Clinical trial NCT05008055
Conditions: Relapsed or Refractory B-cell Non-Hodgkin Lymphoma
Keywords: Follicular Lymphoma Marginal Zone Lymphoma Mantle Cell Lymphoma Capivasertib monotherapy
Sponsor: AstraZeneca
Start date: 2021-11-03; Completion date: 2024-10-25
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is an open-label, multicenter Phase II study of capivasertib administered orally in participants with Relapsed or Refractory (R/R) B-cell Non-Hodgkin's Lymphoma (NHL).

Detailed description:
The study protocol follows a modular design. The study will investigate the safety and efficacy of capivasertib monotherapy in participants with R/R Follicular Lymphoma (FL), Marginal Zone Lymphoma (MZL), and Mantle Cell Lymphoma (MCL).

Arms: arm 1: Participants with R/R FL, R/R MZL, and R/R MCL will receive capivasertib orally until progression of disease (PD) or unacceptable toxicity.
Interventions: intervention 1: Capivasertib
Intervention descriptions: intervention 1: Capivasertib will be taken orally twice a day (BD) 4 days on/ 3 days off.

Protocol documents:
Prot_002.pdf: 
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Clinical Study Protocol 
Study Intervention
Capivasertib
Study Code
D361FC00001
Version
6.0
Date
24 Feb 2022
A Modular Phase II, Open-Label, Multicentre Study to Assess the 
Efficacy and Safety of Capivasertib in Patients with Relapsed or 
Refractory B-cell Non-Hodgkin Lymphoma (CAPITAL)
Sponsor Name: 
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s)
IND 154612
EudraCT: 2021-000870-27
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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Protocol Number: 
Amendment Number: 03
Study Intervention:
Capivasertib (AZD5363)
Study Phase: II
Short Title:
A Phase II trial of capivasertib in R/R B-cell NHL.
Acronym:
CAPITAL
Study Physician Name and Contact Information will be provided separately
International co-ordinating investigators
PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 03 (v6.0)
24 February 2022
Amendment 02 (v3.0)
28 July 2021
Amendment 01 (v2.0)
28 April 2021
Original Protocol (v1.0)
18 February 2021
The summary of changes for Amendment 03 is provided below. Refer to Appendix M for a 
summary of the previous amendments.
Previous numbering inadvertently did not follow global/local versioning guidance, hence
global amendment 03 is named v6.0 (v4.0 was used for local Korea amendment and v5.0 was 
used for local UK amendment).
Amendment 03, v6.0 [24 February 2022]
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
This protocol amendment incorporates changes made for local protocol amendments
applicable in the United Kingdom and South Korea that were prepared in response to queries
from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the South 
Korean Ministry of Food and Drug Safety (MFDS), respectively. In addition, to implement 
updates based on updated capivasertib safety requirements (non-substantial, based on routine 
AZ safety data review), modification of Module 1-specific eligibility criteria in agreement 
with the Study Steering Committee (SSC) to allow a greater number of patients to potentially 
benefit from capivasertib monotherapy, revision of time windows for some study procedures 
and for template and other updates to aid sense and flow of the document.
Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
CORE
Section 2.3.1 (Risk 
Assessment, Table 1)
Addition of erythema 
multiforme to 
identified risks for 
capivasertib.
As part of AstraZeneca’s 
routine safety surveillance 
process and ongoing review of 
the clinical trial safety data, 
erythema multiforme has been 
identified as an identified risk 
for capivasertib.
Non-substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Section 5.1 (Core 
Inclusion Criteria 5 and 
7) & Section 5.3.4 
(Pregnancy and 
Contraception)
Clarification on 
contraception methods 
considered as highly 
effective for both 
male and female 
patients.
Amended in line with MHRA 
request.
Substantial
Section 5.1 (Core 
Inclusion Criteria 6)
Addition of serum for 
pregnancy test.
Clarification that pregnancy 
test should be on serum.
Substantial
Section 5.2 (Core 
Exclusion Criteria)
Exclusion criteria 6d: 
Current criterion 
states that ALT and 
AST must be > 2.5 × 
ULN; Amended to 
clarify that ALT or
AST can fulfil the 
criterion.
Amended to ‘or’ for 
consistency within the 
document.
Substantial
Exclusion criteria 6e: 
Amended to clarify 
the bilirubin criteria 
for patients (ie, > 3 × 
ULN) with 
documented Gilbert’s 
syndrome.
Amended in line with MHRA 
request.
Substantial
Exclusion criteria 12 
c): Criteria has been 
updated to exclude 
“Strong 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 
inhibition of CYP3A4 
within 1 week prior to 
the first dose of study 
treatment.”
Updated for clarity; removed 
restrictions for CYP2D6 and 
CYP2C9 substrates based on 
physiologically-based PK 
modelling; added MATE1 and 
OCT2 transporter substrates 
under the appendix of drugs 
that may be influenced by 
capivasertib.
Substantial
Section 6.5.1 (Drugs 
that Prolong QT 
Interval)
Text has been added 
describing 
management of 
concomitant 
In order to keep the most up-
to-dated list of drugs known to 
or potentially prolonging the 
QT intervals, reference to 
https://www.crediblemeds.org/ 
Non-substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
medications that 
prolong QT interval.
is made rather than referring 
to the list detailed in the study 
protocol. Therefore, this 
section has been added while 
the respective reference in 
Appendix F1 has been 
removed.
Section 7.3 (Lost to 
Follow-up)
Deletion of text 
regarding independent 
third party. 
Third party vendors for the 
collection of vital status are 
not used in this study.
Non-substantial
Section 8 (Study
Assessments and 
Procedures - CORE)
Addition of text 
regarding bone 
marrow 
aspirates/biopsy 
performed as part of 
standard of care and 
up to 12 weeks prior 
to ICF signature.
To avoid unnecessary 
repetition of invasive 
procedures (ie, BM biopsy) 
unless clinically indicated by 
the investigator.
Substantial
Addition of text 
regarding imaging 
assessments 
performed as part of 
standard of care and 
up to 5 weeks prior to 
ICF signature.
To avoid patients to be 
exposed to unnecessary 
radiation by repeating PET/CT
assessment unless clinically 
indicated.
Substantial
Section 8.1.1 (Bone 
Marrow Assessments)
Deletion of text 
describing uses of 
baseline bone marrow 
aspirate/biopsy for 
confirmation of 
disease 
status/profiling.
Updated for clarity as central 
histological disease 
confirmation is not required in 
this study.
Non-substantial
Increase from 14 days 
to 28 days for bone 
marrow 
biopsy/aspirate 
assessment after 
respective radiological 
assessment.
Window for bone 
marrow/biopsy assessments 
increased to 28 days in 
alignment with routine clinical 
practice and to allow more 
time for the site to plan the 
assessments after the 
radiological evaluation.
Substantial
Section 8.1.2 (Imaging 
Assessments)
Amended to allow 
contrast enhanced CT 
to be performed 
before PET if the time 
Clarification to allow contrast 
enhanced CT to be performed 
before PET with sufficient 
Non-substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
between them is more 
than 6 hours.
time between to prevent 
interference in the PET scan.
Section 8.1.4.1 
(Endoscopy)
Addition of 28-day 
period for assessment 
after respective 
radiological 
assessment.
Window for endoscopy 
increased to 28 days in 
alignment with routine clinical 
practice and to allow more 
time for the site to plan the 
assessments after the 
radiological evaluation.
Substantial
Section 8.2.4 (Clinical 
Safety Laboratory 
Assessments) & 
Section 10.1.1 
(Schedule of Activities 
– Capivasertib 
Monotherapy)
 
 
 
 
 
 
Non-substantial
Text ..patients with 
positive serology for 
HBV or HCV..’ has 
been amended to 
‘…patients with 
positive anti HBcAb 
or anti-hepatitis C Ab 
at screening…’
Updated for clarity and 
consistency with eligibility 
criteria.
Non-substantial
Section 8.2.4 (Clinical 
Safety Laboratory 
Assessments, Table 4)
Table 4 footnote 
added for urine 
microscopy “Denmark 
only: U-Microscopy is 
not required”.
Clarification added since it is 
no longer a national standard.
Substantial
Addition of gamma-
glutamyl transferase 
to the laboratory 
safety variables
Amended in line with updated 
safety requirements and to 
ensure comprehensive 
assessment on liver function.
Substantial
Section 8.3.11.1 
(Maternal Exposure) 
and Section 8.3.12.1 
(Paternal Exposure)
Congenital 
abnormality(/ies) 
changed to congenital 
anomaly(/ies)/birth 
defect(s).
Updated in line with current 
template text.
Non-substantial
Section 8.3.13 
(Adverse Events of 
Special Interest)
Removal of urinary 
tract infection, 
pneumonia, and 
Torsades de pointes 
from the AESI list.
Addition of infective 
pneumonia.
Updated in line with current 
list of AESIs for capivasertib. 
Following routine safety data 
review at the program level, 
these terms were found to no 
longer meet AESI criteria as 
defined by internal processes 
Substantial
CCI
CCI


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
including, but not limited to, 
risks for which some sort of 
action is required (eg, 
additional data collection or 
risk mitigation strategy).
Section 8.6.1 
 
 
 
 
 
 
 
 
Substantial
Section 9.4.2.2 
(Secondary Endpoints)
Addition of text for 
DoR confirming the 
use of the same 
censoring rules as 
applied for PFS.
Clarification of censoring 
process. 
Non-substantial
Throughout
Minor administrative 
changes.
Revisions made to correct 
errors in format, typography, 
or language.
Non-substantial
MODULE 1 (Section 10):
Capivasertib Monotherapy in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
Section 10.1.1 
(Schedule of Activities 
– Capivasertib 
Monotherapy, Table 6
and Table 7)
Clarified that HbA1C 
and lipids should be 
monitored starting 
from C1D1.
Updated for clarity.
Non-substantial
Addition of vital signs 
assessment at 30 days 
after last dose follow-
up.
Amended in line with safety 
requirements.
Substantial
ECHO/MUGA 
changed from as 
clinically indicated to 
at end of therapy and 
as clinically indicated 
Amended in line with safety 
requirements and to ensure 
cardiac function is evaluated 
also at the end of treatment.
Substantial 
Addition of new 
footnote k (Table 6) to 
clarify that the post-
dose glucose sample 
can be collected under 
As no significant differences 
in plasma glucose profiles 
were observed following 
capivasertib tablet dosing in 
the fed, partially fasted and 
Non-substantial
CCI
CCI
CCI


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
fasting or non-fasting 
conditions.
fasted status, this clarification 
avoid unnecessary fasting for 
patients.
Deletion of Lugano 
response assessment 
at screening.
Evaluation of disease response 
is only required during study 
drug treatment and therefore is 
not applicable at screening.
Non-substantial
Addition of new 
footnotes to delineate 
central laboratory 
from local laboratory.
Updated for clarity.
Non-substantial
Addition of time 
windows for PK 
sampling.
Updated for clarity to ensure 
standardization in timing of 
PK sampling.
Non-substantial
Serum glucose 
sampling after C2D1 
is pre-dose only.
Updated for clarity.
Non-substantial
Section 13.1.1 
(Additional Inclusion 
Criteria for Cohort 1A 
[R/R FL])
Deletion of text for 
inclusion criteria 4 
stating the maximum 
number of prior lines 
of therapy.
To allow a greater proportion 
of patients to be enrolled as 
endorsed by the Study 
Steering Committee (SSC).
Substantial
Section 13.1.2 
(Additional Inclusion 
Criteria for Cohort 1B 
[R/R MZL])
Deletion of text for 
inclusion criteria 4 
stating the maximum 
number of prior lines 
of therapy.
To allow a greater proportion 
of patients to be enrolled as 
endorsed by the SSC.
Substantial
Section 13.1.3 
(Additional Inclusion 
Criteria for Cohort 1C 
[R/R MCL])
Deletion of text for 
inclusion criteria 3 
stating the maximum 
number of prior lines 
of therapy.
To allow a greater proportion 
of patients to be enrolled as 
endorsed by the SSC.
Substantial
South Korea Only: 
MCL patients must 
not have another 
available beneficial 
treatment option.
Updated in line with MFDS 
request.
Non-substantial
Section 13.2 (Exclusion 
Criteria)
Deletion of text for 
exclusion criteria 3 for 
blastoid or 
pleiomorphic variant 
To allow a greater proportion 
of patients to be enrolled as 
endorsed by the SSC.
Substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
or documented TP53 
mutation.
Section 15.1 
(Discontinuation of 
Study Intervention)
In the event a criterion 
is met to stop or pause 
the study recruitment 
in Module 1, the study 
will only restart after 
submission and 
approval of a 
substantial 
amendment by the 
regulatory authority 
and IRB/IEC.
Amended in line with MHRA 
request.
Substantial
Appendix B2 
(Definition of Serious 
Adverse Events)
Congenital 
abnormality changed 
to congenital 
anomaly.
Updated in line with current 
template text.
Non-substantial
Appendix F (Guidance 
Regarding Potential 
Interactions of 
Capivasertib with 
Concomitant 
Medications)
Appendix has been 
updated with current 
text from updated 
safety requirements.
Updated for clarity; removed 
restrictions for CYP2D6 and 
CYP2C9 substrates based on 
physiologically-based PK 
modelling; added MATE1 and 
OCT2 transporter substrates 
under the appendix of drugs 
that may be influenced by 
capivasertib.
Substantial
Appendix M (Protocol 
Amendment History)
Addition of this 
appendix.
Included as per template 
guidance.
Non-substantial
Throughout
Minor administrative 
changes.
Revisions made to correct 
errors in format, typography, 
or language.
Non-substantial


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS .................................................................................................... 10
1
PROTOCOL SUMMARY ................................................................................ 17
1.1
Synopsis ........................................................................................................... 17
1.2
Schema............................................................................................................. 22
1.3
Schedule of Activities ....................................................................................... 23
2
INTRODUCTION - CORE............................................................................... 24
2.1
Study Rationale ................................................................................................ 24
2.2
Background ...................................................................................................... 24
2.2.1
Role of AKT Inhibition in B-cell Lymphoid Malignancies ................................ 24
2.3
Benefit/Risk Assessment................................................................................... 26
2.3.1
Risk Assessment ............................................................................................... 26
2.3.2
Benefit Assessment........................................................................................... 27
2.3.3
Overall Benefit/Risk Conclusion....................................................................... 28
2.3.4
Benefit/Risk Pertaining to CAPITAL Study Conduct During the COVID-19 
Pandemic.......................................................................................................... 28
3
OBJECTIVES AND ENDPOINTS - CORE...................................................... 30
4
STUDY DESIGN - CORE................................................................................ 35
4.1
Overall Design.................................................................................................. 35
4.1.1
Master Protocol Structure ................................................................................. 35
4.1.2
Master Protocol Study Design........................................................................... 35
4.1.3
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 36
4.2
Scientific Rationale for Study Design ............................................................... 37
4.2.1
Regulatory Amendments for Additional Modules.............................................. 37
4.2.2
Europe and rest of the World............................................................................. 38
4.2.3
United States of America .................................................................................. 38
4.3
Justification for Dose........................................................................................ 38
4.4
End of Study Definition.................................................................................... 38
5
STUDY POPULATION - CORE ...................................................................... 38
5.1
Core Inclusion Criteria...................................................................................... 39
5.2
Core Exclusion Criteria..................................................................................... 40
5.3
Lifestyle Considerations ................................................................................... 44
5.3.1
Meals and Dietary Restrictions ......................................................................... 44
5.3.2
Caffeine, Alcohol, and Tobacco......................................................................... 44
5.3.3
Activity............................................................................................................. 44
5.3.4
Pregnancy and Contraception............................................................................ 44
5.3.4.1
Females ............................................................................................................ 44






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9.4.3.1
Adverse Events................................................................................................. 79
9.4.3.2
Other Safety Endpoint(s) .................................................................................. 80
9.4.4
Other Analyses.................................................................................................. 82
9.4.4.1
Pharmacokinetics.............................................................................................. 82
9.4.4.2
Patient-reported Outcomes (PROs) ................................................................... 82
9.4.5
Exploratory Analyses........................................................................................ 83
9.5
Interim Analyses............................................................................................... 83
9.6
Data Monitoring Committee ............................................................................. 83
MODULE 1 – CAPIVASERTIB MONOTHERAPY IN PATIENTS WITH RELAPSED OR 
REFRACTORY B-CELL NON-HODGKIN LYMPHOMA ................................................ 85
10
INTRODUCTION - MODULE 1...................................................................... 85
10.1
Module Summary – Module 1........................................................................... 85
10.1.1
Schedule of Activities – Capivasertib Monotherapy .......................................... 85
10.2
Rationale for Module 1 ..................................................................................... 95
10.3
Background – Module 1.................................................................................... 95
10.3.1
Cohort 1A – Therapeutic Options for R/R Follicular Lymphoma....................... 95
10.3.2
Cohort 1B – Therapeutic Options for R/R Marginal Zone Lymphoma............... 95
10.3.3
Cohort 1C – Therapeutic Options for R/R Mantle Cell Lymphoma ................... 96
10.4
Benefit/Risk Assessment................................................................................... 96
11
OBJECTIVES AND ENDPOINTS – MODULE 1............................................ 97
12
STUDY DESIGN – MODULE 1 ...................................................................... 97
12.1
Justification for Dose........................................................................................ 98
12.2
End of Study Definition.................................................................................... 99
13
STUDY POPULATION – MODULE 1............................................................. 99
13.1
Inclusion Criteria .............................................................................................. 99
13.1.1
Additional Inclusion Criteria for Cohort 1A (R/R FL)....................................... 99
13.1.2
Additional Inclusion Criteria for Cohort 1B (R/R MZL) ................................. 100
13.1.3
Additional Inclusion Criteria for Cohort 1C (R/R MCL) ................................. 100
13.2
Exclusion Criteria ........................................................................................... 100
13.3
Lifestyle Considerations ................................................................................. 101
14
STUDY INTERVENTION – MODULE 1 ...................................................... 101
14.1
Study Intervention(s) Administered................................................................. 101
14.2
Dose Modification .......................................................................................... 101
14.2.1
Capivasertib Dose Modification and Guidance................................................ 101
15
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL – MODULE 1.................................. 102
15.1
Discontinuation of Study Intervention............................................................. 102
15.2
Temporary Discontinuation............................................................................. 104
16
STUDY ASSESSMENTS AND PROCEDURES – MODULE 1..................... 104
16.1
Overdose ........................................................................................................ 104


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17
STATISTICAL CONSIDERATIONS – MODULE 1....................................... 104
17.1
Statistical Hypotheses..................................................................................... 104
17.2
Sample Size Determination............................................................................. 104
17.3
Statistical Analyses ......................................................................................... 105
17.3.1
General Considerations................................................................................... 105
17.4
Interim Analyses............................................................................................. 106
18
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 108
19
REFERENCES............................................................................................... 179
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 22
Figure 2
Protocol Modular Structure...................................................................... 36
LIST OF TABLES
Table 1
Risk Assessment...................................................................................... 26
Table 2
Objectives and Endpoints......................................................................... 30
Table 3
Acceptable Highly Effective Contraception Options ................................ 45
Table 4
Laboratory Safety Variables..................................................................... 63
Table 5
Populations for Analysis .......................................................................... 75
Table 6
Schedule of Activities (Screening and Treatment Period) – Module 1: 
Capivasertib Monotherapy....................................................................... 86
Table 7
Schedule of Activities (Follow-up Period) – Module 1: Capivasertib 
Monotherapy ........................................................................................... 92
Table 8
Investigational Product .......................................................................... 101
Table 9
Capivasertib Dose Level Modifications.................................................. 102
Table 10
Summary of analyses and data cut-off triggers....................................... 105
Table F11
Drugs Known to be Inhibitors of CYP3A4 or UGT2B7 ......................... 133
Table F12
Drugs Known to be Strong or Moderate Inducers of CYP3A ................. 134
Table F13
Drugs Known to be Sensitive or Moderate Sensitive CYP3A Substrates 
Whose Exposure, Pharmacological Action, and Toxicity May be 
Increased by Capivasertib ...................................................................... 135


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Table F14
Drugs Known to be Substrates for Renal or Hepatic Transporters Whose 
Exposure, Pharmacological Action, and Toxicity May be Increased by 
Capivasertib........................................................................................... 136
Table F15
Restricted Medications/Therapies .......................................................... 137
Table F16
Prohibited Medications/Therapies.......................................................... 137
Table F17
Supportive Medications/Therapies......................................................... 137
Table G15
Dose Modification for General Capivasertib-related Toxicities .............. 139
Table G16
Dose Modifications for Capivasertib-related Hyperglycaemia a.............. 140
Table G17
Dose Modifications for Capivasertib-related Maculo-papular Rash........ 142
Table G18
Dose Modifications for Capivasertib-related Diarrhoea.......................... 143
Table G19
Dose Modifications and Management of Potential Haematological 
Toxicities During Treatment With Capivasertib..................................... 144
Table I20
Response Assessment Criteria for Non-Hodgkin Lymphoma ................. 151
Table J21
FLIPI-1 Criteria..................................................................................... 155
Table J22
FLIPI-2 Criteria..................................................................................... 155
Table J23
GELF Criteria........................................................................................ 156
Table J24
Simplified MIPI..................................................................................... 156
Table J25
Risk Category According to the MIPI.................................................... 156
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 108
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 115
Appendix C
Handling of Human Biological Samples ................................................ 120
Appendix D
Optional Genomics Initiative Sample..................................................... 122
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 125
Appendix F
Concomitant Medications ...................................................................... 131
Appendix G
Management of Capivasertib-related Toxicity........................................ 138
Appendix H
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 146
Appendix I
Lugano 2014 Classification for Non-Hodgkin Lymphoma ..................... 149
Appendix J
Disease Prognostic Scores ..................................................................... 154
Appendix K
Patient-reported Outcomes..................................................................... 157


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Appendix L
Abbreviations ........................................................................................ 169
Appendix M
Protocol Amendment History................................................................. 174






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Objectives
Estimand description
•
To assess patient-reported disease-related 
symptoms, functioning and health-related 
quality of life of the module-defined study 
treatment in each cohort
Patient-reported disease-related symptoms, 
functioning and health-related quality of life as 
measured by EORTC QLQ-C30.
The analysis will include all dosed patients and will 
be summarised descriptively.
The measures of interest are mean and mean change 
from baseline in each of the functional scales, 
symptom scales, and global health status/quality of 
life scores at each time point.
•
To assess patient-reported symptomatic 
AEs/tolerability of module-defined study 
treatment in each cohort
Patient-reported symptomatic AEs and overall side 
effect burden as measured by PGI-TT and selected 
items from PRO-CTCAE.
The analysis will include all dosed patients and will 
be summarised descriptively.
The measures of interest will proportion of patients 
reporting different levels of each symptomatic AEs 
and proportion of patients reporting different levels of 
overall side effect burden at each time point.
•
To estimate the effectiveness of module-defined 
study treatment by assessment of TFST in each 
cohort
Time to first subsequent therapy or death is defined as 
time from date of first dose until the start date of first 
subsequent anti-lymphoma therapy after 
discontinuation of study treatment or death due to any 
cause.
The analysis will include all dosed patients, 
regardless of whether the patient withdraws from 
therapy, receives another anti-lymphoma therapy or 
clinically progresses prior to progression according to 
the Lugano 2014 Classification for NHL.
The measure of interest is the median TFST.
•
To estimate the effectiveness of module-defined 
study treatment by assessment of TTR in each 
cohort
Time to objective response is defined as time from 
date of first dose until the date of first documented 
objective response per the Lugano 2014 Classification 
for NHL as assessed by BICR.
The analysis will include all patients included in the 
response evaluable analysis set who had a response 
regardless of whether the patient withdraws from 
therapy.
The measure of interest is the median of TTR.




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number cannot be reused. Study treatment will be dispensed or administered, as applicable, at 
the study visits summarised in the SoA in the relevant Module.
The study may include module-specific interim analyses. These interim analyses will be 
assessed against a decision framework (Frewer et al 2016). Based on the interim results, study 
enrolment could pause and the sponsor may opt to amend the protocol to adjust the dosing 
schedule based on emerging data, permanently close the specific cohort, or add in a new 
cohort for testing capivasertib in combination with other agents in that population which 
would be detailed in an amendment.
Disclosure Statement:
This is a non-randomised, open-label, modular study with no masking.
Number of Participants:
Refer to the relevant Module for details.
Intervention Groups and Duration:
Refer to the relevant Module for details.
Data Monitoring Committee:
This study will have a Study Steering Committee (SSC). The details of the roles and 
responsibilities of the SSC are provided in a charter separate from the Core Protocol. A Safety 
Review Committee may be established in case a module evaluating capivasertib in 
combination with other agents is added in the future.
Statistical Methods
Analyses will be performed by AstraZeneca or its representatives, including contract research 
organisations (CROs). A comprehensive statistical analysis plan (SAP) will be developed and 
will describe the patient populations to be included in the analyses, the analyses including any 
subgroup analyses or sensitivity analyses, and the procedures to account for missing, unused, 
and spurious data.
Each Cohort will be analysed separately.
The analysis of objective response rate (ORR) will be performed according to the 
Lugano 2014 Classification for NHL (Cheson et al 2014) as assessed by blinded independent 
central review (BICR). Objective response rate will be defined as response of CR or PR.
The efficacy endpoints for tumour response (ORR, duration of response [DoR] and time to 
objective response [TTR]) will be summarised and analysed based on the response evaluable 
analysis set. The efficacy endpoints for overall survival (OS), progression-free survival (PFS), 


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time to first subsequent therapy or death (TFST), and quality of life (QoL) will be summarised 
based on the safety analysis set. Safety and treatment exposure data will be summarised based 
on the safety analysis set.
Continuous data will be summarised by the number of observations, mean, standard deviation, 
median, minimum, and maximum. Geometric mean and coefficient of variation may be 
presented as applicable. Categorical variables will be summarised by frequency counts and 
percentages for each category. Unless otherwise stated, percentages will be calculated from 
the population total. Time to event variables will be presented using the Kaplan-Meier 
methodology, including median time calculated from the Kaplan-Meier curves.
Interim analyses will be further detailed in the relevant Module.
The primary analysis for each cohort will be conducted after all patients treated with 
capivasertib have had the opportunity to be treated for 6 months.
The data cut-off for the final analysis for each cohort will occur approximately 18 months 
after the last patient treated with capivasertib has been enrolled in the cohort or when 70% of 
patients have progressed or died (due to any reason) in the cohort, whichever occurs first.
Additional OS follow-up analyses for each cohort may be performed after the final analysis, 
until 70% of the patients treated with capivasertib have died due to any cause.
Additional data cuts may also be performed, if required.
1.2
Schema
This study will be conducted in independent Modules. Study design is presented in Figure 1.
Figure 1
Study Design
BD: twice a day; FL: follicular lymphoma; MCL: mantle cell lymphoma; MZL: marginal zone lymphoma; 
NHL: non-Hodgkin lymphoma; ORR: objective response rate; R/R: relapsed or refractory.


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Subsequent Modules may be further added via formal protocol amendments based on 
emerging supportive preclinical and clinical data and study rationale.
1.3
Schedule of Activities
Refer to individual schedule of assessments (SoA) for the relevant Module.


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2
INTRODUCTION - CORE
This is a modular, Phase II study of capivasertib in patients with R/R B-cell NHL. The 
structure of the CSP also follows a modular design with the protocol, hereafter referred to as 
the ‘Core Protocol’, presenting study information applicable to all patients in this study, and 
‘Modules’ presenting only module-specific information.
2.1
Study Rationale
Non-Hodgkin lymphoma is the 7th most common cancer in the US and represents 4.3% of all 
new cancer cases in the US. In 2020, it is estimated that there will be 77,420 new cases of 
NHL, with a median age at diagnosis of 67 years, and an estimated 19,940 deaths related to 
this disease (Howlader et al 2020).
AKT is a node of multiple signalling pathways promoting tumorigenesis, inhibiting apoptosis, 
impacting the cell cycle, and promoting invasion and migration. Capivasertib (AZD5363) is a 
potent, selective inhibitor of the kinase activity of all 3 isoforms of AKT (AKT1, AKT2, and 
AKT3) that is administered orally on an intermittent schedule of administration. An estimated 
900 patients with solid tumours have received capivasertib in AstraZeneca sponsored studies, 
as monotherapy or in combination with other anti-cancer agents (refer to the current 
capivasertib IB) showing a manageable safety profile and promising efficacy data. 
Capivasertib is targeting a different node on the PI3K-AKT-TOR signalling pathway to the 
established PI3K inhibitors that have proven efficacy in lymphoma (and currently approved 
for R/R FL) and has shown already promising efficacy data in solid tumours.
Limited preclinical models are available for studying the effect of capivasertib in indolent 
lymphoma either in vitro or in vivo. In an extended cell panel, capivasertib monotherapy 
demonstrated in vitro activity in lymphoma lines representative of MCL and DLBCL at a 
concentration less than 1 µM (Lynch et al 2016). In vitro, capivasertib monotherapy shows 
variable inhibition of MCL cell line growth. It shows 100% tumour growth inhibition in 2 out 
of 7 MCL cell lines (Granta-519, JVM-2) at 3 µM and 50% inhibition in a further 3 cell lines 
at 3 µM (Mino, Jeko, Z-138). In addition, capivasertib shows greater than 30% tumour growth 
inhibition in 2 MCL line models in vivo (data on file).
For these reasons, capivasertib may represent a novel attractive therapeutic option for the 
treatment of patients with haematological malignancies.
2.2
Background
2.2.1
Role of AKT Inhibition in B-cell Lymphoid Malignancies
The PI3K/AKT/PTEN pathway is frequently deregulated in cancers and drives tumour growth 
and cell survival. All 3 AKT isoforms are activated in types of solid tumours (breast, prostate, 


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ovarian, pancreatic, gastric cancers) and in haematological malignancies. This activation is 
often associated with resistance to established cancer therapies as well as advanced disease 
and/or poor prognosis. AKT activation in tumours is largely due to input from other signalling 
pathways upstream of AKT (eg, mutation of oncogenes such as Ras, Bcr-abl, mutation of 
receptor tyrosine kinases such as epithelial growth factor receptor, amplification of HER2, 
loss of PTEN function, and mutations of PI3K).
Inhibition of PI3K, AKT or mTOR kinases have been shown to confer anti-proliferative effect 
and apoptosis in a variety of lymphoma types in vitro (Georgakis and Younes 2006; Jia et al 
2008; Yuan and Cantley 2008; Engelman 2009). Several PI3K inhibitors (ie, idelalisib, 
duvelisib, copanlisib) have been already approved for the treatment of R/R FL (ZYDELIG 
USPI; COPIKTRA USPI; ALIQOPA USPI).
Phosphorylation of AKT represents PI3K pathway activation, and is common in lymphomas. 
Hodgkin lymphoma commonly demonstrates AKT phosphorylation in cell lines and in 63% of 
tumour biopsies (Georgakis et al 2006). In DLBCL, phosphorylation of AKT is common (52% 
to 72% of patient samples) and might be associated with inferior survival (Uddin et al 2006). 
Mantle cell lymphoma demonstrates variable levels of AKT phosphorylation, although the 
aggressive blastoid subtype appears to require constitutive AKT activation for survival 
(Rudelius et al 2006). Follicular lymphoma shows AKT signalling pathway activation, due to 
either AKT phosphorylation or PTEN downregulation, in the absence of PIK3CA mutations 
(Yahiaoui et al 2014).
Several studies have demonstrated that a decrease in AKT activity by AKT inhibitors is 
associated with a reduction in tumour cell proliferation. AKT inhibitors entering clinical 
development include ipatasertib (RG7440), afuresertib (GSK2110183), uprosertib 
(GSK2141795), which, like capivasertib, bind to the adenosine triphosphate active site and 
inhibit AKT activity, thus exerting cytotoxic and antiproliferative activities against human 
cancer cells. Allosteric inhibitors of AKT have also been studied. Perifosine, MK-2206 and 
others alter AKT activity through the suppression of cell growth mediated by the inhibition of 
AKT membrane localisation and subsequent activation (Brown and Banerji 2017). However, 
limited clinical data are available with AKT inhibitors in lymphoma.
Perifosine is a first-generation AKT inhibitor that functions via inhibition of AKT 
translocation to the cell membrane (Kondapaka et al 2003). Combined in a phase II trial with 
the multikinase inhibitor sorafenib, perifosine had an ORR of 28% in relapsed Hodgkin 
lymphoma (Guidetti et al 2014).
A second-generation AKT inhibitor, MK-2206 functions via allosteric AKT inhibition against 
AKT1 and AKT2 and has shown strong preclinical activity in a variety of lymphoma cell lines 
as single agent and in combinations with other agents (Hirai et al 2010; Li et al 2012). 
MK-2206 monotherapy was tested in a Phase II trial in relapsed or refractory lymphoma 


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patients (including cHL, MCL, FL and MZL). The study showed that MK-2206 can induce 
responses in cHL and indolent lymphoma showing a signal of activity with an ORR of 20% in 
cHL, 22% in indolent lymphoma (one CR in small lymphocytic lymphoma lasting for 
3.5 months, and one PR in FL lasting for 5.8 months) and of 9% in MCL. Treatment was 
overall tolerated; dose-dependent rash, hyperglycaemia and haematological toxicities were 
most commonly observed (Oki et al 2015).
2.3
Benefit/Risk Assessment
More detailed information about the expected benefits and potential risks of capivasertib may 
be found in the current capivasertib IB.
2.3.1
Risk Assessment
The risks associated with capivasertib are summarised in Table 1.
Table 1
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study treatment(s) [Capivasertib]
Risks identified for capivasertib:
Important Identified Risks:
diarrhoea, rash, hyperglycaemia, 
hypersensitivity.
Identified Risks: nausea and 
vomiting, stomatitis, dry skin, 
pruritus, decreased appetite, 
erythema multiforme.
Important Potential Risk: QT 
prolongation, reproductive organs 
safety, reproductive and 
developmental toxicity, genotoxic 
effects, drug-drug interaction, 
haematological effects, renal 
effects or renal failure.
Risks identified based on 
non-clinical and clinical data 
available to date and evaluated by 
AstraZeneca.
These risks are monitored via 
routine pharmacovigilance and 
managed via routine risk 
minimisation activities and 
standard treatment practices. 
Further details of these risks can 
be found in the capivasertib 
Investigator’s Brochure.
Risk minimisation activities are 
reflected in the study protocol 
specific inclusion and exclusion 
criteria, alongside the safety 
monitoring strategy (Section 8), 
dose modification guidance 
(Section 6.6), toxicity management 
guidelines (Appendix G) and 
concomitant medication guidance 
(Appendix F).


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study treatment(s) [Capivasertib]
Based on non-clinical data, 
haematological effects are an 
important potential risk of 
capivasertib monotherapy. 
No association between 
capivasertib dose and 
haematological effects have been 
observed in the ongoing clinical 
studies to date, involving 
887 patients in advanced solid 
tumour indications (as of 
04 Oct 2020).
Within the capivasertib non-
clinical programme, effects on the 
haematopoietic system were noted 
in rats, with a related decrease in 
white cells in males. The changes 
were primarily noted at 
100 mg/kg/day dose in males. In 
the 6 month study decreased 
cellularity was noted in the thymus 
and bone marrow of males at 
100 mg/kg/day and females 
150 mg/kg/day. Changes were 
reversible with the exception of 
bone marrow effects. In the dog 
only the thymus was affected and 
was fully reversible.
Due to the target population of 
CAPITAL, and their potential 
predisposition to cytopenia, either 
through disease manifestation, or 
prior anti-cancer treatments, 
haematological parameters will be 
closely monitored at regular 
intervals as specified in the 
schedule of assessments in the 
protocol.
Haematological toxicity-specific 
toxicity management guidelines 
will be included in the protocol to 
support the Investigator in the 
clinical management of any such 
adverse drug reactions secondary 
to capivasertib. 
Additionally, enrolled patients will 
have been screened for adequate 
bone marrow function prior to 
commencing capivasertib as per 
the exclusion criteria in the 
protocol.
The emerging clinical safety profile from the early clinical studies have not identified risks 
that would preclude investigation in this setting. Second, the protocol includes ongoing safety 
monitoring in excess of standard of care monitoring, with the intent of protecting patients 
involved in the study. Furthermore, dose modification strategy for management of 
capivasertib-related 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, and the strength 
of the scientific hypothesis under evaluation, the benefit/risk assessment for this study 
supports the administration of capivasertib in patients with R/R B-cell NHL.
2.3.2 Benefit Assessment
Data from approved PI3K inhibitors support the hypothesis that inhibiting the PI3K-AKT 
pathway may be a valid target for the treatment of B-cell NHL lymphomas. All 3 PI3K 
inhibitors approved for R/R FL so far, and the others in development for indolent lymphoma 
have demonstrated manageable safety and favourable efficacy profiles. Capivasertib targets 
the same pathway with a potent and over-arching mechanism (all 3 AKT forms). It has 


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demonstrated a manageable toxicity profile in solid tumours (refer to the current capivasertib 
IB for details). Also, capivasertib is administered through oral route with an intermittent 
schedule which may lead to improved patient compliance and ease of patient management in 
the post-COVID-19 healthcare setting. 
Capivasertib has demonstrated clinical activity in several settings, particularly those with 
tumours harbouring either an AKT1 mutation or PIK3CA mutation (Banerji et al 2018; 
Hyman et al 2017). In combination, proof of concept was established with first-line paclitaxel 
in patients with metastatic triple negative breast cancer (Schmid et al 2020) and patients with 
advanced AKT1 mutant solid tumours in monotherapy or combination with fulvestrant (ER+ 
breast cancer) (Hyman et al 2017; Smyth et al 2017).
These potential benefits warrant investigation with capivasertib as current data suggests 
capivasertib is an attractive investigational drug in R/R NHL settings and there is a clear 
unmet clinical need in this population failing or not being eligible or not having available 
approved treatment options.
2.3.3 Overall Benefit/Risk Conclusion
While several treatments have been approved for patients with R/R B-cell NHL, none of them 
currently offer a cure to these patients. Therefore, although monotherapy capivasertib has not 
been tested so far in lymphoma patients, based on the pre-clinical data available, capivasertib 
in the R/R B-cell NHL setting does allow the opportunity to assess its activity as monotherapy 
while offering the patient a reasonable chance of achieving an objective response to the 
treatment.
Taking into account the measures taken to minimise risk to patients participating in this study, 
the potential risks identified in association with capivasertib are justified by the anticipated 
benefits that may be afforded to patients with R/R B-cell NHL. Capivasertib has not been 
studied yet in the setting of NHL; therefore, this clinical trial will provide the first clinical 
safety and efficacy data for capivasertib in haematological malignancies.
2.3.4
Benefit/Risk Pertaining to CAPITAL Study Conduct During the 
COVID-19 Pandemic
Cancer patients have an increased risk of exposure to SARS-CoV-2 due to frequent hospital or 
clinic visits for treatment and monitoring. A retrospective cohort study of 28 COVID-19-
infected cancer patients from 3 hospitals in Wuhan, China, reported that a third of patients 
(28.6%; N = 8) were suspected to have acquired the infection by hospital-associated 
transmission (Yu et al 2020, Zhang et al 2020). Patients with cancer may have a higher risk 
from COVID-19 than individuals without cancer but current evidence appears insufficient to 
support a conclusive association between cancer in general and COVID-19 (Kumar et al 2019, 
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CAPITAL will enrol patients with R/R B-cell NHL. Patients in this study will receive 
interventions that lead to inhibition of AKT (capivasertib). They will not be receiving 
chemotherapy, radical radiotherapy, immunotherapy or other continuing antibody treatments 
for cancer as part of the treatment strategy. Overall, the interventions received and procedures 
during the course of this study are considered to have low risk for increasing susceptibility to 
COVID-19 infection.
Furthermore, at this stage of disease, patients would typically have frequent healthcare-related 
visits, irrespective of the participation in a clinical study. Therefore, we anticipate that overall 
their participation in this clinical study should not significantly increase their risk of exposure 
to COVID-19 infection. In addition, the dosing regimen for capivasertib involves oral dosing 
at home (4 days on/3 days off).
Novel treatment options are needed to improve the long-term prognosis for patients with R/R 
B-cell NHL as this disease stage is associated with high risk of developing debilitating 
symptoms and cancer-related death. Capivasertib could be a potentially curative treatment 
option in a R/R patient population with high unmet medical need. The scheduled safety 
monitoring visits that are considered in excess of standard of care monitoring are intended to 
protect patients involved in the study. Thus, although there may be increased risk to patients 
by exposure to SARS-CoV-2 during study visits, this is offset by the benefit that patients may 
receive in the form of an extended period of PFS.
In accordance with EMA and FDA guidelines (EMA-CTFG-EC 2020, FDA 2020), a risk 
assessment will be conducted in collaboration with investigators for each site and patient prior 
to site initiation/patient enrolment and on an ongoing basis throughout the study to assess 
whether additional measures may be necessary to ensure patient safety and data validity. 
Measures may include postponement of study start on a global, country, or site level or 
suspension of recruitment of patients in locations with an increased risk of COVID-19-related 
disruption.
If there is a need to reconsent study patients for the implementation of new urgent changes in 
study conduct, additional guidance on alternative means of obtaining reconsent to avoid 
unnecessary study visits is provided as Appendix A (as a supplement to the standard consent 
procedures in Appendix A 3 of the protocol). Any deviations to the protocol necessary to 
safeguard patient safety or data validity as a result of COVID-19-related disruption will be 
recorded and any permanent changes requiring an amendment to the protocol will be 
communicated to Regulatory Authorities and IRBs/ECs in line with relevant local guidance 
and procedures.




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Objectives
Estimand description
In addition, for sensitivity analysis purposes, DoR 
will be defined as the time from the date of first 
documented response until date of documented 
progression according to the Lugano 2014 
Classification for NHL as assessed by the 
Investigator.
•
To estimate the effectiveness of the 
module-defined study treatment by assessment 
of PFS based on Lugano 2014 Classification 
response criteria in each cohort as determined 
by BICR 
Progression-free survival is defined as the time from 
the date of first dose until documented disease 
progression according to the Lugano 2014 
Classification for NHL as assessed by BICR, or 
death due to any cause.
The analysis will include all dosed patients, 
regardless of whether the patient withdraws from 
therapy, receives another anti-lymphoma therapy or 
clinically progresses prior to progression according to 
the Lugano 2014 Classification for NHL.
The measure of interest is the median PFS.
In addition, for sensitivity analysis purposes, PFS will 
be defined as the time from the date of first dose until 
progression according to the Lugano 2014 
Classification for NHL as assessed by the 
Investigator.
•
To estimate the effectiveness of the 
module-defined study treatment by assessment 
of OS in each cohort
Overall survival is defined as time from the date of 
first dose until the date of death due to any cause.
The analysis will include all dosed patients, 
regardless of whether the patient withdraws from 
therapy or receives another anti-lymphoma therapy.
The measure of interest is the median OS.
•
To assess patient-reported disease-related 
symptoms, functioning and health-related 
quality of life of the module-defined study 
treatment in each cohort
Patient-reported disease-related symptoms, 
functioning and health-related quality of life as 
measured by EORTC QLQ-C30.
The analysis will include all dosed patients and will 
be summarised descriptively.
The measures of interest are mean and mean change 
from baseline in each of the functional scales, 
symptom scales, and global health status/quality of 
life scores at each time point.
•
To assess patient-reported symptomatic 
AEs/tolerability of module-defined study 
treatment in each cohort
Patient-reported symptomatic AEs and overall side 
effect burden as measured by PGI-TT and selected 
items from PRO-CTCAE.
The analysis will include all dosed patients and will 
be summarised descriptively.








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4
STUDY DESIGN - CORE
4.1
Overall Design
4.1.1
Master Protocol Structure
This study is an open-label, multicentre Phase II study of capivasertib administered orally in 
patients with R/R B-cell NHL. The structure of the protocol follows a modular design. 
Patients will be enrolled concurrently in the individual cohorts according to the type of NHL. 
For an overview of the study design, see Figure 1, Section 1.2.
4.1.2
Master Protocol Study Design
This protocol, hereafter referred to as the “Core Protocol” describes core study elements that 
are applicable to all study treatments that will be provided under the study. In addition to the 
Core Protocol, individual complementary “Modules” contain elements specific to each 
individual cohort (Figure 2).
The information in this Core Protocol cannot be superseded by information in the Modules. 
Any change to the study core elements (ie, this Core Protocol) or Modules will be submitted 
to regulatory authorities and ethics committees according to the local legislation/requirements.
Other Modules assessing capivasertib in combination with other agents in patients with R/R 
B-cell NHL may be further added via formal protocol amendments based on emerging 
supportive preclinical and clinical data and study rationale.


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Figure 2
Protocol Modular Structure
AE: adverse event; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; MUGA: 
multiple-gated acquisition; PK: pharmacokinetic(s); SAE: serious adverse event.
4.1.3
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study patients become infected with SARS-CoV-2 or similar pandemic 
infection) which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the patient’s ability to conduct the study. The investigator 
or designee should contact the study sponsor to discuss whether the mitigation plans below 
should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain 
compliance with GCP, and minimise risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options:


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
Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/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 patients. The 
investigator should confirm this with the designated Study Physician.

Home or Remote visit: Performed by a site qualified HCP or HCP provided by a TPV.

Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 

At-home study treatment administration: Performed by a site qualified HCP, HCP 
provided by a TPV, or by the patients or the patient’s caregiver, if possible. Additional 
information related to the visit can be obtained via telemedicine.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix H.
4.2
Scientific Rationale for Study Design
The study will consist of modules, each evaluating the efficacy, safety and tolerability of study 
treatment given to patients with different types of lymphoma.
The study will include module-specific interim analyses. These interim analyses will be 
assessed against a decision framework (Frewer et al 2016). Based on the interim results, study 
enrolment could pause and the sponsor may opt to amend the protocol to adjust dosing 
schedule based on emerging data, permanently close one or more cohorts or add in a new 
cohort evaluating capivasertib in another type of lymphoma or a new module evaluating 
capivasertib in combination with other agents in that population. These new cohorts and/or 
modules may be further added via formal protocol amendments based on emerging supportive 
preclinical and clinical data and study rationale.
4.2.1
Regulatory Amendments for Additional Modules
To support amendments of the protocol for additional Modules, AstraZeneca will provide a 
summary of non-clinical and clinical data to support the proposed new combination and 
dosing schedule; this will include updating the following:

Study objectives

Background information providing rationale for the proposed patient population(s) and 
the proposed treatment plan(s)

Specific study eligibility criteria

A detailed description of the proposed study treatment plans


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
A revised schedule of patient assessments

A summary of safety data from the completed or ongoing cohort(s)/Modules(s) and the 
proposed toxicity management plans for the proposed new combination

A description of any dose modifications and the data (clinical safety information, clinical 
PK data, and non-clinical data) that support the safety of the proposed dose modifications 
for the combination/monotherapy regimen in question

A clearly stated justification for the proposed sample size based on the objectives for that 
specific cohort/module; and

A detailed description of the method and performance characteristics of any test that will 
be used to identify the patient population to be enrolled in the cohort/Module, if the 
population will be selected based on a diagnostic assay.
4.2.2
Europe and rest of the World
AstraZeneca will provide a substantial amendment for review and approval.
4.2.3
United States of America
AstraZeneca will provide an amendment to the FDA 30 days in advance of planned enrolment 
in the cohort for any future combination. AstraZeneca will begin enrolment of patients into 
that cohort in the US no sooner than 30 days from the date of submission and IRB approval.
4.3
Justification for Dose
Refer to the relevant Module in the protocol for information.
4.4
End of Study Definition
The end of study is defined as the last visit of the last patient in the study or last scheduled 
procedure shown in the SoA in the relevant Module for the last patient in the study globally.
A patient is considered to have completed the study when the patient has completed his/her 
last scheduled procedure shown in the SoA in the relevant Module, including follow-up for 
OS.
The study may be stopped if, in the judgement of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings.
Refer to the relevant Module for further information.
5
STUDY POPULATION - CORE
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.


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The inclusion and exclusion criteria specific to each cohort are provided in the relevant 
Module.
Each patient must meet all of the inclusion criteria and none of the exclusion criteria for both 
the Core Protocol and relevant Module. 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.
5.1
Core Inclusion Criteria
Patients are eligible to be included in the study only if all of the following criteria apply:
Age
1
Patient must be ≥18 years of age, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2
ECOG performance status ≤2.
3
Life expectancy > 6 months.
Sex
4
Male and female.
Reproduction
5
Female patients of childbearing potential who are not totally sexually abstinent (ie, 
refraining from heterosexual intercourse during the entire period of risk associated with 
study interventions) and intend to be sexually active with a non-sterilised male partner are 
required to use 1 form of highly effective method of contraception combined with a 
barrier method (male condom, female condom, cervical cap, diaphragm with spermicide, 
or contraceptive sponge with spermicide) of contraception from the time of screening 
until 4 weeks after the last dose of study treatment (see Section 5.3.4).
OR
Female patient must be classified as non-childbearing potential by fulfilling 1 of the 
following criteria at screening:

Post-menopausal – defined as aged > 50 years and amenorrhoeic for at least 
12 months following cessation of all exogenous hormonal treatments.

Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy, but not tubal ligation.


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6
Female patients must not be breast-feeding and must have a negative pregnancy test 
(serum) prior to start of dosing.
7
Non-sterile male patients should use barrier contraception (ie, condoms) from the time of 
screening until 16 weeks after last dose of study treatment. Male patients must not donate 
or bank sperm during this same time period. It is not known whether the preclinical 
changes seen in the male animal reproductive organs, after treatment with capivasertib, 
will be fully reversible or will permanently affect the ability to produce healthy sperm 
following treatment. Therefore, if male patients may wish to father children in the future, 
they should be advised to arrange for freezing of sperm samples prior to the start of study 
treatment.
Informed Consent
8
Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
9
Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of samples for optional genetic research.

If a patient declines to participate in this optional exploratory research and genetic 
component of the study, there will be no penalty or loss of benefit to the patient and 
he/she will not be excluded from other aspects of the study.
Optional Genetic Research
10 Whole blood transfusion given within 120 days of genetic sample collection should be 
leukocyte depleted.
5.2
Core Exclusion Criteria
Patients are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Prior malignancy (other than the disease under study), except for adequately treated basal 
cell or squamous cell skin cancer, in situ cancer, or other cancer from which the patient 
has been disease free for ≥2 years.
2
Major surgical procedure or significant traumatic injury (as judged by the investigator) 
within 28 days before start of treatment, or have not recovered from major side effects, 
open biopsy within 7 days before start of treatment.
3
With the exception of alopecia, any unresolved non-haematological toxicities from prior 
therapy ≥CTCAE Grade 2 at the time of starting study treatment.
4
Known medically apparent CNS lymphoma or leptomeningeal disease.


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5
Any of the following cardiac criteria at screening:
a) Mean resting QTc > 470 ms obtained from 3 consecutive ECGs.
b) Any clinically important abnormalities in rhythm, conduction or morphology of resting 
ECG (eg, complete left bundle branch block, third degree heart block).
c) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia of Grade ≥1, potential for Torsades de Pointes, 
congenital long QT syndrome, family history of long QT syndrome or unexplained 
sudden death under 40 years of age, history of QT prolongation associated with other 
medications thar required discontinuation of that medication, or any concomitant 
medication known to prolong the QT interval.
d) 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 NYHA grade ≥2.
e) Uncontrolled hypotension – SBP < 90 mmHg and/or DBP < 50 mmHg.
f)
Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is 
higher) as measured by ECHO (or MUGA scan if an ECHO cannot be performed or is 
inconclusive).
g) History of arrhythmia (multifocal premature ventricular contractions, bigeminy, 
trigeminy, ventricular tachycardia), which is symptomatic or requires treatment 
(CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or 
asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation 
controlled by medication or arrhythmias controlled by pacemakers may be permitted 
upon discussion with the study physician.
6
Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following laboratory values at screening:
a) ANC < 1.0 × 109/L; < 0.75 × 109/L in patients with known bone marrow involvement 
of malignant disease.
Note: The use of growth factors is permitted at the Investigator’s discretion.
b) Platelets < 75 × 109/L; < 50 × 109/L in patients with known bone marrow involvement 
of malignant disease
c) Anaemia that cannot be managed by standard supportive care.
d) ALT or AST > 2.5 × ULN; > 5 × ULN for patients with liver involvement of 
metastatic disease.
e) Total bilirubin > 1.5 × ULN or > 3 × ULN for patients with liver involvement of 
metastatic disease or in the presence of documented Gilbert’s syndrome (unconjugated 
hyperbilirubinemia).
f)
Creatinine clearance < 50 mL/min per the Cockcroft and Gault formula.


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7
Clinically significant abnormalities of glucose metabolism as defined by any of the 
following at screening:
a) Patients with diabetes mellitus type I or diabetes mellitus type II requiring insulin 
treatment
b) HbA1c ≥8.0% (63.9 mmol/mol)
8
As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, 
including uncontrolled hypertension, active bleeding diatheses, or active infection 
including SARS-CoV-2, CMV, hepatitis B, hepatitis C. Patients with HIV infections are 
excluded.
Note:
o
Patients who are anti-HBc antibody positive and who are surface antigen 
negative will need to have a negative PCR result before enrolment. 
o
Those who are hepatitis B surface antigen positive or hepatitis B PCR positive 
will be excluded.
o
Patients who are hepatitis C antibody positive will need to have a negative PCR 
result before enrolment. Those who are hepatitis C PCR positive will be 
excluded.
9
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.
10 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.
11 Evidence of dementia, altered mental status or any psychiatric condition that would 
prohibit understanding or rendering of informed consent.
Prior/Concomitant Therapy
12 Prior treatment with any of the following:
a) Any investigational agents or study drugs from a previous clinical study within 
5 half-lives or 2 weeks from the first dose of capivasertib in this study.
b) Any other chemotherapy, immunotherapy, immunosuppressant medication (other than 
corticosteroids) or anti-cancer agents within 2 weeks of the first dose of study 
treatment. A longer washout may be required for drugs with a long half-life (eg, 
biologics) as agreed by the sponsor. Any treatment-related toxicity from a prior 
therapy with PI3K inhibitor should be resolved at the time of study entry. Patients 
previously treated with BTK inhibitors can start the study treatment immediately. 


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Earlier initiation of study treatment will be discussed case by case with the Study 
Physician.
c) Strong 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 inhibition of 
CYP3A4 within 1 week prior to the first dose of study treatment. For details, see 
Appendix F.
d) Prior allogenic HSCT within 6 months from the first dose of capivasertib (patients 
> 6 months after allogenic HSCT are eligible in the absence of active graft-versus-host 
disease and concomitant immune-suppressive therapy). Prior cellular therapies (eg, 
CAR-T therapy) and/or autologous HSCT within 3 months from the first dose of 
capivasertib.
e) Receipt of live, attenuated vaccine within 28 days before the first dose of study 
treatment(s).
f)
Patients who, due to other medical conditions /prior history /concomitant medications 
are, in the investigator's opinion, at a risk of a VTE and are not willing to accept the 
VTE prophylaxis, will be excluded.
Note: The initiation of an adequate VTE prophylaxis will be based on treating 
physician risk/benefit assessment and in agreement with the local management 
guidelines.
Prior/Concurrent Clinical Study Experience 
13 Participation in another clinical study with an IMP administered in the last 2 weeks or 
5 half-lives, whichever is longer.
14 History of hypersensitivity to active or inactive excipients of capivasertib or drugs with a 
similar chemical structure or class to module-defined study treatment(s).
Diagnostic Assessments
Not applicable.
Other Exclusions
15 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
16 Judgement by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions, and requirements.
17 Previous enrolment in the present study.
18 For women only - currently pregnant (confirmed with positive pregnancy test) or breast-
feeding.


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5.3
Lifestyle Considerations
The following restrictions apply while the patient is receiving capivasertib and for the 
specified times before and after:
5.3.1
Meals and Dietary Restrictions
There is a potential for delayed and reduced absorption and/or amplified effects on the glucose 
homeostasis if capivasertib is administered with food, in particular together with heavy meals. 
The clinical relevance of this is unknown, but until further information is available a 
conservative approach has been taken to recommend that patients fast from 2 hours before 
dosing to 1 hour after dosing, where possible. 
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 and/or UGT2B7
enzyme activity during study treatment. For example, no more than half a grapefruit, a small 
glass of grapefruit juice, 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
Activity
Not applicable.
5.3.4
Pregnancy and Contraception
5.3.4.1
Females
Women of childbearing potential who are not totally sexually abstinent (ie, refraining from 
heterosexual intercourse during the entire period of risk associated with study interventions) 
and intend to be sexually active with a non-sterilised male partner are required to use one form 
of highly effective contraception combined with a barrier method (male condom, female 
condom, cervical cap, diaphragm with spermicide, or contraceptive sponge with spermicide) 
of contraception starting before entering the study and until 4 weeks after the last dose of 
capivasertib. Table 3 contains appropriate contraception options when participating in this 
study.
It is not known whether capivasertib has the capacity to affect the metabolism of hormonal 
contraceptives, so the highly effective contraception method selected from Table 3 must also 
be combined with a barrier method of contraception.


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Table 3
Acceptable Highly Effective Contraception Options
Acceptable non-hormonal birth control methods:
•
Total/true abstinence: When the patient refrains from any form of sexual intercourse and this is in line 
with their usual and/or preferred lifestyle; this must continue for the total duration of the study treatment 
and for at least 4 weeks (for female patients) or at least 16 weeks (for male patients) after the last dose of 
study treatment. Periodic abstinence (eg, calendar ovulation, symptothermal, post ovulation methods, or 
declaration of abstinence solely for the duration of a trial) and withdrawal are not acceptable methods of 
contraception.
•
Vasectomised sexual partner (with patient assurance that partner received post-vasectomy confirmation 
of azoospermia) combined with a barrier method.
•
Bilateral tubal occlusion combined with a barrier method. 
•
Intrauterine device (provided coils are copper banded) combined with a barrier method.
Acceptable hormonal methods:
•
Mini pill combined with a barrier method: Progesterone-based oral contraceptive pill using desogestrel. 
Cerazette (Merck Sharp & Dohme) is currently the only highly efficacious progesterone-based pill 
available. 
•
Combined pill combined with a barrier method: Normal and low-dose combined oral pills.
•
Injection combined with a barrier method: Medroxyprogesterone injection. 
•
Patch combined with a barrier method: Norelgestromin/ethinyl estradiol transdermal system.
•
Implants combined with a barrier method: Etonorgestrel-releasing implants.
•
Intravaginal device (eg, ethinyl estradiol-/etonogestrel-releasing intravaginal devices) combined with a 
barrier method.
•
Levonorgestrel-releasing intrauterine system combined with a barrier method.
5.3.4.2
Males
Non-sterile men who are not totally sexually abstinent (ie, refraining from heterosexual 
intercourse during the entire period of risk associated with study interventions) and intend to 
be sexually active with a female partner (of childbearing potential) must use a condom upon 
entering the study and until 16 weeks after the last dose of capivasertib. Contraception should 
be used in females’ partners of men taking capivasertib who are of childbearing potential 
during the course of the study and for 16 weeks after the final dose of capivasertib (see 
Table 3 for recommended contraception options for female partners). 
Even if the female partner is pregnant, male patients should still use a condom plus spermicide 
(if available in your country), as indicated above during the clinical study.
Male patients should refrain from donating sperm from the start of dosing until 16 weeks after 
last dose of study treatment.
5.3.5
Other Restrictions
Patients who are blood donors should not donate blood during the study and for 3 months 
following their last dose of study treatment.


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5.4
Screen Failures
Screen failures are defined as patients who consent to participate in the clinical study but are 
not subsequently entered in the study. 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 publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE.
Patients may be rescreened a single time. 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 recorded as screen failure in the eCRF. Rescreened patients should be 
assigned the same patient number as for the initial screening.
6
STUDY INTERVENTION - CORE
Study intervention is defined as any investigational intervention, marketed product or placebo 
intended to be administered to or medical devices utilised by a study patient according to the 
study protocol.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
All patients will receive treatment with the investigational product capivasertib. Refer to the 
relevant Module for further details.
Capivasertib Dosing Instructions 
Capivasertib tablets should be swallowed whole, not crushed, with a glass of water. Where 
possible, all doses of capivasertib 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. Additional fasting restrictions apply on days where fasting glucose is 
to be tested (Section 8.2.4.1).
If vomiting occurs, a replacement dose should not be taken, and the patient should take their 
allotted dose at the next scheduled time.
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. 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 tablets on time.


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Permitted capivasertib dose modifications are described in Section 6.6.
6.2
Preparation/Handling/Storage/Accountability
1)
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.
2)
Only patients enrolled in the study may receive study treatment and only authorised site 
staff may supply or administer study treatment. All study treatment 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.
3)
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).
4)
Further guidance and information for the final disposition of unused study treatments are 
provided in the relevant Module and the Pharmacy Manual.
6.3
Measures to Minimise Bias: Randomization and Blinding
This is an open-label, non-randomised study; no blinding is required. 
6.4
Study Intervention Compliance
When patients are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the study site will be recorded in the source documents and recorded in the 
eCRF. The dose of study treatment and study patient identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study treatment.
Patients will receive a drug diary to record the specific time each dose was taken and to record 
reasons for any missed doses. The patient will be instructed to bring the diary and any 
remaining study treatment to the clinic at their next visit.
When patients self-administer study treatment at home, compliance with study treatment will 
be assessed at each visit. Compliance will be assessed by counting returned tablets during the 
site visits and documented in the source documents and eCRF. Deviation(s) from the 
prescribed dosage regimen should be recorded in the eCRF.
A record of the number of capivasertib tablets dispensed to and taken by each patient must be 
maintained and reconciled with study treatment and compliance records. Intervention start and 
stop dates, including dates for intervention delays and/or dose reductions will also be recorded 


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in the eCRF.
The Investigational Product Storage Manager is responsible for managing the study treatment 
from receipt by the study site until the destruction or return of all unused study treatment.
The investigator is responsible for ensuring that the patient has returned all unused study 
treatment.
Refer to the relevant Module for details.
6.5
Concomitant Therapy
Any concomitant treatment, procedure, or other medication considered necessary by the 
investigator for the patient’s safety and wellbeing, or vaccine (including over-the-counter or 
prescription medicines, blood transfusions, vitamins, and/or herbal supplements) that the 
patient is receiving within 4 weeks prior to the first dose of study treatment or receives during 
the study including the 30-day follow-up period following the last dose of study treatment 
must be recorded in the eCRF along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
If any concomitant therapy is administered due to new or unresolved AE, it should be 
recorded. Investigational agents (eg, investigational agents to treat the underlying disease) are 
not permitted until EOT.
Patients must be instructed not to take any medications, including over-the-counter products 
or herbal remedies, without first consulting with the investigator.
Potential interactions of capivasertib with concomitant medications and restricted, prohibited 
and permitted concomitant medications are described in Appendix F.
6.5.1
Drugs that Prolong QT Interval
Due to the important potential risk of QT prolongation derived from the capivasertib 
non-clinical development programme, it is recommended that administration of any drugs (at 
screening or during study conduct) considered essential for patient management which are 
known to prolong the QT interval is discussed with the AZ Study Physician and that 
consideration should be given for close monitoring of QT interval prolongation through 


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frequent ECG and electrolyte monitoring.
During screening, the drugs that patients are currently using (prescription and 
non-prescription) should be checked against the ArizonaCert website. In addition, drugs 
intended for use during study treatment should be checked against the website. 
(https://www.crediblemeds.org/).
6.6
Dose Modification
Refer to the relevant Module for further details and Appendix G.
6.7
Intervention After the End of the Study
After discontinuation of study treatment (see Section 7.1), the investigator will be at liberty to 
further define the most appropriate anti-lymphoma treatment. Information on subsequent anti-
lymphoma therapies should be recorded in the clinical database. Efficacy assessments should 
continue until PD, even if patients start another anti-lymphoma therapy.
No intervention is planned after the end of the study. However, provisions will be in place for 
patients still enrolled at the end of the study to continue to receive study treatment if, in the 
opinion of the investigator, they are continuing to receive benefit from treatment.
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving treatment with study treatment may be 
transitioned to such study, and the current study would reach its end. The roll-over or safety 
extension study would ensure treatment continuation with visits and assessments per its 
protocol. Any patients who would be proposed to move to such study would be asked to sign a 
new ICF.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL - CORE
7.1
Discontinuation of Study Intervention
Patients must be discontinued from study treatment in the following situations:

Patient decision: The patient is at any time free to discontinue study treatments, without 
prejudice to further treatment.

Pregnancy (see Section 8.3.11.1).

Any AE that meets criteria for discontinuation defined in those modification guidelines 
for management of capivasertib-related toxicity (see Appendix G).

Objective disease progression assessed by investigator per the Lugano 2014 Classification 
for NHL (Cheson et al 2014).


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
Severe noncompliance with the CSP in the judgement of the investigator and/or the 
sponsor.

Patients incorrectly initiated on study treatments.

Intercurrent illness that, in the judgement of the investigator, will affect assessments of 
clinical status to a significant degree or contraindicate further dosing.

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.

Clinical need for concomitant or ancillary therapy that is not permitted in the study.

Initiation of subsequent anti-lymphoma therapy, including another investigational agent.

Death.

General or specific changes in the patient’s condition that are unacceptable for further 
treatment in the judgement of the investigator.
Note that discontinuation from study treatment is NOT the same thing as a withdrawal from 
the study. If study treatment is permanently discontinued, the patient will remain in the study 
to complete the EOT visit within 7 days of discontinuation of study treatment, the 
post-treatment follow-up (30 [± 7] days after last dose) and the long-term follow-up every 
12 weeks.
See the SoA in the relevant Module for data to be collected at the time of intervention 
discontinuation (EOT) and long-term follow-up, and for any further evaluations that need to 
be completed.
Refer to relevant Module for criteria for stopping or pausing the study recruitment.
7.1.1
Temporary Discontinuation
Refer to the relevant Module for details.
7.2
Participant Withdrawal from the Study

A patient may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon.

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).

At the time of withdrawal from the study, if possible, an EOT visit should be conducted, 
as shown in the SoA. See SoA in the relevant Module for data to be collected at the time 


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of study withdrawal and follow-up and for any further evaluations that need to be 
completed.

The patient will discontinue the study treatment and be withdrawn from the study at 
that time.

If the patient withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a patient withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation. The 
investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.
Refer to the relevant Module for details.
7.3
Lost to Follow-up
A patient will be considered lost to follow-up if he or she repeatedly 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 study site for a required 
study visit:

Before a patient is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record.

Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 

Site personnel, will attempt to collect the vital status of the patient within legal and ethical 
boundaries for all patients randomised, including those who did not get investigational 
product. Public sources may be searched for vital status information. If vital status is 
determined as deceased, this will be documented and the patient will not be considered 
lost to follow-up. Sponsor personnel will not be involved in any attempts to collect vital 
status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.


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8
STUDY ASSESSMENTS AND PROCEDURES - CORE

Study procedures and their timing are summarised in the SoA in the relevant Module. 
Protocol waivers or exemptions are not allowed.

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 in the 
relevant Module, is essential and required for the study.

All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the patient’s routine clinical management and obtained 
before signing of the ICF may be utilised for screening or baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA, with the exception of bone marrow aspirates/biopsies (up to 12 weeks 
before the first planned dose of study treatment).

Any imaging assessments (eg PET/CT scan) performed prior to the ICF signature within 
5 weeks may be considered as baseline, provided that:

no anti-lymphoma treatment (including radiotherapy) has been administered between 
the date of the assessment and the first planned dose (with the only exception of 
low-dose steroids ie, < 10 mg prednisolone or equivalent).

there is no significant clinical worsening of the patient.
Disease-specific assessment at screening include collection of prior lines of anti-cancer 
therapies, with their best overall response and relapse date and disease prognostic scores 
(Appendix J).
All efficacy assessments should continue until progression, even if patients stop study 
treatment.
8.1
Efficacy Assessments
Efficacy assessments will be performed as indicated in the SoA in the relevant Module until 
disease progression or relapse, death, lost to follow-up or withdrawal of the consent.
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
Physical examination: attention to node-bearing areas, including Waldeyer’s ring, and to 
the size of liver and spleen

Total body CT, whole body FDG-PET, MRI

Brain imaging (MRI with contrast will be performed at screening only if there is a prior 
history of CNS involvement or if there are neurologic signs or symptoms present or as 
clinically indicated during the study)

Bone marrow biopsy and/or aspirate (Section 8.1.1)

Endoscopic and histopathologic assessments (eg, tumour biopsy, cytology) if applicable
8.1.1
Bone Marrow Assessments
For all patients, a baseline (before first dose of study treatment) bone marrow biopsy and/or 
aspirate is required at screening to assess bone marrow involvement by lymphoma. 
Bone marrow biopsies/aspirates will be read at each site’s local laboratory and will be 
performed as clinically indicated while on study (ie, to confirm CR (if bone marrow was 
involved by lymphoma at baseline, within 28 days after the respective radiological 
assessment) and per standard of care. Furthermore, if bone marrow involvement before the 
start of the study was unknown, a bone marrow evaluation must be conducted to confirm a 
CR. 
Patients with a negative bone marrow aspirate/biopsy (ie, no lymphoma involvement) at 
screening, and patients with a PR, SD or PD at any disease response assessment time point do 
not require a follow-up bone marrow aspirate/biopsy. Locally obtained results should be 
entered into the eCRF. 
Further details on sample processing, handling and shipment are provided in the Manual.
8.1.2
Imaging Assessments
During the screening period, a PET-CT scan will be performed to assess the measurability of 
disease and will serve as baseline (Day -28 to Day -1). Information on extranodal involvement 
will also be recorded.
Subsequent radiological assessment, ie, CT scans with contrast (unless contraindicated) 
covering neck, chest, abdomen, and pelvis and any other disease sites will be performed every 
8 weeks (± 7 days) until Week 24 (ie, Weeks 8, 16, and 24), every 12 weeks (± 7 days) until 
Week 60 (ie, Weeks 36, 48 and 60) and thereafter every 12 weeks (± 7 days) for R/R MCL and 
every 24 weeks (± 7 days) for R/R FL/MZL.
Patients who discontinue study intervention for reasons other than PD will continue to be 
scanned for disease response until documented PD and regardless of starting a new 


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anti-lymphoma treatment following the same schedule, ie, every 8 weeks (± 7 days) until 
Week 24 (ie, Weeks 8, 16, and 24), every 12 weeks (± 7 days) until Week 60 (ie, Weeks 36, 48 
and 60) and thereafter every 12 weeks (± 7 days) for R/R MCL and every 24 weeks (± 7 days) 
for R/R FL/MZL.
PET scans covering whole body from base of skull to mid-thigh (or PET/CT scans) are 
mandatory every 8 weeks (± 7 days) until Week 24 (ie, Weeks 8, 16, and 24) and thereafter to 
confirm CR or as clinically indicated. More frequent PET-CT scan can be performed when 
clinically indicated at the investigator’s discretion.
For MZL patients with FDG-avid disease at baseline, disease response to study treatment will 
be based on both PET and CT-based criteria. For MZL patients with no FDG-avid disease at 
baseline, disease response to study treatment will be based on CT-based criteria only.
PET scans should be performed whenever possible at during the 3 days off of study treatment. 
If a PET/CT is not available, an independent PET and a diagnostic-quality CT scan can be 
used. If PET and CT scans are done on the same day, the PET is recommended to be 
performed prior to the contrast-enhanced CT not to compromise the PET read-out. If the time 
between a contrast enhanced CT and a PET is long enough (eg, > 6 hours), it is possible to 
perform CT with IV contrast prior to the PET scan.
The CT portion of a PET/CT may be submitted in lieu of a dedicated CT; however, certain 
radiographic requirements are needed for acceptance, as described in the Site Radiology 
Manual, provided separately from this protocol.
MRI may be used for imaging assessments if a contrast CT scan is contraindicated or 
unobtainable (in cases where MRI is desirable, the MRI must be obtained at baseline and at all 
subsequent response evaluations).
No anti-cancer treatment other than study treatment can be implemented between the earliest 
date of baseline scans or bone marrow assessment and the start of study treatment. Patients 
should have radiographic tumour measurements done at the participating study centre or an 
acceptable alternate imaging facility using an identical imaging protocol and similar 
equipment. The same imaging equipment should be used for all scans whenever possible. The 
same radiologist should be assigned to read all the scans for a given patient throughout the 
study.
All images for the assessment of response will be collected and stored for BICR. Any 
unscheduled efficacy assessment will also be sent for BICR to an AstraZeneca-designated 
imaging CRO. De-identified copies of all radiology results may be requested by the sponsor.


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8.1.3
Disease Response Assessment
8.1.3.1
Lugano 2014 Classification for Non-Hodgkin Lymphomas
The assessment of response per the Lugano 2014 Classification for NHL (Cheson et al 2014
and Appendix I) will be used to determine the anti-tumour activity of study treatment. 
The efficacy endpoints are based on the overall response assessment (Appendix I).
8.1.4
Other Disease-specific Assessments
8.1.4.1
Endoscopy
Endoscopy with adequate tissue sampling for histopathologic analysis is mandatory to confirm 
CR for any patients with a documented history of gastrointestinal involvement. After CR is 
confirmed histologically (biopsy to be performed within 28 days from the respective 
radiological assessment), subsequent endoscopic assessments are not mandatory for disease 
evaluation, unless there is suspicion of a new or recurrent gastrointestinal involvement.
8.1.4.2
 
 
8.1.4.3
B-symptoms
B-symptoms are constitutional symptoms defined as any one or more of the following 
disease-related symptoms or signs:

Unintentional weight loss of 10% or more within the previous 6 months

Significant fatigue (ie, ECOG performance status 2 or worse; inability to work or perform 
usual activities)

Fevers > 100.5°F or 38.0°C for ≥2 weeks without other evidence of infection

Night sweats for > 1 month without evidence of infection
B-symptoms should not be reported as AEs and will be collected at each disease response 
assessment during treatment and as clinically indicated.
8.1.5
Clinical Outcome Assessments
A COA is any assessment that may be influenced by human choices, judgement, or motivation 
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and may support either direct or indirect evidence of treatment benefit. Clinical outcome 
assessments can be reported by a patient (PRO), a clinician (Clinician-reported Outcome), an 
observer (Observer-reported Outcome), or through a performance based assessment (FDA-
NIH BEST Resource). A COA may be used in clinical studies to provide either direct or 
indirect evidence of treatment benefit. It is important to examine the impact of therapy on 
symptoms, function, and other health-related QoL of the patient to aid understanding of the 
risk benefit profile.
Patient-reported outcome is one type of COA and is a general term referring to all outcomes 
and symptoms that are directly reported by the patient. Patient-reported outcome s have 
become important in evaluating the effectiveness of study treatment in clinical studies and will 
aid in understanding of the benefit/risk evaluation (Kluetz et al 2018). The following PRO 
instruments will be administered in this study:

Health-related QoL questionnaire EORTC QLQ-C30


NCI PRO-CTCAE

Patient-reported anti-diarrhoeal medication 

PGI-TT



Patient-reported outcomes will be administered according to the SoA. The PRO 
questionnaires will be completed by patients if a linguistically-validated version is available in 
their language for the country in which they live. The individual questionnaires are provided 
in Appendix K.
8.1.5.1
EORTC QLQ-C30
The EORTC QLQ-C30 was developed by the EORTC QoL Group 1993. It consists of 
30 items and measures symptoms, functioning, and global health status/QoL (Aaronson et al 
1993) 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 patient (dyspnoea, loss of appetite, insomnia, constipation, and 
diarrhoea), and 1 item on the financial impact of the disease. The EORTC QLQ-C30 is a valid 
and reliable PRO instrument in this patient population.
8.1.5.2
 
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8.1.5.3
PRO-CTCAE
The PRO-CTCAE system has been developed by the NCI and is included to assess tolerability 
from the patients’ perspective. The PRO-CTCAE will only be administered in those countries 
where a linguistically validated version is available. PRO-CTCAE is an item library of 
symptoms experienced by patients while undergoing treatment of their cancer. It has been 
carefully and systematically developed based on the NCI CTCAE to provide patient reported 
assessment of common adverse effects of cancer treatments, including a library of 124 items, 
representing 78 symptomatic toxicities. The items have previously undergone extensive 
qualitative and quantitative evaluation to support their validity and reliability (Basch et al 
2014; Dueck et al 2015; Hay et al 2014). For each symptomatic AE (eg, headache), there are 
up to three questions related to key symptom attributes, including the symptom frequency, 
severity, and interference with daily activates. Each question uses a 7-day recall with a 5-point 
ordinal response scale. The items pre-selected for this study are based on a review of the core 
symptom set from NCI, expected treatment related symptoms, and in consideration of 
symptoms that are already captured in the other PRO instruments with a view to minimize 
patient burden. Pre-selected items that will be administered in this study include dry mouth, 
blurred vision, headache, urinary frequency, diarrhoea, decreased appetite, nausea, vomiting, 
fatigue, dry skin, rash and itching. 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.
The PRO-CTCAE is intended to enhance the precision and reproducibility of adverse event 
reporting to provide data that complements and extends the information provided by 
clinician-reporting using CTCAE, and to represent the patient perspective of the experience of 
symptomatic adverse events. Signs and symptoms assessed with the PRO questionnaires will 
not be considered AEs unless entered as such into the eCRF. Use of PRO-CTCAE is limited to 
describing in aggregate the safety and tolerability of the study drugs and does not include the 
use of PRO-CTCAE for diagnostic, prognostic, or therapeutic purposes in human subjects, or 
the use of PRO-CTCAE to assess the efficacy of the study drugs.
8.1.5.4
Patient-reported anti-diarrhoeal medication
A question is included to capture patient-reported anti-diarrhoeal medication over the past 
1 week: “Did you take any medicine for diarrhoea?”. Patients will be asked to choose the 
responses of “Yes” or “No”. If yes, patients will be asked “how much did it help?” with 
response options: not at all, a little, quite a bit, very much. The questions are included to aid in 
the interpretation of patient-reported diarrhoea.
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8.1.5.5
PGI-TT
The PGI-TT item is included to assess how a patient perceives the overall burden of 
treatment-related side effects of cancer treatment over the past 1 week. Patients will be asked 
to choose the response that best describes the level of burden by the side effect of their cancer 
treatment over the past week. The response options are: not at all, a little bit, somewhat, quite 
a bit, and very much. This item is included to aid in the interpretation of other PRO measures 
and to evaluate the overall impact of treatment-related side effects.
8.1.5.6
 
 
 
 
 
8.1.5.7
 
8.1.5.8
 
 
 
 
 
 
8.1.5.9
Administration of Electronic PRO Questionnaires
Electronic PROs will be self-administered at home by the patients using handheld devices at 
the time points indicated in the SoA in the relevant Module. Patients may complete the ePROs 
at study sites if the assessment time point coincides with a scheduled site visit; otherwise, 
patients should complete the ePROs at home. Similarly, during the follow-up period, patients 
should complete ePROs at home or at the study site if a scheduled visit coincides with the 
time point.
Patients must be instructed to bring the device to all visits.
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The instructions below should be followed when collecting PRO data via an electronic device:

PRO questionnaires must be completed prior to any other study procedures or discussions 
(following informed consent), including medication treatments, and before discussion of 
PD to avoid biasing the patient’s responses to the questions.

PRO questionnaires should be completed by the patient in a quiet and private location.

The patient should be given sufficient time to complete the PRO questionnaires at his/her 
own speed.

The research nurse or appointed site staff should explain to patients the value and 
relevance of these data so that they are motivated to comply with questionnaire 
completion.

The research nurse or appointed site staff should stress that the information is not 
routinely shared with study staff. Therefore, if the participant has any medical problems, 
he/she should discuss them with the doctor or research nurse separately from the ePRO 
assessment.

The research nurse or appointed site staff must train the patient on how to use the ePRO 
device using the materials and training provided by the ePRO vendor.

The research nurse or appointed site staff must provide guidance on whom to call if there 
are problems with the device when the patient is completing the ePRO at home.

All PRO questionnaires are to be completed electronically. If technical or other device-
related issues prohibit completion on the device, appropriate back-up options 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 clarifying items.

The patient must not receive help from relatives, friends, or study site staff to answer the 
ePRO questionnaires. If a patient uses visual aids (eg, spectacles or contact lenses) for 
reading and does not have them when he or she attends the study site, the patient will be 
exempted from completing the ePROs at that study site visit.

Site staff must not read or complete the ePRO 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 
in the designated eCRF.


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
Site staff must administer questionnaires available in the language that the patient speaks 
and understands. Questions must not be read in an available language and translated into 
another language for the patient.

It is vital that the ePRO reporting is initiated at the baseline visit, as specified in the SoA 
in the relevant Module to capture the effect of study treatment.

Reminders should be sent to patients at home as needed to ensure compliance with the 
assessment schedules.
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 source documents and in the designated eCRF. If the site receives an email 
notification regarding the patient's compliance, appropriate action should be taken (eg, 
discussion with patient to improve compliance, a check-in call from the site to ask the patient 
if they have any difficulties in completing questionnaires on schedule, etc). A solution to 
enhance/resolve compliance should be discussed with the patient. Discussions and compliance 
review should be reflected in source documents.
8.1.6
Subsequent Anti-lymphoma Therapy
The following information on subsequent anti-lymphoma therapies will be collected during 
the study: 

Receipt of subsequent anti-lymphoma therapy

Response to subsequent anti-lymphoma therapy
For any subsequent anti-lymphoma therapy, the start date, end date, best response, and date of 
best response should be documented in the appropriate section of the eCRF.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA in the relevant Module.
8.2.1
Physical Examinations
The physical examination includes, at a minimum, the general appearance of the patient, 
height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, 
lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous 
system. The lymphatic system examination will include examination of palpable lymph nodes 
and spleen and liver below the costal margin on the respective side. Only physicians should 
perform the lymphatic system examination. As much as possible, the same person should 
perform all the lymphatic exams for a given patient.
Physical examination will be performed at timelines as specified in the SoA in the relevant 


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Module. Investigators should pay special attention to clinical signs related to previous serious 
illnesses, new or worsening abnormalities may qualify as adverse events, see Section 8.3.4 for 
details.
8.2.2
Vital Signs
Vital signs (including blood pressure, pulse, pulse oxygen saturation, and body temperature) 
will be assessed at timelines as specified in the SoA in the relevant Module. 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.
Blood pressure and pulse 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 sitting position after at least 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, and pulse. Three readings of blood pressure 
and pulse will be taken 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.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.5.
8.2.3
Electrocardiograms
All ECGs to be conducted as triplicate measurements, within approximately 5 minutes of 
starting (the 3 ECGs separated by approximately 1 minute). Assessments should be performed 
as close as possible to, but within 30 minutes of the nominal time point.
Triplicate 12-lead ECGs will be obtained at the time points specified in the SoA in the relevant 
Module.
Additional ECGs may be taken at the discretion of the investigator.
Twelve-lead ECGs will be obtained after the patient has been resting 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 


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intervals PR, R-R, QRS, QT, and QTcF and an overall evaluation will be recorded (normal; 
abnormal, non-clinically significant or abnormal, clinically significant).
Situations in which ECG results should be reported as AEs are described in Section 8.3.5.
8.2.4
Clinical Safety Laboratory Assessments
See Table 4 for the list of clinical safety laboratory tests to be performed and the SoA in the 
relevant Module for the timing and frequency.
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.
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. All patients with Grades 3 or 4 laboratory values at the 
time of completion or discontinuation from study treatment must be followed and have further 
tests performed until the laboratory values have returned to Grades 1 or 2, unless these values 
are not likely to improve because of the underlying disease.
Situations in which laboratory safety results should be reported as AEs are described in 
Section 8.3.5.
All laboratory safety analyses, including 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.
Other safety laboratory tests include assessment for pregnancy, viral serology (HIV 
antibodies, CMV antibodies and hepatitis serology [hepatitis B surface antigen, hepatitis B 
surface antibodies, HBc antibodies, and hepatitis C virus antibodies]), and SARS-CoV-2 PCR 
testing and antibodies (if clinically indicated), and serum immunoglobulins (IgA, IgG, IgM).
For patients with positive anti HBcAb or anti-hepatitis C Ab at screening with documented 
negative HBV DNA or HCV RNA, HBV DNA and/or HCV RNA PCR testing (as applicable) 
will be assessed every 3 months during study treatment (Table 6). Pregnancy tests may be 
performed at the site using a licensed test (urine or serum pregnancy test). Abnormal clinically 
significant laboratory results should be repeated as soon as possible (preferably within 24 to 


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48 hours).
The following laboratory variables will be measured.
Table 4
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry
B-Haemoglobin (Hb)
S/P-Creatinine
B-Glycosylated haemoglobin (HbA1c) (fasting)
S/P-Bilirubin, total
B-Leukocyte count (WBC count)
S/P-Alkaline phosphatase
B-Leukocyte differential count
S/P-AST
Neutrophils
S/P-ALT
Lymphocytes
S/P-Albumin
Eosinophils
S/P-Potassium
B-Platelet count
S/P-Calcium, total
Urinalysis
S/P-Sodium
U-Glucose
S/P-Glucose (fasting)
U-Protein
S/P-Magnesium
U-Blood
S/P-Total protein
U-Microscopy (red blood cells and white blood cells, 
bacteria, casts and crystals) only perform if urinalysis 
is abnormal c
S/P-Free T4 a
S/P-TSH a
S/P-bicarbonate
U-pH
S/P-BUN/urea nitrogen
U-Specific gravity
S/P-chloride
U-bilirubin
S/P-LDH
U-Ketones
S/P-Phosphate
Other
S/P-Uric acid
Beta-2 microglobulin b
S/P-Troponin I or T b
S/P-Lipids (fasting)
S/P-Gamma-glutamyl transferase
a
Test will only be performed on Day 1 in each cycle and when clinically indicated.
b
At screening and then as clinically indicated.
c
Denmark only: U-Microscopy is not required.
NB. In case a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN please refer to 
Appendix E ‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law’, for further 
instructions.
Lipids: triglycerides, high density lipoprotein, low density lipoprotein, and cholesterol.
ALT: alanine aminotransferase; AST: aspartate aminotransferase; B: blood; BUN: blood urea nitrogen; 
P: plasma; S: serum; T4: thyroxine; TSH: thyroid-stimulating hormone; U: urine; ULN: upper limit of normal; 
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8.2.4.1
Glucose and HbA1c
Blood glucose and HbA1c will be assessed according to the SoA in the relevant Module. On 
blood glucose assessment days (incorporating clinical chemistry and glucose) it is requested 
that patients refrain from caloric intake for ≥4 hours prior to the morning dose of study 
treatment.
8.2.4.2
Serum Creatinine
After Cycle 2 onwards, patients taking capivasertib 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.
Patients on metformin should attend the study site for monitoring of serum creatinine at least 
once per week for the first 3 weeks after initiation of metformin, then every 3 weeks 
thereafter.
8.2.5
Other Safety Assessments
8.2.5.1
ECOG Performance Status
ECOG performance status will be assessed at the times specified in the SoA in the relevant 
Module. ECOG performance status is scored as follows:
0 =
Fully active, able to carry out all pre-disease activities without restrictions
1 =
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature (eg, light housework, office work)
2 =
Ambulatory and capable of self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3 =
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 =
Completely disabled, cannot carry on self-care, totally confined to bed or chair
8.2.5.2
Echocardiogram / MUGA Scan
Assessments will be performed at screening and thereafter as clinically indicated. 
Bi-dimensional 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. The patients should also be 
examined using the same machine and operator whenever possible.
Situations in which ECHO or MUGA results should be reported as AEs are described in 
Section 8.3.5.


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8.3
Adverse Events and Serious Adverse Events
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
contents of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse events 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.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from time of signature of the ICF throughout the treatment 
period and including the follow-up period and up to 30 days after discontinuation of study 
treatment.
SAEs will be recorded from the time of signing of the informed consent form.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix B. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
If the investigator becomes aware of a SAE with a suspected causal relationship to the study 
treatment that occurs after the end of the clinical study in a patient treated by him or her, the 
investigator shall, without undue delay, report the SAE to the sponsor.
8.3.2
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 and non-serious AEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the patient is lost to follow-up.
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed up 
by the investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca 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.


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Adverse Event Variables
'The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the study treatment(s) (yes or no)

Action taken with regard to Investigational Product(s)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

Seriousness criteria

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
8.3.3 Causality Collection
The investigator should assess causal relationship between Investigational Product and each 
AE and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by the Investigational Product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure, the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.


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8.3.4 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: ‘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.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests, vital signs, physical examinations, ECGs, 
and ECHO/MUGA scans will be summarised in the CSR. 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs, 
physical examinations, ECGs, and ECHO/MUGA scans should therefore only be reported as 
AEs if they fulfil any of the SAE criteria, are the reason for discontinuation of treatment with 
the investigational product or are considered to be clinically relevant as judged by the 
investigator (which may include but not limited to consideration as to whether treatment or 
non-planned visits were required or other action was taken with the study treatment, eg, dose 
adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.3.6 Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need 
to be reported as SAEs. Please refer to Appendix E for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.


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8.3.7 Disease Progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. Events, 
which are unequivocally due to disease progression, should not be reported as an AE during 
the study.
8.3.8
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. New primary cancers are those that are not the primary reason for 
the administration of study treatment and are identified after the patient’s inclusion in this 
study. They do not include progression or transformation of the original cancer. Patients who 
develop a new cancer should be managed according to institutional guidelines with diagnostic 
evaluations as clinically indicated, and it may be necessary for patients to permanently 
discontinue study treatment. Further guidance is provided in Appendix B 2.
8.3.9
Deaths
All deaths that occur during the Treatment Period, or within the protocol-defined follow-up 
period after the administration of the last dose of study treatment, must be reported as follows:

Death clearly resulting from PD should be documented in the eCRF in the Statement of 
Death page. It should not be reported as an SAE.

Where death is not due (or not clearly due) to PD under study, the AE causing the death 
must be reported as an SAE within 24 hours. It should also be documented in the 
Statement of Death page in the eCRF. The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign the main and contributory causes 
of death.

Deaths with an unknown cause should always be reported as an SAE and documented in 
the Statement of Death page in the eCRF, but every effort should be made to determine a 
cause of death. A post-mortem may be helpful in the assessment of the cause of death, 
and if performed, a copy of the post-mortem results should be forwarded to AstraZeneca 
Patient Safety or its representative within the usual time frames.
Deaths occurring after the protocol-defined follow-up period after the administration of the 
last dose of study treatment should be documented in the Statement of Death page. If the death 
occurred as a result of an event that started after the defined follow-up period and the event is 
considered to be due to a late-onset toxicity to study treatment, then it should also be reported 
as an SAE.


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8.3.10
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will 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 will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one 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 will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day, ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the 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.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug. 
8.3.11
Pregnancy
A pregnancy test will be administered to women of childbearing potential at Screening, on 
Cycle 1 Day 1, at discontinuation of study treatment, 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 except where 
the pregnancy is discovered before the study patient has received any study treatment.
8.3.11.1
Maternal Exposure
If a patient becomes pregnant during the course of the study, capivasertib should be 
discontinued immediately.


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Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomaly(/ies)/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 birth or congenital anomaly/birth defect) 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 (see Section 8.3.10) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
8.3.11.2
Paternal Exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 
16 weeks following the last dose of capivasertib. Patients wishing to father children should be 
advised to arrange for freezing of sperm samples prior to the start of study treatment.
Pregnancy of the patient’s partners is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital anomaly), occurring from the date of the first dose until 16 weeks after the last 
dose should, if possible, be followed up and documented.
8.3.12
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.10) and within 30 days for all other 
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The definition of a Medication Error can be found in Appendix B 4. 
8.3.13
Adverse Events of Special Interest
Adverse events of special interest 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 8.3.10.
A list of AESIs can be seen below:

Hyperglycaemia

Non-infectious diarrhoea

Infective pneumonia

Rash

Stomatitis

QT Prolongation

Haematological effects
8.4
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 clinical protocol. Adverse events associated with overdose 
should be treated in response to symptoms. Any dose, or frequency of dosing, that exceeds the 
dose regimen specified in the study protocol should be reported as an overdose.
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.
If an overdose on an AstraZeneca study treatment occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it.
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relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for overdoses associated with an SAE (see section 8.3.10) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific Laboratory Manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples see Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalisation or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses. Pharmacokinetic samples may be disposed of or 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. Anonymised samples will be retained no more than 
5 years after the CSR is finalised.
8.5.1
Pharmacokinetics

Blood samples will be collected for measurement of plasma concentrations of 
capivasertib as specified in the SoA in the relevant Module.

Samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor, eg, for safety reasons.

Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual.
8.5.1.1
Determination of Drug Concentration
Samples for determination of drug concentration in plasma will be assayed by bioanalytical 
test sites operated by or on behalf of AstraZeneca, using an appropriately validated 
bioanalytical method. Full details of the analytical method used will be described in a separate 
Bioanalytical Report.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Not applicable.


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8.5.3
Pharmacodynamics
Not applicable.
8.6
8.6.1
 
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8.7
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in the SoA in the relevant Module and is subject to agreement in the ICF addendum.
 
 Participation is optional. Patients 
who do not wish to participate in the genetic research may still participate in the study. The 
saliva sample will be collected at 
. If a sample is not collected at that 
time, it may be collected at any time during the study or during a separate post-study visit, if 
necessary.
See Appendix D for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found either in 
the appendices or in the Laboratory Manual. 
For storage and destruction of genetic samples see Appendix D. 
8.8
Medical Resource Utilization and Health Economics
Not applicable.
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9
STATISTICAL CONSIDERATIONS - CORE
9.1
Statistical Hypotheses
Refer to the relevant Module for information.
9.2
Sample Size Determination
Refer to the relevant Module for information.
9.3
Populations for Analyses
The following populations are defined:
Table 5
Populations for Analysis
Analysis set
Description
Enrolled 
All patients who sign the ICF.
Safety
All patients who receive any amount of study treatment.
Safety data will not be formally analysed but summarised using the safety analysis 
set.
Response evaluable
All patients, treated with study treatment, with measurable disease at baseline.
Pharmacokinetic
All patients who receive at least 1 dose of capivasertib, for whom there is at least 
1 reportable PK concentration.
ICF: informed consent form; PK: pharmacokinetic(s).
9.4
Statistical Analyses
The SAP will be finalised within 90 days after First Patient In, but it will be aimed to have it 
finalised prior to First Patient In. It will include a more technical and detailed description of 
the statistical analyses described in this section. This section is a summary of the planned 
statistical analyses of the most important endpoints including primary and secondary 
endpoints.
9.4.1
General Considerations
Analyses will be performed by AstraZeneca or its representatives, including CROs. A 
comprehensive SAP will be developed and will describe the patient populations to be included 
in the analyses, the analyses including any subgroup analyses or sensitivity analyses, and the 
procedures to account for missing, unused, and spurious data.
Unless stated otherwise, each Cohort will be analysed separately.
Continuous data will be summarised by the number of observations, mean, standard deviation, 
median, minimum and maximum. Geometric mean and coefficient of variation may be 


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presented as applicable. Categorical variables will be summarised by frequency counts and 
percentages for each category. Unless otherwise stated, percentages will be calculated from 
the population total. Time to event variables will be presented using the Kaplan-Meier 
methodology, including median time calculated from the Kaplan-Meier curves.
In general, the last observed measurement prior to first dose of study treatment will be 
considered the baseline measurement. For assessments on the day of first dose where time is 
not captured, a nominal pre-dose indicator, if available, will serve as sufficient evidence that 
the assessment occurred prior to first dose. Assessments on the day of first dose, when neither 
time nor a nominal pre-dose indicator are captured, will be considered prior to first dose if 
such procedures are required by the protocol to be conducted before the first dose.
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 study treatment, and other protocol deviations) may be generated. More detail 
will be provided in the SAP.
The efficacy endpoints for tumour response (ORR, DoR, and TTR) will be summarised and 
analysed based upon the response evaluable analysis set. The efficacy endpoints for OS, PFS, 
and TFST, QoL, safety and treatment exposure data will be summarised based upon the safety 
analysis set. Pharmacokinetic data will be summarised based on the PK analysis set. Study 
population and demography data will be summarised based upon the safety analysis set.
Refer to the relevant Module for details on analyses and data cut-off triggers.
9.4.2
Efficacy
9.4.2.1
Primary Endpoint(s)
ORR is defined as the proportion of patients achieving either CR or PR as assessed by BICR 
and will be based on the response evaluable analysis set. In addition, for sensitivity analysis 
purposes, ORR will also be defined as the proportion of patients achieving either CR or PR as 
assessed by the investigator and will be based on the response evaluable analysis set.
Data obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR, regardless of whether the patient withdraws from 
therapy. Patients who discontinue treatment without a response or progression, receive 
subsequent anti-lymphoma therapy and then respond will not be included as responders in the 
ORR.
The ORR will include data of all tumour assessments, regardless of whether it was scheduled 
or not.
ORR will be presented by the number and percentage of patients with a response (CR/PR) 


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including 95% CIs based on exact binomial proportions. 
Best objective response will also be summarised by n (%) for each category, with no formal 
statistical analysis presented.
9.4.2.2
Secondary Endpoint(s)
Primary analysis on secondary endpoints will be based on BICR reviewed data. Sensitivity 
analyses will be performed based on investigator assessments.
Duration of Response (DoR)
DoR will be defined as the time from the date of first documented response until the date of 
documented progression or death due to any cause in the absence of disease progression. The 
end of response should coincide with 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 that was CR or PR.
The analysis will include all patients in the response evaluable analysis set who had a 
response, regardless of whether the patient withdraws from therapy.
If a patient does not progress following a response, then the censoring time will be determined 
by applying the same censoring rules as applied for PFS.
Kaplan-Meier plots of DoR will be presented. Median DoR, including 95% CIs, will also be 
presented, calculated from the Kaplan-Meier curve. In addition, the number of patients still 
responding at 3, 6, and 12 months after initial response will also be presented. Swimmer plots 
that clearly show the profile of each patient who responds will also be produced.
Progression-Free Survival (PFS)
The PFS is defined as the time from date of first dose to date of objective disease progression 
or death (by any cause in the absence of progression) regardless of whether the patient 
withdraws from treatment or receives another anti-lymphoma therapy prior to progression. 
Patients who have not progressed or died at the time of analysis will be censored at the time of 
the latest date of assessment from their last evaluable assessment. The PFS time will always 
be derived based on scan/assessment dates and not on visit dates.
Kaplan-Meier plots of PFS will be presented. Summaries of the number and percentage of 
patients experiencing a PFS event, and the type of event (progression or death) will be 
provided along with the median PFS, its 95% CI, and the proportion of patients who were 
progression free at 6 months, 12 months, and 18 months.
The treatment status at progression of patients at the time of analysis will be summarised. This 
will include the number and percentage of patients who were on treatment at the time of 


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progression, the number and percentage of patients who discontinued study treatment prior to 
progression, the number and percentage of patients who have not progressed and were on 
treatment or discontinued treatment. This will also provide a distribution of number of days 
prior to progression for the patients who have discontinued treatment.
Overall Survival (OS)
The OS is defined as the time from date of first dose until death due to any case regardless of 
whether patient withdraws from treatment or receives another anti-lymphoma therapy. Any 
patient not known to have died at the time of analysis will be censored on the last recorded 
date on which the patient was known to be alive.
Note: Survival follow-up phone calls will be made in the week following the date of DCO for 
the analysis, if patients are confirmed to be alive or if the death date is after the DCO date 
these patients will be censored at the date of DCO.
Overall survival data will be presented similarly to the presentation described for PFS.
Time to First Subsequent Therapy or Death (TFST)
Time to first subsequent anti-lymphoma therapy or death is defined as time from date of first 
dose until the start date of subsequent anti-lymphoma therapy or death due to any cause and 
will include all dosed patients regardless of whether the patient withdraws from therapy, 
receives another anti-lymphoma therapy or clinically progresses prior to progression 
according to the Lugano 2014 Classification for NHL.
Time to first subsequent anti-lymphoma therapy or death data will be presented similarly to 
the presentation described for PFS.
Time to Objective Response (TTR)
Time to objective response is defined as the time from date of first dose until the date of first 
documented objective response and will include all patients in the response evaluable analysis 
set who had a response.
The TTR will be summarised (ie, number of patients [%] based upon the number of 
responders] by scheduled assessment time point that the response was first observed. 
Additionally, descriptive summary statistics will also be presented. Associated Kaplan-Meier 
curves may also be presented.
9.4.3
Safety
Safety analyses will be performed using the safety analysis set. Safety data will be presented 
using descriptive statistics unless otherwise specified.


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9.4.3.1
Adverse Events
Adverse events will be coded using the most recent version of MedDRA that will have been 
released for execution at AstraZeneca/designee.
Adverse events will be presented by SOC and/or PT, covering number and percentage of 
patients reporting at least one event and number of events where appropriate.
Only treatment-emergent AEs will be presented. Adverse events occurring prior to start of 
study treatment and post-treatment AEs will only be listed.
An overview of AEs will present the number and percentage of patients with any AE, AEs 
with outcome of death, SAEs, and AEs leading to discontinuation of treatment, AESIs, as well 
as AEs leading to withdrawal from study, as well as the number of individual occurrences in 
these categories.
Separate AE tables will be provided taking into consideration relationship as assessed by the 
investigator, maximum CTCAE grading, seriousness, death and events leading to 
discontinuation of treatment as well as other action taken related to treatment, events of 
special interest, other significant AEs and timing of events.
An additional table will present number and percentage of patients with most common AEs. 
Most common (eg, frequency of > x%, ≥x%) will be defined in the SAP.
Key patient information will be presented for patients with AEs with outcome of death, SAEs, 
AEs leading to discontinuation of treatment and AEs leading to treatment delay.
An AE listing for the safety analysis set will cover details for each individual AE.
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to treatment discontinuation. 
Based on the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered OAEs and reported as 
such in the CSR. A similar review of laboratory/vital signs/ECG data will be performed for 
identification of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment.


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Treatment emergent AE
The following events are considered treatment emergent:

AEs with an onset date on or after the first dose of study treatment and within 30 days 
after last dose of study treatment or up to the day prior to start of subsequent therapy, 
whichever comes first.

Worsening of pre-existing events on or after first dose of study treatment and within 
30 days after last dose of study treatment or up to the day prior to start of subsequent 
therapy.
Full details of AE analyses will be provided in the SAP.
9.4.3.2
Other Safety Endpoint(s)
Full details of the analysis of safety data will be provided in the SAP.
Exposure
Duration of exposure will be summarised appropriately.
Laboratory Safety Variable
For each scheduled post-baseline visit, descriptive statistics for all clinical chemistry and 
haematology parameters will be presented for observed values and change from baseline.
A shift table presenting number of patients with their laboratory status (eg, low, normal, high, 
or CTCAE grades) from baseline to maximum and minimum on-treatment values will be 
provided.
Elevation in liver parameters for assessments of Hy’s Law will be done and reported 
appropriately if potential cases have been identified during the course of the study.
Key patient information will be presented for patients with treatment-emergent changes in 
laboratory parameters outside of predefined criteria.
A frequency table of urinalysis presenting the number of patients reporting at least one 
treatment-emergent increase in baseline category will be provided. A shift table for urinalysis 
presenting the baseline assessment against the maximum on-treatment category will also be 
provided.
Supportive laboratory listings covering observed values and changes from baseline for each 
individual patient as well as abnormalities will be presented. 
Details of analyses of laboratory safety variables will be provided in the SAP.


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Vital Signs
For each scheduled post-baseline visit, descriptive statistics for all vital sign parameters will 
be presented for observed values and change from baseline.
A shift table presenting number of patients with their abnormality status (eg, low, normal, 
high,) from baseline to maximum and minimum on-treatment values will be provided.
Key patient information will be presented for patients with treatment-emergent changes in 
vital signs outside of predefined criteria.
Supportive vital sign listings covering observed values and changes from baseline as well as 
abnormalities will be provided.
Details of vital signs analyses, including definition of abnormality criteria (eg, definition of 
low, normal, high) and project specific criteria for treatment-emergent changes in vital signs 
parameters will be provided in the SAP.
Electrocardiogram
For each scheduled post-baseline assessment, descriptive statistics for all ECG parameters will 
be presented for observed values and change from baseline.
Uncorrected QT interval results will be corrected according to the Fridericia’s formula.
For QTcF a frequency table presenting number of patients with values exceeding thresholds of 
450 ms, 480 ms and 500 ms at any time during the treatment will be provided. Similarly, 
number of patients with change from baseline in QTcF exceeding 30 ms, 60 ms and 90 ms at 
any time during the treatment, as well as the combination of thresholds on observed values 
and change from baseline values will be provided.
A table presenting the interpretation of the ECG reading (normal, abnormal) at baseline and 
last assessment on treatment will be provided, including shifts in interpretation as compared to 
baseline.
Key patient information will be presented for patients with treatment-emergent ECG values 
outside of predefined criteria.
Supportive ECG listings covering observed values and change from baseline for each patient 
will be presented.
Details of ECG analyses, including definition of reference values and abnormalities will be 
provided in the SAP.


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Death
Details of any death will be listed for all patients.
9.4.4
Other Analyses 
9.4.4.1
Pharmacokinetics
Pharmacokinetic analyses will be performed based on the PK analysis set. Any exclusion of 
data will be documented and justified.
The plasma concentration-time data will be analysed by population PK methods using 
non-linear mixed-effects modelling. Pharmacokinetic 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.
Details will be outlined in a separate modelling analysis plan finalised before database lock 
and results may be reported separately.
Data from this study may be pooled with data from other capivasertib studies.
9.4.4.2
Patient-reported Outcomes (PROs)
Patient-reported outcome data from the EORTC QLQ-C30, 
, PRO-CTCAE, patient 
reported anti-diarrhoeal medication, PGI-TT, 
 will be analysed by 
descriptive summaries and graphical presentations. The analysis will be based on the all dosed 
patients.
The actual value and change from baseline in each of the functional scales, symptom scales 
and global health status/QoL scores in EORTC QLQ-C30 will be summarised descriptively at 
each time point in each cohort.
PRO-CTCAE, PGI-TT and patient-reported anti-diarrhoeal medication data will be 
summarised descriptively over time in each cohort, including the proportion of patients 
reporting different levels of each symptomatic AEs, overall side effects burden and 
anti-diarrhoeal medication use.
 
 
The compliance of each PRO questionnaires will also be summarised.
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The clinically meaningful change in EORTC QLQ-C30 subscale scores will be explored using 
anchor-based methods and distribution-based methods. Time to deterioration and proportion 
of patients with deteriorated, stable and improved scores in EORTC QLQ-C30 subscales will 
also be explored. Additional analyses for PRO-CTCAE data and other PRO measures may 
also be considered.
Further details will be included in the SAP.
9.4.5
Exploratory Analyses
 
 
 
 
 
 
 
 
Data from this study may be pooled with data from other capivasertib studies.
9.5
Interim Analyses
Interim analyses will be conducted separately for each Module and are described in the 
relevant Module.
9.6
Data Monitoring Committee
This study will have a Study Steering Committee (SSC). The details of the roles and 
responsibilities of the SSC are provided in a charter separate from the Core Protocol (see also 
Appendix A 5). The SSC will be reviewing safety data approximately every 6 months and 
additional SSC review may be triggered in case of significant new safety findings. A Safety 
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Review Committee may be established in case a module evaluating capivasertib in 
combination with other agents is added in the future.


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MODULE 1 – CAPIVASERTIB MONOTHERAPY IN PATIENTS WITH 
RELAPSED OR REFRACTORY B-CELL NON-HODGKIN 
LYMPHOMA
10
INTRODUCTION - MODULE 1
10.1
Module Summary – Module 1
10.1.1
Schedule of Activities – Capivasertib Monotherapy
The SoAs for Module 1 are presented in Table 6 (Screening and Treatment Period) and 
Table 7 (Follow-up Period).


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Table 6
Schedule of Activities (Screening and Treatment Period) – Module 1: Capivasertib Monotherapy
Study Cycles
(28-Day)
Screening a
Treatment Period
Notes
Details in 
CSP Section 
or Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle
4
Cycle 
5
Cycle 
6
Cycles 
7-12
Cycle ≥13 b
Cycle Day
-28 to -1
1
8
15
22
1
15
1
15
1
1
1
1
1
Visit Window
±2 d
±7 d
Informed consent
X
Appendix A 3
Inclusion and 
exclusion criteria
X
5.1; 5.2;13.1; 
13.2
Demography
X
5.1
Medical history
X
5.1
Disease 
characteristics c
X
5.1
Disease 
prognostic scores
X
8, Appendix J
Previous anti-
lymphoma 
therapies
X
5.1
Physical 
examination d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C1D1: Pre-dose; 
C1D15: post dose; 
Pre-dose at all 
other visits
8.2.1
Height
X
8.2.1
Weight
X
X
X
X
X
X
X
X
X
8.2.1
Vital signs d,e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pre-dose
8.2.2
ECOG 
performance 
status d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.5.1
12-lead ECG 
(triplicate) f
X
X
X
Pre-dose C3D1 and every 12 weeks thereafter, and as clinically 
indicated
C1D1: (Pre-dose 
and 1 to 2 h post 
dose)
8.2.3
ECHO/MUGA
At Screening and as clinically indicated
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Study Cycles
(28-Day)
Screening a
Treatment Period
Notes
Details in 
CSP Section 
or Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle
4
Cycle 
5
Cycle 
6
Cycles 
7-12
Cycle ≥13 b
Cycle Day
-28 to -1
1
8
15
22
1
15
1
15
1
1
1
1
1
Visit Window
±2 d
±7 d
Brain MRI/CT 
scan g
Only if clinically indicated 
8.1.2
Fresh or archival 
tumour sample h, r
X
When available 
(eg, at relapse)
8.6.1
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3
Concomitant 
medication and 
non-drug 
therapies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
Study treatment
Capivasertib 
dispensation
X
X
X
X
X
X
X
X
6
Capivasertib 
intake
BD 4 days on / 3 days off in each week of a 28-day cycle until PD or unacceptable toxicity
6.1
Capivasertib 
treatment 
compliance i
X
X
X
X
X
X
X
X
X
X
X
X
X
6.4
Laboratory assessments
Pregnancy test 
(WOCBP)
X (serum)
Urine pregnancy tests pre-dose on C1D1 and as clinically indicated
8.2.4
Haematology d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.4
Clinical chemistry
d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C1D1: pre-dose 
and 1 to 2 h post-
dose 
8.2.4
Viral serology j
X
For patients with positive anti HBcAb or anti-HCV Ab at screening, HBV DNA or HCV RNA every 
3 months from C1D1
8.2.4
SARS-CoV-2
X
As clinically indicated
8.2.4
Urinalysis d
X
X
X
X
X
X
X
X
X
X
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Study Cycles
(28-Day)
Screening a
Treatment Period
Notes
Details in 
CSP Section 
or Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle
4
Cycle 
5
Cycle 
6
Cycles 
7-12
Cycle ≥13 b
Cycle Day
-28 to -1
1
8
15
22
1
15
1
15
1
1
1
1
1
Visit Window
±2 d
±7 d
Serum IgA, IgG, 
IgM
X
X
X
(C7 
only)
8.2.4
HbA1c (fasted)
X
Every 12 weeks starting from C1D1 and as clinically indicated
8.2.4
Serum glucose 
(fasted) k
X
Pre-dose and 4 hours post-dose on C1D1. Pre-dose only at Day 1 of each subsequent cycle and as 
clinically indicated
8.2.4
Serum lipids 
(fasted)
X
Every 12 weeks starting from C1D1 and as clinically indicated
8.2.4
Tumour Assessments
CT scan l
X
Weeks 8, 16, 24, 36, 48, and 60 and thereafter every 24 weeks for FL/MZL and every 12 weeks for 
MCL, until disease progression
Window for CT 
scan: ± 7 days
8.1.2
PET scan n
X
Week 8, 16, and 24 and thereafter to confirm CR or as clinically indicated m
Window for PET 
scan: ± 7 days
8.1.2
Bone marrow 
(biopsy or 
aspirate) o
X
To confirm CR (if prior bone marrow involvement) and as 
clinically indicated
8.1.1
Response 
assessment 
Lugano 2014 
Classification
Weeks 8, 16, 24, 36, 48, and 60 and thereafter every 24 weeks for FL/MZL and every 12 weeks for 
MCL, or as clinically indicated until radiological PD
Window for 
response 
assessment: 
± 7 days
8.1.3.1
B symptoms
X
At every tumour assessment scan
8.1.4.3
Endoscopy/
histology
X (as 
clinically 
indicated)
To confirm CR (if prior gastrointestinal involvement), and as clinically indicated
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Study Cycles
(28-Day)
Screening a
Treatment Period
Notes
Details in 
CSP Section 
or Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle
4
Cycle 
5
Cycle 
6
Cycles 
7-12
Cycle ≥13 b
Cycle Day
-28 to -1
1
8
15
22
1
15
1
15
1
1
1
1
1
Visit Window
±2 d
±7 d
PRO collection
Prepare ePRO 
device and train 
patient
X
8.1.5
EORTC QLQ-
C30
C1D1 and every 4 weeks from C1D1 for the first 24 weeks and then every 12 weeks 
thereafter until 12 weeks post progression
8.1.5.1, 
Appendix K 1
C1D1 and every 12 weeks from C1D1 for the first 24 weeks
8.1.5.2, 
Appendix K 2
PRO-CTCAE
C1D1, every week from C1D1 for the first 4 weeks, every 4 weeks for the next 8 weeks (ie, at 
Week 8, Week 12), and every 12 weeks afterwards until EOT
8.1.5.3, 
Appendix K 3
Patient-reported 
anti-diarrhoeal 
medication
C1D1, every week from C1D1 for the first 4 weeks, every 4 weeks for the next 8 weeks (ie, at 
Week 8, Week 12), and every 12 weeks afterwards until EOT
8.1.5.4, 
Appendix K 4
PGI-TT
C1D1, every week from C1D1 for the first 4 weeks, every 4 weeks for the next 8 weeks (ie, at 
Week 8, Week 12), and every 12 weeks afterwards until EOT
8.1.5.5, 
appendix K 5
C1D1, every 4 weeks from C1D1 for the first 24 weeks and then every 12 weeks 
thereafter until 12 weeks post progression
8.1.5.6, 
Appendix K 6
Every 12 weeks from C1D1 for the first 24 weeks
8.1.5.7, 
Appendix K 7
C1D1 and every 12 weeks from C1D1 until 12 weeks post progression
8.1.5.8, 
Appendix K 8
a
Screening tests should be performed within 28 days before the first administration of capivasertib, unless otherwise indicated.
b
Treatment with capivasertib may be continued for as long as there is no PD or unacceptable toxicity. In the case of a capivasertib 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 days long.
c
Including also disease stage (I, II, III, IV) and extent (S [splenic involvement], E [extranodal disease], X [bulky disease], bone marrow involvement) as 
determined by the investigator at screening.
d
Unscheduled assessments are allowed as clinically indicated.
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Table 7
Schedule of Activities (Follow-up Period) – Module 1: Capivasertib Monotherapy
Study Cycles
(28-Day)
Follow-up Period
Notes
Details in CSP Section 
or Appendix
EOT a
Post-
treatment 
follow-up
LTFU b
Study Day
30 days after 
last dose
Every 
12 weeks
Visit Window
±7 d
Physical examination c
X
X
8.2.1
Weight
X
X
8.2.1
Vital signs c,d
X
X
8.2.2
ECOG performance status c
X
8.2.5.1
12-lead ECG (triplicate) e
X
X
8.2.3
ECHO/MUGA
X
As clinically 
indicated
8.2.5.2
Fresh or archival tumour 
sample f, j
X (optional at 
progression)
Unscheduled tumour biopsies may be 
submitted to central laboratory if available
8.6.1
Adverse events
X
X
X g
8.3
Concomitant medication and 
non-drug therapies
X
X
X h
6.5
Laboratory assessments
Pregnancy test (WOCBP)
X (urine)
X (urine)
8.2.4
Haematology c
X
X
8.2.4
Clinical chemistry c
X
X
8.2.4
Urinalysis c
X
X
8.2.4
Serum IgA, IgG, IgM
X
8.2.4
HbA1c (fasted)
X
8.2.4
Serum glucose (fasted)
X
X
8.2.4
Serum lipids (fasted)
X
X
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10.2
Rationale for Module 1
The overall rationale for investigating capivasertib in B-cell NHL is presented in Section 2.1
of the Core Protocol. Module 1 Cohorts 1A, 1B, and 1C plan to investigate the safety and 
efficacy of capivasertib monotherapy in patients with R/R B-cell NHL.
10.3
Background – Module 1
10.3.1
Cohort 1A – Therapeutic Options for R/R Follicular Lymphoma
Follicular lymphoma is the most frequent subtype of indolent NHL and accounts for 
approximately 20% of all NHLs. This histology is further divided into 3 different grades 
(Grades 1 to 3) reflecting the heterogeneity in the biology of the disease. Although median OS 
is > 15 years, FL remains an incurable disease in most of the patients exhibiting a relapsing 
and remitting pattern. Median PFS progressively shorten over time with each subsequent line 
of therapy beyond the first (eg, 18, 9.6, 8.2 and 8.1 months after second, third, fourth, and 
≥fifth lines of therapy respectively), highlighting a clear unmet need for R/R patients (Link et 
al 2019).
The management of R/R disease include anti-CD20 based chemo-immunotherapy, autologous 
HSCT and chemo-free options such combination of lenalidomide and rituximab, PI3K 
inhibitors, and tazemetostat. Three PI3K inhibitors (idelalisib, duvelisib, copanlisib) have 
been approved for use in the US (only 1 in Europe, idelalisib) in FL that relapsed after at least 
2 prior systemic therapies based on single-arm, Phase II studies. In idelalisib-treated FL 
patients, ORR was 56%, while median PFS was 11.0 months (Salles et al 2018). In copanlisib-
treated FL patients, ORR was 59% and median DoR was 12.2 months (ALIQOPA USPI). In 
duvelisib-treated FL patients, ORR was 42% (CR 1%), and median DoR was 10 months 
(Flinn et al 2019). However, the associated safety profile (in particular, life-threatening 
infections, pneumonitis, transaminitis, colitis) together with their schedule of administration 
(eg, IV use for copanlisib) often hampers their extensive use in clinical practice. Recently, the 
EZH inhibitor tazemetostat has been approved based on an open-label Phase II trial. In 
patients with EZH2mut disease, ORR was 69% with a median DoR of 10.9 months and a 
median PFS of 13.8 months. In patients with wild-type EZH2, the ORR was 35%, median 
DoR was 13 months and median PFS was 11.1 months (Morschhauser et al 2020).
10.3.2
Cohort 1B – Therapeutic Options for R/R Marginal Zone Lymphoma
Marginal zone lymphomas represent the second most common subtype of indolent lymphoma 
accounting for 5-15% of NHL, although individually the 3 variants – nodal MZL, splenic 
MZL and extranodal MZL of mucosa-associated lymphoid tissue lymphoma (Sehn 2016). For 
patients with MZL relapsing disease after at least one CD20-based FDA-approved 
chemotherapy-free options include the BTK inhibitor ibrutinib (approved in MZL on the basis 
of Study 1121, a phase II trial showing ORR of 46%, CR of 3% [IMBRUVICA USPI]) and 
combination of lenalidomide and rituximab for patients after > 1 line of treatment of 


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lenalidomide (REVLIMID SmPC). However, in a post-hoc analysis in MZL subset, despite 
the ORR higher in lenalidomide and rituximab combination vs rituximab monotherapy (64% 
vs 44%) no PFS improvement was observed in this cohort compared to other histologies 
(Leonard et al 2019).
10.3.3
Cohort 1C – Therapeutic Options for R/R Mantle Cell Lymphoma
Mantle cell lymphoma is considered an aggressive lymphoma representing 5% to 7% of NHL 
and it’s defined by the translocation (11;14)(q13;q32) and resulting in constitutive 
overexpression of cyclin D1. PI3K-dependent AKT activation leads to inhibition of glycogen 
synthase kinase 3β, which, when activated, phosphorylates cyclin D1, triggering its nuclear 
export and proteasomal degradation (VanArsdale et al 2015). Constitutive activation of PI3K 
in MCL alters CD1d-mediated antigen processing and presentation, ultimately resulting in 
decreased anti-tumour NKT cell responses. MCL is a heterogeneous disease with variable 
presentations, clinical and biologic risk factors, and treatment approaches. (Maddocks 2018) 
that often respond well in the frontline setting with combination chemotherapy, although the 
responses are often not durable with a median PFS after second, third, fourth, and ≥ fifth lines 
of therapy of 14, 6.5, 5, and 3.3 months, respectively (Kumar et al 2019). Treatment options 
for R/R MCL include the BTK inhibitors ibrutinib and acalabrutinib; bortezomib, 
lenalidomide with or without rituximab, and brexucabtagene autoleucel (IMBRUVICA USPI; 
CALQUENCE USPI; VELCADE USPI; REVLIMID USPI;TECARTUS USPI). Although the 
response rates with single-agent BTK inhibitors are relatively high, approximately one-third 
of patients display primary resistance to BTK inhibitors, and nearly all patients eventually 
progress. The outcomes of patients who progress following BTK inhibitors are relatively poor 
with an ORR ranging between 25% and 42% and median OS between 6 and 10 months with 
salvage therapies (Martin et al 2016; Epperla et al 2009; Jain et al 2018).
Recently, brexucabtagene autoleucel, a CD19-directed CAR-T therapy has been approved for 
R/R MCL failing ≥2 lines of systemic therapy including a BTK inhibitor, showing an ORR of 
85% and a 12-month PFS and OS of 61% and 83%, respectively (Wang et al 2020).
Promising data from CAR-T therapies and bi-specifics antibody have also recently emerged in 
the landscape of indolent and aggressive lymphomas. However, toxicities related to fatal cases 
of cytokine release syndrome / neurotoxicity and costs should be taken into account in the 
treatment choice for R/R patients in future. In particular, for older patients and for those with 
co-morbidities that preclude aggressive treatment and for whom dependence on hospitals for 
infusional therapies represents a significant challenge, are likely to benefit greatly from oral 
monotherapy (Flinn et al 2019).
10.4
Benefit/Risk Assessment
See Section 2.3 of the Core Protocol, for an overall benefit-risk assessment for capivasertib.


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11
OBJECTIVES AND ENDPOINTS – MODULE 1
See Section 3 of the Core Protocol.
12
STUDY DESIGN – MODULE 1
Module 1 is to be used in conjunction with the Core Protocol for the conduct of the study. This 
Module contains information required for investigators to conduct the study of capivasertib 
monotherapy in patients with FL, MZL, and MCL.
This Module includes 3 cohorts:

Cohort 1A: capivasertib monotherapy in patients with R/R FL

Cohort 1B: capivasertib monotherapy in patients with R/R MZL

Cohort 1C: capivasertib monotherapy in patients with R/R MCL
Capivasertib will be taken at 480 mg orally BD 4 days on/3 days off until disease progression 
unless there is evidence of unacceptable toxicity or if the patient/investigator requests to stop 
the treatment.
Module 1 for capivasertib monotherapy will include:

A Screening Period of 28 days 

A Treatment Period comprised of 28-day treatment cycles, during which patients will 
receive study treatment.

A Follow-up Period which includes:

An EOT visit to be conducted within 7 days after discontinuation of study treatment.

A post-treatment follow-up visit to be conducted 30 days (± 7 days) after last dose of 
study treatment.

A LTFU Period including collection of subsequent anti-lymphoma therapy, 
drug-related SAEs, concomitant medication and non-drug therapies related to the 
management of drug-related SAEs, and survival will be assessed every 12 weeks 
(± 7 days) and response assessments for patient who stop study treatment without 
PD.
A total of 272 patients will be enrolled:

94 patients in Cohort 1A

94 patients in Cohort 1B

84 patients in Cohort 1C


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An interim analysis focusing on safety will be conducted when approximately 30 patients 
across the three cohorts have had the opportunity to be treated for 8 weeks and may inform 
preliminary efficacy based on Investigator-assessed ORR.
An interim analysis bridging Cohorts 1A and 1B will be performed for efficacy, based on 
BICR, after a total of n = 28 patients in Cohort 1A plus Cohort 1B have had the opportunity to 
be treated for 4 months. 
An interim analysis for efficacy, based on BICR, will be performed after n = 24 patients in 
Cohort 1C have had the opportunity to be treated for 4 months.
Enrolment will not pause whilst awaiting the interim data analysis. Additional details on the 
interim analyses will be provided in the SAP.
12.1
Justification for Dose
Oral capivasertib 480 mg BD given intermittently (4 days on/3 days off) is the recommended 
Phase II dose regimen for monotherapy. This corresponds to the maximum tolerated dose.
Although in the dose-escalation Phase I study (Banerji et al 2018) in patients with solid 
tumours, capivasertib 480 mg BD given intermittently (4 days on/3 days off) was defined as 
the maximum tolerated dose for the intermittent schedule 4 days on/3 days off, the selection of 
recommended Phase 2 dose for monotherapy trials, including CAPITAL, considered not only 
safety and long-term tolerability, but also evidence of target engagement and PK/PD 
relationships. 
Following assessment of the multiple dosing regimens explored (either continuous or 
intermittent schedules), capivasertib 480 mg BD given intermittently (4 days on/3 days off)
was considered the optimal balance between tolerability and efficacy. Refer to the current 
capivasertib IB for details.
The following evidences support the choice of the starting dose in the CAPITAL study and 
provide a justification of the selected intermittent schedule.

Better long-term tolerability compared to other tested schedules (Banerji et al 2018).

Significant biological activity as shown by target engagement/inhibition (Robertson et al 
2020).

Well-characterized and manageable safety profile based on wide clinical experience to 
date (refer to the current capivasertib IB), with similar clinical behaviour and PK/PD 
profiles both in Western and Asian population (Tamura et al 2016).


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12.2
End of Study Definition
See Section 4.4 of the Core Protocol for end of study definition.
For the purpose of the primary analysis for each cohort, the DCO will be after all patients 
treated with capivasertib in that cohort have had the opportunity to be treated for 6 months. At 
the time of this DCO, the data analysis will be performed, and a cohort-specific CSR may be 
written.
After the primary DCO, efficacy and safety data will continue to be collected. 
The DCO for the final analysis for each cohort will occur approximately 18 months after the 
last patient treated with capivasertib has been enrolled in the cohort or when 70% of patients 
have progressed or died (due to any reason) in the cohort, whichever occurs first.
Additional OS follow-up analyses may be performed separately for each cohort after the final 
analysis, until 70% of the patients treated with capivasertib have died due to any cause.
13
STUDY POPULATION – MODULE 1
13.1
Inclusion Criteria
In addition to meeting all core inclusion criteria (Section 5.1), patients are eligible to be 
included in the study cohort only if all of the following cohort-specific criteria apply.
13.1.1
Additional Inclusion Criteria for Cohort 1A (R/R FL)
1
Histologically confirmed diagnosis of FL Grade 1, 2, or 3a as assessed by investigator or 
local pathologist.
2
Current need for systemic treatment based on the Investigator’s opinion.
3
Relapsed, progressed, or refractory (defined as failure to achieve at least a PR) after at 
least 2 prior systemic lines of therapy (including anti-CD20mAb and an alkylating agent).
The treating physician should discuss with the patient all available treatment 
options, including the use of CAR-T cell therapy, evaluating benefits and risks before 
considering enrolment in this study.
4
This criterion was removed in Amendment 03; refer to Protocol Amendment Summary of 
Changes Table for more information.
5
Bi-dimensionally measurable disease on cross sectional imaging by CT or MRI with at 
least one nodal lesion > 1.5 cm in the long axis or at least one extranodal lesion > 1 cm in 
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13.1.2
Additional Inclusion Criteria for Cohort 1B (R/R MZL)
1
Histologically confirmed MZL including splenic, nodal, and extranodal subtypes as 
assessed by investigator or local pathologist.
2
Current need for systemic treatment based on the Investigator’s opinion.
3
Relapsed, progressed or refractory (defined as failure to achieve at least a PR) after at 
least 2 prior systemic lines of therapy (including at least one anti-CD20mAb directed 
regimen either as monotherapy or as chemoimmunotherapy; Helicobacter pylori
eradication and radiation therapy alone will not be considered a systemic treatment 
regimen).
4
This criterion was removed in Amendment 03; refer to Protocol Amendment Summary of 
Changes Table for more information.
5
Bi-dimensionally measurable disease on cross sectional imaging by CT or MRI with at 
least one nodal lesion > 1.5 cm in the long axis or at least one extranodal lesion > 1 cm in 
long axis.
13.1.3
Additional Inclusion Criteria for Cohort 1C (R/R MCL)
1
Histologically confirmed MCL, with documentation of monoclonal B cells that have a 
chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1, as assessed 
by investigator or local pathologist.
2
Relapsed, progressed, or refractory (defined as failure to achieve at least a PR) after at 
least 2 prior systemic lines of therapy.
3
Patients must have received as prior therapies:

BTK inhibitor and

Anti-CD20mAb therapy.
The treating physician should discuss with the patient all available treatment 
options, including the use of CAR-T cell therapy, evaluating benefits and risks before 
considering enrolment in this study.
4
Bi-dimensionally measurable disease on cross sectional imaging by CT or MRI with at 
least one nodal lesion > 1.5 cm in the long axis or at least one extranodal lesion > 1 cm in 
long axis.
5
South Korea Only: In the case of patients with MCL, eligibility is limited to cases where 
there is no beneficial treatment available in South Korea.
13.2
Exclusion Criteria
The additional exclusion criteria for Module 1 are:
1
Follicular lymphoma grade 3B.


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2
Known transformation to aggressive lymphoma, eg, large cell lymphoma.
3
This criterion was removed in Amendment 03; refer to Protocol Amendment Summary of 
Changes Table for more information.
4
Patients who, in the Investigator’s opinion, require immediate cytoreductive therapy for 
disease control.
13.3
Lifestyle Considerations
There are no additional lifestyle considerations for this Module.
14
STUDY INTERVENTION – MODULE 1
14.1
Study Intervention(s) Administered
All patients will receive treatment with the investigational product capivasertib.
Table 8
Investigational Product
Intervention name
Capivasertib (AZD5363)
Type
Drug
Dose formulation
Tablet
Unit dose strength(s)
mg
mg
Dosage level(s)
Starting dose:
480 mg
(
mg) BD
Reduced dose 1:
mg
(
mg) BD
Reduced dose 2:
mg
(
mg) BD
Given as an intermittent schedule: Days 1 to 4 in each week of a 28-day treatment 
cycle, depending on tolerability. Morning and evening doses taken approximately 
12 ± 2 hours apart (at the same hour of the day).
Route of administration
Oral
Use
Experimental
IMP and NIMP
IMP
Sourcing
Supplied by AstraZeneca
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.
BD: twice daily; IMP: investigational medicinal product; NIMP: non-investigational medicinal product.
14.2
Dose Modification
14.2.1
Capivasertib Dose Modification and Guidance
Substantial acute toxicities should be managed as medically indicated and with temporary 
suspension of capivasertib as appropriate. Recommendations for the management of general 
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and specific capivasertib-related toxicities are provided in Appendix G of the Core Protocol.
Dose reductions or holds are allowed as clinically indicated by the Study Physician. For each 
patient, a maximum of 2 dose reductions will be allowed. Guidance on dose level reduction is 
presented in Table 9.
Table 9
Capivasertib Dose Level Modifications
Dose Level
Capivasertib Oral Daily Dose
Starting Dose
intermittent (4 days on / 3 days off), 480 mg 
(
-mg tablets) BD
-1 Dose Level
intermittent (4 days on / 3 days off), 
mg 
(
-mg tablets) BD
-2 Dose Levels
intermittent (4 days on / 3 days off), 
mg 
(
-mg tablets) BD
BD: twice daily.
Dose re-escalations are not allowed.
15
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL –
MODULE 1
15.1
Discontinuation of Study Intervention
There are no additional criteria for a patient to be discontinued from capivasertib 
monotherapy. Refer to the Core Protocol, Section 7.1.
Criteria for stopping or pausing the study recruitment
At any time point during the trial, the study recruitment will pause if at least one of the 
following events occur:

Fatal event deemed related to study therapy by the sponsor and in discussion with the 
SSC (probable or certain causality based on World Health Organisation-Uppsala 
Monitoring Centre after full aetiological work-up). This will also result in a 
comprehensive review of safety.

Unexpected and life-threatening non-hematologic events deemed related to study therapy 
by the sponsor and in discussion with the SSC. Note: As hyperglycaemia, rash, diarrhoea 
and hypersensitivity reactions are expected adverse reactions these events will be further 
addressed at the time of the safety interim analysis described below and will not be 
considered as stopping criteria.

Sponsor decision that study participants are placed at undue safety risk.
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
Sponsor decision to discontinue the development of the study treatment in the proposed 
indications.
At the time of interim safety analysis (after approximately 30 patients in Module 1 have had 
the opportunity to be treated for 8 weeks), the study recruitment may be paused, pending 
investigation by the sponsor in discussion with SSC, if at least one of the following events 
occur:

An increase in the incidence of Grade ≥ 3 Important Identified Risks of hyperglycaemia, 
diarrhoea, and rash (irrespective of Investigator-determined causality), compared to the 
reported incidence in solid tumour patients. The proposed limits would correspond to:

> 34% participants experiencing Grade ≥ 3 diarrhoea

> 40% participants experiencing Grade ≥ 3 hyperglycaemia

> 27% participants experiencing Grade ≥ 3 maculo-papular rash

≥2 patients experiencing systemic drug hypersensitivity reactions

>22% of participants discontinuing study treatment due to any grade, causally-related AE 
( ie, > 10% increase compared to the reported incidence is solid tumour patients).

≥ 3 patients (≥ 10%) developing a persistent (ie, lasting more than 21 days despite 
supportive care) Grade ≥ 3 cytopenia (ie, neutropenia, anaemia or thrombocytopenia) 
within the first 28 days of capivasertib treatment, that in the opinion of the Investigator, 
cannot be clearly attributable to baseline bone marrow involvement by lymphoma or to 
extraneous cause.
In the event that the accrual is paused, AZ will notify Investigators, IRB and Regulatory 
Authorities immediately.
Study recruitment initially paused will restart only upon approval by Regulatory Authorities 
and IRB/IEC of a substantial protocol amendment, containing additional information on 
benefit/risk and safety measures as applicable.
For patients who are receiving capivasertib while the decision to stop or pause study accrual is 
under consideration:

The Investigator should promptly inform the patients of the possible harm.

An individual risk/benefit assessment should be conducted by the Investigator and by the 
sponsor in order to decide whether the risks of continuing the study treatment overweight 
the benefit, taking into account multiple factors including the disease response to 
treatment, the number of cycles already received, prior comorbidities and AEs 
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
Overall decision to stop dosing should be taken in conjunction with SSC.
All potential safety signals arising from Grade ≤4 treatment-related AEs will be reviewed in 
the context of the overall benefit-risk. Upon review, any AE deemed to adversely affect the 
overall benefit risk, will trigger an ad hoc SSC for comprehensive safety review and protocol 
amendment as needed.
15.2
Temporary Discontinuation
Treatment with capivasertib may be interrupted up to 21 days, for the management of 
capivasertib-related toxicities and may be restarted, as recommended in Appendix G of the 
Core Protocol. If treatment cannot be restarted within 21 days (except for rash, within 
28 days), it will be permanently discontinued.
16
STUDY ASSESSMENTS AND PROCEDURES – MODULE 1
16.1
Overdose
The maximum tolerated dose for capivasertib and recommended dosing schedule is 480 mg 
BD 4 days on / 3 days off as monotherapy on intermittent dosing schedule.
17
STATISTICAL CONSIDERATIONS – MODULE 1
17.1
Statistical Hypotheses
Cohorts 1A (FL) and 1B (MZL)
For ORR the following hypothesis will be analysed at the 5% 2-sided level for each of the 
cohorts.
H0: ORR = 40% versus
H1: ORR = 55%.
Cohort 1C (MCL)
For ORR the following hypothesis will be analysed at the 5% 2-sided level:
H0: ORR = 25% versus
H1: ORR = 40%.
17.2
Sample Size Determination
Cohorts 1A (FL) and 1B (MZL)
 
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Cohort 1C (MCL)
 
 
17.3
Statistical Analyses
17.3.1
General Considerations
Table 10 details which data will be analysed at each time point.
Table 10
Summary of analyses and data cut-off triggers
Analysis
Trigger
Data type included
Safety Interim
After approximately 30 patients in 
Module 1 have had the opportunity to 
be treated for at least 8 weeks.
Safety data.
Preliminary efficacy data based on
investigator responses will also be 
included.
Efficacy Interim
Cohorts 1A and 1B: After 28 patients 
(either FL or MZL) treated with 
capivasertib have had the opportunity 
to be treated for 4 months.
Cohort 1C: After 24 patients (MCL) 
treated with capivasertib have had the 
opportunity to be treated for 4 months.
Efficacy data (including ORR, DoR, 
PFS, TTR, and TFST).
Safety data will also be included.
Primary Analysis
After all patients treated with 
capivasertib have had the opportunity 
to be treated for 6 months. Analyses 
will be conducted separately for each 
cohort.
All data (including summary OS data 
available at the time of the primary 
analysis).
Final Analysis
Approximately 18 months after the last 
patient treated with capivasertib has 
been enrolled in the cohort or when 
70% of patients have progressed or 
died (due to any reason) in the cohort, 
whichever occurs first. Analyses will 
be conducted separately for each 
cohort.
All data (including summary OS data 
available at the time of the final 
analysis).
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Analysis
Trigger
Data type included
OS Follow-up Analysis
After the final analysis until 70% of 
patients treated with capivasertib have 
died due to any cause. Analyses will be 
conducted separately for each cohort.
OS
DoR: duration of response; FL: follicular lymphoma; MCL: mantle cell lymphoma; MZL: marginal zone 
lymphoma; ORR: objective response rate; OS: overall survival; PFS: progression-free survival, TFST: Time to 
first subsequent therapy or death; TTR: Time to objective response.
Additional data cuts may also be performed, if required.
17.4
Interim Analyses
Interim analysis for safety
An interim analysis for safety will be conducted after approximately 30 patients across the 
three cohorts 1A, 1B, and 1C in Module 1 have had the opportunity to be treated for at least 8 
weeks. 
A comprehensive review of all available clinical and PK/PD data (if available) will be 
performed by AZ together with the SSC. Based on these findings should any new safety 
signals emerge, AZ may opt to amend the protocol to adjust dosing schedule and/or toxicity 
management guidelines.
This interim analysis will also include preliminary efficacy data using results based on 
investigator response. 
Recruitment will not be paused while the interim analysis is evaluated. The SAP will describe 
the planned interim analysis in greater detail.
Interim analysis for efficacy
Cohorts 1A (FL) and 1B (MZL)
An interim analysis will be performed after a total of 28 patients enrolled in Cohort 1A plus 
Cohort 1B have had the opportunity to be treated for 4 months.
The interim analysis will be performed using results from BICR.
This interim analysis will be assessed against a decision framework (Frewer et al 2016) for 
ORR based on a lower reference value of 40% and a target value (a desired signal to be 
observed) of 55%. The interim analysis will be based on data from patients from the 2 cohorts 
combined. 
With 28 patients treated with capivasertib monotherapy who have had the opportunity to be 
treated for 4 months, it may be considered futile to continue development of these cohorts if 


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there is < 10% probability for the ORR to be greater than 55%. This translates into observing 
11 or fewer responders out of 28 patients; an ORR of 40% which has a 2-sided exact binomial 
80% CI of 26.7% to 53.2%; wherein the upper confidence limit is below 55%.
Additionally, a greater than 80% probability for the ORR to be above 40% may be considered 
a good signal. This translates into observing 14 or more responders out of 28 patients; an ORR 
of 50%, which has a 2-sided exact binomial 60% CI of 40.4% to 59.6% wherein the lower 
confidence limit is above 40%.
Recruitment will not be paused while the interim analysis is evaluated.
Based on the interim results, study enrolment could pause and the sponsor may opt to amend 
the protocol to adjust dosing schedule based on emerging data, permanently close the specific 
cohort or add in a new cohort evaluating capivasertib in combination with other agents in that 
population which would be detailed in an amendment.
The SAP will describe the planned interim analysis in greater detail.
Cohort 1C (MCL)
An interim analysis will be assessed against a decision framework (Frewer et al 2016) for 
ORR based on a lower reference value of 25% and a target value (a desired signal to be 
observed) of 40%.
With 24 patients treated with capivasertib monotherapy who have had the opportunity to be 
treated for 4 months, it may be considered futile to continue development of this cohort if 
there is < 10% probability for the ORR to be greater than 40%. This translates into observing 
6 or fewer responders out of 24 patients; an ORR of 25% which has a 2-sided exact binomial 
80% CI of 13.7% to 39.8%; wherein the upper confidence limit is below 40%.
Additionally, a greater than 80% probability for the ORR to be above 25% may be considered 
a good signal. This translates into observing 9 or more responders out of 24 patients; an ORR 
of 38%, which has a 2-sided exact binomial 60% CI of 27.8% to 48.2% wherein the lower 
confidence limit is above 25%.
Recruitment will not be paused while the interim analysis is evaluated.
Based on the interim results, study enrolment could pause and the sponsor may opt to amend 
the protocol to adjust the dosing schedule based on emerging data, permanently close the 
specific cohort or add in a new cohort evaluating capivasertib in combination with other 
agents in that population which would be detailed in an amendment.
The SAP will describe the planned interim analysis in greater detail.


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18
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study patients.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations
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 patients and the safety of a 
study treatment under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilising medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

European Medical Device Regulation 2017/745 for clinical device research (if 
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
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 IB and will notify the IRB/IEC, if appropriate according to 
local requirements.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 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 and they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the 
study. Patients or their legally authorised representative will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
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 the written consent was obtained. 
The authorised person obtaining the informed consent must also sign the ICF.

Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the patient or the patient’s legally authorised 
representative.
Patients who are rescreened are not required to sign a new ICF if the rescreening occurs 
within 28 days of the signing of the ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorised 
designee will explain to each patient the objectives of the analysis to be done on the samples 
and any potential future use. Patients will be told that they are free to refuse to participate in 
any optional samples or the future use and may withdraw their consent at any time and for any 
reason during the retention period.


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Potential Changes to Informed Consent During the COVID-19 Outbreak
General Principles
The rights, safety, and wellbeing of the study patients are the most important considerations 
and should prevail over interests of science and society. All informed consent activities must 
follow ICH GCP; the CSP; and local laws, regulations, and guidance. Prospective protocol 
waivers with respect to enrolment remain unacceptable. Patients should not be included in 
studies without written informed consent according to national laws and regulations and 
proper eligibility assessment.
The reconsent process described in this appendix must be adopted only at sites/countries 
affected by the COVID-19 outbreak where reaching the site means placing the study patient 
under unnecessary risk. The described process does not overrule local laws, regulations and 
guidance; where differences arise, the latter must be followed.
If the need for re-consenting study patients arises, visiting the investigator sites for the sole 
purpose of obtaining reconsent should be avoided.
Any validated and secure electronic system already used in the study for obtaining informed 
consent can be used as per usual practice and if in compliance with local regulations.
Process for Reconsent of Study Patients at Sites Affected by the COVID-19 Outbreak
Before reconsent is obtained, the approved updated patient information sheet and consent 
form should be provided to study patients by email. If the study patient is not able to receive 
emails, courier or mail should be used.
Verbal consent via phone or teleconference is allowed.
If possible, verbal consent should be supplemented with email confirmation. The investigator 
should emphasise that study patients should only use email to confirm their ICF consent and 
that the patient should not include any sensitive personal identifier (eg, date of birth, social 
security number) or medical information including AEs.
Please note: Study patients should not sign the document at home after giving verbal consent. 
The phone call or teleconference should be informative. The document will be signed and 
filed with the patient’s source data once the study patient is able to attend the site. Under no 
circumstances should the study patient scan and send the document back via email.
Verbal consent and print-out of the email confirmation (if available and once possible) must 
be documented by the investigator or delegate (if applicable) in the study patient’s medical 
records.
Documentation should include details on when the contact took place, the reason why the 


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study patient could not reach the site, any important details of the consenting call/concerns 
raised, and any questions raised (especially on safety measures) by the study patient and that 
these were answered satisfactorily by the site consenting party.
At the earliest possible occasion, consent must be documented via standard consent process. 
This would not apply if the study patient is lost to follow-up, dies, or the study ends before the 
COVID-19 outbreak is over. In this case the reason why the study patient did not sign the 
document in person has to be documented in the study patient’s medical records.
A 4
Data Protection

Patients will be assigned a unique identifier by the sponsor. Any patient records or 
datasets that are transferred to the sponsor will contain the identifier only; 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 and use of 
their data must also be explained to the patient in the informed consent. 

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.
A 5
Committees Structure
The safety of all clinical studies is closely monitored on an on-going basis by the sponsor in 
consultation with Patient Safety. Issues identified will be addressed; for instance, this could 
involve amendments to the protocol and letters to investigators.
This study will have an SSC. The primary responsibility of the SSC will be to provide 
guidance on design, conduct, analysis, and reporting of this trial at the sponsor’s request. 
Decisions and recommendations of the Committee are not binding on the Company. Full 
details on the SSC are provided in a charter separate from this protocol.
A Safety Review Committee may be established in case a module evaluating capivasertib in 
combination with other agents is added in the future.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the main study results when they are available. The clinical study and/or 
summary of main study results may also be available on other websites according to the 
regulations of the countries in which the main study is conducted.


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A 7
Data Quality Assurance

All patient data relating to the study will be recorded on 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 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.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, CROs).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the 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 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.

Data entered in 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.

Definition of what constitutes source data can be found in the source data agreement for 
each site.


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A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
patients.
The first act of recruitment is the first site open and will be the study start date.
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. 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 patients by the investigator

Discontinuation of further study treatment development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the patient and 
should assure appropriate patient therapy and/or follow-up.
Patients from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 


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


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malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 
is being treated by the Investigational Product under study and is not the development of new 
or progression of existing metastasis to the tumour under study). Malignant tumours that – as 
part of normal, if rare, progression – undergo transformation (eg, Richter’s transformation of 
B-cell chronic lymphocytic leukaemia into diffuse large B-cell lymphoma) should not be 
considered a new malignant tumour.
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).
Hospitalisation
Outpatient treatment in an emergency room is not in itself an serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important Medical Event or Medical Treatment
Medical judgement should be exercised in deciding whether a case is serious in situations 
where important medical events may not be immediately life threatening or result in death, 
hospitalisation, disability or incapacity but may jeopardise the patient or may require medical 
treatment to prevent one or more outcomes listed in the definition of serious. These should 
usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse


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Intensity Rating Scale:
The grading scales found in the revised NCI CTCAE v5 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 B 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 B 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 B 2.
B 3
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 judgement. With no available facts or arguments to suggest a 
causal relationship, 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.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study treatment that either causes harm to the patient 
or has the potential to cause harm to the patient. 
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 patient.
Medication error includes situations where an error. 

Occurred

Was identified and intercepted before the patient received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the patient

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 


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


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
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) and 
records relevant processing information related to the samples whilst at site.
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 record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives 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 or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample 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.
C 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/repatriated, and the action documented. If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures patient’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that patient, if stored at the study 
site, are immediately identified, disposed of as appropriate, and the action documented.

Ensures that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 


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and the action is documented and study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
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. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
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, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content


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Appendix D
Optional Genomics Initiative Sample
D 1
Use/Analysis of DNA

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. This 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. Therefore, where local regulations and IRB/IEC 
allow, a saliva sample will be collected for DNA analysis from consenting patients.

This optional 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 a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
D 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population

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.
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 and in the relevant Module and: Provide 
informed consent for the Genomics Initiative sampling and analyses.
Exclusion Criteria

Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
Withdrawal of Consent for Genetic Research

Patients may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 
withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
Section 7.2 of the main Clinical Study Protocol.


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Collection of Samples for Genetic Research

 
Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding patients who may withdraw due to an AE. Only one 
sample should be collected per patient for genetics during the study.
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 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).

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 A.
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 this 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 addendum for the Genomics Initiative 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 PI(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.
CCI


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Participant 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. 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 genetic 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 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.


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


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elevations in transaminases and TBL must occur.
E 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
Local Laboratories Being Used:
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 Section E 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
E 4
Follow-up
E 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.
E 4.2
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
intervention (see Section E 6).

Notify the AstraZeneca representative who will then inform the central Study Team. 

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.


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
For patients that met PHL criteria prior to starting study treatment, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the patient’s 
condition.

The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up (including any further laboratory testing) and 
the continuous review of data.

Subsequent to this contact the investigator will:

Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.

Complete the three 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 TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
study treatment, to ensure timely analysis and reporting to health authorities within 
15 calendar days from date PHL criteria was met. The AstraZeneca Global Clinical Lead or 
equivalent and Global Safety Physician will also be involved in this review together with 
other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
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


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
If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study treatment:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of PHL, (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to study treatment and 
seriousness criteria is medically important, according to CSP process for SAE reporting.

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
E 6
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Intervention
This section is applicable to participants with liver involvement by the disease who meet PHL 
criteria on study treatment, having previously met PHL criteria at a study visit prior to starting 
study intervention.
At the first on-study intervention occurrence of PHL criteria being met the investigator will 
determine if there has been a significant change in the participants’ condition# compared with 
the last visit where PHL criteria were met#

If there is no significant change no action is required


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
If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Section E 4.2
E 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found 
to be the disease under study eg, chronic or progressing malignant disease, severe 
infection or liver disease or did the participant meet PHL criteria prior to starting study 
intervention and at their first on-study intervention visit as described in section E 6 of
this Appendix?
If No: follow the process described in Section E 4.2 for reporting PHL as an SAE
If Yes: Determine if there has been a significant change in the patient’s condition# compared 
with when PHL criteria were previously met

If there is no significant change no action is required

If there is a significant change# follow the process described in Section E 4.2 for reporting 
PHL as an SAE
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.
E 8
References
Aithal et al 2011
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al Case definition 
and phenotype standardization in drug-induced liver injury. Clin Pharm Therap 
2011;89(6):806-15.


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FDA Guidance for Industry July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation.


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Appendix F
Concomitant Medications
F 1
Guidance Regarding Potential Interactions of Capivasertib With 
Concomitant Medications
Authorized/approved COVID-19 vaccines can be given to patients enrolled in this trial as long 
as these do not represent a prohibited concomitant medication as detailed in Table F16. 
Investigators should follow the Clinical Study Protocol, their local prescribing information, 
and policies when considering if vaccination against COVID-19 is appropriate for their 
patients participating in an AstraZeneca clinical trial.
The use of any natural/herbal products or other “folk remedies” should be discouraged, but 
use of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the eCRF.
POTENTIAL PHARMACOKINETIC INTERACTIONS
Before study treatment
Drugs that should not be combined with capivasertib must have been discontinued prior to the 
start of administration of study treatment in accordance with guidance provided in Table F11
to Table F13.
During study treatment
It is recommended that drugs which should not be combined with capivasertib are not 
co-administered in accordance with guidance provided in Table F11 to Table F14; however, if 
it is considered essential for patient management to co-administer these drugs with 
capivasertib, participants should be monitored closely for possible drug interactions.
Drugs That May Influence Capivasertib Pharmacokinetics
Based on results from in vitro studies, capivasertib is primarily metabolised by CYP3A4 and 
UGT2B7 enzymes. Therefore, inhibitors or inducers of these enzymes may increase or 
decrease exposure, respectively, to capivasertib. 
Co-administration of the strong CYP3A4 inhibitor itraconazole increased capivasertib Cmax 
by 70% and AUC by 95% (study D3614C00004) and co-administration with the strong 
CYP450 inducer enzalutamide was estimated to result in approximately 50% reduction in 
capivasertib AUC and Cmax (RE AKT study; Kolinsky et al 2017).
Strong inhibitors and strong inducers of CYP3A4 must not be combined with capivasertib and 
must be stopped at least 2 weeks before the first dose of capivasertib (3 weeks for St John’s 
Wort and 4 weeks for enzalutamide). Strong inhibitors must not be used for 2 days following 
discontinuation of capivasertib. Moderate inhibitors and inducers of CYP3A4 or UGT2B7 


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inhibitors and inducers are permitted, but caution should be exercised and participants 
monitored closely for possible drug interactions.
Drugs known to be inhibitors and inducers of CYP3A4 or UGT2B7 are presented in Table F11
and Table F12, respectively. These lists are not intended to be exhaustive, and similar 
restrictions will apply to other agents that are known to modulate CYP3A4 or UGT2B7 
activity.
Table F11
Drugs Known to be Inhibitors of CYP3A4 or UGT2B7
Must be stopped 2 weeks prior to capivasertib 
administration. Must not be used concomitantly with 
capivasertib and for 2 days following discontinuation 
of capivasertib:
Drugs are permitted but caution should 
be exercised and participants monitored 
closely for possible drug interactions:
Strong CYP3A4 inhibitors
boceprevir
clarithromycin (+TdP risk)
cobicistat
danoprevir and ritonavir a
elvitegravir and ritonavir a
indinavir and ritonavir a
itraconazole
ketoconazole
lopinavir and ritonavir a
nefazodone
nelfinavir
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) a
posaconazole
ritonavir a
telaprevir
telithromycin
tipranavir and ritonavir a
troleandomycin
voriconazole
Moderate CYP3A4 inhibitors aprepitant
ciprofloxacin (+TdP risk)
cyclosporine
diltiazem
erythromycin (+TdP risk)
fluconazole (+TdP risk)
fluvoxamine 
tofisopam
verapamil
Strong or Moderate CYP3A4 inhibitors AND Sensitive 
CYP3A substrates 
Follow Guidance in Table F13:
conivaptan
dronedarone
saquinavir a
UGT2B7 inhibitors
cannabidiol b
a
Ritonavir has dual effects of simultaneous CYP3A inhibition and induction; the net pharmacokinetic 
outcome during chronic ritonavir therapy is inhibition of CYP3A activity. Ritonavir is usually given in 
combination with other protease inhibitors. Please refer to the full Prescribing Information for these drugs 
prior to co-administration with capivasertib.


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b
Cannabidiol is also a CYP3A4 substrate.
CYP=Cytochrome P450
TdP risk= Known risk of Torsades de Pointes according to the Arizona Centre for Education and Research on 
Therapeutics (ArizonaCert) website (https://www.crediblemeds.org/). Consider additional ECG monitoring.
Table F12
Drugs Known to be Strong or Moderate Inducers of CYP3A
Must be stopped 2 weeks (3 weeks for St 
John’s Wort) prior to capivasertib 
administration. Must not be used 
concomitantly with capivasertib
Drugs are permitted but caution should be 
exercised and participants monitored closely 
for possible drug interactions:
Strong CYP3A inducers
carbamazepine
phenytoin
rifampicin/rifampin
St. John’s wort
Moderate CYP3A inducers
bosentan
efavirenz
etravirine
phenobarbital
primidone
CYP=Cytochrome P450
Drugs That May be Influenced by Capivasertib
There are currently no data confirming that there are any PK interactions between capivasertib 
and drugs metabolized by CYP450 enzymes. Likewise, there are no confirmed interactions 
with renal or hepatic transporter substrates. The potential interactions are considered on the 
basis of preclinical data and physiology-based PK modelling. These suggest that capivasertib 
may be a moderate to strong inhibitor of CYP3A4, but a less potent inhibitor of some drug 
transporters and may thus increase the exposure of some drugs. Capivasertib also inhibited 
CYP2D6 and CYP2C9 in vitro. However, based on physiology-based PK modelling, the 
increase in exposure of sensitive substrates for these isoenzymes is not predicted to be 
clinically relevant (<10%). 
The guidance below (Table F13 and Table F14) are based on the predicted magnitude of 
increase in exposure and the expected clinical significance of that increase (therapeutic 
window and/or QT liability). The lists are not intended to be exhaustive, and similar 
restrictions will apply to other agents that are known to be sensitive to inhibition of CYP3A or 
transporter proteins. Please refer to the full Prescribing Information for all drugs prior to co-
administration with study intervention and consider dose reduction where clinically 
applicable.


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Table F13
Drugs Known to be Sensitive or Moderate Sensitive CYP3A Substrates 
Whose Exposure, Pharmacological Action, and Toxicity May be 
Increased by Capivasertib
Must be stopped 1 week prior to capivasertib 
administration. Must not be used concomitantly 
with capivasertib and for 1 week following 
discontinuation of capivasertib.
Drugs are permitted but caution should be 
exercised and participants monitored closely for 
possible drug interactions.
Sensitive substrates
alfentanil
avanafil
conivaptan
dronedarone
eletriptan
eplerenone
ivabradine
lomitapide
lovastatin
lurasidone
naloxegol
nisoldipine
quetiapine
saquinavir a
simvastatin
sirolimus
tacrolimus
ticagrelor
tolvaptan
triazolam
vardenafil 
Sensitive substrates
budesonide
buspirone
darifenacin
darunavira
eastine
felodipine
indinavir a
maraviroc
midazolam
sildenafil
tipranavir a
Moderate sensitive substrates
alprazolam
atorvastatin
eliglustat
pimozide (+TdP risk)
Moderate sensitive substrates
amlodipine
aprepitant
buprenorphine
codeine
colchicine
fentanyl
haloperidol
methylprednisolone
oxycodone
rivaroxaban b
sertraline
tadalafil
a
Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor. No clinically 
significant additional increase in exposure is expected by capivasertib when combined with ritonavir.
b
Rivaroxaban must not be used concomitantly with both capivasertib and P-gp inhibitors. 
CYP=Cytochrome P450


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TdP risk= Known risk of Torsades de Pointes according to the Arizona Centre for Education and Research on 
Therapeutics (ArizonaCert) website (https://www.crediblemeds.org/). Consider additional ECG monitoring.
Table F14
Drugs Known to be Substrates for Renal or Hepatic Transporters Whose 
Exposure, Pharmacological Action, and Toxicity May be Increased by 
Capivasertib
Medication
Usage
Rationale
Dofetilide
May be used with caution a
MATE1 and OCT2 substrate with a narrow 
therapeutic window whose exposure may be 
increased by capivasertib (TdP risk)
Metformin
See Appendix G 2.1
MATE1, MATE-2K and OCT2 substrate whose 
exposure may be increased by capivasertib
Procainamide
May be used with caution a
OCT2 substrate with a narrow therapeutic window 
whose exposure may be increased by capivasertib
(TdP risk)
Pitavastatin
Pravastatin
Rosuvastatin
May be used with caution a
The dose may need to be 
reduced
OATP1B1 substrates 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.
MATE1: Multidrug And Toxin Extrusion Protein 1; MATE2: Multidrug And Toxin Extrusion Protein 2; OCT2: 
Organic Cation Transporter 2.
TdP risk=drug with a known risk of Torsades de Pointes according to the Arizona Centre for Education and 
Research on Therapeutics (ArizonaCert) website (https://www.crediblemeds.org/). Consider additional ECG 
monitoring.
Additional Resources
For additional inhibitors, inducers, and substrates please refer to:
https://didb.druginteractionsolutions.org/
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm093664.htm
F 2
Restricted, Prohibited, and Permitted Concomitant 
Medications/Therapies
Restricted, prohibited, and permitted concomitant medications/therapies are described in 
Table F15, Table F16, and Table F17. Refer also to the dose modification guidelines for 
management of study treatment -related toxicities in Appendix G.


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Table F15
Restricted Medications/Therapies
Medication/class of drug/therapy
Usage (including limits for duration permitted and 
special situations in which it’s allowed)
Corticosteroids
Chronic immunosuppressive therapies should be 
avoided, including systemic corticosteroids. Steroids 
given for physiological replacement, as anti-emetics 
or inhaled as well as short course of oral/topical 
steroids given for allergic reactions or asthma flares 
are allowed.
Some drugs that may interact pharmacokinetically 
with capivasertib
May be used with caution.
For details, see Table F11 to Table F14
CYP: cytochrome P450.
Table F16
Prohibited Medications/Therapies
Prohibited medication/class of drug/therapy 
Usage
Any anti-cancer therapy other than those under 
investigation in this study (except palliative 
radiotherapy) 
Must not be given concomitantly while the patient is 
on study treatment. No additional investigational or 
commercial anti-cancer agents such as chemotherapy, 
immunotherapy, targeted therapy, biological response 
modifiers, or endocrine therapy will be permitted 
during the active treatment phase.
Herbal and natural remedies that may interfere with 
interpretation of study results
Must not be given concomitantly unless agreed by the 
sponsor
Other investigational drugs while on study
Must not be given concomitantly unless agreed by the 
sponsor
Live attenuated vaccines (eg, Influenza vaccine 
delivered as nasal spray)
Not permitted
Inactivated vaccines or protein/RNA immunogen 
vaccines are permitted
Some drugs that may interact pharmacokinetically 
with capivasertib
For details, see Table F11 to Table F14
Table F17
Supportive Medications/Therapies
Supportive medication/class of drug/therapy
Usage
Concomitant medications or treatments (eg, 
acetaminophen or diphenhydramine) deemed 
necessary to provide adequate adverse event 
management, except for those medications identified 
as “prohibited,” as listed above
To be administered as prescribed by the investigator 
except for those medications identified as 
“prohibited,” as listed in Table F16.


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Supportive medication/class of drug/therapy
Usage
Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management [including 
palliative radiotherapy, etc]) except for those 
medications identified as “prohibited,” as listed above
Should be used, when necessary, for all patients 
except for those medications identified as 
“prohibited,” as listed in Table F16
Haematopoietic growth factors (eg, G-CSF, 
GM-CSF) 
Primary or secondary prophylactic use of G-CSFs 
may be used to treat treatment emergent neutropenia 
as indicated by the current ASCO guideline and 
according to investigator’s clinical judgement.
Erythropoietin 
May be used at the investigator's discretion for the 
supportive treatment of anaemia
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
Non-sedating oral antihistamines (eg, cetirizine, 
fexofenadine, loratadine)
Can be given as needed on a prophylactic and 
treatment basis in compliance with the standards of 
the centre’s local policy. For symptomatic treatment 
of rash, as indicated in the toxicity management 
guideline (Appendix G 2.2)
Anti-diarrhoeal therapy 
For symptomatic treatment of diarrhoea, as indicated 
in the toxicity management guideline 
(Appendix G 2.4).
Anti-diabetic agents (metformin, insulin) 
For symptomatic treatment of hyperglycaemia, as 
indicated in the toxicity management guideline 
(Appendix G 2.1).
Required for management of other medical conditions
As required except for those identified as 
“prohibited,” as listed in Table F16
5-HT3: 5-hydroxytryptamine; ASCO: American Society of Clinical Oncology; G-CSF: granulocyte 
colony-stimulating factor; GM-CSF: granulocyte macrophage colony-stimulating factor.
F 3
References
Kolinsky et al 2020
M P Kolinsky MP, Rescigno P, Bianchini D, Zafeiriou Z, Mehra N, Mateo J, et al. A phase I 
dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 
(capivasertib) in patients with metastatic castration-resistant prostate cancer. Ann Oncol 
2020;31(5):619-625.


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Appendix G
Management of Capivasertib-related Toxicity
G 1
Dose Modifications Due to General Capivasertib-related Toxicities
Treatment with capivasertib should be temporarily interrupted for any intolerable AE 
regardless of grade or for any AEs ≥Grade 3 that occur despite optimal supportive care, are 
not attributable to the disease under investigation, or 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 G15 below. 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 treatment due to toxicities. 
Please see Section G 2 for the management of capivasertib specific toxicities including 
hyperglycaemia, maculo-papular rash and other skin reactions, and diarrhoea.
Table G15
Dose Modification for General Capivasertib-related Toxicities
NCI CTCAE v5.0 Toxicity Grade
Action
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 1 reduced dose 
level as clinically appropriate
•
Does not resolve within 21 days of onset
•
Discontinue study treatment and observe patient 
until resolution
Non-life-threatening 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 same dose or one reduced 
dose level as clinically appropriate
•
Grade ≥3 toxicity for > 21 days
•
Discontinue study treatment and observe patient 
until resolution
Life-threatening events
Discontinue study treatment and observe patient until 
resolution
CTCAE: Common Terminology Criteria for Adverse Events; NCI: National Cancer Institute.
G 2
Dose Modifications Due to Specific Capivasertib-related Toxicities
G 2.1
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 G16. In addition, for all grades, patients may receive education on lifestyle changes (eg, 
a diabetic diet) and consider beginning home glucose monitoring (eg, fasting SBGM once 
daily) at the discretion of the investigator. If glucose home monitoring is instituted, the 
capivasertib treatment decision should be based on the morning fasting glucose value obtained 
prior to the dose of capivasertib.
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).
Table G16
Dose Modifications for Capivasertib-related Hyperglycaemia a
NCI CTCAE v5 Toxicity Grade
Action
Grade 1
(Abnormal glucose above baseline with no medical 
intervention)
Maintain same capivasertib dose level
Grade 2
(Change in daily management from baseline for a 
diabetic; oral antiglycaemic agent initiated; workup 
for diabetes)
Asymptomatic:
•
Maintain same capivasertib dose level
•
Treatment as per local guidelines, consider the 
use of oral antidiabetic (eg, metformin) on 
capivasertib dosing days [see further guidance 
on choice of antidiabetic agents in text above 
and below the table]
Symptomatic: Appropriate clinical management as 
per local guidelines
•
Interrupt capivasertib until resolution of 
symptoms and fasting blood glucose is 
≤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


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NCI CTCAE v5 Toxicity Grade
Action
Grade 3
(Insulin therapy initiated; hospitalisation indicated)
Hold capivasertib up to 21 days, until resolution of 
symptoms. Consult with diabetologist
•
If fasting blood glucose decreases to 
≤160 mg/dL or ≤8.9 mmol/L within 21 days 
and under appropriate antidiabetic treatment, 
resume capivasertib 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
Non-life-threatening Grade 4
(Urgent intervention indicated)
Appropriate clinical management of hyperglycaemia 
per local guidelines. Consider consult with the 
diabetologist
Consider permanent cessation of capivasertib
Life-threatening Grade 4
Discontinue capivasertib and observe patient until 
resolution
a
Patients may receive education on lifestyle changes (eg, a diabetic diet) and consider beginning home 
glucose monitoring (eg, fasting SBGM once daily) at the discretion of the investigator. If glucose home 
monitoring is instituted, the capivasertib treatment decision should be based on the morning fasting glucose 
value obtained prior to the dose of capivasertib.
CTCAE: Common Terminology Criteria for Adverse Events; NCI: National Cancer Institute; SBGM: self-blood 
glucose monitoring.
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/capivasertib 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 inhibition of renal 
transporters [eg, OCT2] involved in the excretion of metformin), when taking both 
capivasertib and metformin concurrently, patients should attend the study site for monitoring 
of serum creatinine at least once per week for the first 3 weeks after initiation of metformin, 
then at the investigator’s discretion.
Metformin should only be given on the days when capivasertib is also administered (the half-
life of capivasertib is approximately 7 to 15 hours), and should be withdrawn when treatment 
with capivasertib is withdrawn, unless otherwise clinically indicated.
Consider withholding of metformin on the days patients are due to have imaging with contrast 


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(in order to reduce the already low risk of lactic acidosis) as per local guidelines.
G 2.2
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 G17. 
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 G17
Dose Modifications for Capivasertib-related Maculo-papular Rash
NCI CTCAE v5 Toxicity Grade
Action
Grade 1 or 2
Continue dosing at current dose and initiate 
dermatological treatment:
•
Topical steroid of moderate strength BD
•
Non-sedating oral antihistamines
Non-life-threatening Grade ≥3 or 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 treatment a and restart 
dosing at same dose
•
Improves to Grade 2 and tolerable within 
28 days from onset
•
Continue dermatological treatment a 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 treatment a and 
discontinue capivasertib
Life-threatening event
Discontinue capivasertib and observe patient until 
resolution
•
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 and observe patient until 
resolution
a
In patients with persistent rash or previous occurrence of Grade 3 consider secondary prophylaxis by 
continuing topical steroids and/or non-sedating oral antihistamines.
BD: twice daily; BSA: body surface area; CTCAE: Common Terminology Criteria for Adverse Events; 
IV: intravenous; NCI: National Cancer Institute.
G 2.3
Hypersensitivity
In the case of hypersensitivity reactions, capivasertib 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 rechallenge is 
not recommended; any subsequent consideration on rechallenge with capivasertib at the same 
or a lower dose, with its potential for recurrence of such or more severe events should be 


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carefully considered against the potential benefits to the individual patient from continuation 
of capivasertib therapy. Further management should follow local guidelines on management 
of hypersensitivity reactions.
G 2.4
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 G18.
If diarrhoea is reported, additional details regarding this AE will be collected in the eCRF.
Table G18
Dose Modifications for Capivasertib-related Diarrhoea
NCI CTCAE v5 Toxicity Grade
Action
Grade 1
Maintain same capivasertib 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 dose (up to 21 days) until recovery 
to ≤Grade 1 and resume dosing at same dose level. 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).
Consider secondary prophylaxis a
Non-life-threatening Grade ≥3
Interrupt capivasertib dose (up to 21 days) and institute 
appropriate anti-diarrhoeal treatment
•
Improves to Grade ≤1 within 21 days
•
Resume dosing at same dose or one reduced dose 
level as clinically appropriate maintaining treatment 
for toxicity as necessary and/or start secondary 
prophylaxis a
•
Does not improve to Grade ≤1 after 21 days
•
Discontinue drug
Life-threatening Grade 4
Discontinue capivasertib and observe patient until 
resolution
Recurrence of Grade ≥2 or clinically 
significant or intolerable toxicity despite 
secondary prophylaxis
Interrupt capivasertib dose (up to 21 days), maintaining 
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NCI CTCAE v5 Toxicity Grade
Action
•
Improves to Grade ≤1 or becomes clinically 
tolerable within 21 days
Resume dosing up to 2 reduced dose levels as clinically 
appropriate maintaining treatment for toxicity as 
necessary and/or maintaining secondary prophylaxis a
•
Does not improve to Grade ≤1 clinically 
significant/remains clinically intolerable 
after 21 days
•
Discontinue capivasertib
•
Event assessed to be life-threatening
•
Discontinue capivasertib and observe patient until 
resolution
a
In patients with persistent Grade 1 diarrhoea (eg, loperamide 2 mg, 2 to 4 times daily).
CTCAE: Common Terminology Criteria for Adverse Events; NCI: National Cancer Institute.
G 2.5
Haematological Toxicities
If a patient experiences a clinically significant and/or unacceptable haematological toxicity
unless clearly attributable to baseline bone marrow involvement by lymphoma or to 
extraneous cause, dosing in subsequent cycles will be withheld and may subsequently be 
reduced or discontinued. See the toxicity management guidelines below for recommendations. 
To help determine the relatedness of the event to capivasertib versus the underlying condition, 
consider clinical characteristics such as baseline blood counts, bone marrow involvement by 
the underlying disease, long-standing toxicities from prior therapies, and any other clinically 
significant datapoints.
Dose modifications and management of potential haematological toxicities during 
treatment with capivasertib.
Refer to Table G19 for dose modifications in case of drug-related haematological toxicities. 
Capivasertib dose level modification options are presented in the relevant Module.
Table G19
Dose Modifications and Management of Potential Haematological 
Toxicities During Treatment With Capivasertib
NCI CTCAE v5.0 
Toxicity Grade
Clinical Supportive Care
Capivasertib Action
Febrile neutropenia / 
neutropenic infection 
Grade 3
Consider introducing growth 
factors (eg, G-CSF), evaluate 
subject for infection, and begin 
antibiotic treatment per 
institutional guidelines.
Withhold capivasertib until 
fever/infection is resolved, antibiotics 
are no longer required (except 
prophylactic antibiotics) and ANC 
≥1.0 × 109/L or has returned to 
baseline
First episode: Resume capivasertib at 
next lowest dose level (1 level dose 
reduction)
Second episode: Discontinue 
treatment




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NCI CTCAE v5.0 
Toxicity Grade
Clinical Supportive Care
Capivasertib Action
Grade 4 
thrombocytopenia 
without bleeding
Monitor platelet counts within 7 days 
and then at least weekly thereafter. 
Platelet transfusion according to local 
policies
Withhold capivasertib.
•
If recovery to ≥ 50 × 109/L occurs 
within 7 days: Restart with 
capivasertib at same dose level
•
If recovery to ≥ 50 × 109/L occurs 
between 7 to 21 days: resume dosing 
at 1 level dose level reduction
•
If no recovery to ≥ 50 × 109/L after 
21 days: consider discontinuation
Grade 3 anaemia
(Hgb <8.0 g/dL; 
transfusion indicated)
Manage with supportive care, blood 
transfusion according to local policies
Continue current capivasertib dose.
Grade 4 anaemia
(acute and unexpected 
onset with
life-threatening 
consequences)
Manage with supportive care, blood 
transfusion according to local policies
Discontinue capivasertib.
ANC: absolute neutrophil count; CTCAE: Common Terminology Criteria for Adverse Events; G-CSF: 
granulocyte colony stimulating factor; NCI: National Cancer Institute.


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Appendix H
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with SARS-CoV-2 or similar pandemic infection) 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 
notification from the sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions and other measures implemented to ensure the 
patient’s safety. If in doubt, please contact the AstraZeneca Study Physician.
H 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 Sections H 2 to H 6. 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 consent/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.
H 2
Rescreening of 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 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 5.4, 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 5.4 must be undertaken to confirm eligibility using the same 
randomisation number as for the patient.


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H 3
Home or Remote Visit to Replace On-site Visit (Where 
Applicable)
A qualified HCP from the study site or TPV service will visit the patients 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 HCP will be expected to collect 
information per the CSP.
H 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 a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the patients will allow AEs, concomitant medication, and PRO questionnaires to be 
reported and documented.
H 5
At-home or Remote Location Study Intervention Administration 
Instructions
If a site visit is not possible, at-home or remote location administration of study treatment may 
be performed by a qualified HCP, provided this is acceptable within local regulation/guidance, 
or by the patient or his/her caregiver. 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 travelling to the study site. This will also minimise interruption of study 
treatment administration during other study disruptions, eg, site closures due to natural 
disaster. 
H 5.1
At-home or Remote Location Study Intervention Administration by a 
Qualified HCP or TPV Service (if Applicable)
A qualified HCP from the study site or TPV service should administer the study treatment at 
the patient’s home or other remote location according to the CSP, if applicable. 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.
H 5.2
At-home or Remote Location Study Intervention Administration by the 
Patient or His/Her Caregiver
Prior to at-home or remote location study treatment administration the investigator must 
assess the patient or his/her caregiver to determine whether they are appropriate for at-home 


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or remote location administration of study treatment. Once the patient or his/her caregiver is 
deemed appropriate for at-home or remote location administration, he/she must receive 
appropriate training. All necessary supplies and instructions for administration and 
documentation of study treatment administration will be provided. More information related 
to the visit can be obtained via a telemedicine or home / remote visit.
H 6
Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home / remote visits will be captured by the qualified 
HCP from the study site or TPV service, or by the patient.


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Appendix I
Lugano 2014 Classification for Non-Hodgkin Lymphoma
Disease response assessment will be evaluated using the Lugano 2014 Classification for NHL 
(Cheson et al 2014).
Response assessments will be done by the investigators and independently assessed by the 
BICR, as determined by Lugano 2014 Classification response criteria. The BICR will conduct 
response evaluations in accordance with the BICR charter (provided separately from this 
protocol). Primary and secondary efficacy endpoints will be based on BICR review. Blinded 
independent central review assessment will not be reported back to Sites. Investigator's 
assessment overall disease response will also be collected in eCRF.
Tumour assessment will be made for target lesions (ie, measurable disease), non-target lesions 
(ie, non-measurable disease), organ enlargement (eg, spleen, liver), and new lesions on CT 
and combined with visual assessment of PET-CT for response assessment (Cheson et al 2014, 
Table I20).
Visual Interpretation of PET-CT Scans
Variation in FDG uptake in a nodal or extranodal sites indicative for lymphoma will be 
visually assessed using the Deauville 5-point scale.
Target lesions
Up to a maximum of 6 dominant, measurable lymph nodal or extranodal lesions should be 
assessed as target lesions and documented at baseline and throughout the study.
A lesion will be considered measurable if:

For nodal lesions: LDi > 1.5 cm

For extranodal lesion: LDi > 1 cm
Lesions visible on PET but not on CT/MRI to be assigned as non-target lesions.
Target nodal or extranodal lesions nodes should be selected according to all of the following:

They should be clearly measurable in at least 2 perpendicular dimensions

If possible, they should be from disparate regions of the body

They should include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved
The perpendicular long and short axis diameters will be measured and recorded in the 
transverse plane at baseline and follow-up.


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For the selected target lymph nodal lesions, the sum of the product of the perpendicular 
diameters will be calculated with the percentage change from baseline for assessment of 
response and nadir for assessment of progression.
Non-target lesions:
All other lesions (including nodal, extranodal, and assessable disease) not selected as target 
lesions, as well as truly non-measurable sites of disease should be followed as nonmeasurable 
disease (eg, cutaneous, gastrointestinal, bone, spleen, liver, kidneys, pleural or pericardial 
effusions, ascites) and should be factored into the overall response assessment. Non-target 
lesions will be documented at baseline and throughout the study. Measurement of these 
lesions is not required to be documented on the eCRFs. 
Spleen involvement
Spleen will be considered to be normal if size of its vertical length (cranial-caudal 
measurement) is ≤13 cm. For patients with splenomegaly at baseline, spleen vertical length 
will be assessed at screening and all subsequent response evaluations.
Liver involvement
Intrahepatic lesions should be considered as target, non-target or new lesion as applicable. For 
patients with baseline hepatomegaly, the longest diameter of the liver will be assessed at 
screening and all subsequent response evaluations.
Bone Marrow involvement
Bone marrow involvement by lymphoma documented by aspirate and/or biopsy will be 
reported on the eCRF as present or absent.
Table I20
Response Assessment Criteria for Non-Hodgkin Lymphoma
Response and Site
PET-CT Based response
CT-Based Response
Complete:
Complete metabolic response:
Complete radiologic response (all of 
the following):
Lymph nodes and 
extralymphatic sites 
(target lesions)
Score 1, 2, or 3 a with or without a 
residual mass on 5PS b
Target nodes/nodal masses must 
regress to ≤1.5 cm in LDi
No extralymphatic sites of disease 
(0 × 0 cm)
Nonmeasured lesion 
(Non-target)
Not applicable
Absent/normal
Organ enlargement
Not applicable
Regress to normal; spleen vertical 
length is ≤13 cm
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if 
indeterminate, IHC negative


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Response and Site
PET-CT Based response
CT-Based Response
Partial:
Partial metabolic response:
Partial remission (all of the 
following):
Lymph nodes and 
extralymphatic sites
Score 4 or 5 b with reduced uptake 
compared with baseline and residual 
mass(es) of any size
≥50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites
Nonmeasured lesions
Not applicable
Absent/normal, regressed, but no 
increase
Organ enlargement
Not applicable
Spleen must have regressed by > 50% 
in length beyond normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake 
compatible with reactive changes from 
chemotherapy allowed). If there are 
persistent focal changes in the marrow 
in the context of a nodal response, 
consideration should be given to further 
evaluation with MRI or biopsy or an 
interval scan
Not applicable
No response or stable 
disease:
No metabolic response:
Stable disease:
Target nodes/nodal 
masses, extranodal 
lesions
Score 4 or 5 with no significant change 
in FDG uptake from baseline at interim 
or end of treatment
< 50% decrease from baseline in SPD 
of up to 6 dominant, measurable nodes 
and extranodal sites; no criteria for 
progressive disease are met
Nonmeasured lesions
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive disease:
Progressive metabolic disease:
Progressive disease requires at least 
1 of the following
Individual target 
nodes/nodal masses
Score 4 or 5 with an increase in 
intensity of uptake from visually 
determined nadir and/or
PPD progression:


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Response and Site
PET-CT Based response
CT-Based Response
Extranodal lesions
New FDG-avid foci consistent with 
lymphoma
An individual node/lesion must be 
abnormal with:
LDi > 1.5 cm and
Increase by ≥50% from PPD nadir and
An increase in LDi or SDi from nadir
0.5 cm for lesions ≤2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the 
splenic length must increase by 
> 50% of the extent of its prior 
increase beyond baseline (eg, a 15 cm 
spleen must increase to > 16 cm). If 
no prior splenomegaly, must increase 
by at least 2 cm from baseline 
New or recurrent splenomegaly
Nonmeasured lesions
None
New or clear progression of 
pre-existing nonmeasured lesions
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another 
aetiology (eg, infection, inflammation). 
If uncertain regarding aetiology of new 
lesions, biopsy or interval scan may be 
considered
Regrowth of previously resolved 
lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and must 
be attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
a
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of 
an interim scan. However, in studies involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid under treatment). Measured dominant 
lesions: Up to 6 of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly 
measurable in 2 diameters. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid 
organs (eg, liver spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or those noted on 
palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of 
suspected disease that would be difficult to follow quantitatively with measurement, including pleural 
effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be 
confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone 
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but 
should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of 
chemotherapy of myeloid growth factors).


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b
PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma.
Adapted from Table 3: Cheson et al 2014.
5PS: Deauville 5-point scale; CT: computed tomography; FDG: fluorodeoxyglucose; GI: gastrointestinal; 
IHC: immunohistochemistry; LDi: longest transverse diameter of a lesion; MRI: magnetic resonance imaging; 
PET: positron emission tomography; PPD: cross product of the LDi and perpendicular diameter; SDi: shortest 
axis perpendicular to the LDi; SPD: sum of the product of the perpendicular diameters for multiple lesions.
Assessment of new lesions
Appearance of any new lesions > 1.5 cm in any axis during or at the end of therapy, even if all 
other lesions are decreasing should be considered progression. Increased FDG uptake in a 
previously unaffected site should only be considered progression after confirmation with other 
modalities (eg, CT, MRI, biopsy).
In patients with no history of pulmonary lymphoma, new nodules identified by CT are benign 
and should be considered negative for lymphoma. These lesions typically represent infectious 
or inflammatory lesions; therefore, if FDG positive, should not be considered positive for 
lymphoma in the absence of confirmatory tests, (eg, histology).
The presence or absence of new lesions will be recorded in the eCRF.
Overall Response Assessment
The efficacy endpoints are based on the overall response assessment, which is combining the 
radiological response from PET/CT scans, the bone marrow findings (if applicable) and any 
additional clinical finding, including cytologic or histopathologic findings for each disease 
response assessment during the study. The possible outcomes for ORR as CR, PR, SD, PD, 
Unknown. The Investigator-assessed ORR and respective date will be captured on the eCRF.




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Table J23
GELF Criteria
Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm
Any nodal or extranodal tumour mass with a diameter of ≥7 cm
B symptoms
Splenomegaly
Pleural effusions or peritoneal ascites
Cytopaenias (leukocytes < 1.0 × 109/L and/or platelets < 100 × 109/L)
Leukaemia (< 5.0 × 109/L malignant cells)
GELF: Groupe d’Etude des Lymphomes Folliculaires.
J 2
Mantle Cell Lymphoma Prognostic Score
Table J24
Simplified MIPI
Point
Age (years)
ECOG
LDH ULN
WBC (109/L)
0
< 50
0-1
< 0.67
< 6.700
1
50-59
-
0.67-0.99
6.700-9.999
2
60-69
2-4
1.000-1.49
1.000-14.999
3
≥70
-
≥1.5000
≥15000
For each prognostic factor, 0 to 3 points were given to each patient and points were summed up to a maximum of 
11. ECOG performance status was weighted with 2 points if patients were unable to work or were bedridden 
(ECOG 2-4). LDH was weighted according to the ratio of the ULN. Thus for an ULN of 240 U/L, the cutpoints 
were 180 U/L, 240 U/L, and 360 U/L, for example.
- indicates not applicable.
ECOG: Eastern Cooperative Oncology Group; LDH: lactate dehydrogenase; MIPI: Mantle Cell Lymphoma 
International Prognostic Index; ULN: upper limit of normal; WBC: white blood cell.
Table J25
Risk Category According to the MIPI
MIPI Score
Risk
0-3
low 
4-5
intermediate
6-11
high
MIPI: Simplified Mantle Cell Lymphoma International Prognostic Index.


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J 3
References
Federico et al 2009
Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U, et al. 
Follicular lymphoma international prognostic index 2: a new prognostic index for follicular 
lymphoma developed by the international follicular lymphoma prognostic factor project. J 
Clin Oncol 2009;27(27):4555-62.
Hoster et al 2008
Hoster E, Dreyling M, Klapper W, Gisselbrecht C, van Hoof A, Kluin-Nelemans HC, et al. A 
new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 
2008;111(2):558-65.
NCCN Guidelines
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) B-Cell Lymphomas. 
Version 1.2021. Available from https://www.nccn.org/professionals/physician_gls/pdf/b-
cell.pdf (accessed 11 February 2021).
Solal-Céligny et al 2004
Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, et al. Follicular 
lymphoma international prognostic index. Blood 2004;104(5):1258–65.


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Appendix K
Patient-reported Outcomes
K 1
EORTC QLQ-C30
CCI






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K 3
NCI PRO-CTCAE


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K 5
PGI-TT
CCI












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Appendix L
Abbreviations
Abbreviation or special 
term
Explanation
5-HT3
5-hydroxytryptamine
5PS
Deauville 5-point scale
AE
Adverse event
AESI
Adverse event of special interest
AKT
Activation of Protein Kinase B
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/transaminase
ANC
Absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase/transaminase
AUC
Area under plasma concentration-time curve
AUCss
Area under plasma concentration-time curve at steady state
B
Blood
BD
Twice daily
BICR
Blinded independent central review
BSA
Body surface area
BTK
Bruton's tyrosine kinase
BUN
Blood urea nitrogen
C
Cycle
CAR-T
Chimeric antigen receptor T
CD
Cluster of differentiation
CFR
Code of Federal Regulations
cHL
Classic Hodgkin lymphoma
CI
Confidence interval
CL
Central laboratory collection
CMV
Cytomegalovirus
CNS
Central nervous system
COA
Clinical outcome assessment
COVID-19
Coronavirus disease 2019
CR
Complete response
CRF
Case report form
CRO
Contract Research Organisation
CSP
Clinical Study Protocol


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Abbreviation or special 
term
Explanation
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Observed lowest drug concentration reached before the next dose is administered
CYP
Cytochrome P450
d/D
Day
DBP
Diastolic blood pressure
DCO
Data cut-off
DILI
Drug Induced Liver Injury
DLBCL
Diffuse large B-cell lymphoma
DNA
Deoxyribonucleic acid 
DoR
Duration of response
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic data capture
EMA
European Medicines Agency
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30
EOT
End of treatment
ePRO
Electronic patient-reported outcome
EZH
Enhancer of zeste homolog
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FFPE
Formalin-fixed paraffin embedded
FL
Follicular lymphoma
FLIPI
Follicular Lymphoma International Prognostic Index
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GELF
Groupe d’Etude des Lymphomes Folliculaires
GM-CSF
Granulocyte macrophage colony-stimulating factor
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Abbreviation or special 
term
Explanation
HbA1c
Glycosylated haemoglobin A1c
HBc
Hepatitis B core
HBV
Hepatitis B virus
HCP
Health Care Professional
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HL
Hy’s Law
HSCT
Haematopoietic stem cell transplant
IATA
International Airline Transportation Associations
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
Intravenous
LDH
Lactate dehydrogenase
LDi
Longest transverse diameter of a lesion
LL
Local laboratory collection
LTFU
Long-term follow-up
LVEF
Left ventricular ejection fraction
mAb
Monoclonal antibody
MATE1
Multidrug And Toxin Extrusion Protein 1
MCL
Mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MFDS
Ministry of Food and Drug Safety
MHRA
Medicines and Healthcare Products Regulatory Agency
MIPI
Mantle Cell Lymphoma International Prognostic Index
MRI
Magnetic resonance imaging
mTOR
Mammalian target of rapamycin
MUGA
Multiple-gated acquisition
CCI
CCI


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Abbreviation or special 
term
Explanation
MZL
Marginal zone lymphoma
NCI
National Cancer Institute
NHL
Non-Hodgkin lymphoma
NIMP
Non-investigational medicinal product
NK
Natural killer
NKT
Natural killer T
NYHA
New York Heart Association
OAE
Other significant adverse event
OCT2
Organic Cation Transporter 2
ORR
Objective response rate
OS
Overall survival
P
Plasma
PCR
Polymerase chain reaction
PD
Progression of disease
PET
Positron emission tomography
PFS
Progression-free survival
PGI-TT
Patient Global Impression of Treatment Tolerability
PHL
Potential Hy’s Law
PI
Principal investigator 
PI3K
Phosphatidylinositol 3-kinase
PIK3CA
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
PK
Pharmacokinetic(s)
PPD
Cross product of the LDi and perpendicular diameter
PR
Partial response
PRO
Patient-reported outcome
PRO-CTCAE
Patient-reported Outcomes-Common Terminology Criteria for Adverse Events
PT
Preferred term
PTEN
Phosphatase and tensin homologue
QoL
Quality of life
QTc
Corrected QT interval
QTcF
QT Interval corrected using Fridericia's formula
R/R
Relapsed or refractory
RECIL
Response Evaluation Criteria in Lymphoma
CCI
CCI
CCI
CCI


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Abbreviation or special 
term
Explanation
RNA
Ribonucleic acid
RTSM
Randomisation and Trial Supply Management
S
Serum
SAE
Serious adverse event 
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus-2
SBGM
Self-blood glucose monitoring
SBP
Systolic blood pressure
SD
Stable disease
SDi
Shortest axis perpendicular to the LDi
SmPC
Summary of Product Characteristics
SoA
Schedule of Activities
SOC
System organ class
SPD
Sum of the product of the perpendicular diameters for multiple lesions
SSC
Study Steering Committee
T4
Thyroxine
TBL
Total bilirubin
TFST
Time to first subsequent therapy or death
TOR
Target of rapamycin
TP53
Tumour protein 53
TPV
Third-party vendor
TSH
Thyroid-stimulating hormone
TTR
Time to objective response
U
Urine
ULN
Upper limit of normal
US
United States
USPI
United States prescribing information
VAS
Visual analogue scale
VTE
Venous thromboembolism
WBC
White blood cell
WOCBP
Woman of child bearing potential


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Appendix M Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 02, v3.0 (28 July 2021)
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union.
Overall Rationale for the Amendment:
This protocol amendment incorporates changes requested by the French National Agency for 
the Safety of Medicines and Health Products (ANSM) arising from review of version 2.0 of 
the protocol, dated 28 April 2021.
Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Section 13.1.1 
(Additional Inclusion 
Criteria for Cohort 1A);
Section 13.1.3 
(Additional Inclusion 
Criteria for Cohort 1C)
Updated to clarify 
physicians should 
discuss CAR-T cell 
therapy for R/R FL and 
MCL patients prior to 
study enrolment
Updated in line with 
ANSM request
Non-substantial
Amendment 01, v2.0 (28 April 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
This protocol amendment incorporates changes requested by the United States Food and Drug 
Administration (FDA) arising from review of version 1.0 of the protocol, dated 
18 February 2021.


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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Section 1.1 (Synopsis)
Updated to clarify the DCO date for final analysis of each cohort.
Updated in line with FDA request
Non-substantial
Section 5.2
(Core Exclusion Criteria)
•
Amended to exclude patients with increased risk of VTE not 
willing to receive VTE prophylaxis.
•
Amended to exclude the concomitant use of UGT2B7 
inhibitors/inducers.
Amended in response to FDA 
request
Substantial
Section 5.3.1 (Meals and 
Dietary Restrictions)
Additional information added on dietary restrictions with 
capivasertib.
Updated in line with FDA request
Substantial
Section 8.1.2 (Imaging 
Assessments) and Section 10.1 
(SoA, Module 1)
Updated to clarify the use of PET and CT in disease response 
assessment for MZL patients with and without FDG uptake on 
baseline.
Updated in line with FDA request
Non-substantial
Section 8.2.2
(Vital Signs) and Section 10.1 
(SoA, Module 1)
Updated to align the patient posture requirement (sitting) and 
resting time (5 minutes) preceding the vital signs assessments
Amended to align the text 
between 2 sections for 
consistency
Non-substantial
Section 8.2.3
(ECG) and Section 10.1 (SoA, 
Module 1)
Updated to align the patient posture requirement (supine) and 
triplicate ECG time interval (1 minute) during ECG assessments
Amended to align the text 
between 2 sections for 
consistency
Non-substantial
Section 9.6 and Appendix A5
(Data Monitoring Committee)
Amended to clarify the frequency of safety data review by the 
Study Steering Committee
Amended in response to FDA 
request
Non-substantial
Section 9.4.5
Exploratory Analyses
 
Updated in line with FDA request
Substantial
Section 12 
Figure 1
(Study Design – Module 1)
Amended to include details of planned interim analysis for safety 
and preliminary efficacy.
Amended in response to FDA 
request
Substantial
Section 12.1
Updated to include further details on the selection of the dose for 
capivasertib monotherapy and to provide the rationale for the 
proposed intermittent dosing schedule
Updated in line with FDA request
Substantial
CCI


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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
(12.1
Justification for Dose 
– Module 1)
Section 12.2
(End of Study Definition)
Updated to clarify the DCO date for the final analysis of each 
cohort.
Updated in line with FDA request
Non-substantial
Section 13.1.1 (Additional 
Inclusion Criteria for Cohort 
1A) 
Updated to include the current need for systemic treatment and to 
clarify that all patients with FL must have relapsed, progressed, 
or be refractory after at least 2 prior lines of systemic therapy 
Updated in line with FDA request
Substantial
Section 13.1.2
(Additional Inclusion Criteria 
for Cohort 1B)
Updated to include the current need for systemic treatment and to 
clarify that patients with MZL must have relapsed, progressed, or 
be refractory after at least 2 prior lines of systemic therapy 
instead of 1
Updated in line with FDA request
Substantial
Section 13.1.3 (Additional 
Inclusion Criteria for Cohort 
1C)
Updated to clarify that patients with MCL must have relapsed, 
progressed, or be refractory after at least 2 prior lines of systemic 
therapy instead of 1
Updated in line with FDA request
Substantial
Section 13.2 (Exclusion 
Criteria)
Amended to clarify that patients with an immediate need for 
cytoreductive treatment are excluded. 
Amended in response to FDA 
request
Substantial
Section 15.1 (Discontinuation 
of study intervention and 
Stopping Criteria)
Amended to include criteria that would stop or pause study 
recruitment 
Amended in response to FDA 
request
Substantial
Section 17.3 Statistical 
Analyses
Table 10 amended to include details of interim analyses for 
safety and clarify the DCO date for the final analysis of each 
cohort.
Amended in response to FDA 
request
Substantial
Section 17.4 Interim Analyses
Amended to include interim analysis for safety.
Amended in response to FDA 
request
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Appendix G (General 
Capivasertib-Related 
Toxicities)
G 1, G 2.1, G 2.2, G 2.4
Table G15-Table G18 updated to include guidance on treatment 
dosing in patients who experience life-threatening events 
Updated in line with FDA request
Substantial
Appendix G 2.5 
Haematological Toxicities
Table G19 updated to include treatment dosing in patients with 
severe cytopenia. Typographical errors corrected. 
Updated in line with FDA request
Substantial
Appendix F Guidance 
Regarding Potential 
Interactions of Capivasertib 
with Concomitant Medications
Amended to include UGT2B7 inhibitors and inducers as drugs 
that may influence pharmacokinetics. 
Table F11 updated to include restrictions in the use of 
cannabidiol 
Table F13 updated to include details on concomitant use with 
statins.
Amended in response to FDA 
request
Substantial
Abbreviations: CT: computed tomography; DCO: data cut-off; ECG: electrocardiogram; FL: follicular lymphoma; IA: interim analysis; FDA: Food and Drug 
Administration; FDG: Fluorodeoxyglucose; MCL: mantle cell lymphoma; MZL: marginal zone lymphoma; PET: positron emission tomography; R/R: relapsed 
or refractory; SoA: schedule of assessments; VTE: venous thromboembolism.


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19
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SIGNATURE PAGE
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Document Name: d361fc00001-csp-v6
Document Title:
D361FC00001 Clinical Study Protocol version 6
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SAP_001.pdf: 
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Statistical Analysis Plan
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Parexel International
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D361FC00001 
A Modular Phase II, Open-Label, Multicentre Study to Assess the Efficacy and Safety of 
Capivasertib in Patients with Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (CAPITAL)
Statistical Analysis Plan
Version: 3.0
Parexel Project Number: 256606


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Parexel International
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Statistical Analysis Plan
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TABLE OF CONTENTS
1
INTRODUCTION ............................................................................................................... 11
2
STUDY OBJECTIVES AND ENDPOINTS ........................................................................ 11
2.1
Core
..................................................................................................................... 11
2.1.1 Primary Objective....................................................................................................... 11
2.1.2 Secondary Objectives.................................................................................................. 12
2.1.3 Exploratory Objectives................................................................................................ 15
2.2
Module 1 .................................................................................................................... 16
3
INVESTIGATIONAL PLAN .............................................................................................. 16
3.1
Overall Study Design and Plan.................................................................................... 16
3.1.1 Core Module............................................................................................................... 16
3.1.2 Module 1 .................................................................................................................... 16
3.2
Planned Analyses........................................................................................................ 17
3.2.1 Module 1 .................................................................................................................... 17
4
STATISTICAL METHODS ................................................................................................ 19
4.1
Data Quality Assurance............................................................................................... 19
4.2
General Presentation Considerations ........................................................................... 19
4.3
General Variables ....................................................................................................... 20
4.3.1 Study Day Definitions................................................................................................. 20
4.3.2 Time Windows ........................................................................................................... 20
4.3.3 Handling of Missing Data ........................................................................................... 21
4.3.3.1
Imputations of Partial Dates.......................................................................... 21
4.3.4 Imputation Rules for Laboratory Values Outside of Quantification Range................... 22
4.4
Software ..................................................................................................................... 22
4.5
Analysis Sets .............................................................................................................. 22
4.6
Study Patients ............................................................................................................. 24
4.6.1 Disposition of Patients ................................................................................................ 24
4.6.2 Protocol Deviations..................................................................................................... 25
4.7
Demographics and Baseline Characteristics ................................................................ 26
4.8
Medical History .......................................................................................................... 27
4.9
Prior Anti-lymphoma Therapy .................................................................................... 27
4.10 Concomitant Medications and Other Treatments......................................................... 27
4.11 Efficacy Evaluation..................................................................................................... 28
4.11.1
Analysis and Data Conventions..................................................................... 28
4.11.1.1
Multi-centre Studies...................................................................................... 29
4.11.1.2
Adjustments for Covariates........................................................................... 29
4.11.1.3
Handling of Dropouts or Missing Data.......................................................... 29
4.11.1.4
Multiple Comparisons/Multiplicity ............................................................... 29
4.11.1.5
Blinded Independent Central Review (BICR)-Module 1................................ 29
4.11.1.6
Efficacy Interim Analyses............................................................................. 29
4.11.1.7
Examination of Subgroups............................................................................ 31
4.11.2
Primary Efficacy Variable – Objective response rate..................................... 31
4.11.3
Secondary Efficacy Variables ....................................................................... 33
4.11.3.1
Duration of Response (DoR)......................................................................... 33
4.11.3.2
Progression-free Survival (PFS).................................................................... 34


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4.11.3.3
Overall Survival (OS) ................................................................................... 36
4.11.3.4
Time to First Subsequent Therapy or Death (TFST)...................................... 37
4.11.3.5
Time to Objective Response (TTR)............................................................... 37
4.11.4
Pharmacokinetics.......................................................................................... 38
4.11.4.1
Pharmacokinetic Concentrations ................................................................... 38
4.11.5
B Symptoms ................................................................................................. 39
4.12 Safety Evaluation........................................................................................................ 39
4.12.1
Extent of Exposure........................................................................................ 39
4.12.2
Duration on study.......................................................................................... 40
4.12.3
Adverse Events............................................................................................. 41
4.12.4
Overdose....................................................................................................... 44
4.12.5
Deaths........................................................................................................... 44
4.12.6
Clinical Laboratory Evaluation ..................................................................... 44
4.12.7
Vital Signs and Weight ................................................................................. 46
4.12.8
Electrocardiogram......................................................................................... 48
4.12.9
Eastern Cooperative Oncology Group performance status (ECOG PS).......... 49
4.12.10
Echocardiogram (ECHO)/ MUGA Scan........................................................ 49
4.12.11
Safety Interim Analysis-Module 1................................................................. 49
4.13 Other Analyses ........................................................................................................... 50
4.13.1
Patient-reported Outcome (PRO) .................................................................. 50
4.13.1.1
EORTC QLQ-C30 ........................................................................................ 50
4.13.1.2
PRO-CTCAE................................................................................................ 52
4.13.1.3
Patient-reported anti-diarrhoeal medication................................................... 52
4.13.1.4
PGI-TT......................................................................................................... 52
4.14 Determination of Sample Size- Module 1.................................................................... 52
4.15 Changes in the Conduct of the Study or Planned Analysis........................................... 53
5
REFERENCES .................................................................................................................... 53
6
APPENDICES..................................................................................................................... 54
Appendix A Time windows for Module 1 ............................................................................ 54


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REVISION HISTORY
Version No.
Effective Date
Summary of Change(s)
1.0
01-Feb-22
New document.
2.0
07-Jul-22

Updated to be aligned with CSP v6.0.

Updated Section 1 (Introduction).

Section 4.7 minor updates for MCL Cohort 1C .

Section 4.9 summary for prior regimens replaced with 
summary of prior lines.

Concordance between BICR and investigator´s assessment 
added (4.11.2).

Summary of censoring rules for PFS added (4.11.3.2).

Duration on study section added (4.12.2) .

Updated Adverse event section (4.12.3, Adverse Events of 
Special Interest), to be in line with current list of AESIs for 
capivasertib. Removal of urinary tract infection, pneumonia
and Torsades de pointes from the AESI list; addition of 
infective pneumonia.
One characteristic of diarrhoea AEs removed from 
summaries and the other was updated.

Overdose section added (4.12.4)

Deletion of T/B/NK from “Table 5 Laboratory Safety 
Variables”. T/B/NK cell count are not part of clinical safety 
laboratory assessment.
Addition of gammaglutamyl transferase to “Table 5
Laboratory Safety Variables”.

Appendices section included. Time windows for Module 1 
added.
3.0
19-May-23
SAP updated to follow
“Early Onc SAP Template 
lymphoma_v1.0 2022-12”.
Section 4.5

ECOG [0-1 vs 2] category was removed.
Section 4.11.2

Sum of the product of the perpendicular diameters is 
collected in cm2 and will be reported in cm2 .
Section 4.7


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22-Sep-23
13-Nov-23

Prior bispecific TCEs added.
Section 4.11.4 updated to include description for PK analysis.
Identified any analyses not to be conducted or presented due to 
early termination of the study.
Section 3.2.1 updated to include that interim analyses will not 
be performed due to early termination of the study.
Section 4.2 updated to include details about summaries 
presentation.
Section 4.3.2 updated to add further clarification.
Section 4.6 Updated information to be included in Disposition 
of Patient summaries and added in information for the analysis 
sets summaries.
Section 4.6.1 updated to remove ‘site’ from description of 
summaries by country and site.
Section 4.7 removed patient recruitment as this is mentioned in 
Section 4.6.1.
Section 4.11.1.7 Prior bispecific TCEs added.
Section 4.11.2 added further details and clarification for BoR 
and Tumour assessments. Included Overall disease response 
into Tumour assessment details. 
Section 4.11.3 added further details, formulas, and clarification 
for DoR, PFS, OS, TFST and TTR.
Section 4.12.1 Included “+1” in the formula for duration of an 
interruption. Definitions added for Planned total dose and 
Actual total dose. 


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Section 4.12.3 “total number of diarrhoea events patients 
experience” removed. Included “+1” in the formulas for time to 
onset and duration of AESI.
Section 4.12.6 Minor updates made to Table 5 Laboratory 
Safety Variables. 
Section 4.12.8 RR typo corrected to PR. 








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1
INTRODUCTION
This is a modular, Phase II, open-label, multicentre study of capivasertib in patients with relapsed or 
refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL).
The statistical analysis plan (SAP) provides a technical elaboration of the statistical analysis to be 
performed as outlined in the clinical study protocol (CSP). All analyses described in this SAP are 
applicable for all modules and cohorts unless otherwise stated. Details provided in this document will 
also support the statistical analysis for conferences and publications.
The analyses described in this SAP are based upon the following study document:

Study Protocol, Version 6.0 (February 24, 2022)
The specifications for tables, listings and figures are contained in a separate document.
2
STUDY OBJECTIVES AND ENDPOINTS
2.1
Core
2.1.1
Primary Objective
Objectives
Estimand description
•
To estimate the effectiveness of the module-
defined study treatment by assessment of ORR
based on Lugano 2014 Classification response
criteria in each cohort as determined by BICR
Objective response rate is defined as the proportion 
of patients achieving either CR or PR according to 
the Lugano 2014 Classification for NHL as assessed 
by BICR.
The analysis will include all patients included in the 
response evaluable analysis set.
Data obtained from first dose up until progression, 
or the last evaluable assessment in the absence of 
progression, will be included in the assessment of 
ORR, regardless of whether the patient withdraws 
from therapy. Patients who go off treatment without 
a response or progression, receive a subsequent 
therapy, and then respond will not be included as 
responders in the ORR.
The measure of interest is the estimate of ORR.
In addition, for sensitivity analysis purposes, ORR 
will be defined as the proportion of patients 
achieving either a CR or PR according to the 


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Objectives
Estimand description
Lugano 2014 Classification for NHL assessed by 
the Investigator.
BICR: blinded independent central review; CR: complete response; NHL: non-Hodgkin lymphoma; ORR: objective 
response rate; PR: partial response.
2.1.2
Secondary Objectives
Objectives
Estimand description
•
To estimate the effectiveness of the 
module-defined study treatment by assessment 
of DoR based on Lugano 2014 Classification 
response criteria in each cohort as determined 
by BICR 
Duration of response is defined as the time from the 
date of first documented response until date of 
documented progression according to the 
Lugano 2014 Classification for NHL as assessed by 
BICR, or death due to any cause.
The analysis will include all patients included in the 
response evaluable analysis set who had a response, 
regardless of whether the patient withdraws from 
therapy.
The measure of interest is the median DoR.
In addition, for sensitivity analysis purposes, DoR 
will be defined as the time from the date of first 
documented response until date of documented 
progression according to the Lugano 2014 
Classification for NHL as assessed by the 
Investigator.
•
To estimate the effectiveness of the 
module-defined study treatment by assessment 
of PFS based on Lugano 2014 Classification 
response criteria in each cohort as determined 
by BICR 
Progression-free survival is defined as the time from 
the date of first dose until documented disease 
progression according to the Lugano 2014 
Classification for NHL as assessed by BICR, or 
death due to any cause.
The analysis will include all dosed patients, 
regardless of whether the patient withdraws from 
therapy, receives another anti-lymphoma therapy, or 
clinically progresses prior to progression according 
to the Lugano 2014 Classification for NHL.
The measure of interest is the median PFS.
In addition, for sensitivity analysis purposes, PFS 
will be defined as the time from the date of first 
dose until progression according to the 
Lugano 2014 Classification for NHL as assessed by 
the Investigator.


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Objectives
Estimand description
•
To estimate the effectiveness of the 
module-defined study treatment by assessment 
of OS in each cohort
Overall survival is defined as time from the date of 
first dose until the date of death due to any cause.
The analysis will include all dosed patients,
regardless of whether the patient withdraws from 
therapy or receives another anti-lymphoma therapy.
The measure of interest is the median OS.
•
To assess patient-reported disease-related 
symptoms, functioning and health-related 
quality of life of the module-defined study 
treatment in each cohort
Patient-reported disease-related symptoms, 
functioning and health-related quality of life as 
measured by EORTC QLQ-C30.
The analysis will include all dosed patients and will 
be summarised descriptively.
The measures of interest are mean and mean change 
from baseline in each of the functional scales, 
symptom scales, and global health status/quality of 
life scores at each time point.
•
To assess patient-reported symptomatic 
AEs/tolerability of module-defined study 
treatment in each cohort
Patient-reported symptomatic AEs and overall side 
effect burden as measured by PGI-TT and selected 
items from PRO-CTCAE.
The analysis will include all dosed patients and will 
be summarised descriptively.
The measures of interest will be proportion of 
patients reporting different levels of each 
symptomatic AEs and proportion of patients 
reporting different levels of overall side effect 
burden at each time point.
•
To estimate the effectiveness of the 
module-defined study treatment by assessment 
of TFST in each cohort
TFST is defined as time from date of first dose until 
the start date of first subsequent anti-lymphoma 
therapy after discontinuation of study treatment or 
death due to any cause.
The analysis will include all dosed patients 
regardless of whether the patient withdraws from 
therapy, receives another anti-lymphoma therapy, or 
clinically progresses prior to progression according 
to the Lugano 2014 Classification for NHL.
The measure of interest is the median TFST.
•
To estimate the effectiveness of the 
module-defined study treatment by assessment 
of TTR in each cohort
TTR is defined as time from date of first dose until 
the date of first documented objective response per 
the Lugano 2014 Classification for NHL as assessed 
by BICR.


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Objectives
Estimand description
The analysis will include all patients included in the 
response evaluable analysis set who had a response 
regardless of whether the patient withdraws from 
therapy.
The measure of interest is the median of TTR.
Safety 
•
To assess safety and tolerability of the 
module-defined study treatment in each cohort
Safety and tolerability will be evaluated in terms of 
AEs, vital signs, clinical laboratory, and ECGs.
Assessments related to AEs cover:
•
Occurrence/frequency
•
Relationship to the module-defined study 
treatment as assessed by investigator
•
CTCAE grade
•
Seriousness
•
Death
•
AEs leading to discontinuation of the module-
defined study treatment
•
AESIs
•
Other significant AEs
The analysis will include all dosed patients and will 
be summarised descriptively.
Pharmacokinetic 
•
To determine the PK of capivasertib when 
administered in patients in each cohort
Plasma concentration of capivasertib pre-dose 
(Ctrough) and post-dose (eg, 1 h, 2 h and 4 h).
Plasma PK parameters derived from a population 
PK model, as permitted by the data.
AE: adverse event; AESI: adverse event of special interest; BICR: blinded independent central review; CTCAE: Common 
Terminology Criteria for Adverse Events; Ctrough: observed lowest drug concentration reached before the next dose is 
administered; PK: pharmacokinetics; DoR: duration of response; ECG: electrocardiogram; EORTC QLQ-C30: European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; NHL: non Hodgkin 
lymphoma; PFS: progression-free survival; PGI-TT: Patient Global Impression of Treatment Tolerability; PRO-CTCAE: 
Patient-reported Outcomes-Common Terminology Criteria for Adverse Events; TFST: time to first subsequent therapy 
or death; TTR: time to objective response.


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2.1.3
Exploratory Objectives
Objectives
Estimand description
•
 
 
 
 
•
 
 
 
•
 
 
 
 
•
 
 
 
 
 
•
 
 
 
 
 
 
•
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Objectives
Estimand description
•
 
 
 
 
 
 
 
Exploratory endpoints will be reported outside of the CSR and will therefore not be described further 
within this SAP.
2.2
Module 1
Refer to Section 2.1 of the SAP.
3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
3.1.1
Core Module 
This is a modular, open-label, multicentre Phase II study of capivasertib administered orally in 
patients with R/R B-cell NHL. 
The core module provides the overall framework for the study and specific details are described 
separately for each module. A substantial protocol amendment with relevant supportive rationale will 
be approved before starting a new module.
3.1.2
Module 1
Module 1 is investigating capivasertib (AZD5363) monotherapy, administered orally in an
intermittent twice daily (BD) (4 days on/3 days off) regimen to patients with R/R FL, R/R MZL, R/R 
MCL.
The study design is presented in Figure 1.
CCI
CCI
CCI


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Figure 1
Study Design
BD: twice a day; FL: follicular lymphoma; MCL: mantle cell lymphoma; MZL: marginal zone lymphoma; NHL: non-
Hodgkin lymphoma; ORR: objective response rate; R/R: relapsed or refractory.
Module 1 for capivasertib monotherapy will include:

A Screening Period of up to 28 days

A Treatment Period comprised of 28-day treatment cycles, during which patients will 
receive treatment

A Follow-up Period which includes:
o
An EOT visit to be conducted within 7 days after discontinuation of study treatment.
o
A post-treatment follow-up visit to be conducted 30 days (± 7 days) after last dose of 
study treatment
o
A long-term follow-up period including collection of subsequent anti-lymphoma 
therapy, drug-related SAEs, concomitant medication and non-drug therapies related 
to the management of drug-related SAEs.  Survival will be assessed every 12 weeks 
(± 7 days) and response assessments for patient who stop study treatment without 
PD.
3.2
Planned Analyses
3.2.1
Module 1
Table 1
Summary of analyses and data cut-off triggers1 details the analyses planned during 
the conduct of Module 1 and the data cut-off triggers.
Table 1
Summary of analyses and data cut-off triggers
Analysis
Trigger
Data type included
Safety Interim
After approximately 30 patients in 
Module 1 have had the opportunity to 
be treated for at least 8 weeks.
Safety data.
Preliminary efficacy data based on 
investigator responses will also be 
included.


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Analysis
Trigger
Data type included
Efficacy Interim
Cohorts 1A and 1B: After 28 patients 
(either FL or MZL) treated with 
capivasertib have had the opportunity 
to be treated for 4 months.
Cohort 1C: After 24 patients (MCL) 
treated with capivasertib have had the 
opportunity to be treated for 
4 months.
Efficacy data (including ORR, DoR, 
PFS, TTR, and TFST).
Safety data will also be included.
Primary Analysis
After all patients treated with 
capivasertib have had the opportunity 
to be treated for 6 months. Analyses 
will be conducted separately for each 
cohort.
All data (including summary OS data 
available at the time of the primary 
analysis).
Final Analysis
Approximately 18 months after the 
last patient treated with capivasertib 
has been enrolled in the cohort or 
when 70% of patients have progressed 
or died (due to any reason) in the 
cohort, whichever occurs first. 
Analyses will be conducted separately 
for each cohort.
All data (including summary OS data 
available at the time of the final 
analysis).
OS Follow-up Analysis
After the final analysis until 70% of 
patients treated with capivasertib have 
died due to any cause. Analyses will 
be conducted separately for each 
cohort.
OS
DoR: duration of response; FL: follicular lymphoma; MCL: mantle cell lymphoma; MZL: marginal zone lymphoma; 
ORR: objective response rate; OS: overall survival; PFS: progression-free survival, TFST: Time to first subsequent 
therapy or death; TTR: Time to objective response.
Additional data cuts may also be performed, if required.
The interim safety and efficacy analyses will not be performed due to early termination of the study 
(number of patients required for analyses not met).


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4
STATISTICAL METHODS
4.1
Data Quality Assurance
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Parexel procedures.
4.2
General Presentation Considerations
Summaries and analyses will be presented either by cohort and overall, or by cohort alone. Details
for each output display are described in TFL-Shells document.
The following considerations will be applicable to all modules.
Continuous data will be summarised using descriptive statistics (number of observations, mean, 
standard deviation [SD], median, 25th and 75th percentiles [where appropriate], minimum and 
maximum). Geometric mean and coefficient of variation (CV) may be presented as applicable.
If data are available for less than 3 patients, no summary statistics other than minimum, maximum 
and number of observations will be presented.
For continuous data, the mean, median and geometric mean will be rounded to one additional decimal 
place compared to the original data. The SD and CV will be rounded to two additional decimal places 
compared to the original data. Minimum and maximum will be displayed with same accuracy as the 
original data. The maximum number of decimal places reported will be four for any summary statistic.
Categorical data will be summarised by frequency counts and percentages for each category. Unless 
otherwise stated, percentages will be calculated from the population total within that cohort. 
Percentages will be presented to one decimal place. Percentages will not be presented for zero counts.  
Time to event variables will be presented using the Kaplan-Meier methodology where appropriate, 
including median time calculated from the Kaplan-Meier curves.
Confidence intervals (CIs) and p-values, when presented, will generally be constructed at the 2-sided 
alpha level specified for each module. For Module 1, a 2-sided 95% CIs will be constructed and 
presented to one additional decimal place compared to the original data.  
In general, baseline will be the last non missing value obtained prior to the first dose of study 
medication and any information taken after first dose of study medication will be regarded as post 


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baseline information. If two visits are equally eligible to assess participant status at baseline (e.g., 
screening and baseline assessments both on the same date prior to first dose with no washout or other 
intervention in the screening period), the average is taken as the baseline value. For non-numeric 
laboratory tests (i.e. some of the urinalysis parameters) where taking an average is not possible then 
the best value will be taken as baseline as this is the most conservative. In the scenario where there 
are two assessments on Day 1 prior to first dose, one with time recorded and the other without time 
recorded, the one with time recorded is selected as baseline. Where safety data are summarised over 
time, study day will be calculated in relation to date of first treatment. If no value exists before the 
first dose/administration, then the baseline value will be treated as missing.
In all summaries:
Change from baseline = post-baseline value - baseline value. 
Percent change from baseline =
post-baseline value - baseline value
baseline value
×100.
4.3
General Variables
4.3.1
Study Day Definitions
Study day 1 is defined as the date of first dose of study treatment (Cycle 1 Day 1). 
For visits (or events) that occur on or after first dose of study treatment, study day is defined as (date 
of visit [event] – date of first dose of study treatment + 1).  For visits (or events) that occur prior to 
first dose, study day is defined as (date of visit [event] – date of first dose of study treatment).  There 
is no study day 0 defined for this study.
4.3.2
Time Windows
For safety and tumour assessments, time windows will be defined for any presentations that 
summarise values by visit.  The following conventions will apply:
For tumour assessments:

The protocol assigned windows for tumour assessments will be used to assign the result to a 
particular visit.

For safety assessments: The time windows will be exhaustive so that data recorded at any 
timepoint has the potential to be summarised.  Inclusion within the time window will be based 
on the actual date and not the intended date of the visit.

All unscheduled visit data will have the potential to be included in the summaries.


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
The window for the visits following baseline will be constructed in such a way that the upper
limit of the interval falls halfway between the two visits (the lower limit of the first post-
baseline visit will be Day 2).  If an even number of days exists between two consecutive visits, 
then the upper limit will be taken as the midpoint value minus 1 day. Refer to Appendix A for 
visit windows examples.

Windowing will be done separately for each assessment based on the schedule of events 
specific to that assessment.

Should study day be missing (due to partial or missing dates), then the visit will be assigned 
to the nominal visit at which the assessment was recorded, and no windowing will be 
performed.

Visit windowing will be conducted up and including the EOT visit. That is the EOT visit will 
be reassigned to a scheduled visit based on the study day the EOT visit occurred at. Follow-up 
visits will not be windowed.

For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on treatment will be used (regardless of where it falls in an interval).

Listings will display all values contributing to a timepoint for a patient.

For visit-based summaries: If there is more than one value per patient within a time window 
then the closest value to the scheduled visit date will be summarised, or the earlier, in the 
event the values are equidistant from the nominal visit.  The listings will highlight the value 
for the patient that contributed to the summary table, wherever feasible.  In summaries of 
extreme values all post-baseline values collected are used including those collected at 
unscheduled visits regardless of whether the value is closest to the scheduled visit date, or not.
For summaries at the patient level, all values will be included, regardless of whether they 
appear in a corresponding visit-based summary.
4.3.3
Handling of Missing Data
In general, other than for the below described, or where otherwise specified in the particular analysis, 
missing data will not be imputed and will be treated as missing.
4.3.3.1
Imputations of Partial Dates
Concomitant medication and adverse events start dates

Missing day: impute with the 1st of the month, unless month and year are the same as month 
and year of first dose of study treatment, then impute with first dose date.

Missing day and month: impute with the 1st of January unless the year is the same as the year 
of first dose of study treatment, then impute with first dose date.

Completely missing: impute with date of first dose of study treatment, unless the end date 
suggests it could have started prior to this in which case impute with 1st January of the same 
year as the end date.


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When imputing a start date care should be taken to ensure the start date is sensible, i.e., prior to the 
end date.
Concomitant medication and adverse events end dates

Missing day: impute the last day of the month unless both the month and the year are the same 
as the last dose date or the primary analysis data cut-off (DCO) date then impute the last dose 
date or the primary analysis DCO date.

Missing day and month: Impute 31st December unless the year is the same as the last dose 
date or the primary analysis DCO date then impute the last date or the primary analysis DCO 
date.

Completely missing: before imputing a date, consider whether the AE/medication is still 
ongoing and also when it started in relation to study drug. If the ongoing flag is missing then 
assume that AE is still present/ medication is still being taken (i.e., do not impute a date). If 
the AE/medication has stopped and start date is prior to first dose date, then impute first dose 
date. Or if it started on or after first dose date then impute a date that is after the last dose of 
study drug date.
Generally, the imputation of dates is used to decide if an observation is treatment emergent for AEs 
or concomitant for medications.  Flags will be retained in the database indicating where any 
programmatic imputation has been applied, and in such cases, durations and study days will not be 
calculated.
4.3.4
Imputation Rules for Laboratory Values Outside of Quantification Range
Values of the form “< x” (i.e., below the lower limit of quantification [LLOQ]) or “> x” (i.e., above 
the upper limit of quantification [ULOQ]) will be imputed as “x” in the calculation of summary 
statistics but displayed as “< x” or “> x” in the listings.
4.4
Software
All report outputs will be produced using SAS® version 9.4 or a later version in a secure and validated 
environment.
4.5
Analysis Sets
Details of the analysis sets are presented in Table 2.
Table 2
Analysis Sets
Analysis set
Description
Enrolled 
All patients who sign the ICF.
Safety
All patients who receive any amount of study treatment.


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Analysis set
Description
Safety data will be summarised using the safety analysis set.
Response evaluable
All patients, treated with study treatment, with measurable disease* at 
baseline.
Pharmacokinetic
All patients who receive at least 1 dose of capivasertib, for whom there is 
at least 1 reportable PK concentration.
ICF: informed consent form; PK: pharmacokinetic(s).
* Bi-dimensionally measurable disease on cross sectional imaging by CT or MRI with at least one nodal lesion > 1.5 cm 
in the long axis or at least one extranodal lesion > 1 cm in long axis
Upon database release, protocol deviations and analysis set outputs will be produced and will be sent 
to AZ for review.  Prior to database lock for the final analysis, an analysis set classification meeting 
will be arranged to discuss the outputs and to decide which patients and/or patient data will be 
excluded from certain analyses.  Decisions made regarding the exclusion of patients and/or patient 
data from analyses will be made prior to database hard lock for the final analysis and will be 
documented and approved by AZ.
A summary on which analysis set will be used for each outcome variable is provided in Table 3.
Table 3 Summary of outcome variables and analysis sets
Outcome variable
Analysis Sets
Study population/Demography Data
Disposition of patients
Enrolled
Demography characteristics 
Safety
Baseline and disease characteristics
Safety
Important protocol deviations
Enrolled
Medical History
Safety
Prior anti-lymphoma therapy
Safety
Concomitant Medication
Safety
Subsequent anti-lymphoma therapy
Safety
Efficacy Data
ORR
Response evaluable
DoR
Response evaluable
TTR
Response evaluable


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Outcome variable
Analysis Sets
OS
Safety
PFS
Safety
TFST
Safety
Safety data
Exposure
Safety
AEs
Safety
Laboratory measurements
Safety
Vital Signs
Safety
ECGs
Safety
Pharmacokinetics
Pharmacokinetic variables
PK
Patient-reported Outcome Data
EORTC QLQ-C30, PRO-CTCAE, PGI-TT
Safety
DoR duration of response; ORR objective response rate; OS overall survival; PFS progression free survival; PK 
pharmacokinetic; TFST: time to first subsequent therapy or death; TTR: time to objective response.
4.6
Study Patients
4.6.1
Disposition of Patients
A clear accounting of the disposition of all patients who enter the study will be provided, from 
screening to study completion.
Patient disposition including screen failures and reason for screen failure will be summarised and 
listed based on all subjects enrolled/screened (i.e. informed consent received) by cohort.
Summaries will include the number and percentage of patients: 

Patients enrolled /screened (informed consent received)

Screen failures

Patients assigned to treatment

Patients assigned to treatment , but who were not treated

Patients ongoing in study at data cut-off (DCO)

Patients ongoing treatment at DCO

Patients who discontinued treatment


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
Patients who discontinued study
A breakdown of the primary reason for discontinuation treatment and/or study will be presented for 
all patients.
Subject discontinuation will be listed, including description of cohort, disposition terms, date, and 
total treatment duration (days) derived as described in section 4.12.1.
The number of patients recruited in each country will be presented by cohort.
Patients who withdraw from study due to COVID-19 will be presented separately. Study disruptions 
due to the COVID-19 will also be presented. Listings for patients affected by COVID-19 will also be 
presented.
The analysis sets will be summarised by cohort and overall. Any exclusions from analysis sets will 
be listed.
4.6.2
Protocol Deviations
Important protocol deviations (IPDs) are defined as those deviations from the protocol likely to have 
an impact on the perceived efficacy and/or safety of study treatments.  
This assessment will be performed at a Data Review Meeting (DRM) shortly before database lock. 
Results and population assignments will be summarized in a DRM report which will be signed off 
by Parexel Lead Biostatistician, PM , AZ Global Product Statistician and AZ Physician.
Important protocol deviations and any action to be taken regarding the exclusion of subjects or 
affected data from specific analyses are defined in the project-specific Protocol Deviation 
Specification.
IPDs will be listed and summarised by cohort and overall for Enrolled Analysis Set. Important 
protocol deviations related to COVID-19 will be summarized separately.
A full list of protocol deviations can be found in the study-specific Protocol Deviation Specification.


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4.7
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarised and listed for all patients in the Safety 
Analysis Set by cohort: 

Demographic characteristics (age[years], age group [ ≥18-< 64; ≥65], sex [female; male], race, 
ethnicity).

Patient characteristics at baseline (height[cm], weight [kg], and body mass index [BMI] [kg/m2]). 

Disease stage (I, II, III, IV) at study entry.

Presence of bulky disease (Y/N) [Bulky disease is defined as the presence of a single lesion with 
largest diameter being 7 cm or larger. The presence of bulky disease will be determined by the 
investigator when baseline disease extent is evaluated]

Bone marrow involvement, yes (%)

Other extranodal involvement, yes (%)

Prior exposure to CART therapy, yes (%)

Prior exposure to PI3K, yes (%)

Prior autologous stem cell transplant (auto HSCT), yes (%)

Prior allogenic stem cell transplant (allo HSCT), yes (%)

Prior bispecifics, yes (%) (as identified during physician reviewed before DCO date)

Disease Status at study entry
o
Relapsed after the last line of therapy (i.e BOR to last line is CR or PR, followed by 
relapse), n %

Relapsed <6 months from completion of last line of therapy, n %
o
Refractory to last line of therapy (i.e. BOR to last line is SD or PD) n, %

Time from diagnosis to study treatment calculated as (date of study entry – date of initial 
diagnosis) / 365.25
Prior bispecifics TCEs and/or preferred drug codes already provided.
FL, Cohort 1A 

Histological Grade (Grade 1, 2, 3A)

FLIPI score High (≥3), Intermediate (2), Low (0,1)

FLIPI-2 score High (≥3), Intermediate (2), Low (0,1)

High tumour burden per GELF criteria, yes (%)

Progression of disease within 2 years (POD24), yes (%)

Double Refractory (refractory to both anti-CD20mAb and alkylating agent), yes (%)
POD24 is defined as relapse within 24 months from completion of first line therapy;
POD24 (months)= (date of PD First Regimen-First line – Stop date of first line of therapy+1) 
/(365.25/12).


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Double refractory will be derived by selecting the patients with a BOR or either PD/SD following an 
anti-CD20 mAb or and alkylating agent in any of the prior lines. 
MZL, Cohort 1B

MZL subtypes: nodal, extranodal/MALT, splenic, n %
MCL, Cohort 1C

MCL histological variants: blastoid vs other

t (11; 14) or Cyclin D1 overexpression, yes (%)

TP53 alteration

Simplified Mantle Cell Lymphoma International Prognostic Index (s-MIPI) high vs 
intermediate/low

Reason for BTK (Bruton's tyrosine kinase) discontinuation (PD vs toxicity/other)
A comprehensive review of all investigational BTK agents will be performed by AZ. AZ will provide 
a list with ATC categories to identify the participants who discontinued BTK as described above.
4.8
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA). All 
medical history (past and current) will be listed and the number and percentage of patients with any 
medical history will be summarised for the safety analysis set by system organ class (SOC) and 
preferred term (PT) separate for each cohort.
4.9
Prior Anti-lymphoma Therapy
Prior cancer surgery will be listed and summarised similarly to Medical History.
Prior anti-lymphoma drugs will be summarized using frequency tabulations by ATC classification 
and generic drug name (World Health Organization [WHO] dictionary term).
The following summaries will be produced by cohort using the safety analysis set:

Number of prior lines

Previous cancer therapies
4.10 Concomitant Medications and Other Treatments
Information on any concomitant treatment, procedures, or other medication considered necessary by 
the investigator for patient´s safety and wellbeing (including supportive care e.g. transfusions and 
vaccines) that the patient is receiving within 4 weeks prior to first dose of study treatment or receives 


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during the study including 30-day follow up period following the last dose if study treatment must be 
recorded in the eCRF along with reason for use.
Treatments received prior to, concomitantly, or post-treatment will be coded using the Word Health 
Organisation (WHO) Drug Dictionary (WHODD) Anatomical Therapeutic Chemical (ATC) 
classification codes.  Concomitant medications will be summarised for the safety analysis set by ATC 
classification codes.
For the purpose of inclusion in prior and/or concomitant medication summaries, incomplete 
medication start and stop dates will be imputed as detailed in Section 4.3.3.1.
Prior medications, concomitant and post-treatment medications are defined based on imputed start 
and stop dates as follows:

Prior medications are those taken prior to study treatment with a stop date prior to first dose
of study treatment.

Concomitant medications are those with a stop date on or after the first dose date of study 
treatment (and could have started prior to or during treatment).

Post treatment medications are those with a start date after the last dose date of study 
treatment.
Concomitant medication summary will be produced by cohort using the safety analysis set.
All prior, concomitant and medication and post study treatment medication data will be listed.
Missing coding terms should be listed and summarised as “Not coded”.
4.11 Efficacy Evaluation
4.11.1 Analysis and Data Conventions
Module 1:
Each cohort will be analysed separately for the primary, secondary and safety endpoints.
Cohorts 1A (FL) and 1B (MZL)
For ORR the following hypothesis will be tested at the 5% 2-sided level for each of the cohorts.
H0: ORR = 40% versus
H1: ORR = 55%.
Cohort 1C (MCL)


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For ORR the following hypothesis will be tested at the 5% 2-sided level:
H0: ORR = 25% versus
H1: ORR = 40%.
4.11.1.1
Multi-centre Studies
No adjustments for centre will be performed in this study.
4.11.1.2
Adjustments for Covariates
No adjustments for covariates will be performed.
4.11.1.3
Handling of Dropouts or Missing Data
Summary statistics will be based on non-missing values unless otherwise specified. 
4.11.1.4
Multiple Comparisons/Multiplicity
There will be no formal adjustment for multiplicity.
4.11.1.5
Blinded Independent Central Review (BICR)-Module 1
A Blinded Independent Central Review comprised of independent experts will support primary
endpoint (ORR) and secondary endpoints (DOR, PFS, TTR).
Full details on the BICR procedures and processes can be found in the BICR Charter.
4.11.1.6
Efficacy Interim Analyses
Descriptive summaries and the analysis methods for the outputs required for the interim analysis will 
follow the methodology outlined in this SAP. The list of tables, listings and figures required for 
interim analysis will be prepared as per AZ standards; and they will be flagged in the list of TLFs.
Due to early termination of the study, the Efficacy Interim Analyses will not be conducted.
Module 1:
Cohort 1A (FL) and Cohort 1B (MZL)
An interim analysis will be performed after a total of 28 patients enrolled in Cohort 1A plus Cohort 
1B have had the opportunity to be treated with capivasertib monotherapy for 4 months.
The interim analysis will be performed using results from BICR.


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This interim analysis will be assessed against a decision framework (Frewer et al 2016) for ORR 
based on a lower reference value of 40% and a target value (a desired signal to be observed) of 55%. 
The interim analysis will be based on data from patients from the 2 cohorts combined. 
 
 
 
 
 
 
 
Recruitment will not be paused while the interim analysis is evaluated.
Based on the interim results, study enrolment could pause and the sponsor may opt to amend the 
protocol to adjust dosing schedule based on emerging data, permanently close the specific cohort or 
add in a new cohort evaluating capivasertib in combination with other agents in that population which 
would be detailed in an amendment.
Cohort 1C (MCL)
An interim analysis will be assessed against a decision framework (Frewer et al 2016) for ORR based 
on a lower reference value of 25% and a target value (a desired signal to be observed) of 40%.
 
 
 
 
 
 
 
Recruitment will not be paused while the interim analysis is evaluated.
Based on the interim results, study enrolment could pause and the sponsor may opt to amend the 
protocol to adjust the dosing schedule based on emerging data, permanently close the specific cohort 
or add in a new cohort evaluating capivasertib in combination with other agents in that population 
which would be detailed in an amendment.
CCI
CCI
CCI
CCI


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4.11.1.7
Examination of Subgroups
The following subgroup analysis will be performed for ORR (the primary efficacy variable) by 
comparing ORR in the following groups:
Cohort 1A (FL) and Cohort 1B (MZL)

Age at screening (< 65 years versus ≥ 65 years)

Relapsed versus Refractory

Prior lines of therapy ( 2 versus ≥3)

Prior CART (yes/no)

Prior bispecific TCE (yes/no)

Prior PI3K inhibitor (yes/no)

Prior HSCT (yes/no)

Bulky disease (yes/no)

FLIPI (low/intermediate versus high)

GELF (yes/no)
For Cohort 1B (MZL) a summary table of ORR according to MZL subtype will be produced.
Cohort 1C (MCL)

Age at screening (< 65 years versus ≥ 65 years)

Relapsed versus Refractory

Prior lines of therapy ( 2 versus ≥3)

Prior CART (yes/no)

Prior bispecific TCE (yes/no)

Prior HSCT (yes/no)

Bulky disease (yes/no)

MIPI ( low/intermediate versus high)

Prior BTK discontinued for PD /Prior BTK discontinued for AE/other
In addition, the ORR estimate with its 95% CI will be presented graphically on a forest plot for each 
component of each subgroup.
Due to early termination of the study, subgroup analysis will not be conducted.
4.11.2 Primary Efficacy Variable – Objective response rate
ORR is the primary efficacy variable for Module 1.
The ORR is defined as the proportion of patients who achieve either complete response (CR) or partial 
response (PR) as best response as determined by blinded independent central review (BICR) per 
Lugano 2014 criteria prior to any evidence of progression and will be based on the response evaluable 
analysis set. In addition, for sensitivity analysis purposes, ORR will also be defined as the proportion 


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of patients achieving either CR or PR as best response as assessed by the investigator and will be 
based on the response evaluable analysis set. Data obtained from first dose up until progression, or 
the last evaluable assessment in the absence of progression, will be included in the assessment of 
ORR, regardless of whether the patient withdraws from therapy. Patients who discontinue study 
treatment without a response or progression, receive a subsequent anti-lymphoma therapy and then 
respond will not be included as responders in the ORR (i.e. the visit contributing to a response must 
be prior to subsequent therapy for the patient to be considered as a responder). 
The ORR will be based on the BICR Lugano data and using all scans regardless of whether they were 
scheduled or not. 
Measurable disease at baseline is defined as Bi-dimensionally measurable disease on cross sectional 
imaging by CT or MRI with at least one nodal lesion > 1.5 cm in the long axis or at least one 
extranodal lesion > 1 cm in long axis
Summaries will be produced to present the number and percentage of patients with a response 
(CR/PR) based upon the number of patients with measurable disease at baseline per BICR. ORR will 
be calculated and binomial exact confidence intervals at 95% will be presented for patients in the 
response evaluable analysis set. 
Summary showing concordance between BICR and investigator´s assessments may be presented. The 
concordance rate is the number of patients that are concordant over the total number of patients 
assessed. The patients are concordant when the investigator and BICR conclude the same response 
assessment for a patient.
Best objective response (BoR)
BoR is calculated based on the overall visit responses recorded in the BICR dataset. It is the best 
response a patient has had following enrolment, but prior to starting any subsequent anti-lymphoma 
therapy and up to and including Lugano progression or the latest evaluable assessment in the absence 
of Lugano progression. Categories of BoR will be based on Lugano criteria using the following 
response categories: CR, PR, SD, PD, not evaluable (NE) and unknown.  
BoR will be summarised by number of patients and percentage for each category (CR, PR, SD, PD
and NE). No formal statistical analyses are planned for BoR.
Tumour assessments
Tumour assessment will be made for target lesions (ie, measurable disease), non-target lesions (ie, 
non-measurable disease), organ enlargement (eg, spleen, liver), and new lesions on CT and combined 
with visual assessment of PET for response assessment (refer to Appendix I of CSP).
The change in tumour burden, as measured by the sum of the product of the perpendicular diameters 
(SPD) of the selected lesions (reported as target lesions), from baseline to post-baseline nadir will be 
summarized in absolute numbers (cm2) and percentage. A graphical summary of the best percentage 
change in the target lesion tumor size will be presented in a vertical bar chart with each patient’s best 


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percent change from baseline to nadir displayed as a vertical bar, with color coding that indicates best 
response attained (“waterfall” plot). Only patients included in the response evaluable analysis set with 
at least one post-baseline radiographic assessment (e.g. CT scan) will be included in the waterfall 
plot. Spider plots of tumour burden change over time will be presented. Only patients with 
measurable disease will be included in summaries.
The following tumour assessments details for NHL will be collected and listed by patient:

Target lesion size

Non-target lesion 

New lesion 

Spleen/Liver Disease 

Overall disease response

Split target lesion 
4.11.3 Secondary Efficacy Variables
Primary analysis on secondary efficacy variables will be based on BICR reviewed data. Sensitivity 
analyses will be performed based on investigator assessments. 
4.11.3.1 Duration of Response (DoR)
DoR is a secondary efficacy variable for Module 1.
DoR is defined as the time from the date of first documented objective response (CR or PR) until date 
of documented disease progression per Lugano classification or death (by any cause in the absence 
of disease progression).
DoR (months) = (date of PFS event [progression/death] or censoring – date of first objective response 
+ 1) / (365.25/12).
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 that was CR or PR. If a patient does not progress following a response, then 
their DoR is censored on the PFS censoring date. Only patients who have achieved objective response 
(CR or PR) are evaluated for DoR
The analysis will include all patients in the response evaluable analysis set who had response, 
regardless of whether the subject withdraws from therapy. Patients who had the event after the start 
of subsequent therapy, or are progression free and alive at the time of data cut-off, or have unknown 
status will be censored at the last tumour assessment on or before the start of subsequent therapy. 
Descriptive data will be provided for the DoR in responding patients, including the associated


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Kaplan Meier curves, medians (utilising Kaplan-Meier methodology) and corresponding 95% CIs. 
DoR will be calculated by KM estimates with 95% CI and presented. In addition, the percentage of 
patients remaining in response at 3, 6, 12 and 18 months after initial response will also be presented. 
Swimmer plots that clearly show the profile of each patient who responds will also be produced.
4.11.3.2 Progression-free Survival (PFS)
PFS is a secondary efficacy variable for Module 1.
PFS is defined as the time from date of first dose until documented disease progression, as assessed 
by investigator/BICR, or death from any cause.
The analysis will include all dosed patients, regardless of whether the patient withdraws from therapy, 
receives another anti- lymphoma therapy, or clinically progresses prior to Lugano progression. 
Patients who had the event after the start of subsequent therapy, or who are progression free and alive 
at the time of data cutoff,or have unknown status will be censored at the time of their last disease 
assessment on or before the data cutoff. Subjects with no post-baseline disease assessment will be 
censored on Day 1. The PFS time will always be derived based on the scan/assessment dates and not 
visit dates.
PFS (months) = (date of PFS event [progression/death] or censoring – date of first dose + 1) / 
(365.25/12).
Kaplan-Meier plots of PFS will be presented.  Summaries of the number and percentage of patients 
experiencing a PFS event, and the type of event (progression or death) will be provided along with 
the median PFS (utilising Kaplan-Meier methodology), its 95% CI, and the proportion of patients 
who were progression free at 6 months, 12 months and 18 months.
The treatment status at progression of patients at the time of analysis will be summarised. This will 
include the number and percentage of patients who were on treatment at the time of progression, the 
number and percentage of patients who discontinued study treatment prior to progression, the number 
and percentage of patients who have not progressed and were on treatment or discontinued treatment. 
This will also provide a distribution of number of days prior to progression for the patients who have 
discontinued treatment.
A summary of censoring rules and the date of PD/death or censoring are given in Table 4. Note that 
censoring overrides event in certain specified cases and that this table does not indicate the order for 
programming,


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Table 4 Summary of Censoring Rules for PFS
Situation
Date of PD/Death or Censoring
PFS Outcome
Documented Progressive Disease (PD) or death in 
the absence of progression
Date of earliest documentation of PD 
or date of death in the absence of 
progression
Event
Either no assessment at baseline or no evaluable 
assessments post-baseline AND death prior to 
second scheduled post-baseline disease 
assessment
Date of death
Event 
Either no assessment at baseline or no evaluable 
assessments post-baseline AND no death prior to 
second scheduled post-baseline disease 
assessment
Date of first dose (Day 1)
Censored
PD or death (in the absence of progression) 
immediately after ≥ 2 consecutive missed disease 
assessments as per the protocol specified 
assessment schedule
Last evaluable progression-free 
disease assessment prior to missed 
assessments
Censored
On-going with neither PD nor death at the time of 
analysis or lost to follow-up or withdrawn consent
Date of last evaluable disease 
assessment
Censored
Initiation of subsequent anti-cancer therapy prior 
to PD or death
Date of last evaluable disease 
assessment prior to initiation of 
subsequent anti-cancer therapy
Censored for 
sensitivity analysis 
only
Abbreviations: PD, progressive disease; PFS, progression-free survival
In addition, the number of patients prematurely censored will be summarised. A patient would be 
defined as prematurely censored if they had not progressed (or died in the absence of progression) 
and the last scan prior to DCO was more than one scheduled Lugano assessment interval plus 2 weeks 
prior to the DCO date.
Additionally, summary statistics will be given for the number of days from censoring to DCO for all 
censored patients.
A summary of the duration of treatment will be summarised using median time from first dose to date 
of censoring (date last known to not have progressed) in censored (not progressed) patients only.
Additionally, summary statistics for the number of weeks between the time of progression and the 
last Lugano assessment prior to progression will be presented.
All collected Lugano data will be listed for all dosed patients.
A sensitivity analysis will be conducted to assess the potential impact of COVID-19 related deaths 


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on PFS. That is patients who had a PFS event due to death where the primary or secondary cause of 
death was COVID-19 infection or COVID-19 infection was reported as a fatal AE, will be censored 
at the last available Lugano assessment prior to COVID-19 infection related death.
4.11.3.3 Overall Survival (OS)
OS is a secondary efficacy endpoint for Module 1.
OS is defined as the time from date of first dose until the date of death from any cause. 
OS (months) = (date of death or censoring – date of first dose + 1) / (365.25/12).
The analysis will include all dosed patients, regardless of whether the patient withdraws from 
treatment or receives another anti-lymphoma therapy. Patients who have not died by the analysis 
DCO date will be censored at their last date known to be alive before the DCO date. Patients known 
to be alive or dead after the DCO date will be censored at the DCO date. Patients lost to follow-up 
will be censored at the date the patient is last known to have been alive.
Survival follow-up phone calls will be made in the weeks following the date of DCO for the analysis; 
if patients are confirmed to be alive or if the death date is after the DCO date these patients will be 
censored at the date of DCO. The status of ongoing, withdrawn (from study) and “lost to follow-up” 
patients at the time of final OS analysis should be obtained by the site personnel by checking the 
patient’s notes, hospital records, contacting the patient’s general practitioner and checking publicly 
available death registries.  In the event that the patient has actively withdrawn consent to the 
processing of their personal data, the vital status of the patient can be obtained by site personnel from 
publicly available resources where it is applicable to do so under applicable local laws.
For any OS analysis performed prior to the final OS analysis, in the absence of survival calls being 
made, it is necessary to use all relevant eCRF fields to determine the last recorded date on which the 
patient was known to be alive for those patients still on treatment.
If a patient is known to have died where only a partial death date is available, then the date of death 
will be imputed as the latest of the last date known to be alive + 1 from the database and the death 
date using the available information provided:

For missing day only – using the 1st of the month

For missing day and month – using the 1st of January
If there is evidence of death, but the date is entirely missing, it will be treated as missing, i.e., censored 
at the last known date alive.
Kaplan-Meier plots of OS will be presented.  Summaries of the number and percentage of patients 
experiencing an OS event will be provided along with the median OS (utilising Kaplan-Meier 


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methodology), its 95% CI, and the proportion of patients who were known to be alive at 6 months, 
12 months and 18 months.
A sensitivity analysis will be conducted to assess the impact of COVID-19 related deaths on OS. That 
is, patients who had a death event where the primary or secondary cause of death was COVID-19 
infection or COVID-19 infection was reported as a fatal AE, will be censored at the date of their 
COVID-19 infection related death.
The number of patients prematurely censored will be summarised.  A patient would be defined as 
prematurely censored if there is no indication that the patient died, but there is no survival available 
in the 13 weeks prior to the DCO.
Due to early termination of the study, the sensitivity analysis will not be conducted.
4.11.3.4 Time to First Subsequent Therapy or Death (TFST)
TFST is a secondary efficacy endpoint for Module 1.
TFST is defined as time from date of first dose until the start date of subsequent anti-lymphoma 
therapy (including local radiotherapy) or death due to any cause. The analysis will include all dosed 
patients regardless of whether the patient withdraws from therapy, receives another anti-lymphoma 
therapy or clinically progresses prior to progression according to the Lugano 2014 Classification for 
NHL.
TFST (months) = (date of subsequent anti-lymphoma therapy – date of dose + 1) / (365.25/12).
TFST will be summarised using Kaplan-Meier methodology. Same methodology as for PFS will be 
used.
Due to early termination of the study, TFST is not presented.
4.11.3.5 Time to Objective Response (TTR)
TTR is a secondary efficacy endpoint for Module 1.
TTR is defined as the time from the date of first dose until the date of first documented objective 
response per Lugano classification as assessed by BICR. The analysis will include all patients in the 
response evaluable analysis set who had a response. 
TTR (months) = (date of first objective response – date of first dose + 1) / (365.25/12).
The TTR will be summarised (ie, number of subjects [%] based upon the number of patients with CR 
or PR) by time point that the response was first observed. Descriptive data (i.e., median and quartiles) 
will be provided for TTR in responding subjects (utilising Kaplan-Meier methodology), including the 


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associated Kaplan Meier curves, and corresponding 95% CIs.
4.11.4 Pharmacokinetics
Pharmacokinetic analyses will be performed based on the PK analysis set. Any exclusion of 
data will be documented and justified.
The PK data from this study may be pooled with data from other studies for population PK and 
exposure-response analyses. The results from such analyses will be reported separately.
4.11.4.1 Pharmacokinetic Concentrations
Plasma concentrations of capivasertib will be listed by patient and time-point.
Plasma concentrations will be summarised by cohort and scheduled time point using the following 
descriptive statistics, based on the PK analysis set:

n

n below LLOQ

geometric mean (gmean)

geometric coefficient of variance (%) (gCV)

arithmetic mean (mean)

arithmetic standard deviation (Std Dev)

median

minimum (min) 

maximum (max)
The gmean is calculated as exp(μ), where μ is the mean of the data on the natural log scale.
The gCV is calculated as 100 x sqrt[exp(s2)-1], where s is the Std Dev of the data on the natural log 
scale.
Handling of Non-Quantifiable Concentrations
Individual concentrations below the LLOQ of the bioanalytical assay are reported as NQ in the 
listings with the LLOQ defined in the footnotes of the relevant Table/Listing. Individual plasma 
concentrations that are Not Reportable are reported as NR and those that are missing are reported as 
NS (No Sample) in the listing. Plasma concentrations that are NQ, NR or NS are handled as follows 
for the provision of descriptive statistics:

Any values reported as NR or NS are excluded from the summary table.

At a time point where less than or equal to 50% of the concentration values are NQ, all NQ 
values are set to the LLOQ, and all descriptive statistics are calculated accordingly.

At a time point where more than 50% (but not all) of the values are NQ, the gmean and 
gCV% are set to Not calculable (NC). The maximum value is reported from the individual 
data, and the minimum and median are set to NQ.


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
If all concentrations are NQ at a time point, no descriptive statistics are calculated for that 
time point. The gmean, minimum, median and maximum are reported as NQ and the gCV% 
as NC.
Three observations > LLOQ are required as a minimum for a plasma concentration to be summarised. 
Two observations > LLOQ are presented as minimum and maximum with the other summary 
statistics as NC.
Precision and Rounding Rules for Pharmacokinetic Data
PK concentration data 
PK concentration data listings present to the same number of significant figures as the data received 
from the bioanalytical laboratory (usually but not always to 3 significant figures) and against the same 
units as received.
PK concentration descriptive statistics present 4 significant figures with the exception of the min and 
max which present 3 significant figures and n and n<LLOQ which present as integers.
4.11.5 B Symptoms
Information on B symptoms (unintentional weight loss within previous 6 months, fevers > 38 C, night
sweats, significant fatigue) will be listed for all patients and visits.
4.12 Safety Evaluation
All safety summaries and analyses will be based upon the Safety Analysis Set and presented by 
cohort.
Safety analysis across all modules in this study will be analysed in a similar fashion as described 
below.
4.12.1 Extent of Exposure 
Module 1
Exposure data will be summarised and listed for safety analysis set.
Duration of exposure is defined as:
1. Total treatment duration = (min (last dose date where dose > 0 mg, date of death, date of 
DCO) − date of first dose +1).
2. Actual treatment duration = total treatment duration-total duration of dose interruptions, 
where the total duration of dose interruption is defined as any length of time where the patient 
has not taken any of the planned doses.
For handling exposure and dose interruptions, the following rules will be considered. 


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If a patient permanently discontinues study treatment during a dose interruption, then the date of last 
administration of study medication recorded on the eCRF will be used in the programming.
Total dose of capivasertib will be calculated as the sum of all doses received during the study. 
The duration of an interruption will be calculated as [date/time treatment resumed – date/time 
treatment stopped+1].  Overall duration of interruption will be determined as the sum of all individual 
interruptions during the study for a particular patient. Duration of dose interruption is defined as any 
length of time where the participant has not taken any of the planned doses; after four days of dosing 
patients are covered by the drug for an additional three days before having to take drug again. Missed 
or forgotten doses will not be included as dose interruptions in the summary tables but the information
appears in the listing for dosing. However, these missed and forgotten doses will be considered in the 
derivation of actual exposure.
Dose intensity of capivasertib will be addressed by considering relative dose intensity (RDI). RDI is 
the percentage of the actual dose delivered relative to the intended dose up to treatment 
discontinuation. RDI will be defined as:
RDI(%)= 100 *d/D, 
where:
d is the actual cumulative dose delivered up to the last day of dosing,
    and 
D is the intended cumulative dose up to the last day of dosing (ie, that would have been delivered 
without a modification of the dose or schedule).
Planned total dose will be defined as total dose of capivasertib that would have been delivered if there 
were no modification to dose.
Actual total dose will be defined as the sum of all doses received during the study per patient.
The following summaries will be produced:

Summary of interruptions and reductions of study treatment

Summary of RDI

Summary of intended and actual exposure of capivasertib

Summary of total dose
4.12.2 Duration on study
Duration of follow-up (months)= (min (date of death, date of DCO, study end date, date of 
withdrawal) – randomization date/date of first dose +1) / (365.25/12)


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Summary statistics will be provided for duration on study.
4.12.3 Adverse Events
Adverse events (AEs) and serious AEs (SAEs) will be collected from the time of signing of the 
informed consent throughout the treatment period and including the follow-up.
AEs will be coded using the latest or current Medical Dictionary for Regulatory Activities (MedDRA) 
version. AEs will be graded according to the National Cancer Institute of Common Terminology 
Criteria for AEs (CTCAE version 5.0).
Adverse events of special interest 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.
These AESIs will be identified as a list of categories provided by the patient safety team.
Reviews will take place prior to database lock to determine whether any AE should be classified as 
AESIs.  The review will identify which higher-level terms, and which preferred terms should 
contribute to each AESI.
The following are considered to be AESIs:
•
Hyperglycaemia
•
Non-infectious diarrhoea
•
Infective pneumonia
•
Rash
•
Stomatitis
•
QT Prolongation
•
Haematological effects
The following events are considered treatment emergent:

AEs with an onset date on or after the first dose of study treatment and within 30 days+7 days
after last dose of study treatment or up to the day prior to start of subsequent therapy, 
whichever comes first.

Worsening of pre-existing events on or after first dose of study treatment and within 30 days +7
days after last dose of study treatment or up to the day prior to start of subsequent therapy.
Unless otherwise stated, only AEs defined as treatment emergent will be included in the summary 
tables. Adverse events not classified as treatment emergent will only be listed.


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All reported AEs will be listed along with the actual treatment received, cohort, study day of start, 
duration of event, CTCAE grade, relationship to study treatment, seriousness, action taken and 
outcome.  Frequencies and percentages of patients reporting each preferred term will be presented 
(i.e., multiple events per patient will not be accounted for, except for event level summaries).
Summary information (the number and percentage of patients by treatment) by MedDRA SOC and 
PT will be tabulated for:

All AEs

All AEs causally related to capivasertib (as determined by the reporting investigator)

AEs of CTCAE grade 3 or higher

AEs of CTCAE grade 3 or higher, causally related to capivasertib (as determined by the 
reporting investigator)

AEs with outcome of death

AEs with outcome of death, causally related capivasertib (as determined by the reporting 
investigator)

AE leading to dose reduction of capivasertib

AEs leading to dose interruption of capivasertib

All SAEs

All SAEs causally related to capivasertib (as determined by the reporting investigator)

AEs leading to discontinuation of capivasertib

AEs leading to discontinuation of treatment, causally related to capivasertib (as determined 
by the reporting investigator)

SAEs leading to discontinuation of capivasertib

SAEs leading to discontinuation of treatment, causally related to capivasertib (as determined 
by the reporting investigator)

AESIs 
An overall summary of the number and percentage of patients in each of the above categories will be 
presented, as well as an overall summary of number of events in each of the above categories. In 
addition, a table of most common AESIs, showing all events that occur in at least 2 of patients will 
be summarized by PT, by decreasing frequency.
In addition, an event level summary will be presented for all AEs by PT.
Summaries of the number and percentage of patients with AEs will also be produced by maximum 
reported CTCAE grades, SOC, and PT and of most common AEs of CTCAE grade 3 or higher by 
SOC and PT.


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Summaries of the number and percentage of patients with AEs will also be produced by maximum 
reported CTCAE grades, SOC, and PT and of most common AEs of CTCAE grade 3 or higher by 
SOC and PT.
For diarrhoea events, the overall summary for all AEs reporting the number and percentage of patients 
in each category (e.g. any diarrhoea AE possibly relatedto capivasertib) will be repeated for diarrhoea 
events.
For diarrhoea events the number of patients with any diarrhoea AE occurring only on
dosing days and occurring only on off days .
In addition, AEs with outcome death, SAEs, AEs leading to discontinuation of treatment and AEs 
leading to treatment delay and AESIs will be listed separately.
The following additional summaries will be presented should more than 2% of the patients treated in 
this study have COVID-19 infection:

All AEs, excluding AEs associated with COVID-19 infection

All AEs associated with COVID-19 infection

AEs with outcome of death, excluding AEs associated with COVID-19 infection

AEs associated with COVID-19 infection with outcome of death

AEs leading to discontinuation of study intervention, excluding AEs associated with 
COVID-19 infection

AEs associated with COVID-19 infection leading to discontinuation of study intervention
The above categories will also be included in the overall AE summaries.
Further COVID-19 related summaries related to AEs may be added if required.
In addition, summaries of treatment emergent AESIs will be presented by maximum reported CTCAE 
grade, by AE outcome, including time of resolution (on-treatment or follow-up), whether treatment 
was received (yes/no) and action taken.
Descriptive statistics for time to onset and duration of first AESI for patients experiencing AESIs will 
be presented.  Time to onset will be derived as [AESI start date – Treatment start date + 1] while 
duration will be derived as [AESI end date – AESI start date + 1]. If the AESI is ongoing at the 
respective DCO, the DCO date will be imputed as the end date for duration calculations. Time to 
onset and duration will be presented in days.
The following characteristics of diarrhoea AEs will also be summarised separately for


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events on dosing days and on off dosing days:
• Duration of events for on dosing days only (days)
• Pattern of event (intermittent / continuous)
• Duration of CTCAE grade 3 diarrhoea (days) 
4.12.4 Overdose
The maximum tolerated dose for capivasertib and recommended dosing schedule is 480 mg
BD 4 days on / 3 days off as monotherapy on intermittent dosing schedule.
Any dose, or frequency of dosing, that exceeds this dose regimen will be reported as an overdose.
A summary of overdose will be provided with the number and percentage of patients categorised as:

Number of patients with an overdose associated with an AE.

Number of overdoses per patient.

Frequencies of overdose, n (%).

Time to first overdose (weeks).
Due to early termination of the study, Overdose is not presented.
4.12.5 Deaths
A summary of deaths will be provided with the number and percentage of patients categorised as: 
•
Total number of deaths 

Related to disease under investigation only

AE outcome of death only

AE with outcome of death only and onset date <= 30 days + 7 days after last dose of
study treatment

Other deaths
A corresponding listing will also be produced.
Due to early termination of the study, Deaths are listed only.
4.12.6 Clinical Laboratory Evaluation
All local laboratory results collected will be listed.
Summaries for safety laboratory will only include the parameters specified in Table .


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Table 5 Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry
B-Glycosylated haemoglobin (HbA1c) (fasting)
B-Haemoglobin (Hb)
S/P-Creatinine
S/P-Bilirubin, total
B-Leukocyte count (WBC count)
S/P-Alkaline phosphatase
B-Leukocyte differential count
S/P-AST
Neutrophils
S/P-ALT
Lymphocytes
S/P-Albumin
Eosinophils
S/P-Potassium
B-Platelet count
S/P-Calcium, total
Urinalysis
S/P-Sodium
U-Glucose
S/P-Glucose (fasting)
U-Protein
S/P-Magnesium
U-Blood
S/P-Total protein
S/P-Free T4 a
S/P-TSH a
S/P-bicarbonate
U-pH
S/P-BUN/urea nitrogen
U-Specific gravity
S/P-chloride
U-bilirubin
S/P-LDH
U-Ketones
S/P-Phosphate
Other
S/P-Uric acid
Beta-2 microglobulin b
S/P-Troponin I or T b
S/P-Lipids (fasting)
S/P-Gamma-glutamyl transferase
a
Test will only be performed on Day 1 in each cycle and when clinically indicated.
b
At screening and then as clinically indicated.
NB. In case a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN please refer to 
Appendix E of CSP ‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law’, for 
further instructions.
Lipids: triglycerides, high density lipoprotein, low density lipoprotein, and cholesterol.
ALT: alanine aminotransferase; AST: aspartate aminotransferase; B: blood; BUN: blood urea nitrogen; P: plasma; S: 
serum; T4: thyroxine; TSH: thyroid-stimulating hormone; U: urine; ULN: upper limit of normal; WBC: white blood 
cell.
All values will be classified as low (below range), normal (within range), or high (above range) based 
on local laboratory reference ranges. Results will be converted to standard units. For assessments 
included in CTCAE version 5.0, the CTCAE grade will be calculated.


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All clinical laboratory results will be listed. 
For all continuous laboratory assessments, absolute value and change from baseline will be 
summarised using descriptive statistics at each scheduled assessment time by cohort.
For clinical chemistry and haematology, shift tables will present movements from baseline to 
maximum and minimum values on-treatment according to reference range classification.  CTCAE 
grade changes from baseline to the maximum grade on-treatment will also be provided.  
Corresponding shift tables (“Negative”, “Trace”, “Positive”, “0”, “+”, “++”, “+++”) will be produced 
for urinalysis.  
Due to early termination of the study, minimum shift tables, and CTCAE grade changes not presented.
Due to early termination of the study, Urinalysis is not presented.
Key patient information will be presented for patients with treatment-emergent changes in laboratory 
parameters outside of predefined criteria.
Plots for both maximum post-baseline alanine transaminase (ALT) and aspartate transaminase (AST) 
versus the maximum post-baseline total bilirubin (expressed as multiples of their upper limit of 
normal [ULN] reference range) will be produced with reference lines at 3 x ULN for ALT and AST 
and 2 x ULN for total bilirubin.  Box plots of absolute values and change from baseline values for all 
haematology and clinical chemistry parameters will also be presented.
Liver biochemistry test results over time for patients who show elevated ALT or AST (≥ 3 x ULN) 
and elevated bilirubin (≥ 2 x ULN) (elevated results do not need to be present at the same visit) or 
ALT or AST of ≥ 5 x ULN, will be tabulated and plotted.
Due to early termination of the study, ALT and AST plots are not presented.
Due to early termination of the study, box plots of change from baseline are not presented. 
Due to early termination of the study, Liver biochemistry results over time are tabulated only.
4.12.7 Vital Signs and Weight
The following vital signs will be assessed and listed:

Systolic blood pressure (SBP) [mmHg].

Diastolic blood pressure (DBP) [mmHg].

Pulse rate (bpm).

Pulse oxygen saturation (%)


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
Oral body temperature (°C).

Weight (kg)
Vital signs data described above will be listed by patient and timepoint including reference range 
indicator for measurements that are outside the reference range (low, normal, high).
Change from baseline in vital signs parameters will be calculated for each post-baseline visit.
Descriptive statistics for absolute values and changes from baseline will be presented for pulse, 
systolic and diastolic blood pressure, body temperature and weight by cohort.
A shift table of baseline to maximum and minimum value on treatment for blood pressure and pulse 
will also be presented using the normal ranges in Table .
Table 6 Vital Sign Normal Ranges
Vital Sign
Outside AZ 
defined 
reference 
range lower 
limit if
Outside AZ 
defined 
reference 
range upper 
limit if
Treatment 
emergent 
decrease if
Treatment 
emergent 
increase if
Systolic blood 
pressure (mmHg)
< 90
> 140
< -20
> 20
Diastolic blood 
pressure (mmHg)
< 50
> 90
< -10
> 10
Pulse (bpm)
< 50
> 100
< -20
> 10
Key patient information will be presented for patients with treatment-emergent changes in vital signs 
outside of predefined criteria.
Supportive vital sign listings covering observed values and changes from baseline as well as 
abnormalities will be provided.
In addition, box plots of absolute values and change from baseline in blood pressure, pulse, body 
temperature and weight will also be presented.
Due to early termination of the study, shift tables are not presented. 
Due to early termination of the study, box plots of change from baseline are not presented.


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4.12.8 Electrocardiogram
The following parameters will be assessed in 12-lead ECGs:
PR-interval (msec).
QRS-duration (msec). 
RR-interval (msec).
QT-interval (msec).
QT-interval corrected using the Fridericia correction formula (QTcF) (msec).
Heart rate (beats per minute [bpm]).
All ECGs will be conducted as triplicate measurements. The average of the three measurements will 
be used in summaries and data listings. If one measurement is missing the average of the two 
measurements will be used. If there is only one measurement, this will be used in the summary table.
ECG parameters will be listed by patient including changes from baseline for numeric ECG 
parameters. The individual measurements will be displayed in the data listings. 
Descriptive statistics for absolute values and changes from baseline will be presented by cohort.
QTcF outliers (defined as values following study treatment that are greater than 450 msec or increases 
from baseline greater than 30 msec) will be summarised using cumulative counts and percentages 
under the following categories:

Absolute value > 450 msec

Absolute value > 480 msec

Absolute value > 500 msec

Change from baseline > 30 msec

Change from baseline > 60 msec

Change from baseline > 90 msec

Absolute value > 450 msec and change from baseline > 30 msec

Absolute value > 500 msec and change from baseline > 60 msec
All ECG data received will be presented in data listings.  
For each scheduled post-baseline assessment, descriptive statistics for all ECG parameters will be 
presented for observed values and change from baseline.
Overall evaluation on of ECG results will be summarised descriptively. A table presenting the 
interpretation of the ECG reading (normal, abnormal) at baseline and last assessment on treatment 
will be provided, including shifts in interpretation as compared to baseline.
Box plots of absolute values and change from baseline in ECG parameters over time will be presented.  


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Shift table from baseline to maximum and minimum value on-treatment will be presented using the 
normal ranges in Table .
Due to early termination of the study, shift tables are not presented.
Table 7 ECG Normal Ranges
ECG Parameter
Outside AZ defined 
reference range lower 
limit if
Outside AZ defined 
reference range upper 
limit if
Heart rate (bpm)
< 40
> 100
RR (msec)
< 600
> 1200
PR (msec)
< 120
> 200
QRS (msec)
< 60
> 109
QT (msec) and QTcF (msec)
< 320
> 450
Key patient information will be presented for patients with treatment-emergent ECG values outside 
of predefined criteria.
Supportive ECG listings covering observed values and change from baseline for each patient will be 
presented.
4.12.9 Eastern Cooperative Oncology Group performance status (ECOG PS)
The ECOG performance status will be listed and summarised as frequency counts by cohort.
4.12.10Echocardiogram (ECHO)/ MUGA Scan
All echocardiogram data received will be presented in data listings.
Left Ventricular Ejection Fraction will be assessed at screening and thereafter as clinically indicated. 
A listing of LVEF by visit will be presented
4.12.11 Safety Interim Analysis-Module 1
An interim analysis for safety will be conducted after approximately 30 patients across the three 
cohorts 1A, 1B, and 1C have had the opportunity to be treated for at least 8 weeks.
The patient disposition, demographic characteristics, baseline patient and disease characteristics, 
exposure, baseline and post-baseline safety parameters (AEs, clinical laboratory assessments, vital 
signs and ECG data) will be summarised by cohort (Cohort 1A, Cohort 1B, Cohort 1A+1B, Cohort 
1C). Preliminary efficacy data based on investigator responses may also be included.


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Descriptive summaries and the analysis methods for the outputs required for the interim analysis will 
follow the methodology outlined in this SAP.
The list of tables, listings and figures required for safety interim analysis will be prepared as per AZ 
standards; and they will be flagged in the list of TLFs. 
Due to early termination of the study, the Safety Interim Analyses will not be conducted.
4.13 Other Analyses
4.13.1 Patient-reported Outcome (PRO) 
PRO data assessed using the following measures:

EORTC QLQ-C30

PRO-CTCAE

PGI-TT
Will be analysed by descriptive summaries and graphic presentations. The analyses will be based on 
all dosed patients. Missing data will not be imputed and the analyses will be based on observed non-
missing data. 
Due to early termination of the study, PRO will not be presented.
4.13.1.1 EORTC QLQ-C30 
The EORTC-QLQ-C30 was developed to assess the health-related quality of life of cancer patients 
participating in international clinical trials.
The EORTC QLQ-C30 consists of 30 questions, which can be grouped to produce five multi-item 
functional scales, three multi-item symptom scales, six individual items (five items assessing 
additional symptoms commonly reported by cancer patients and one item on the financial impact of 
the disease) and a two-item global measure of health status/quality of life. For further details refer to 
EORTC-QLC-C30 scoring manual
The global health status/ QoL, functional scales and symptom scales, including the items included in 
each of these scales are presented in Table .


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Table 8 Scoring the QLQ-C30
Scale
Number of Items
Item Range a
Item Numbers
Global 
Health 
Status/QoL
Global Health Status
QL2
2
6
29, 30
Functional Scales
Physical functioning
PF2
5
3
1 to 5
Role functioning
RF2
2
3
6, 7
Emotional functioning
EF
4
3
21 to 24
Cognitive functioning
CF
2
3
20, 25
Social functioning
SF
2
3
26, 27
Symptom Scales/ 
Items
Fatigue
FA
3
3
10, 12, 18
Nausea and vomiting
NV
2
3
14, 15
Pain
PA
2
3
9, 19
Dyspnoea
DY
1
3
8
Insomnia
SL
1
3
11
Appetite loss
AP
1
3
13
Constipation
CO
1
3
16
Diarrhoea
DI
1
3
17
Financial difficulties
FI
1
3
28
a Item range is the difference between the possible maximum and the minimum response to individual items; most items 
take values from 1 to 4, giving range = 3.
Descriptive statistics for subscale scores, including changes from baseline will be presented by time 
point and cohort. Plots of mean change from baseline in total and subscale scores over time will also 
be presented with indicators for the number of patients at each visit.  
Other methods 
including distribution-based methods, cumulative distribution function, and probability density 
function curves, and methods using other anchors may also be considered. Once the clinically 
meaningful change thresholds are established, time to deterioration analyses and proportion of 
patients with deteriorated, stable and improved EORTC QLQ-C30 scores will also be explored. 
These analyses will be conducted separately and the detailed methodology will be described in a 
separate PRO SAP. 
CCI


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4.13.1.2 PRO-CTCAE
PRO-CTCAE data will be summarised descriptively in each cohort for each patient-reported 
symptomatic AE item. The summary will include 
1.
Number and proportion of patients reporting different levels of symptomatic AE at each time 
point
2. Number and proportion of the worst response option reported by patients within 24 weeks
3. Number and proportion of patients who report the presence of the symptom at baseline 
4. Number and proportion of patients who report any worsening from baseline within 24 weeks
5. Number and proportion of patients who worsen from a score <4 (on a 0 – 5 scale) at baseline 
to a score 4 or 5 within 24 weeks.
Some symptomatic AEs may have multiple attributes (frequency, interference, severity, 
presence/absence), and the analyses above will be applied to each attribute. 
4.13.1.3 Patient-reported anti-diarrhoeal medication
Patient-reported anti-diarrhoeal medication data will be listed and summarised descriptively at each 
time point in each cohort. The summary will include the number and proportion of patients reporting 
any medication for diarrhoea during the past week. Among patients reporting anti-diarrhoea 
medication, the number and proportion of patients reporting different levels of helpfulness will also 
be summarised. 
4.13.1.4 PGI-TT 
PGI-TT will be summarised descriptively at each time point in each cohort. The summary will 
include the number and proportion of patients reporting different levels of overall side effects 
burden as measured by PGI-TT.
4.14 Determination of Sample Size- Module 1
Cohorts 1A (FL) and 1B (MZL)
 
 
Cohort 1C (MCL)
 
 
CCI
CCI


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4.15 Changes in the Conduct of the Study or Planned Analysis
Not Applicable to this study.
5
REFERENCES
1. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-
Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32(27):3059-67
2. Frewer P, Mitchell P, Watkins C, Matcham J. Decision-making in early clinical drug 
development. Pharm Stat 2016;15(3):255-63.
3. SAS Institute Inc. 2013. SAS® 9.4 Statements: Reference. Cary, NC: SAS Institute Inc.
4. The SAS System Requirements for SAS® 9.4 Foundation for Microsoft Windows: Copyright 
©2020. SAS Institute Inc. SAS and all other SAS Institute Inc. product or service names are 
registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA.
5. Hematol 2020 Jul;99(7):1595-1604. doi: 10.1007/s00277-020-04025-2. Epub 2020 May 16


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6
APPENDICES
Appendix A Time windows for Module 1 
Visit
Window
Physical examination | Vital 
signs | ECOG | Haematology 
| Clinical chemistry
12-lead ECG
Cycle 1 Day 1
1
1
Cycle 1 Day 8
2 – 11
Cycle 1 Day 15
12 – 18
Cycle 1 Day 22
19 – 25
Cycle 2 Day 1
26 – 36
2-43
Cycle 2 Day 15
37 – 50
Cycle 3 Day 1
51 – 71
44-98
Cycle 4 Day 1
72 – 99
Cycle 5 Day 1
100– 127


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