Table 11.  
However, these management guidelines can be used for other skin toxicities at the discretion 
of the investigator and/or following consultation with the dermatologist.  
Table 11
Dose modifications for capivasertib-related maculo-papular rash 
NCI CTCAE v5 Toxicity Grade:
Actions:
Grade 1 or 2
Continue dosing at current dose and initiate dermatological 
treatment:

Topical steroid of moderate strength twice-daily

Non-sedating oral antihistamines
Grade ≥3 or any grade clinically intolerable
Withhold dosing for up to 28 days and initiate 
dermatological tr atment (topical steroid of moderate 
strength and non-sedating oral antihistamines) with oral 
steroid for a short course (e.g., up to 2 weeks).  
Consultation with dermatologist is advised

Improves to grade ≤1 and tolerable within 
28 days from onset

Continue dermatological treatmenta and restart dosing 
at same dose

Improves to grade 2 and tolerable within 
28 days from onset

Continue dermatological treatmenta and restart dosing 
at reduced dose (1 dose level reduction)

Does not improve to grade 2 and tole able 
within 28 days from onset

Continue dermatological treatmenta and discontinue 
capivasertib/placebo
Recurrence of Grade 3, or Grade 4 (e.g., 
severe bullous, blistering o  exfoliating skin 
conditions), or any % BSA associated with 
extensive superinfection, with IV antibiotics 
indicated; life-threatening consequences
Discontinue capivasertib/placebo
a
In patients with persistent rash or previous occurrence of grade 3 rash, consider secondary prophylaxis by 
continuing topical steroids and/or non-sedating oral antihistamines.
BSA, body surface area; NCI CTCAE v5, National Cancer Institute Common Terminology Criteria for Adverse 
Events Version 5.0.
Hypersensitivity
In the case of hypersensitivity reactions, capivasertib/placebo should be discontinued and 
symptomatic/supportive therapy should be initiated (including with antihistamines and/or 
steroids) as considered appropriate by the investigator/treating physician.  Drug re-challenge 
is not recommended; any subsequent consideration on re-challenge with capivasertib at the 
same or a lower dose, with its potential for recurrence of such or more severe events should be 
carefully considered against the potential benefits to the individual patient from continuation 
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
Approved
ating ora
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dosing for up to 
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of capivasertib therapy and agreed with the sponsor.  Further management should follow local
guidelines on management of hypersensitivity reactions.  
Diarrhoea
Patients should be instructed to promptly contact investigators if they develop diarrhoea.  
Alternative aetiologies should be ruled out prior to initiating the dose modifications.  
Investigators are recommended to prescribe anti-diarrhoeal treatment at the first visit so that 
patients can start treatment at the first sign of diarrhoea, should it occur.  
Loperamide is the preferred anti-diarrhoea agent for the management of diarrhoea occurring in 
patients participating in studies of capivasertib. Dose modifications for capivasertib-related 
diarrhoea are provided in Table 12.  
If diarrhoea is reported, additional details regarding this AE will be collected in the eCRF.
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Approved
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d
ng this AE will 
d
s AE will
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Table 12
Dose modifications for capivasertib-related diarrhoea
NCI CTCAE v5 Toxicity Grade:
Actions:
Grade 1
Maintain same capivasertib/placebo dose.  Anti-diarrhoeal 
treatment (e.g., loperamide) should be initiated at first report 
of diarrhoea.  Maximise the supportive care (e.g., dietary
modifications, appropriate hydration therapy and electrolyte 
supplements as clinically indicated).  
Grade 2
Interrupt capivasertib/placebo dose (up to 21 days) until 
recovery to grade ≤1 and resume dosing at same dose level.  
Anti-diarrhoeal (e.g., loperamide) treatment should be initiated 
at first report of diarrhoea.  Maximise the supportive care (e.g., 
dietary modifications, appropriate hydration therapy and
electrolyte supplements as clinically indicated).  
Consider starting secondary prophylaxisa.  
Grade ≥3
Interrupt capivasert b/placebo dose (up to 21 days) and 
institute appropriate anti diarrhoeal treatment

Improves to grade ≤1 within 21 days

Resume dosing at same dose level or 1 reduced dose level 
as clinically appropriate, maintaining treatment for 
toxicity as necessary and/or start secondary prophylaxisa

Does not improve to grade ≤1 after 
21 days 

Discontinue capivasertib/placebo
Recurrence of grade ≥2 or clinically 
significant or intolerable toxicity despit  
secondary prophylaxis
Interrupt capivasertib/placebo dose (up to 21 days) 
maintaining appropriate anti-diarrhoeal treatment

Improves to grade ≤1 or becomes 
clinically tolerable withi  21 days

Resume dosing up to 2 reduced dose levels maintaining 
treatment for toxicity as necessary and/or maintaining 
secondary prophylaxisa

Does not improve to grade ≤1 or 
remains clinically 
significant/intolerable after 21 days

Discontinue capivasertib/placebo
a
In patients with persistent grade 1 diarrhoea (e.g., loperamide 2 mg, 2 to 4 times daily).  
NCI CTCAE v5, National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0.  
8.5
Pharmacokinetics
Blood samples of approximately 2 mL will be collected from each patient for measurement of 
plasma concentration of capivasertib as per the SoA (Section 1.1).  Samples from patients 
dosed with placebo will not be analysed (for exceptions, see Section 8.5.1).  The 
randomisation list will be supplied to the bioanalytics team before sample analysis.  
Results will only be reported for samples shipped within a timeframe for which the stability of
capivasertib in the samples has been validated and shown to be acceptable.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
Approved
me
d
me
ng secondary
d
ng secondary
pivasert b/placebo do
ed
pivasert b/placebo
appropriate anti
ed
appropriate anti diarrh
d
diarr
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v
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dosing at same
as clinically appropri
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as clinically appropri
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toxicity as necessa

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
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A
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Samples may be collected at additional time points 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 will be used to evaluate the PK of capivasertib.  Samples collected for analyses of 
capivasertib plasma concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study.  
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.  
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but 
separately in a bioanalytical report.  
8.5.1
Determination of drug concentration
Samples for determination of capivasertib concentrations in plasma will be analysed by
Covance on behalf of Clinical Bioanalysis Alliance, AstraZeneca R&D, using an appropriate 
bioanalytical method.  Full details of the analytical method used will be described in a 
separate bioanalytical report.  
For each placebo patient, samples will only be analysed on a 'for cause' basis, e.g., if no 
quantifiable concentrations were obser ed in a patient's samples when the drug was expected 
to be present.  
8.5.2
Storage and destruction of pharmacokinetic samples
8.5.2.1
Samples collected in China
PK samples will be disposed of after the bioanalytical report finalisation or 6 months after 
issuance of the draft bioanalytical report (whichever is earlier).  
8.5.2.2
Samples collected outside of China
PK samples will be disposed of after the bioanalytical report finalisation or six 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.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
pproved
e pe
d
e pe
will not be
d
will not be
ntration
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8.6
Genetics
  
  
  
8.6.2
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic 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 r ported 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.  
8.7
Biomarkers
Mandatory collection of tumour tissue and blood samples for biomarker research is required 
as a part of this study.  Optional tumour tissue samples should be collected from consenting 
patients only.  The following samples will be collected from all patients in this study as 
specified in the SoA (Section 1.1).  See Appendix F for additional information on the handling 
of biological samples.  
8.7.1
Tumour tissue sample
8.7.1.1
Mandatory tumour tissue samples for biomarker analysis
All randomised patients must provide an archival or newly collected FFPE tumour sample 
(see Section 1.1) collected as part of routine clinical practice, for central testing.  This should 
preferably be a tissue block to enable the analyses described below. If a block is not possible, 
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
Approve
of 
o
of genetic sample
ov
genetic sample
and storage of sam
ov
and storage of sam
dent
r
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ialit
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ro
y.  Sampl
ro
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p
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pr
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pp
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dentifying the ind
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with the DNA
A
with the DNA
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8.7.1.3
Collection, analysis and reporting of tumour samples
Mandatory tumour samples will be collected as detailed in the Laboratory Manual and the 
Diagnostic Testing Manual.  Patients must consent to provide an archival or newly FFPE 
tumour sample, collected as part of routine clinical practice, for analysis.  
Mandatory tumour samples meeting the minimum tumour content and tissue volume, as 
specified in the Laboratory Manual and Diagnostic Testing Manual, will be tested with the 
primary intent to detect tumour DNA alterations in the following genes; AKT1, PIK3CA, and 
PTEN.  If the first sample submitted for testing is inconclusive due to technical test failure, a 
further sample may be submitted for t sting   Submission and testing of additional samples 
can only be performed if the origina  testing failed due to technical reasons (ie, failed test 
result).  Please refer to the Laboratory Manual and the Diagnostic Testing Manual for further 
details regarding retesting procedures.  Central testing may generate results on genes other 
than AKT1, PIK3CA, and PTEN, and the results may be provided at the time of treatment 
discontinuation upon individual request by the investigator in order to avoid bias during the 
treatment period.  
Optional tumour biopsy samples will be collected from consenting patients only.  The optional 
tumour biopsies collected at disease progression meeting the minimum tumour content and 
tissue volume, as specified in the Laboratory Manual and Pathology and Genomic Testing 
Manual, will be tested centrally by NGS using the same central test as described above for the 
mandatory tumour samples.  The primary intent is to detect changes in the tumour DNA 
alterations that may be associated with treatment resistance.  The results of this central testing 
of the optional tumour biopsy obtained at disease progression will be provided to the 
investigator.
Test results will be reported to AstraZeneca.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
pproved
mou
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ailed in the L
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8.7.3
Storage, re-use and destruction of biomarker samples
Biological 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 to generate hypotheses to be tested in future research. 
8.8
Any unused or partially used tumour samples collected in China 
for the purpose of PIK3CA/AKT1/PTEN-alternation assessment 
with appropriate patient inform consent and regulatory approval 
(e.g. HGR) might be used for companion diagnostics per the 
requirements of China regulatory approval. The unused or 
partially used samples will be destroyed or repatriated maximally 
1 year after the final CSR is published according to China 
regulatory approval. Healthcare resource use
The impact of treatment and disease on healthcare resource use will be captured in this study
on an event-driven basis.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
Ap
e
A
e-
A
-use and destru
Ap
use and destru
will be stored for a 
Ap
will be stored for a 
f
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fter whi
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ter whi
ftf
A
ftf
ch they
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ch they
he CSR
A
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th
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The Hospital Admission (HOSPAD) module will be used to collect information on key health
care resource use beyond study mandated visits.  The site should complete the HOSPAD form 
at the site at every scheduled clinic visit up to and including the post-study treatment 
discontinuation follow-up visit.  If a patient discontinues study treatment for reasons other 
than RECIST v1.1 progression, the HOSPAD form should continue to be administered until 
progression has been confirmed.  Study mandated visits should not be included as a hospital 
admission.  
The data may be used as input to cost analyses for example cost utility analysis or cost 
effectiveness analysis.  
9
STATISTICAL CONSIDERATIONS 
9.1
Statistical hypotheses
The null hypotheses for the primary time to event endpoint (PFS) are that there is no 
difference between capivasertib + fulvestrant and placebo + fulvestrant in the probability of a 
progression event in the overall population and the PIK3CA/AKT1/PTEN-altered population.  
The intention of the study is to demonstrate the superiority of capivasertib + fulvestrant over 
placebo + fulvestrant in either or both of the ov rall and PIK3CA/AKT1/PTEN-altered 
populations.  
9.2
Sample size determination
Assuming a significance level of 5%, a total of 492 OS events will be required to achieve 90% 
power to detect a treatment effect of an average HR 0.74 in the overall population, assuming a 
12-month delay to a treatment effe t and an HR of 0.64 after the delay.  Assuming 70% 
maturity at the time of the final analysis, approximately 700 patients will need to be 
randomised.  Of these 700 randomised patients, it is expected that a minimum of 280 patients 
will have a tumour harbouring an eligible PIK3CA/AKT1/PTEN alteration based on a 
prevalence of ~40-45% (Cristofanilli et al 2016, Curtis et al 2012, Di Leo et al 2018,
Hortobagyi et al 2016, Pereira et al 2016, Spoerke et al 2016), and a minimum of 
approximately 224 patients will be in the PIK3CA/AKT1/PTEN-altered subgroup assuming a 
test failure rate of 20%.  
The primary objective of this study is to assess the efficacy of capivasertib + fulvestrant vs 
placebo + fulvestrant by assessment of PFS in the overall and the PIK3CA/AKT1/PTEN-
altered populations.  The PFS Primary Analysis will take place after PFS reaches 
approximately 77% maturity (542 events) in the overall population, of which approximately
217 PFS events are expected to have occurred in patients whose tumours harbour an eligible 
PIK3CA/AKT1/PTEN alteration based on a prevalence of ~40-45% (and 174 events will have 
been observed if a test failure rate is 20%).  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
proved
nt endpo
ed
nt endpoint
ed
int (PFS) 
ed
(PFS a
and placebo +
ed
and placebo + fu
d
fulv
d
lv
and the
ve
and the PIK3CA/A
ve
PIK3CA/A
ate the superi
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ate the superiori
v
ority
ty
ititi y
of the ov rall and 
ov
of the ov rall and P
termination
pr
termination
App
vel of 5%, a total o
pp
vel of 5%, a total o
ent effect of an aver
App
ent effect of an aver
eatment effe t and 
Ap
eatment effe t and 
of the 
A
of the final
Ap
final analysi
Ap
analysi
700 randomis
A
700 randomis
ring an
A
ring an
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After all the pre-defined PFS endpoints have been tested, the remaining alpha will be used for 
testing OS in the PIK3CA/AKT1/PTEN-altered population and subsequently for OS in the 
overall population. ORR in the PIK3CA/AKT1/PTEN-altered populations and the overall 
population will be tested sequentially only if OS in the overall population is statistically 
significant.
The OS Interim Analysis is expected to occur when approximately 394 OS events have been 
observed in the overall population and similar maturity has been reached in the altered 
population (56% maturity, 80% information fraction).  If the time between the PFS analysis 
and the OS interim analysis is approximately 3 months or less, then the PFS DCO may be 
delayed and the analyses combined.  The OS Final Analysis will take place when 
approximately 70% maturity has been observed in both the overall and PIK3C/AKT1/PTEN-
altered populations. The exact significance level will be determined according to the O’Brien 
& Fleming method (Lan and DeMets 1983) based on the ac ual number of events observed at 
the OS Interim Analysis. 
Table 13 and Table 14 show the critical values at vari u  significance levels for PFS and OS
testing.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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be dete
d
be dete
on the ac ual 
d
on the ac ual 
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Table 13
Statistical considerations for dual primary PFS endpoints
Analysis
Significance 
level
Number of 
events 
(assuming 
20% test 
failure 
rate)
Critical value in HR 
[corresponding median 
PFSa]
Power 
(Assuming 
HR=0.64)
PFS Analysis (altered 
subgroup, assuming 
77% maturity)
0.021b
217 (174)
0.73 (7.5 months) 
[0.71 (7.7 months)]
83.7% (73.9%) 
0.05c
217 (174)
0.77 (7.2 months)
[0.74 (7.4 months)]
90.8% (83.7%)
PFS Analysis (overall 
population, assuming 
77% maturity)
0.035
542
0.83 (6.6 months)
>99% 
HR, hazard ratio; PFS, progression-free survival.
a
Assuming median PFS for placebo + fulvestrant arm is 5 5 months and PFS is exponentially distributed.  
b
Assuming the null hypothesis for the PFS Analysis in the overa l population is not rejected at α=0.035 level 
and the observed ratio of the number of events between the altered subgroup and overall population is 0.4.  
c
Assuming the null hypothesis for the PFS Final Analy is in the altered subgroup is rejected at α=0.035
level.  
Table 14
Statistical considerations for OS endpoint
Analysis
Significance 
level
Number 
of events 
(assuming 
20% test 
failure 
rate)
Critical value in HR 
[corresponding median 
OSa]
Power 
(Assuming HR=0.74)
OS Interim Analysis 
(altered subgroup, 
assuming 80% 
information fraction)
0.0056b
158 (127)
0.642 (33.7 months) 
[0.610 (40.9 months)]
13% (6%) 
0.0244c
158 (127)
0.698 (30.8 months)
[0.670 (35.2 months)]
28% (16%)
OS Final Analysis 
(altered subgroup)
0.0133b
197 (158)
0.702 (29.3 months)
[0.673 (32.0 months)]
36% (21%)
0.0429c
197 (158)
0.749 (27.9 months)
[0.724 (29.7 months)]
53% (36%)
OS Interim Analysis 
(overall population, 
assuming 80% 
information fraction)
0.0056b
394
0.756 (28.5 months)
44%
0.0244c
394
0.796 (27.2 months)
64%
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
Approved
m is 5 5 months and P
ed
m is 5 5 months and 
sis
v
sis in the 
ve
in the overa l popu
ve
overa l popu
s between the altered s
ve
s between the altered s
inal Analy is 
ov
inal Analy is in the alt
v
in the alt
sideration
ro
siderations
ro
s for OS
ro
for OS
pp
Significance 
Ap
Significance 
level
A
level
App
pp
pp
Numb
pp
Numb
of e
p
of e
(a
p
(a
App
App
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Analysis
Significance 
level
Number 
of events 
(assuming 
20% test 
failure 
rate)
Critical value in HR 
[corresponding median 
OSa]
Power 
(Assuming HR=0.74)
OS Final Analysis 
(overall population)
0.0133b
492
0.799 (26.5 months)
80%
0.0429c
492
0.833 (25.8 months)
90%
HR, hazard ratio; OS, overall survival.
a
Assuming median OS for placebo + fulvestrant arm is 23 months and OS follows a Weibull distribution 
with β=1.5.  
b
Assuming the null hypothesis for the PFS Final Analysis in th  overall population is not rejected at α =
0.035 level.  
c
Assuming the null hypothesis for the PFS Final Analysis in the overall population is rejected at α = 0.035
level.  
9.3
Populations for analyses
For purposes of analyses, the populations described in Table 15 are defined.  
Table 15
Analysis populations
Population
Description
Full Analysis Set (FAS)
The FAS will be used as the primary population for 
reporting efficacy data and to summarise baseline 
characteristics.  
This comprises all patients randomised into the study, 
excluding patients randomised in China after the
global cohort last patient first visit (LPFV), and will 
be analysed according to randomised treatment 
regardless of the treatment received (intention-to-treat 
[ITT] principle).  Any important deviations from 
randomised treatment will be listed and considered 
when interpreting the efficacy data.  
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Population
Description
Safety Analysis Set
The safety analysis set comprises all patients included 
in the FAS, who received at least 1 dose of study drug 
(fulvestrant, capivasertib, placebo) and will be 
analysed according to the treatment received.  If a 
patient receives at least 1 dose of capivasertib or
placebo they will be summarised in the capivasertib 
arm for safety summaries (e.g., capivasertib arm will 
include patients randomised to capivasertib who 
receive at least 1 dose of capivasertib or placebo 
patients who receive at least 1 dose of capivasertib in 
error at any time).  If a patient randomised to 
capivasertib receives only placebo treatment, then 
they will be summarised as part of the placebo arm.  
Patients who receive only fulvestrant will also be 
included in th  safety analysis set and will be 
included in the treatment arm to which they were 
randomised.
Altered Subgroup FAS
This co prises all patients included in the FAS with 
a PIK3CA/AKT1/PTEN-altered result from a valida
biomarker test as determined by central testing.  
Altered Subgroup Safety Analysis Set
This comprises all patients included in the Safety 
Analysis Set with a PIK3CA/AKT1/PTEN-altered 
tumour as determined by central testing.  
Pharmacokinetic (PK) Analysis Set
This comprises all patients included in the FAS who 
received at least 1 dose of capivasertib with at least 
one reportable concentration.
a
The definition of a valid biomarker st will be pre-specified in the SAP prior to any efficacy analysis.
9.4
Statistical analyses
Analyses will be performed by AstraZeneca or its representative.  A comprehensive SAP will 
be developed and finalised before the primary PFS analysis database lock and will describe 
the patient populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.  This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.  Any deviations from this plan will be
reported in the CSR.  
9.4.1
Efficacy analyses
Efficacy analyses will be performed based on the Full Analysis Set (FAS) (intention-to-treat 
[ITT]) for the overall population and on the Altered Subgroup FAS for the 
PIK3CA/AKT1/PTEN-altered subgroup.  
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Depending on the extent of any impact, summaries of data relating to patients diagnosed with 
COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, delayed or 
discontinued IP, and other protocol deviations) may be generated.  More details will be 
provided in the SAP.
9.4.1.1
Primary endpoint: PFS in the overall population
PFS is defined in Section 8.1.1.1 together with the details of censoring.
PFS in the overall population will be analysed using a stratified log-rank test adjusting for the 
stratification factors (Section 4.1).  
The stratification variables in the statistical modelling will be based on the values entered into 
IVRS at randomisation.  If there are insufficient events per strata, the strata will be pooled 
following a pooling strategy that will be prespecified in the SAP.  
From the stratified Cox proportional hazards model (ties = Efron) the HR (capivasertib + 
fulvestrant vs placebo + fulvestrant) together with its corresponding 95% CI (calculated using 
a profile likelihood approach) will be presented   An HR less than 1 will favour capivasertib + 
fulvestrant.
Subgroup analyses will be conducted to assess PFS by the stratification factors (see 
Section 4.1) and the following (but not limited to) subgroups of the FAS:

Age at randomisation (<65 vs ≥65 years of age)

PIK3CA/AKT1/PTEN mut tion status in tissue (PIK3CA/AKT1/PTEN-altered vs 
confirmed PIK3CA/AKT1/PTEN-non-altered + unknown)
Additional subgroup analyses (e.g., menopausal status, type of endocrine resistance) may be 
conducted and the details outlined in the SAP.  
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment arms. The purpose of the subgroup analyses is to assess the 
consistency of treatment effect across expected prognostic and/or predictive factors. Forest 
plots will be presented. 
No adjustment to the significance level for testing of the subgroup and sensitivity analyses 
will be made, since all these analyses will be considered supportive of the analysis of PFS.
For each subgroup level of a factor, the HRs and associated CIs will be calculated from a Cox 
proportional hazards model (ties = Efron) that only contains a term for treatment.  The Cox 
models will be fitted using SAS® PROC PHREG with the Efron method to control for ties and
using a BY statement for the subgroup factor.  The HRs and 95% CIs will be presented on a 
forest plot.  
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ed in the SAP
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Further sensitivity analyses will be described in the SAP.
Supplementary analysis
PFS defined by BICR in the overall population will be analysed as described for the 
investigator-assessed PFS endpoint (see above).  
9.4.1.2
Primary endpoint: PFS in the PIK3CA/AKT1/PTEN-altered subgroup
PFS in the PIK3CA/AKT1/PTEN-altered subgroup will be analysed as described for the 
investigator-assessed PFS endpoint (Section 9.4.1.1) and stratified by the stratification factors 
(Section 4.1).  
Additional sensitivity and subgroup analyses may be performed (including outcomes based on 
BICR).
9.4.1.3
Secondary endpoint: OS in the overall population
OS is defined in Section 8.1.2 together with details of censoring.
OS will be analysed as described for the investigator assessed PFS endpoint (Section 9.4.1.1), 
including subgroup analyses, and stratified by the stratification factors (Section 4.1).  
9.4.1.4
Secondary endpoint: OS in the PIK3CA/AKT1/PTEN-altered subgroup
OS in the PIK3CA/AKT1/PTEN-altered subgroup will be analysed as described for the 
investigator-assessed PFS endpoi t (Section 9.4.1) and stratified by the stratification factors 
(Section 4.1). 
Additional sensitivity and subgroup analyses may be performed.
9.4.1.5
Secondary endpoint: PFS2 in the overall and altered FAS populations
PFS2 is defined in Section 8.1.3 together with details of censoring.
PFS2 in the overall and the PIK3CA/AKT1/PTEN-altered populations will be analysed as 
described for the investigator-assessed PFS endpoint (Section 9.4.1.1) and stratified by the 
stratification factors (Section 4.1).  
9.4.1.6
Secondary endpoint: ORR in the overall and altered FAS populations
The ORR will be compared between capivasertib + fulvestrant vs placebo + fulvestrant, for 
both the overall and the PIK3CA/AKT1/PTEN-altered populations, using logistic regression 
models adjusting for the stratification factors (Section 4.1).  The results of the analysis will be 
presented in terms of an odds ratio (an odds ratio greater than 1 will favour capivasertib + 
fulvestrant) together with its associated profile likelihood 95% CI and p-value.  If there are not 
enough responses for a meaningful analysis using logistic regression, then a Cochran-Mantel
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details of censoring
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Haenszel (CMH) test will be presented. The CMH test will be stratified using the same 
stratification factors as the primary endpoint.
ORR will be presented with a two-sided 95% CIs using the Clopper-Pearson method (Clopper 
and Pearson 1934). 
9.4.1.7
Secondary endpoint: DoR in the overall and altered FAS populations
DoR is defined in Section 8.1.1.3 together with details of censoring.
Descriptive data will be provided for the DoR in responding patients, including the associated 
Kaplan-Meier (KM) plots for both the overall and the PIK3CA/AKT1/PTEN-altered 
populations.  
9.4.1.8
Secondary endpoint: CBR in the overall and altered FAS populations
CBR is defined in Section 8.1.1.2.  
CBR in the overall and the PIK3CA/AKT1/PTEN-altered populations will be analysed as 
described for the ORR analysis (Section 9.4.1.6)   
9.4.1.9
Secondary endpoint: PK
The plasma concentration-time data will be analysed by population PK methods using 
non-linear mixed-effects modelling.  PK parameters, including variability parameters, will be 
estimated as data permits.  The influence of intrinsic (e.g., ethnicity, gender, age, weight, renal 
function and hepatic function) and extrinsic (e.g., concomitant medication) factors will be 
evaluated and exposure-response relationships will be explored.  Details will be outlined in a 
separate modelling analysis plan and results may be reported separately.  
In the subgroup of approximately 6 Japanese patients with rich capivasertib PK data, the area 
under the plasma concentration-time curve from zero to 12 hours (AUC0-12h), the maximum 
observed plasma (peak) concentration (Cmax), and the time to reach peak or maximum 
observed concentration following drug administration (tmax) will be derived.  
PK analyses will be performed based on the PK Analysis Set and any exclusion of data will be 
documented and justified.  
Data from this study may be pooled with data from other studies.
9.4.1.10
Secondary endpoints: EORTC QLQ-C30 and EORTC QLQ-BR23
The EORTC QLQ-C30 and EORTC QLQ-BR23 will be scored according to the EORTC 
Scoring Manual (Fayers et al 2011).  An outcome variable consisting of a score from 0 to 100 
will be derived for each of the symptom scales, each of the functional scales, and the global 
measure of health status scale according to the EORTC Scoring Manual.  Higher scores on the 
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global measure of health status and functional scales indicate better health status/function, but 
higher scores on symptom scales represent greater symptom severity.  For each subscale, if 
<50% of the subscale items are missing, then the subscale score will be divided by the number 
of non-missing items and multiplied by the total number of items on the subscales (Fayers et 
al 2011).  If at least 50% of the items are missing, then that subscale will be treated as 
missing.  Missing single items are treated as missing.  The reason for any missing 
questionnaire will be identified and recorded.  
The main PRO measures identified in the secondary objectives are global health status/QoL, 
physical function, role function, fatigue, pain and appetite loss subscales of the 
EORTC QLQ-C30.  However, separate analysis will be conducted for each EORTC 
QLQ-C30 and EORTC QLQ-BR23 scale/symptom score.  
The primary assessment of global health status/QoL, physi al function, role function, or 
symptoms will focus on comparing mean change from baseline between treatment arms.  To 
examine the change from baseline and time to deterioration, the analysis population will be a 
modified FAS (ITT) which includes all randomised pati nts with an evaluable baseline 
assessment and at least one evaluable post-baseline assessment.  Similarly, analyses may be 
repeated in a modified PIK3CA/AKT1/PTEN altered population, which includes patients 
whose tumours harbour a qualifying PIK3CA/AKT1/PTEN-alteration and have an evaluable 
baseline assessment and at least one evaluable post-baseline assessment, where appropriate.  
Change from baseline will be analysed using a mixed model repeated measurements analysis 
of all the post-baseline scores.  The model will include treatment arm, visit, and treatment by 
visit interaction and stratification factors as explanatory variables, and the baseline score and 
baseline score by visit as covariates   Adjusted mean change from baseline estimates per 
treatment arm and correspondi g 95% CIs will be presented, along with an overall estimate of 
the treatment difference, 95% CI, and p-value.  
Time to deterioration will be analysed using the same approach as described for the PFS and 
OS endpoints (Section 9.4.1.1).  Separate analyses will be conducted for global health 
status/QoL, physical function, role function, fatigue, pain and appetite loss.  The effect of 
treatment arms will be estimated by the HR together with its corresponding 95% CI and 
p-value.  KM plots will be presented by treatment arm.  Summaries of the number and 
percentage of patients who have an event as well as who were censored will be provided along 
with the median time to deterioration for each treatment arm.  The HR, p-value, and 95% CI 
estimates will be presented.  
Summary tables of responses for each EORTC QLQ-C30 and EORTC QLQ-BR23 scale/item 
score (global health status/QoL, 5 functions, symptom scales) for each assessment 
(improvement, deterioration, and no change) will be presented by treatment arm.  
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Finally, summaries of absolute and unadjusted change from baseline values of each 
EORTC QLQ-C30 and EORTC QLQ-BR23 scale/item score will be reported by assessment 
timepoint for each treatment arm.  Graphical presentations may also be produced as 
appropriate.  
Full details of the statistical analyses and appropriate sensitivity analyses will be described in 
full in the SAP.  
9.4.1.11
Secondary endpoint: time to definitive deterioration of the ECOG 
performance status in the overall and the PIK3CA/AKT1/PTEN-altered
populations
Time to definitive deterioration of the ECOG performance status is defined in Section 8.1.4
together with details of censoring.
Time to definitive deterioration of the ECOG performance status in the overall and the 
PIK3CA/AKT1/PTEN-altered populations will be analysed as described for the investigator-
assessed PFS endpoint (Section 9.4.1.1) and stratified by the stratification factors 
(Section 4.1).  
9.4.2
Safety analyses
Safety analyses will be performed based on the Safety Analysis Set for the overall population
and key safety results will be presented for the Altered Subgroup Safety Analysis Set for the 
PIK3CA/AKT1/PTEN-altered subgr up.
Depending on the extent of any impact, summaries of data relating to patients diagnosed with 
COVID-19, and impact f COVID-19 on study conduct (in particular missed visits, delayed or 
discontinued IP, and other protocol deviations) may be generated.  More details will be 
provided in the SAP.
9.4.2.1
Adverse events
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) that will have been released for execution at AZ/designee.
Safety data will be presented using descriptive statistics unless otherwise specified.
AEs will be presented for each treatment group by SOC and PT covering number and 
percentage of patients reporting at least one event and number of events where appropriate.  
AEs occurring prior to start of IMP, treatment emergent AEs and post-treatment AEs will be 
presented separately.  
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An overview of AEs will present for each treatment group the number and percentage of 
patients with any AE, AEs with outcome of death, serious AEs, and AEs leading to 
discontinuation of IMP, as well as AEs leading to IMP dose interruptions and AEs leading to 
IMP dose reductions. 
Separate AE tables will be provided taken into consideration relationship as assessed by the 
investigator, CTCAE grade, seriousness, death and events leading to discontinuation of IMP 
as well as other action taken related to IMP, events of special interest and other significant 
adverse events.
An additional table will present number and percentage of patients with most common AEs.  
In accordance with the requirements of the FDA, a separate table will present non-serious AEs 
occurring in more than 5% of patients in any treatment gr up.
Key patient information will be presented for patients with AEs with outcome of death, 
serious AEs, and AEs leading to discontinuation of IMP.  
An AE listing for the safety analysis set will cover details for each individual AE.  
Full details of AE analyses will be provided in the SAP.
Treatment emergent
The following events are conside d treatment emergent:

Adverse events with an onset date on or after first dose of IMP

Worsening of pre-existing events on or after first dose of IMP
9.4.2.2
Other safety analysis
Other safety data including physical examinations, clinical haematology, chemistry, 
urinalysis, vital signs and ECGs will be summarized using descriptive statistics. The analysis 
will be performed based on the Safety Analysis Set for the overall population and on the 
Altered Subgroup Safety Analysis Set for the PIK3CA/AKT1/PTEN-altered subgroup, as 
defined in the SAP.
9.4.3
Other analyses
  
9.4.4
Methods for multiplicity control
To control the family-wise error rate in the strong sense at 5% for the treatment comparisons 
in OS and PFS, a predefined MTP with an alpha-exhaustive recycling strategy (Burman et al
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2009) taking into account intrinsic correlation between test statistics (Spiessens and Debois 
2010), will be applied. The MTP is outlined in Figure 4. According to alpha (test mass) 
splitting and alpha recycling, if the higher-level hypothesis in the MTP is rejected for 
superiority, then the next lower level hypothesis will be tested. The test mass that becomes 
available after each rejected hypothesis is recycled to lower level hypotheses not yet rejected. 
Tests will be grouped into 2 main families: one for the comparisons in PFS, the other for the 
comparisons in OS. Within the PFS and OS families, there are 2 sets of tests, one in the 
overall population, the other in the altered subgroup. The PFS family will be tested first, the 
OS family will be tested later (Figure 4). This testing procedure stops when the entire test 
mass is allocated to non-rejected hypotheses. Implementation of this predefined testing 
procedure, including recycling, will control the family wise type I error in the strong sense at 
5% (2-sided), among all key hypotheses.  
Figure 4
Illustration of data cut-offs and associated treatment comparisons
The significance level of α1 at PFS primary analysis in the altered subgroup will be determined as follows:

If the p-value for PFS in the overall population is significant at 3.5% level, then the α level of 0.035 tested for the overall 
population will be recycled, making α1=0.05.

If the p-value for PFS in the overall population is not significant at 3.5% level, then the α1 is determined by the observed ratio of 
#events in the altered subgroup and overall population using Spiessens and Debois method.
The significance level of α2 at OS interim analysis and α4 at OS final analysis for the altered subgroup will be determined by the observed 
information fraction (O’Brien & Fleming approach [Lan and DeMets 1983]) based on the remaining α available: 

If the p-value for PFS in the overall population is significant at 3.5% level, then the remaining α=0.05

If the p-value for PFS in the overall population is not significant at 3.5% level, then the remaining α=0.015.
Similarly, if the p-value for OS in the altered subgroup is significant at α2 level at the OS interim analysis, OS in the overall population will 
be tested using the O’Brien & Fleming approach [Lan and DeMets 1983] based on the remaining α available. If the p-value for OS in the 
altered subgroup is significant at α4 level at the OS final analysis, all remaining α available after PFS primary analysis will be used to test OS 
in the overall population, i.e. either 1.5% or 5% based on the outcome of PFS hypothesis testing in the overall population.
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If the OS endpoint is successful at either interim or final analysis in both the overall 
population and PIK3CA/AKT1/PTEN-altered subgroup, the remaining alpha will be recycled 
to test. ORR in the PIK3CA/AKT1/PTEN-altered subgroup. If significant, the remaining 
alpha will be recycled to test ORR in the overall population.
Data at PFS primary analysis DCO will be used to test ORR.
9.5
Interim analyses 
The OS Interim Analysis is expected to occur when approximately 394 OS events have been 
observed in the overall population and similar maturity has been reached in the 
PIK3CA/AKT1/PTEN-altered population (56% maturity, 80% information fraction).  The 
significance level for OS will be based on the significance level available after the PFS 
primary analysis and will be determined according to the O’Brien and Fleming method (Lan 
and DeMets 1983).  
The Statistical Analysis Plan will describe the planned interim analysis in greater detail.  
9.5.1
Independent data monitoring committee (IDMC)
An IDMC will be established to assess the safety of capivasertib in an unblinded manner. The 
IDMC will be responsible for reviewing the safety data accruing in the study at regular 
intervals prior to the primary PFS analysis database lock, to provide a recommendation to 
AstraZeneca whether the study should continue unchanged, be stopped, or be modified in any 
way. The IDMC will consist of at least 2 physicians with expertise in breast cancer and one 
biostatistician. Further information on the IDMC and schedule of meetings will be defined in 
the IDMC Charter.
Appendix C provides more details on the rationale for and the remit of the committee.  
9.6
China cohort
The global cohort will enrol approximately 930 patients to randomise approximately 
700 patients. The China cohort will consist of approximately 134 randomised patients from
National Medical Product Administration (NMPA)-certified sites. The global cohort will 
consist of patients recruited by the documented date of LPFV of the global cohort. In the 
event that recruitment of China cohort is not completed during global recruitment of 
approximately 700 patients, the recruitment of China cohort will continue until approximately 
134 Chinese patients have been randomised from NMPA-certified sites. Patients randomised 
in the China cohort prior to the LPFV of the global cohort enrolment will be included in both 
the FAS and the China FAS. A patient randomised in the China cohort after the LPFV of the 
global cohort enrolment will be included only in the China FAS. 
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Per NMPA guidance, in addition to the evaluation of the global cohort data for primary, 
secondary and safety objectives, evaluation of consistency in efficacy and safety in Chinese 
populations is required to facilitate the benefit-risk assessment for Chinese patients. Hence, 
the safety and efficacy data in the China cohort will be analysed separately where the same 
endpoint definitions (as described in Section 8.1) and the same analysis methods (as detailed 
in Section 9.4) are applied.  
The China FAS will include all patients randomised in the China cohort including those who 
were recruited prior to the closure of the global cohort and are therefore included in the 
analyses of efficacy and safety for the main study. The China altered subgroup FAS will 
include all patients in the China FAS with a PIK3CA/AKT1/PTEN-altered result from a valid 
biomarker test as determined by central testing. Both China FAS and China altered subgroup 
FAS will be used for China-only efficacy analyses.
The China safety analysis set will consist of all patients included in the China FAS who 
received at least 1 dose of study treatment.  The China altered subgroup safety analysis set 
will consist of all patients included in the China safety analysis set with a 
PIK3CA/AKT1/PTEN-altered result from a valid biomarker test as determined by central 
testing.
Efficacy analyses for the China cohort will be performed when the PFS and/or OS data from 
the patients from the China cohort ar  of similar maturity at which significant clinical efficacy 
is established in the global cohort, e g., if OS efficacy is established at the OS Interim 
Analysis, a similar maturity will be used for the consistency evaluation.
 No adjustment for multiplicity will be 
made and the procedure for hierarchical testing detailed in Section 9.4 will not be followed. 
Details of the China cohort analyses will be specified in the China SAP, which is to be 
finalised before the global cohort database lock for the PFS primary analysis.
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10
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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
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Appendix A
Guidelines for evaluation of objective tumour response using 
RECIST v1.1 Criteria (Response Evaluation Criteria in Solid 
Tumours)
Introduction
This appendix details the implementation of Response Evaluation Criteria in Solid Tumours 
version 1.1 (RECIST v1.1) guidelines (Eisenhauer et al 2009).  Investigator assessments will 
use the RECIST v1.1 guidelines described in this appendix. 
Imaging modalities and acquisition specifications for RECIST v1.1
A summary of the imaging modalities that can be used for tumour assessment of target lesions 
(TLs), non-target lesions (NTLs), and new lesions (NLs) is provided in Table 16.
Table 16
Summary of imaging modalities for tumour assessment
Target lesions 
Non-target lesions
New lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
FDG-PET/CT
CT Computed tomography; MRI Magneti  resonance imaging; FDG-PET/CT 18F-Fluoro-deoxyglucose 
positron emission tomography/CT 
CT and MRI
Computed tomography (CT) with intravenous (IV) contrast, is the preferred imaging modality,
and magnetic resonance imaging (MRI) with IV contrast being acceptable should CT be 
contraindicated, to generate reproducible anatomical images for tumour assessments, ie, for 
measurement of TLs, assessment of NTLs, and identification of NLs.  It is essential that the 
same correct imaging modality, image acquisition parameters (eg, anatomic coverage, 
imaging sequences, etc.), imaging facility, tumour assessor (eg, radiologist), and method of 
tumour assessment (eg, RECIST v1.1) are used consistently for each patient throughout the 
study.  The use of the same scanner for serial scans is recommended, if possible.  It is 
important to follow the image collection/tumour assessment schedule as closely as possible 
(refer to the clinical study protocol Schedule of Activities [Section 1.1], and this on-study
imaging schedule MUST be followed regardless of any delays in dosing or missed imaging 
visits.  If an unscheduled assessment is performed (eg, to investigate clinical signs/symptoms 
of progression), and the patient has not progressed, every attempt should be made to perform 
the subsequent scan acquisitions at the next scheduled imaging visit.
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Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice.  Body
scans should be performed with breath-hold scanning techniques if possible.  Therefore, CT of 
the chest is recommended over MRI due to significant motion artefacts (heart, major blood 
vessels, breathing) associated with MRI.  MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity and measurement.  Furthermore, the 
availability of MRI is variable globally.  The modality used at follow-up should be the same 
as was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence.  In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition.  It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. 
The most critical CT and MRI image acquisition param ters for optimal tumour evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the chest, 
abdomen and pelvis.  Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that 
may be involved based on signs and symptoms of individual patients.  Because a lesion 
later identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up timepoints.  This will enable 
better consistency not only of tumour measurements but also identification of a new 
disease.
Required anatomical regions to be imaged for assessment of tumour burden (TLs and/or 
NTLs) at baseline and foll w-up visits vary according to the study, and these are specified in 
the main clinical study protocol (eg, Schedule of Activities [Section 1.1]).  Examples include 
the following:

IV contrast enhanced CT of chest-abdomen (including the entire liver and both 
adrenal glands) and pelvis

Non-contrast CT of chest and IV contrast enhanced abdomen (including the entire 
liver and both adrenal glands) and pelvis

IV contrast enhanced CT or MRI of the head and neck

IV contrast enhanced MRI (preferred) or CT of the brain
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumours require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning.  An adequate volume of a suitable contrast agent should be given so that the tumour 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
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examinations for any given patient.  Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen and pelvis. 
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) with ≤5 mm slice thickness throughout the 
entire anatomic region of interest for optimal lesion measurements.  Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses greater than 5 mm.  If 
this occurs, the minimum size of measurable lesions at baseline should be twice the slice 
thickness of the baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered.  When measuring lesions, 
the TL should be measured on the same window setting for repeated examinations throughout 
the study.
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL.  Chest X-ray can, however, be 
used to assess NTL and to identify the presence of NLs.  However, there is preference that a 
higher resolution modality such as CT be used to confirm the presence of NLs.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence 
of new bone lesions. 
Isotopic bone scan 
A bone scan should be performed at screening; thereafter, a bone scan should only be 
performed in the event of clinical suspicion of progression of existing bone lesions that cannot 
be visualised on CT or MRI, the development of new bone lesions or in the assessment of a 
complete response (CR), if any disease was evident at screening.  
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits.  NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 
equivocal hot-spot on a bone scan which cannot be verified with correlative imaging (CT, 
MRI, X-ray) of the same anatomical region shall not be the only trigger for a progressive 
disease (PD) assessment at that timepoint. 
FDG-PET/CT
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography/CT 
(FDG-PET/CT) scans may be used as a method for identifying new extrahepatic lesions (but 
not intrahepatic lesions) for RECIST v1.1 assessments, according to the following algorithm: 
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NLs will be recorded where there is positive 18F-Fluoro-deoxyglucose uptake1 not present on 
baseline or a prior FDG-PET scan or in a location corresponding to an NL on a companion 
CT/MRI collected close in time to the FDG-PET scan.  The PET portion of the PET/CT 
introduces additional data that may bias an investigator if it is not routinely or serially 
performed.  Therefore, if there is no baseline or prior FDG-PET scan available for 
comparison, and no evidence of NLs on companion CT/MRI scans, then follow-up CT/MRI 
assessments should continue as per the regular imaging schedule in order to verify the 
unequivocal presence of NLs.
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT scan 
are of limited use in anatomically-based efficacy assessments, and it is therefore suggested 
that they should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumour 
measurements by RECIST v1.1.  In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with
intravenous contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT 
can be used for RECIST v1.1 tumour assessments.  Caution that this is not recommended 
because the PET portion of the CT introduces additional (PET) data that may bias an 
investigator if it is not routinely or serially performed.
Ultrasound 
Ultrasound examination will not be used for RECIST v1.1 assessment of tumours as it is not a 
reproducible acquisition method (operator dependent), is patientive in interpretation and may
not provide an accurate assessment of true tumour size.  Tumours identified by ultrasound will 
need to be assessed by correlative CT or MRI anatomical scan.
Other tumour assessments 
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST v1.1 assessments.  Tumours identified by clinical examination will 
need to be assessed by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour assessment.
Histology and cytology
                                               
1 A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of 
the surrounding tissue or liver is observed.
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Histology or tumour markers on tumour biopsy samples will not be used as part of the tumour 
response assessment as per RECIST v1.1. 
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, pleural effusion) that appears or worsens during the study will not be 
used as part of the tumour response assessment as per RECIST v1.1. 
Furthermore, an overall assessment of complete response (all other disease disappears/reverts 
to normal) would be changed to partial response if an effusion remains present radiologically.
Measurability of tumour lesions at baseline
RECIST v1.1 measurable lesions at baseline:
A tumour lesion that can be accurately measured at baseline as ≥10 mm in the longest 
diameter for non-nodal lesions or ≥15 mm in short axis2 diameter for lymph node lesions with 
IV contrast-enhanced CT or MRI and that is suitable f r ac urate repeated measurements.  
Please see additional RECIST v1.1 guidance below on measurability of intrahepatic 
hepatocellular carcinoma (HCC) lesions and porta hepatis lymph nodes.
Non-measurable lesions at baseline:

Truly non-measurable lesions include the following: 

Bone lesions (see exception below for soft tissue component)

Leptomeningeal disease

Ascites, pleural, or pe icardial effusion

Inflammatory b ast diseas

Lymphangitic involvement of skin or lung

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline3)

Previously irradiated lesions4

Brain metastasis
                                               
2 The short axis is defined as the longest in-plane axis perpendicular to long axis.
3 Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs.
4 Localised post-radiation changes which affect lesion sizes may occur.  Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of 
the NTL assessment.
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Special considerations regarding lesion measurability at baseline:

Bone lesions

Bone scan, PET scan or plain X-ray are not considered adequate imaging techniques 
to measure bone lesions; however, these techniques can be used to confirm the 
presence or disappearance of bone lesions

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability

Blastic bone lesions are considered non-measurable

Cystic lesions thought to represent 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, th se should be selected over cystic 
lesions as TLs
RECIST v1.1 target lesion selection at baseline:
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TLs at baseline.  TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis diameter 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 la gest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion, which can be measured 
reproducibly, should be selected
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph node locations as TLs.  A bilateral organ (eg, 
adrenal glands), a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each 
considered as a single organ.
The site and location of each TL should be documented as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes).  All measurements should be 
recorded in millimeters.  At baseline the sum of the diameters for all TL will be calculated and 
reported as the baseline sum of diameters.  At follow-up visits the sum of diameters for all TL 
will be calculated and reported as the follow-up sum of diameters.
Special cases for target lesion assessment at baseline:

For TL measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter
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
When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass.  Non-nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter

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

Tumour lesions selected for fresh screening biopsy should not be selected as TLs, unless 
imaging occurred at least ~2 weeks after biopsy, allowing time for healing
RECIST v1.1 non-target lesion selection at baseline:
All other lesions, including non-measurable lesions and surplus measurable lesions not 
recorded as TLs should be identified as NTLs at baseline.  Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up.
Evaluation of tumour response and progression 
RECIST v1.1 target lesion assessment at follow-up
This section defines the criteria used to determine objective tumour visit response for 
RECIST v1.1-defined TLs.  The imaging modality, location, and scan date of each TL 
identified previously at baseline should be documented at follow-up visits with the long axis 
diameter for non-nodal lesions or short axis diameter for lymph node lesions.  All 
measurements should be recorded in millimeters.  The sum of the diameters for all TL at each 
follow-up visit will be compared to the baseline sum of diameters (for response or stable 
disease) or to the smallest prior (nadir) sum of diameters (for progression) (Table 17). 
Special cases for target lesion assessment at follow-up:

If a lesion has completely disappeared, the diameter should be recorded as 0 mm.  If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL

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 1 of the lesions and 0 mm recorded for the other lesion(s).  If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion.  If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the vector of the longest diameter of the coalesced mass should be used to 
determine the perpendicular vector for the maximal short axis diameter

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.  The choice of ‘Too large to measure’ in the case report form will 
trigger an overall visit response of PD
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
When a TL has had any intervention eg, definitive radiotherapy, embolisation, surgery, 
transcatheter arterial chemoembolization (TACE), etc, during the study, the size of the TL 
should still be provided where possible and the intervention recorded in the RECIST v1.1 
case report form for the current imaging visit and all subsequent visits.  If a TL has been 
completely removed (surgery) or disappears, the longest diameter should be recorded as 
0 mm
Table 17
RECIST v1.1 evaluation of target lesions
Complete response (CR)
Disappearance of all TLs since baseline.  Any pathological lymph 
nodes selected as TLs must have a reduction in short axis diameter 
to <10 mm.
Partial response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters
Stable disease (SD)
Neither sufficient decrease n sum of diameters to qualify for PR nor 
sufficient increa e to qualify for PD
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir) – 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 from nadir
Not evaluable (NE)
Only relev nt if any of the TLs at follow-up were not assessed or not 
evalu ble (eg, missing anatomy) or had a lesion intervention at this 
visit   NOTE: if the sum of diameters meets the progressive disease 
iteria, progressive disease overrides not evaluable as a TL response
Not applicable (NA)
Only relevant if no TLs present at baseline
CR  complete response; PR  partial response; PD  progression of disease; NE  not evaluable; SD  stable disease; 
TL  target lesion.
RECIST v1.1 non-target lesion assessment at follow-up
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.
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 stable disease or 
partial response in TLs, the overall tumour burden has increased sufficiently to merit 
unequivocal progression by NTLs.  A modest ‘increase’ in the size of one or more NTLs is 
usually not sufficient to qualify for unequivocal progression status.  The designation of overall 
progression solely on the basis of change in non-target disease in the face of stable disease 
(SD) or progressive disease (PD) of target disease will therefore be extremely rare (Table 18).
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App
partial response; PD  p
et lesion a
A
et lesion a
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Table 18
RECIST v1.1 evaluation of non-target lesions
Complete response (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 one or more NTL
Progression (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
Not evaluable (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
Not applicable (NA)
Only relevant if no NTLs present at baseline
CR  complete response; PR  partial response; PD  progression of disease; NE  not evaluable; NTL  non-target 
lesion; TL  target lesion.
RECIST v1.1 new lesion identification at follow-up
Details including the imaging modality, the date of scan, and the location of any NLs will be 
recorded in the case report form.  The presence of 1 or more NLs is assessed as progression.  
The finding of an NL 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 an NL is equivocal, for example because of its small size, the treatment and 
tumour assessments should be continued until the previously (pre-existing) new lesion has 
been assessed as unequivocal at a follow-up visit, and then the progression date should be 
declared using the date of the initial scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression.
RECIST v1.1 evaluation of overall visit response at follow-up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs is identical between RECIST v1.1 and RECIST v1.1 using the algorithm shown in 
Table 19.
Table 19
RECIST v1.1 overall visit response
Target lesions
Non-target lesions
New lesions
Overall visit response
CR
CR
No
CR
CR
NA
No
CR
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at thi
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d
b
y relevant if no NTLs
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y relevant if no NT
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ession of disease; NE  
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Target lesions
Non-target lesions
New lesions
Overall visit response
NA
CR
No
CR
CR
Non-CR/Non-PD 
No
PR
CR
NE
No 
PR
PR
Non-PD or NE or NA
No
PR
SD 
Non-PD or NE or NA
No
SD
NA
Non-CR/Non-PD
No
SD (Non-CR/Non-PDa)
NE
Non-PD or NE or NA
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Y s
PD
b
Non-CR/Non-PD for overall response if only non-target lesions (no TLs) are present at baseline.
NOTE: An overall assessment of complete response (all other dis ase disappears/reverts to normal) would be 
changed to partial response if ascites remains present radiologically.
CR complete response; NA not applicable; NE not evaluable; PD progressive disease; PR partial response; 
(only relevant if there were no target lesions at baseline or no non-target lesions at baseline); SD stable disease; 
TL target lesion. 
The following overall visit responses are possible depending on the extent of tumour disease 
at baseline:

For patients with TLs (at baseline): CR, PR, SD, PD, or NE

For patients with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE
Central imaging
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed imaging Contract Research Organisation (iCRO) for QC, storage, and 
for Blinded Independent Central Review (BICR).  Digital copies of all original scans should 
be stored at the investigator site as Source documents.  Electronic image transfer from the 
sites to the iCRO is strongly encouraged.  A BICR of images will be performed at the 
discretion of AstraZeneca.  Results of these independent reviews will not be communicated to 
investigators, and results of investigator tumour assessments will not be shared with the 
central reviewers.  The management of patients will be based in part upon the results of the 
tumour assessments conducted by the investigator.  Further details of the BICR will be 
documented in an Independent Review Charter.
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es
d
es
Y s
d
Y s
d
roved
get lesions (no TLs) a
ed
get lesions (no TLs
other dis ase disappea
ed
other dis ase disappe
adiologically.
ved
adiologically.
evaluable; PD
ve
evaluable; PD progr
e
progr
seline or no non
ve
seline or no non-
v
-
Appr
target
ve
target
nses are possible de
pro
nses are possible de
(at baseline): CR, 
App
(at baseline): CR, 
NTLs only (at basel
App
NTLs only (at basel
uled vi
A
uled vi
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REFERENCE
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.
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Appendix B
ECOG/WHO Performance Status
The Eastern Cooperative Oncology Group (ECOG)/ World Health Organisation (WHO)
performance scale is presented in Table 20.  
Table 20
ECOG performance status scale (Oken et al 1982)
Grade
0
Fully active and able to carry on all pre-disease performance without restriction 
(Karnofsky 90-100).  
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work (Karnofsky 70-80).  
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up 
and about more than 50% of waki g hours (Karnofsky 50-60).  
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
(Karnof ky 3
40).  
4
Completely disabled. Cannot carry out any s lf-care.  Totally confined to bed or chair 
(Karnofsky 10-20).  
REFERENCE
Oken et al 1982
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.  Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol.1982;5(6):649-655.
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ed
ut una
d
ut una
f waki g ho
d
f waki g ho
fined to bed or chair 
ed
fined to bed or cha
(Karnof ky 3
ed
(Karnof ky 3
40).  
d
40).  
d
ve
carry out any s lf
ve
carry out any s lf-
e
-f-f
e
f-f care
care
(Karnofsky 10
ve
(Karnofsky 10-2
-2
e
prov
App
mey DC, Horton J, 
pp
mey DC, Horton J, 
stern Cooperative O
App
stern Cooperative O
55.
A
55.
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Appendix C
Regulatory, ethical and study oversight considerations
C 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, informed consent form (ICF), Investigator’s Brochure, 
and other relevant documents (eg, advertisements) must be submitted to an institutional 
review board (IRB)/independent ethics committee (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 he 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 (Code of Federal Regulations), ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.
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Approved
nt form (I
d
nt form (I
) must be submit
d
) must be subm
tee (IEC) by
ed
tee (IEC) by the in
d
the i
y
d
y
init
v
initiated.  
ve
iated.  
quire IRB/IEC appr
ov
quire IRB/IEC appr
cept for changes ne
ov
cept for changes ne
nsible for he fo
pr
nsible for he follo
r
llow
mmaries of the statu
App
mmaries of the statu
dance with the requ
App
dance with the requ
RB/IEC of SAEs o
A
RB/IEC of SAEs o
s
A
s
he c
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
A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study.

If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
they become aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authorities and other regulatory agencies about such breaches.

AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trial Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the EMA CTIS. It is important to note that redacted 
versions of serious breach reports will be available to the public via CTIS.

The investigator should have a process in place to ensure that:

The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach.
A (potential) serious breach is promptly reported to AstraZeneca or delegated party, through 
the contacts (e-mail address or telephone number) provided by AstraZeneca.
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S. I
d
S. I
vailable to
d
vailable to
ace to ensure that:
ed
ace to ensure th
egated by
ed
egated by the inves
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the inve
y
ed
y
tial) serious breach
ve
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y reported to AstraZ
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y reported to AstraZ
hone number) pr
rov
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C 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.  
C 3
Informed consent process
The investigator or his/her representative will explain the nature of the study to the patient or 
his/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 guid lines, 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 and time 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
 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.  
A patient who is rescreened is not required to sign another ICF if the rescreening occurs 
within 28 days from the previous ICF signature date.  
  Patients who decline to participate 
in this optional research will indicate this in the ICF.  If a patient withdraws consent to the use 
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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vo
d
volu
d
lunt
d
ntary
d
ary
a statement of in
d
a statement of 
ns, ICH guid lines,
ed
ns, ICH guid line
nts, where applicab
ve
nts, where applicab
tem
o
tement that wri
ov
ent that written
v
tten
iti
v
iti
he study
ro
he study and the da
ro
and the da
y
ro
y
App
obtaini
pr
obtaining the info
pro
ng the info
ed to the most curre
pp
ed to the most curre
A
m
A
must be provi
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ust be provi
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A
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cipate
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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.  
C 4
Data protection
Each patient will be assigned a unique identifier by the sponsor.  Any patient records or data 
sets transferred to the sponsor will contain only the identifier; patient names or any
information which would make the patient identifiable will not be transferred.  
The patient must be informed that his/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 his/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.  
The patient must be informed that data will be collected only for the business needs. We will 
only collect and use the minimum amount of personal data to support our business activities 
and will not make personal data available to anyone (including internal staff) who is not 
authorised or does not have a business ne d to know the information.
The patient must be informed that in some cases their data may be pseudonymised. The 
General data Protection Regulation (GDPR) defines pseudonymisation as the processing of 
personal data in such a way that the personal data can no longer be attributed to a specific 
individual without the use of additional information, provided that such additional information 
is kept separately and protected by technical and organisational measures to ensure that the 
personal data are not attributed to an identified or identifiable natural person.
C 5
Committees structure
A Trial Steering Committee (TSC) that includes Principal Investigators for this study and that 
may include Principal Investigators from the other pivotal studies will provide:

Advice on any aspect of the study design or conduct based on requests from the 
sponsor

Review relevant research (completed, ongoing, and pending) which may impact upon 
the study, assure consistency across the entire capivasertib pivotal programme, and to 
support the study team with interpretation of study outcomes
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Approved
records m
d
records may
d
ay b
d
b
y
d
y e
personnel appo
ed
personnel appoint
d
in e
ctors from regulato
ve
ctors from regulato
will be collected on
ov
will be collected on
ount of personal da
ov
ount of personal da
ailable to any
ro
ailable to anyone (i
o
one (i
o
o
o
iness ne d to know
pro
iness ne d to know
d that in some case
pp
d that in some case
Regulat
Ap
Regulatio
Ap
io
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n (GDPR) 
App
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way
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that the perso
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A Steering Committee Charter will define the primary responsibilities of the steering 
committee, its members, and the purpose and timing of meetings.  
An Independent Data Monitoring Committee (IDMC) will be established to assess the safety 
of capivasertib in an unblinded manner. The IDMC will be responsible for reviewing the 
safety data accruing in the study at regular intervals prior to the primary PFS analysis database 
lock, to provide a recommendation to AstraZeneca whether the study should continue 
unchanged, be stopped, or be modified in any way. The IDMC will consist of at least 2 
physicians with expertise in breast cancer and one biostatistician. Further information on the 
IDMC and schedule of meetings will be defined in the IDMC Charter.
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 clinical study protocol and 
letters to investigators.  
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d
nt Sa
ents to the c
d
ents to the c
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C 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 D3615C00001 study results when 
they are available.  The clinical trial and/or summary of D3615C00001 study results may also 
be available on other websites according to the regulations of the countries in which the 
D3615C00001 study is conducted.  
C 7
Data quality assurance
All patient data relating to the study will be recorded on an electronic case report form (eCRF) 
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 eCRF.  
The investigator must maintain accurate documentation (s
rce data) that supports the 
information entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direc  access to source data documents.  
AstraZeneca or designee is responsible for medical oversight throughout the conduct of the 
study which includes clinical reviews of study data in accordance with the currently approved 
protocol. 
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 eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for a minimum of 25 years after study archiving or as required 
by local regulations, according to the AstraZeneca GRAD Schedule. No records may be 
destroyed during the retention period without the written approval of AstraZeneca. No records 
may be transferred to another location or party without written notification to AstraZeneca.  
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
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es ar
d
es ar
mentation (s
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ed
mentation (s
rce 
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C 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 eCRF 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.  
C 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 
judgment of AstraZeneca, trial subjects 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 drug

Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject 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 subjects  int rests.
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
proved
dy
d
dy
sor. The s
d
sor. The s
d at undue risk b
d
d at undue risk 
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C 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 
coordinating 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 D
Guidance regarding potential interactions of capivasertib 
with concomitant medications
NOTE: Patients are not eligible to enter the study if they have received any of the medications 
specified in the Exclusion Criterion 22 or are unable to meet the cautions and restrictions 
described below.
D 1
Drugs that may influence capivasertib pharmacokinetics
Based on results from in vitro studies, capivasertib is a substrate of CYP3A4, although data 
suggests that glucuronidation may be the major metabolic route.  Co-administration of some 
CYP3A4 inhibitors may increase exposure to capivasertib and hence potentially affect 
toxicity, while CYP3A4 inducers may decrease the exposure to capivasertib and may
potentially affect efficacy.  
The following lists (Table 21) are not intended to be exhau tive and a similar restriction will 
apply to other agents that are known to modulate CYP3A4 activity.  Appropriate medical 
judgment is required.  Please contact AstraZeneca with any queries you have on this issue.  
Table 21
CYP3A4-interacting medica ion that must be avoided or used with 
caution
Medication
R commendation
Rationale
Clarithromycin
Cobicistat
Itraconazole
Ketoconazole
Nefazodonea
Posaconazole 
Protease inhibitors (ritonavir, 
saquinavir, indinavir, tipranavir, 
telaprevir, elvitegravir, lopinavir, 
nelfinavir, boceprevir)
Telithromycin 
Troleandomycin
Voriconazole 
Must be avoided 2 weeks prior to 
capiv sertib administration and for 
2 days following discontinuation of 
capivasertib.  
Potent CYP3A4 inhibitors, 
which may increase the 
capivasertib exposure.  
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ulate CYP3A4 activiv
aZeneca with any q
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ng medica ion tha
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pr
R commen
ro
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pr
Must be avoide
pr
be avoide
capiv sertib a
pp
capiv sertib a
2 day
App
2 days follo
pp
s follo
pr
Ap
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Medication
Recommendation
Rationale
Carbamazepinea
Enzalutamide 
Phenobarbital 
Phenytoin 
Rifabutin 
Rifampicin
Mitotane
St John’s wort
Must be avoided 2 weeks 
(3 weeks for St John’s Wort and 
4 weeks for enzalutamide) prior to 
capivasertib administration.  
Potent CYP3A4 inducers, which 
may reduce the capivasertib 
exposure.  
Aprepitant
Diltiazem
Erythromycin 
Fluconazole 
Verapamil 
May be used with cautionb.  
Moderate CYP3A4 inhibitors 
which might increase the 
capivasertib exposure.  
a
Carbamazepine and nefazodone must be avoided prior to capivasertib administration and 1 week following 
discontinuation of capivasertib. Carbamazepine is a potent CYP3A4 inducer and a CYP3A4 substrate; 
nefazodone is a potent CYP3A4 inducer.
b
Drugs are permitted but caution should be exercised and patients monitored closely for possible drug 
interactions. Please refer to full prescribing information for all drugs prior to co-administration with 
capivasertib.  
D 2
Drugs that may be influenced by capivasertib
There are currently no data confirming that there are any pharmacokinetic (PK) interactions 
between capivasertib and CYP3A4   Likewise, there are no confirmed interactions with 
MATE1 or OCT2 substrates.  The potential interactions detailed below (Table 22 and 
Table 23) are considered on the bas s of preclinical data and physiologically based 
pharmacokinetic (PBPK) modelling.  The following list is not intended to be exhaustive, and a 
similar restriction will apply to other agents that are known to be sensitive to inhibition of 
CYP3A4 metabolism and/or MATE1 or OCT2 transport and have a narrow therapeutic 
window. Appropriate medical judgment is required. Please contact AstraZeneca with any 
queries you have on this issue.  
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Table 22
CYP3A4 substrates that must be avoided or used with caution
Medication
Usage
Rationale
Alfentanil 
Atorvastatin
Carbamazepinea
Cerivastatin
Cyclosporin
Diergotamine
Ergotamine
Fentanyl
Lovastatin
Simvastatin
Sirolimus 
Tacrolimus
Must be avoided 1 week prior to 
capivasertib administration and for 
1 week following discontinuation of 
capivasertib.  
CYP3A4 substrates, whose 
exposure may be increased by 
capivasertib.  
Alprazolam 
Domperidone
Erythromycin 
Felodipine 
Haloperidol
Isradipine
Midazolam 
Methylprednisolone
Nifedipine 
Pimozide 
Quinidine
Sertraline
Tamoxifen
Trazodone 
Triazolam
May be used with c utionb   
CYP3A4 substrates, whose 
exposure may be increased by 
capivasertib.  
a
Carbamazepine must be avoided prior to capivasertib administration and 1 week following discontinuation 
of capivasertib. Carbamazepine is a potent CYP3A4 inducer and a CYP3A4 substrate.
b
Drugs are permitted but caution should be exercised and patients monitored closely for possible drug 
interactions.  Please refer to full prescribing information for all drugs prior to co-administration with 
capivasertib.
Table 23
MATE1 and/or OCT2 transporter substrates that should be used with 
caution
Medication
Recommendation
Rationale
Dofetilide
May be used with cautiona  
MATE1 and OCT2 substrate with a narrow
therapeutic window whose exposure may be
increased by capivasertib
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Medication
Recommendation
Rationale
Metformin
See Section 8.4.5.3
MATE1 and OCT2 substrate whose exposure
may be increased by capivasertib
Procainamide
May be used with cautiona  
OCT2 substrate with a narrow therapeutic
window whose exposure may be increased by
capivasertib
a
Drugs are permitted but caution should be exercised and patients monitored closely for possible drug 
interactions.  Please refer to full prescribing information for all drugs prior to co-administration with 
capivasertib.
D 3
Guidance for statins
Atorvastatin, cerivastatin, lovastatin, and simvastatin must be avoided due to the potential for 
increased exposure through inhibition of CYP3A4 by capivasertib (Table 22). 
Fluvastatin, pravastatin, and rosuvastatin are minimally influenced by CYP3A4 inhibitors, 
conveying a relatively low potential for clinically significant drug-drug interactions via this 
mechanism.  
Capivasertib also has a potential to inhibit the organic-anion-transporting polypeptide 1B1 
(OATP-1B1) transporter, which is implicated in he distribution and clearance of many of the 
statins.  The predicted increase in the area under the plasma concentration-time curve (AUC) 
is 1.3-fold for pravastatin and 1.5-fold for rosuvastatin.  It is, therefore, recommended that 
doses of pravastatin be capped to 40 mg once daily and rosuvastatin be capped to 10 mg once 
daily when combined with capivas rtib, including 1 week prior to capivasertib administration 
and for 1 week following discontinuation of capivasertib.   
In summary, rosuvastatin (up to 10 mg once daily), pravastatin (up to 40 mg once daily) and 
fluvastatin are appropriate agents to be used in patients included in capivasertib studies who 
require statin therapy.  
D 4
Additional resources
For additional inhibitors, inducers and substrates please refer to:
https://drug-interactions.medicine.iu.edu/Clinical-Table.aspx
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm093664.htm
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capiva
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pp
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statin (up to 10 mg
Ap
statin (up to 10 mg
A
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A
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Appendix E
Adverse event definitions and additional safety information
E 1
Definition of adverse events
An adverse event (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.  
AEs of special interest events will be identified and actively monitored during the study.  
E 2
Definitions of serious adverse event
A serious adverse event 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 abnormality or birth defect

Is an important medical event that may jeopardise the patient or may require medical 
treatment to prevent one of the outcomes listed above
AEs for malignant tumours reported during a study should generally be assessed as Serious 
AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a Non-
Serious AE. For example, if the tumour is included as medical history and progression occurs 
during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as Serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as Non-Serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
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and actively mo
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and actively monit
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n
verse event
ve
verse event
rring during any st
ov
rring during any st
e or more of the fo
ro
e or more of the fol
atening
pp
atening
ospi
Ap
ospitalisat
App
talisat
iti
Ap
iti
io
pp
ion or pr
pp
n or pr
nt or significant dis
Ap
nt or significant dis
abnormalit
Ap
abnormality 
Ap
y or bi
Ap
or birt
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A
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A
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ne of th
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The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 
is being treated by the investigational medicinal 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.
E 3
Life-threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).  
E 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE (SAE), although the 
reasons for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or 
surgical operations planned before or during a study are not considered AEs if the illness or 
disease existed before the patient was enrolled in the study, provided that it did not deteriorate 
in an unexpected way during the study   
E 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 e ents may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.  
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.  

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
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d without hep
m is not i
ve
m is not in
ve
n it
ve
itself a s
ve
self a s
m, laryngeal oedem
ov
m, laryngeal oedem
during a study
ov
during a study are
v
are
y
v
y
was enrolled in the 
ro
was enrolled in the 
e study
pr
e study
pr
medical event or
pp
medical event or
judgement should b
Ap
judgement should b
portant medical e e
Ap
portant medical e e
, di
A
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A
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A
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iti
A
iti
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A
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A
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as
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E 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).  The applicable 
version of CTCAE should be described clearly.  
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 E 2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix E 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 E 2.  
E 7
A guide to interpreting the causality question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.  

Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?  

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?  

De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?  

No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.  

Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped?  AstraZeneca would not normally recommend or support a 
re-challenge.  

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.  
In difficult cases, other factors could be considered such as:
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For exa
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d
t not a SAE u
roke that results in
ed
roke that results 
t would be a SAE w
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t would be a SAE w
ng the causality 
ov
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ausalit
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ausality 
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consider th
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der th
an AE m
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an AE may have b
pr
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re to suspect drug. 
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re to suspect drug. 
ccur i
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ini
Ap
ini
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h known drug pro
Ap
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suspect drug (
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
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 judgment.  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.  
E 8
Medication error, drug abuse and drug misuse
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP that either auses 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 sit ations where an error:

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors include:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, eg, wrong route, dose (error greater than ± 10%), 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 refridgerator when it should be at room
temperature 
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d
tudy
d
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d
y
lit
d
lity.
d
y.
d
se and drug mis
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se and drug mi
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o
medicat
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ion error
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n error
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hat either auses ha
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hat either auses ha
ck of efficacy o
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p
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n control of the stu
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
Wrong participant received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/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
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.  
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP for a perceived reward or desired non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded 
to the DES using the Drug Abuse Report Form.  This form should be used both if the drug 
abuse happened in a study participant or if the drug abuse regards a person not enrolled in the 
study (such as a relative of the study participant).
Examples of drug abuse include but are not limited to:

The drug is used with the intent of getting a perceived reward (by the study participant or 
a person not enrolled in the study)

The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high. 
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP for 
medicinal purposes outside of the authorised product information, or for unauthorised IMPs, 
outside the intended use as specified in the protocol, and includes deliberate administration of 
the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form.  This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant).
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ay
d
ay o
d
o
y
d
y
defined as the pers
ve
defined as the pers
r a perceived rewar
ov
r a perceived rewar
without as
ro
without associ
ro
sociated A
o
ated A
Report Form.  Thi
pro
Report Form.  Thi
cipant or if the dru
pr
cipant or if the dru
he study
pp
he study parti
pp
parti
y
pp
y
Ap
cipan
p
cipan
 include but are no
App
 include but are no
d with the intent o
Ap
d with the intent o
led in the stud
A
led in the stud
f
A
f a tab
A
a tab
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Examples of drug misuse include but are not limited to:

The drug is used with the intention to cause an effect in another person

The drug is sold to other people for recreational purposes

The drug is used to facilitate assault in another person

The drug is deliberately administered by the wrong route

The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole

Only half the dose is taken because the study participant feels that they were feeling better 
when not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug.
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Appendix F
Handling of human biological samples
F 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 AstraZeneca-assigned biobanks and will 
be registered by the AstraZeneca Biobank Team during the entire life cycle.  
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.  
F 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.  
As collection of the biological samples is an integral part of the study, then the patient is 
withdrawn from further study participation.  
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
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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.  
F 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   
The investigator ensures that samples are labelled and shipped in accordance with the 
Laboratory Manual and the Biological Substanc , Category B Regulations.
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 Substan es 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
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
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used
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Appendix G
Genetics
G 1
Use/analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity
and progression of disease.  Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease aetiology; and/or molecular subtype of the disease being treated.  Therefore, 
where local regulations and institutional review board (IRB)/independent ethics committee 
(IEC) allow, a blood sample will be collected for DNA analysis from consenting patients.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis 
of diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.  
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.  
Genetic research may consist of the analysis of the structure of the patient´s DNA (ie, the 
entire genome).  
The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary.  
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.  
The samples will be retained while research on study treatment or study treatments of this 
class or indication continues but no longer than 15 years or other period as per local 
requirements.  
G 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All patients will be asked to participate in this genetic research.  Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit.  The patient will 
not be excluded from any aspect of the main study.  
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Inclusion criteria
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol (CSP) and provide informed consent for the 
genetic sampling and analyses.  
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study.  
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 7.3 of the main 
CSP.  
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients at screening.  
Although DNA is stable, early sample collection is preferred to avoid introducing bias through 
excluding patients who may withdraw due to an adverse event (AE), such patients would be 
important to include in any genetic analysis.  If for any reason the sample is not drawn at 
screening, it may be taken at any visit until the last study visit.  Only one sample should be 
collected per patient for genetics during the study.  Samples will be collected, labelled, stored, 
and shipped as detailed in the Laboratory Manual.  
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of
15 years, from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.  
An additional second code will be assigned to the blood sample either before or at the time of 
DNA extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable only by the second, unique number.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).  
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any t
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The link between the patient enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations.  The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.  
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix G.  
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the g netic component.  To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study centre.  The 
investigator(s) is responsible for ensuring that consent is given freely and that the patient 
understands that they may freely withdrawal from the genetic aspect of the study at any time.  
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family member  general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data.  In addition, regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.  
Data management
Any genotype 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 genetic 
differences from groups of individuals with a disease) from this genetic 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 
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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 genetic data 
in a suitable secure environment separate from the clinical database.  
Statistical methods and determination of sample size
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A statistical
analysis plan may be prepared where appropriate.  
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Appendix H
Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s law
H 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.  Specific guidance 
on managing liver abnormalities can be found in Section 8.3.8.  
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 adverse event (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 investigational 
medicinal product (IMP).  
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.  
H 2
Definitions
Potential Hy’s Law
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × upper limit of 
normal (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).  
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Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
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.  
H 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 H 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laborat
y data into the laboratory eCRF
H 4
Follow-up
H 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 clinical study protocol (CSP).  
H 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
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
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; 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 IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change in the patient’s condition***
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, and complete 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 eCRF modules as information becomes available
***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 i  consultation with the study physician if there is any 
uncertainty.
H 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 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from 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.  
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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 eCRF

If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE CRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the c se 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:

Provide any further update to the previously submitted SAE of PHL (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to IMP 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 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined
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I 3
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Appendix J
Abbreviations
The following abbreviations and special terms are used in this study Clinical Study Protocol.  
Abbreviation or special 
term
Explanation
ABC
Advanced breast cancer
AE
Adverse event
AESI
Adverse Event of Special Interest
AI
Aromatase inhibitor
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time urve
AUC0-12h
Area under the plasma concentrat on-time curve from zero to 12 hours
BD
Twice-daily
BICR
Blinded Independent Cen ral Review
BRCA1/2
Breast cancer gene 1/2
CBR
Clinical benefit rate
CI
Confidence interval
Cmax
Maximum observ d plasma (peak) concentration
CMH
Cochra
Mantel Haenszel
COVID-19
Novel oronavirus disease 2019
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computer tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumour DNA
CTIS
Clinical Trials Information System
CYP
Cytochrome P450
DCO
Data cut-off
DNA
Deoxyribonucleic acid
DoR
Duration of response
ECG
Electrocardiogram
ECHO
Echocardiography
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
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oncentrat on-
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-time curv
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time cur
ed
e
ent 
ent Cen ral Review
v
Cen ral Review
ve
gene 1/2
o
gene 1/2
ov
nefit rate
ro
nefit rate
o
nce interval
pro
nce interval
ro
ximum observ d plasm
pr
ximum observ d plasm
pr
Cochra
p
Cochra
Mantel Haens
pp
Mantel Haens
pp
N
A
Novel oronavirus d
App
ovel oronavirus d
App
A
Clinical study pr
Ap
Clinical study pr
Ap
Ap
A
Clinical stud
A
Clinical stud
Ap
A
Compute
A
Compute
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Abbreviation or special 
term
Explanation
EDC
Electronic data capture
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of Cancer
EORTC QLQ-BR23
EORTC Quality of Life Questionnaire-breast cancer specific module
EORTC QLQ-C30
EORTC Quality of Life Questionnaire-Core 30 items
ePRO
Electronic patient-reported outcomes
EQ-5D-5L
European Quality of Life 5-Domain 5-Level Scale
ER
Estrogen receptor 
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
FFPE
Formalin-fixed paraffin-embedded
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
HbA1c
Glycosylated haemoglobin
HER2
Human epidermal growth factor receptor 2
HIV
Human immunod ficiency virus
HOSPAD
Hospital Admissi n
HR
Hazard ratio
HR+
Horm ne receptor positive
HRQoL
Health-relat d quality of life
IA
Interim analysis
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IMP
Investigational medicinal product
IRB
Institutional Review Board
ITT
Intent-to-treat
IV
Intravenous
IVD
In-vitro diagnostic
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KM
Kaplan-Meier
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ormone
ve
ormone
e
tice
tice
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aemoglobin
ov
aemoglobin
ov
dermal growth
ro
dermal growth factor r
o
factor r
o
immunod ficiency viru
pro
immunod ficiency viru
ro
pital Admissi n
pr
pital Admissi n
pr
azard ratio
pp
azard ratio
p
Horm ne receptor p
App
Horm ne receptor p
pp
A
Health
Ap
Health-
Ap
-relat d qu
Ap
relat d qu
Ap
Ap
Interim analy
A
Interim analy
Ap
A
Informed 
A
Informed 
A
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Abbreviation or special 
term
Explanation
LHRH
Luteinising-hormone releasing hormone
LTED
Long-term estrogen deprivation
LMWH
Low molecular weight heparin
LPFV
Last patient first visit
LVEF
Left ventricular ejection fraction
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
mTOR
Mammalian target of rapamycin
MTP
Multiple testing procedure
MUGA
Multiple-gated acquisition
NCCN
National Comprehensive Cancer Network
NCI 
National Cancer Institute
NGS
Next-Generation Sequencing
NL
New lesion
NMPA
National Medical Produ t Administration
NTL
Non-target lesion
ORR
Objective response rate
OS
Overall survival
PFS
Progression-fr e survival
PFS2
Time from randomisation to second progression or death
PGIC
Patient Global Impression–Change
PGIS
Patient Global Impression–Severity
PGI-TT
Pa ient Global Impression–Treatment Tolerability
PI3K
Phosphatidylinositol-3-kinase
PK
Pharmacokinetics
PR
Partial response
PRO
Patient-reported outcome
PRO-CTCAE
Patient-reported outcomes version of the Common Terminology Criteria for 
Adverse Events
PTEN
Phosphatase and tensin homolog
QoL
Quality of life
QT
ECG interval measured from the onset of the QRS complex to the end of the 
T wave
QTc
Corrected QT interval
QTcF
QT corrected by Fridericia’s formula
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e
ve
al Produ t Administra
ov
al Produ t Administra
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r
lesion
o
ve response rate
pro
ve response rate
ro
all survival
pr
all survival
pr
rogression
pp
rogression-
pp
-fr
pp
fr e surviv
pp
e surviv
p
Time from randomis
App
Time from randomis
pp
A
Patient Global Im
Ap
Patient Global Im
Ap
A
Patient Globa
A
Patient Globa
Ap
A
Pa ient Gl
A
Pa ient Gl
A
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Abbreviation or special 
term
Explanation
RECIST
Response Evaluation Criteria in Solid Tumours.  This study will use RECIST 
version 1.1. 
RNA
Ribonucleic acid
SAE
Serious adverse event 
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBGM
Self-blood glucose monitoring
SERD
Selective estrogen receptor degrader
SoA
Schedule of Activities
TFSC
Time to first subsequent chemotherapy
TL
Target lesion
tmax
Time to reach peak or maximum obs rved concentration following drug 
administration
TNBC
Triple-negative breast cancer
TSC
Trial Steering Committee
ULN
Upper limit of normal
VHP
Voluntary Harmonisati n Procedure
vs
Versus
WHO
World Heal h Organisation
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st cancer
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st cancer
ve
ommittee
ov
ommittee
v
f normal
o
f normal
ov
Harmonisati n Proce
ro
Harmonisati n Proce
ro
ro
orld Heal h Organisatio
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orld Heal h Organisatio
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Appendix K
Changes Related to Mitigation of Study Disruptions Due to 
COVID-19 Outbreak - Temporary Measures
Note: Changes below should be temporarily implemented only during study disruptions due to 
COVID-19 outbreak (eg, during quarantines and resulting site closures, regional travel
restrictions and considerations if site personnel or study patients become infected with 
COVID-19) during which patients may not wish to or may be unable to visit the study site for 
study visits.  These changes should only be implemented if allowable by local/regional
guidelines and following agreement from the Sponsor.
Study sites may continue to recruit new patients into ongoing studies provided the following 
activities to preserve study integrity can be met: 

Upon discussion with the site monitor, the study site has confirmed the ability to enrol
and manage new subjects effectively and in compliance with the protocol

Data will continue to be entered into the eCRF and qu ries resolved in a timely manner. 
K 1
Reconsent of Study Patients During Study Interruptions
During study interruptions, it may not be possible for the patients to complete study visits and 
assessments on site and alternative means for carrying out the visits and assessments may be 
necessary, eg, remote visits.  Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Section 1.1.  Local and regional regulations and/or guidelines regarding reconsent 
of study patients should be checked and followed.  Reconsent may be verbal if allowed by
local and regional guidelines (note, in the case of verbal reconsent the ICF should be signed at 
the patient’s next contact with the study site).  Visiting the study sites for the sole purpose of 
obtaining reconsent should be avoided.
K 2
Rescreening of Study Patients to Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened patients.  The investigator should confirm this with the designated 
AstraZeneca study physician.  In addition, during study disruption there may be a delay 
between confirming eligibility of a patient and either enrolment into the study or commencing 
of dosing with study treatment.  If this delay is outside the screening window specified in 
Section 1.1, the patient will need to be rescreened to reconfirm eligibility before commencing 
study procedures.  This will provide another opportunity to re-screen a patient in addition to 
that detailed in Section 5.4.  The procedures detailed in Section 1.1 must be undertaken to 
confirm eligibility.
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pro
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K 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified health care professional from the study site or third party vendor service may visit 
the patient’s home/or other remote location as per local standard operating procedures, as 
applicable.  Supplies will be provided for a safe and efficient visit.  The qualified health care 
professional will be expected to collect information per the CSP.
K 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During the COVID-19 outbreak, visits may be replaced by a telemedicine visit if allowed by
local/regional guidelines.  Having a telemedicine contact with the patients will allow adverse 
events, concomitant medication and other relevant data to be collected according to study
requirements to be reported and documented.
K 5
At-home or Remote Location Study Treatment Administration 
Instructions
If a site visit is not possible, at-home or rem te location administration of study treatment may 
be performed, where available on a case by case basis by a qualified health care professional, 
provided this is acceptable within local regulation/guidance.  Please contact your monitor.  
The option of at-home or remote location study treatment administration ensures patients 
safety in cases of a pandemic where patients may be at increased risk by traveling to the 
site/clinic.  This will also minimise interruption of study treatment administration during other 
study disruptions, eg, site closures due to COVID-19.
K 5.1
At-home or Remote Location Study Treatment Administration by a 
Qualified Health Care Professional or Third Party Vendor Service
A qualified health care professional from the study site or third party vendor service may 
administer the study treatment at the patient's home or a remote location according to the CSP.  
All necessary supplies and instructions for administration and documentation of study
treatment administration will be provided.  Additional information related to the visit can be 
obtained via a telemedicine or home visit.
K 6
At-home or Remote Delivery of Capivasertib/Placebo
Alternative secure delivery methods for oral drug supply (capivasertib/placebo) may be 
permitted if the patient is unable to attend the site, but only provided the critical safety 
assessments have been performed and the delivery methods are in line with local regulatory
requirements.
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mote location stud
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App
emic where patient
lso minimise interr
Ap
lso minimise interr
g, site closures due
Ap
g, site closures due
Remote
A
Remote
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K 7
Data Capture During Telemedicine or Remote Visits
Data collected during telemedicine or remote visits will be captured in the source documents 
by the qualified health care professional from the study site or third party vendor service, or 
from the patient themselves.
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Appendix L
Guidance during the COVID-19 Outbreak
L 1
COVID-19 Risk Assessment 
The safety of participants is of primary importance.  Any potential risks of participating in the 
study, particularly with the added challenges due to COVID-19 outbreak, should be weighed 
against the anticipated benefit (see also principle 2.2 of ICH GCP).  Investigators are advised 
to use clinical judgment in determining infection prevention precautions for study participants.
The emergence of SARS-CoV-2 presents a potential safety risk for cancer patients.  
Participants enrolling in this study may require more frequent visits to the site for study
treatment administration and for study assessments compared to participants receiving 
standard of care.  Therefore, several risk mitigation factors have been implemented related to 
study conduct during the COVID-19 outbreak, for patient management in an event of 
COVID-19, and actions to be taken on study treatment (see Appendix L 4).  With these 
measures in place, it is considered that the anticipated potential benefits for the participants 
enrolled in this study outweigh the potential risks.  All implemented measures prioritise trial 
participant safety and data validity; in case these two conflict with each other, trial participant 
safety should always prevail (see also EMA 2020). 
Notably, participants with active COVID-19 infection confirmed by local laboratory testing 
will not be eligible for study enrolment (see Section 5.2, Exclusion Criterion 12). 
L 2
Potential Risks during COVID-19
Every effort should be made to follow the CSP.  This appendix provides a dose modification 
and management plan for participants with confirmed or suspected COVID-19 who are being 
treated with study intervention capivasertib/placebo.   
The risk-benefit assessment should be carefully considered for each participant enrolling in 
the study based on the known safety risks related to COVID-19, individual needs, and local 
guidelines and restrictions.  Investigators must continue to use their best clinical judgment in 
determining the most optimal care for participants and utmost diligence in determining their 
eligibility for study participation, continued study treatment, and overall assessment of 
benefit/risk of study treatment or participation.
The sponsor must be promptly notified of a site’s inability to perform study activities due to 
COVID-19 outbreak in order to minimise any potential risks.
L 3
New Participant Enrolment
Study sites may continue to recruit new participants into the study provided the following 
activities to preserve study integrity can be met:
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ov
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OVID
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OVID-
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lment (see Section
pro
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ks during COVI
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ks during COVI
ade to follow the C
App
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for participants wit
Ap
for participants wit
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A
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
Upon discussion with the site monitor, the study site has confirmed the ability to enrol
and manage new participants effectively and in compliance with the protocol.

Data will continue to be entered into the eCRF and queries resolved in a timely manner. 
Per CSP Exclusion Criterion 12 (see Section 5.2), participants with evidence of severe or 
uncontrolled systemic diseases, including but not limited to, ongoing or active infection are 
not eligible for the study participation and hence such participants (including those who have 
confirmed COVID-19) should not be included for study participation. 
Per Exclusion Criterion 26 (see Section 5.2), patients who have circumstances that could limit 
compliance with study requirements should also be excluded.  Please consider this criterion 
carefully considering evolving circumstances, travel restrictions and health care delivery in 
your local area that may impact the continued treatment in the study. 
The Study Physician should be contacted if any additional guidance or clarification is needed 
via the local monitor or directly.
L 4
Study Treatment Administration
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
participants’ treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the CSP
Adverse events, SAEs, cycle delays and/or treatment suspensions associated with COVID-19 
along with logistical issues should be reported according to the eCRF Completion Guidelines. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should 
be followed, and the End of Treatment Form(s) completed.
L 5
Vaccination against COVID-19
Protocol restrictions applying to live attenuated vaccines are relevant for live attenuated 
COVID-19 vaccines as well.  Investigators should apply their discretion assessing the risk 
benefit of other types of COVID-19 vaccines for participants in clinical trials.  Ideally, 
administration of the vaccine should be done on a different day other than the day of study
drug administration to differentiate any potential AEs seen from the vaccine and study drug.  
The administration of the vaccine and any potential AEs associated with the vaccine are to be 
documented on the concomitant medication and AE eCRFs, respectively.
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L 6
Capivasertib/Placebo: Product Specific Guidance In Relation To 
The Ongoing And Emerging Novel Coronavirus (COVID-19) 
Pandemic
For Ongoing Patients: 

Patients must continue to have safety blood tests as per protocol schedule.  Alternative 
methods for safety assessments include using local laboratories and follow up by phone 
contact, virtual visits can be used (see Appendix K for mitigation procedures)

If it becomes unfeasible to perform the required safety blood tests for a patient, then study
treatment should be interrupted until this can resumed and the reason clearly documented, 
with reference to COVID-19. 

If a patient tests positive for the COVID-19 virus, interrupting capivasertib/placebo 
treatment for 14 days or until symptoms resolve should be considered.  Factors that 
should be taken into consideration might include: 
o
Severity of COVID-19 symptoms 
o
Status of safety blood results, particularly haemoglobin, neutrophils, and 
lymphocytes 
o
Benefit risk for the individual patients including curative vs. palliative intent of 
treatment and response to capivasertib/placebo 

If patients present with new or worsening respiratory symptoms such as dyspnoea, cough 
and fever, or an abnormal chest radiologic finding is observed, capivasertib/placebo 
treatment should be interrupted and prompt investigation initiated to determine whether 
symptoms are due to COVID 19 or potentially drug-induced pneumonitis. 

The use of capivasertib/placebo with the concomitant use of some antibiotics and 
antivirals (eg, telithr mycin, clarithromycin, protease inhibitors boosted with ritonavir or 
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir and telaprevir) is not 
recommended.  Please review Appendix D for details.
REFERENCES
Curigliano et al 2020 
Curigliano G, Banerjee S, Cervantes A, Garassino M, Garrido P, Girard N. Managing cancer 
patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus. Ann 
Oncol 2020;31(10):1320-35.
EMA 2020
EMA, Clinical Trials Facilitation and Coordination Group, European Commission. Guidance 
on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, Version 
2, 27 March 2020. Available from: URL: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. Accessed: 17 December 2020.
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d
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articularly haemog
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articularly haemog
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dual patie
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ov
nts includ
ov
s includ
to capivasertib/pla
rov
to capivasertib/pla
or worsening respir
pro
or worsening respir
chest radio
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chest radiolo
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rrupted and prompt
pp
rrupted and prompt
COVID
p
COVID
Ap
19 or poten
pp
19 or poten
rtib/placebo with th
App
rtib/placebo with th
t
A
thr
A
hr mycin, clarithr
Ap
mycin, clarithr
avir, saquinavir, n
Ap
avir, saquinavir, n
ease review
A
ease review A
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SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d3615c00001-csp-v5-china
Document Title:
D3615C00001 Clinical Study Protocol China local version 5
Document ID:
Doc ID-004612302
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
12-Dec-2023 10:17 UTC
Content Approval
04-Dec-2023 15:49 UTC
Content Approval
08-Dec-2023 13:33 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
D3615C00001 - CN  Protocol | VV-TMF-006461786 | 5.0
oved
ST APPR
d
ST APPR
ved
ved
M
ve
prov
ov
ov
o
pr
pr
App
d in ANGEL, an Ast
pr
d in ANGEL, an Ast
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