A Modular Phase 2a Multicentre Open-Label Study to Investigate DNA-damage Response Agents (or Combinations) in Patients With Advanced Cancer Whose Tumours Contain Molecular Alterations (PLANETTE)
Phase: PHASE2
Conditions: Advanced Solid Tumours
Sponsor: AstraZeneca



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Clinical Study Protocol
Study Intervention
DNA-damage response agents
Study Code
D5339C00001
Version
Amendment 4
Date
04 November 2022
A Modular Phase 2a Multicentre Open-Label Study to Investigate 
DNA-damage Response Agents (or Combinations) in Patients 
With Advanced Cancer Whose Tumours Contain Molecular 
Alterations (PLANETTE)
Sponsor Name: AstraZeneca AB
Legal Registered Address: 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s)
EudraCT number: 2020-002529-27
IND number: 150711
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: D5339C00001
Amendment Number: 4
Study Intervention: DNA-damage response agents
Study Phase: 2a
Short Title: A Study Investigating DNA-damage Response Agents in Molecularly Altered 
Advanced Cancer
Acronym: PLANETTE study
Medical Monitor Name and Contact Information will be provided separately

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International co-ordinating investigators
 New 
York, NY, 10065-5606, USA.
 San Francisco, CA, 94158, USA.
PPD
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4
04-Nov-2022
Amendment 3
04-Apr-2022
Amendment 2
27-May-2021
Amendment 1
12-Aug-2020
Original Protocol
17-Jun-2020
The summary of changes for Amendment 4 is provided below. Refer to Appendix M for a
summary of the previous amendment.
Amendment 4 (04-Nov-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
To clarify access to IMP and management of patients ongoing on treatment at final Data Cut 
off (DCO)
Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
CORE
6.1 Intervention 
after Final DCO
Addition of text to core protocol to 
clarify options for continuation of 
treatment for patients receiving 
benefit at time of final DCO.
Please see overall rationale
Substantial
MODULE 1 (Section 11):
Ceralasertib Monotherapy in ATM Altered Advanced Solid Tumours (aST) and Prostate Cancer
11.1.1 Synopsis, 
patient numbers 
Correction of typo
Typo
Non-substantial
11.6.7 Intervention 
after Final DCO
Addition of text to detail 
management of patients ongoing 
on treatment post final DCO. 
Please see overall rationale
Substantial

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 3
TABLE OF CONTENTS...................................................................................................... 4
1
PROTOCOL SUMMARY - CORE................................................................... 10
1.1
Synopsis ........................................................................................................... 10
1.2
Schema............................................................................................................. 11
1.3
Schedule of Activities....................................................................................... 11
2
INTRODUCTION - CORE............................................................................... 12
2.1
Study Rationale ................................................................................................ 12
2.2
Background ...................................................................................................... 12
2.3
Benefit/Risk Assessment................................................................................... 13
3
OBJECTIVES AND ENDPOINTS - CORE ..................................................... 13
4
STUDY DESIGN - CORE................................................................................ 15
4.1
Overall Design.................................................................................................. 15
4.1.1
Modular Protocol Structure............................................................................... 15
4.1.2
Regulatory Amendment for Additional Modules............................................... 15
4.1.3
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 16
4.2
Scientific Rationale for Study Design ............................................................... 17
4.3
Justification for Dose........................................................................................ 17
4.4
End of Study Definition.................................................................................... 17
5
STUDY POPULATION - CORE...................................................................... 17
5.1
Inclusion Criteria .............................................................................................. 18
5.2
Exclusion Criteria ............................................................................................. 18
5.3
Lifestyle Considerations ................................................................................... 19
5.3.1
Contraception ................................................................................................... 20
5.4
Screen Failures ................................................................................................. 20
6
STUDY INTERVENTION - CORE.................................................................. 20
6.1
Intervention after the Final DCO....................................................................... 21
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL - CORE ............................................ 21
7.1
Discontinuation of Study Intervention............................................................... 21
7.1.1
Temporary Discontinuation............................................................................... 22
7.1.2
Procedures for Handling Participants Incorrectly Initiated on Study 
Intervention ...................................................................................................... 22
7.2
Participant Withdrawal from the Study ............................................................. 23
7.3
Lost to Follow-up ............................................................................................. 23

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8
STUDY ASSESSMENTS AND PROCEDURES - CORE................................ 24
8.1
Efficacy Assessments........................................................................................ 24
8.2
Safety Assessments........................................................................................... 24
8.2.1
Physical Examinations...................................................................................... 24
8.2.2
Vital Signs........................................................................................................ 24
8.2.2.1
Seated blood pressure and pulse rate................................................................. 24
8.2.2.2
Body temperature ............................................................................................. 25
8.2.3
Electrocardiograms........................................................................................... 25
8.2.4
Performance Status........................................................................................... 25
8.2.5
Clinical Safety Laboratory Assessments............................................................ 26
8.3
Adverse Events and Serious Adverse Events..................................................... 26
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 26
8.3.2
Follow-up of AEs and SAEs ............................................................................. 27
8.3.3
Causality Collection.......................................................................................... 28
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 28
8.3.5
Adverse Events Based on Examinations and Tests............................................ 28
8.3.6
Hy’s Law.......................................................................................................... 29
8.3.7
Disease Progression.......................................................................................... 29
8.3.7.1
New cancers ..................................................................................................... 29
8.3.7.2
Handling of deaths............................................................................................ 29
8.3.8
Reporting of Serious Adverse Events................................................................ 30
8.3.9
Pregnancy......................................................................................................... 30
8.3.9.1
Maternal Exposure............................................................................................ 30
8.3.9.2
Paternal Exposure............................................................................................. 31
8.3.10
Medication Error............................................................................................... 31
8.4
Overdose .......................................................................................................... 32
8.5
Human Biological Samples............................................................................... 32
8.5.1
Pharmacokinetics.............................................................................................. 32
8.5.2
Pharmacodynamics........................................................................................... 32
8.6
Human Biological Sample Biomarkers ............................................................. 33
8.7
Optional Genomics Initiative Sample................................................................ 33
8.8
Health Economics or Medical Resource Utilisation and Health Economics....... 33
9
STATISTICAL CONSIDERATIONS - CORE................................................. 33
10
REFERENCES - CORE.................................................................................... 34
11
MODULE 1: CERALASERTIB MONOTHERAPY IN ATM ALTERED 
ADVANCED SOLID TUMOURS (AST) AND PROSTATE CANCER........... 36
11.1
MODULE SUMMARY - MODULE 1 ............................................................. 36
11.1.1
Synopsis ........................................................................................................... 36
11.1.2
Schema............................................................................................................. 38
11.1.3
Schedule of Activities (SoA)............................................................................. 39
11.2
INTRODUCTION - MODULE 1...................................................................... 44
11.2.1
Module Rationale ............................................................................................. 44
11.2.1.1
Advanced Solid Tumours.................................................................................. 45

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11.2.1.2
Prostate Cancer................................................................................................. 46
11.2.2
Background ...................................................................................................... 47
11.2.2.1
Role of ATR ..................................................................................................... 47
11.2.2.2
Disease Linkage................................................................................................ 47
11.2.3
Benefit/Risk Assessment................................................................................... 48
11.2.3.1
Risk Assessment............................................................................................... 48
11.2.3.2
Benefit Assessment........................................................................................... 48
11.2.3.3
Overall Benefit: Risk Conclusion...................................................................... 49
11.3
OBJECTIVES AND ENDPOINTS - MODULE 1 ............................................ 49
11.3.1
Cohort A: aST................................................................................................... 49
11.3.2
Cohort B: mCRPC ............................................................................................ 50
11.4
MODULE DESIGN - MODULE 1................................................................... 51
11.4.1
Overall Design.................................................................................................. 51
11.4.1.1
Cohort A........................................................................................................... 51
11.4.1.2
Cohort B........................................................................................................... 52
11.4.1.3
Confirmation of ATM Protein Expression and ATM Mutation Status ............... 53
11.4.2
Scientific Rationale for Study Design ............................................................... 54
11.4.3
Justification for Dose........................................................................................ 54
11.4.4
End of Study Definition.................................................................................... 55
11.5
MODULE POPULATION - MODULE 1......................................................... 55
11.5.1
Inclusion Criteria (Cohort A [aST] and Cohort B [mCRPC]) ............................ 56
11.5.1.1
Screening Part 1 (Molecular eligibility) ............................................................ 56
11.5.1.2
Screening Part 2 (Study eligibility) .................................................................. 57
11.5.1.3
Cohort A – aST................................................................................................. 57
11.5.1.4
Cohort B – mCRPC .......................................................................................... 58
11.5.2
Exclusion Criteria (Cohort A [aST] and Cohort B [mCRPC]) ........................... 59
11.5.3
Lifestyle Considerations ................................................................................... 61
11.5.3.1
Meals and Dietary Restrictions ......................................................................... 61
11.5.3.2
Skin.................................................................................................................. 61
11.5.3.3
Contraception ................................................................................................... 61
11.5.4
Screen Failures ................................................................................................. 61
11.6
STUDY INTERVENTION - MODULE 1 ........................................................ 62
11.6.1
Study Intervention Administered....................................................................... 62
11.6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 62
11.6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 63
11.6.4
Study Intervention Compliance......................................................................... 63
11.6.5
Concomitant Therapy........................................................................................ 63
11.6.5.1
Therapy that may NOT be administered............................................................ 65
11.6.5.2
Drug-Drug Interaction Between Ceralasertib and Other Drugs.......................... 65
11.6.6
Dose Modification ............................................................................................ 67
11.6.6.1
General Guidance ............................................................................................. 67
11.6.6.2
Guidance for Dose Modification and Interruption ............................................. 68
11.6.6.3
Individual Stopping Criteria.............................................................................. 71
Cardiovascular.................................................................................................................... 71
Hepatic ............................................................................................................................... 71
11.6.7
Intervention after the Final DCO....................................................................... 71

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LIST OF FIGURES
LIST OF TABLES
Table 1
Objectives and Endpoints......................................................................... 14
Table 2
Eastern Cooperative Oncology Group Performance Status....................... 25
Table 3
Schedule of Activities.............................................................................. 39
Table 4
 
....................................... 45
Table 5
Objectives and Endpoints – Cohort A ...................................................... 49
Table 6
Objectives and Endpoints – Cohort B....................................................... 50
Table 7
Investigational Products........................................................................... 62
Table 8
Guidance for Dose Modifications, Interruptions and Discontinuations for 
Ceralasertib ............................................................................................. 68
Table 9
Dose Reduction Levels for Ceralasertib ................................................... 70
Table 10
Requirements for Documentation of Progression ..................................... 75
Table 11
Laboratory safety variables...................................................................... 77
Table 12
Populations for Analysis .......................................................................... 81
Table 13
Summary of Analyses and Data Cut-off Triggers..................................... 82
Table 14
Drugs Known to be Inhibitors of CYP3A4............................................. 103
Table 15
Drugs Known to be Inhibitors and Inducers of CYP2C8 ........................ 104
Table 16
Drugs Known to be Inhibitors or Inducers of P-gp ................................. 104
Table 17
Drugs Known to be Inhibitors or Inducers of BCRP............................... 106
Table 18
Drugs Known to be Metabolised by CYP3A4 and/or CYP2B6 and Have 
a Narrow Therapeutic Index................................................................... 107
Table 19
Drugs Known to be Substrates of OATP1B1.......................................... 108
Table 20
Drugs known to be substrates of BCRP.................................................. 108
Table 21
Summary of Methods of Assessment ..................................................... 117
Table 22
Overall Visit Response for Target Lesions............................................. 121
Table 23
Overall Visit Response for Non-Target Lesions ..................................... 122
Table 24
Overall Visit Response .......................................................................... 123
Table 25
Bone Progression Status ........................................................................ 128
Table 26
Overall Radiological Visit Response...................................................... 129
Table 27
Best Overall Response When confirmation of CR and PR Required....... 129
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Table 28
Look-up List for Missense and Synonymous Variants............................ 142
Table 29
Look-up List for Deleterious Intronic Variants....................................... 142
LIST OF APPENDICES
Appendix A
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis .............................. 94
Appendix B
Regulatory, Ethical, and Study Oversight Considerations......................... 96
Appendix C
New York Heart Association ................................................................. 101
Appendix D
Guidelines Regarding Potential Interactions of Ceralasertib with 
Concomitant Medications ...................................................................... 102
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 110
Appendix F
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 (Response Evaluation Criteria in Solid Tumours)............... 116
Appendix G
Guidelines for Evaluation of Objective Tumour Response Using 
PCWG3 (Prostate Cancer Working Group Criteria 3) in Bone Lesions .. 127
Appendix H
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 131
Appendix I
Handling of Human Biological Samples ................................................ 136
Appendix J
Optional Genomics Initiative Sample..................................................... 138
Appendix K
ATM Alterations Classification Guidance.............................................. 141
Appendix L
Abbreviations ........................................................................................ 144
Appendix M
Protocol Amendment History................................................................. 150

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Overall Design
This is a modular, phase 2a, open-label, multicentre study of DNA-damage response agents 
(or combinations) administered to participants with advanced/metastatic solid tumours and/or 
haematological malignancies with molecular alterations.
This study is modular in design and the core module provides the overall framework for the 
study and specific details of the participant population and molecular alterations will be 
described in each module. A substantial protocol amendment with relevant supportive 
rationale will be approved before starting a new module.
Number of Participants:
Please refer to individual modules for details.
Intervention Groups and Duration:
This protocol has a modular design, with the potential for future treatment arms to be added 
via protocol amendment. 
This protocol refers to the following modules and study drugs. For specific information on 
each of the study drugs, please refer to the relevant module.

Module 1 (Section 11): Ceralasertib monotherapy in ATM altered tumours
Data Monitoring Committee: No
Statistical methods
Please refer to individual modules for details.
1.2
Schema
Please refer to individual modules for details.
1.3
Schedule of Activities
Please refer to individual modules for details.

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2
INTRODUCTION - CORE
This is a modular, phase 2a, open-label, multicentre study of DDR agents (or combinations), 
administered to participants with advanced/metastatic solid and/or haematological 
malignancies with molecular alterations. This protocol provides the overall framework for the 
study (core module) and specific details of the participant population and molecular 
alterations will be described in each module. A substantial protocol amendment with relevant 
supportive rationale will be approved before starting a new module.
The term “study intervention” throughout the protocol, refers to study treatment/drug.
2.1
Study Rationale
In an era of precision medicine, the use of biomarkers to select patients who can benefit from 
treatment with a specific anti-cancer agent has the potential to both improve patient outcomes 
and accelerate drug development. Hence, drugs are increasingly being developed to target 
subgroups of patients whose tumours contain actionable biomarkers.
This is a phase 2a modular study in which a number of hypotheses may be tested in selected 
molecularly altered tumours. Examples of relevant molecular alterations may include, but are 
not limited to, ATM, ARID1A and relevant tumour indications may be confined to a single 
tumour type, a collection of specific tumour types, or disease agnostic. The participant 
populations considered are those with advanced/metastatic solid and/or haematological 
malignancies with molecular alterations.
2.2
Background
Precision medicine trials use rationally incorporated biomarker targets and molecularly 
selective anti-cancer agents to test the clinical applicability of pairing actionable mutations 
with targeted therapy (Coyne et al, 2017).
During the last 20 years a deeper understanding of the genomic landscape in the majority of 
cancer types and the development of sequencing techniques have paved the way towards 
precision medicine in oncology. This approach has significantly contributed to unravel the 
complexity of cancer genetic alterations and to provide to cancer patients targeted therapy. 
The clear objective of precision medicine in oncology is to change clinical practice by treating 
cancer patients according to their individual molecular profile.
Many potential targets on genetic level, which are essential for proliferation, survival and 
metastatic spread of cancer cells, were identified. Some of those - so-called driver-mutations –
have been elucidated as highly efficient therapeutic targets and nowadays there is a rapid 
progress in the development of new and more potent molecular targeted therapies to prevent 
or circumvent primary and secondary resistance mechanisms (Tan et al, 2016).

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With this gaining knowledge in cancer genomics, molecular biology and the development of 
targeted therapies, the classic concept of phase I-III trials has been extended by new clinical 
trial designs. Basket and umbrella trials entered the field of clinical research (Zimmer et al, 
2019). One of the biggest molecular profiling trials, the NCI-MATCH (Molecular Analysis 
for Therapy Choice) Trial is a landmark precision medicine which is aiming to evaluate > 100 
mutations in a basket study design.
Currently, the leading example is the use of BRCA1/2 mutations to select patients whose 
tumours may be hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitor treatment 
(Bryant et al, 2005 and Farmer et al, 2005), which has brought impressive survival rates in 
ovarian (Moore et al, 2018.), breast (Robson et al, 2017) and pancreatic cancer (Golan et al, 
2019).
Furthermore, effective drugs have been approved for tumour agnostic cancers based on studies 
where patients have been selected according to molecular profiling. For instance, larotrectinib 
(Vitravki) as monotherapy is indicated for the treatment of adult and paediatric patients with 
solid tumours that display a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion, 
who have a disease that is locally advanced, metastatic or where surgical resection is likely to 
result in severe morbidity, and who have no satisfactory treatment options (Vitravki SMPC). 
Pembrozilumab was approved for the treatment of adult and paediatric patients with 
unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair 
deficient: solid tumours that have progressed following prior treatment and who have no 
satisfactory alternative treatment options, or colorectal cancer that has progressed following 
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved 
under accelerated approval based on tumour response rate and durability of response 
(Keytruda SMPC).
2.3
Benefit/Risk Assessment
The benefit/risk assessments of the specific DDR agents (or combinations) are outlined in the 
respective modules. More detailed information about the known and expected benefits and 
risks and reasonably expected AEs are provided in the respective IBs.
3
OBJECTIVES AND ENDPOINTS - CORE
Please see individual modules for detailed objectives and endpoints.

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Europe and Rest of World
AstraZeneca will provide a substantial amendment for review and approval.
United States of America
AstraZeneca will provide an amendment to the FDA approximately 30 days in advance of 
planned enrolment into any new cohort. AstraZeneca will begin enrolment of patients into that 
cohort in the Unites States after IRB approval.
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 participants 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 participant’s ability to conduct the study. The 
investigator or designee should contact the study sponsor to discuss whether the mitigation 
plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimize risks to study integrity. 
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options:

Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the ICF should be signed at the participant’s next contact with the 
study site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. The 
investigator should confirm this with the designated AstraZeneca study physician. 

Home or Remote visit: Performed by a site qualified health care professional or health 
care professional provided by a third-party vendor.

Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 

At-home study intervention administration: Performed by a site qualified health care 
professional, health care professional provided by a third-party vendor or by the 
participants or the participant’s caregiver, if possible. Additional information related to 
the visit can be obtained via telemedicine. 

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For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix A.
4.2
Scientific Rationale for Study Design
Key aspects of the study, such as the non-comparative design, primary and secondary 
endpoints, participant population with advanced tumours, cohort size are based upon accepted 
methodology for efficacy signal detection in phase 2 oncology studies. The study may consist 
of several treatment modules, each evaluating the efficacy, safety and tolerability of specific 
study interventions and their combinations. The modular study design will allow the tailoring 
of study procedures and endpoints to specific treatment regimens and indications.
The sponsor plans to include investigations into variations in 
 
 
. There are many potential benefits of this exploratory 
research, including the possibility to identify participants most likely to benefit from 
treatment, explain outliers or non-responders or explain adverse reactions related to drug 
exposure. This research may result in an understanding of the impact of variation between 
individuals and how this information can be utilised to bring better drugs to clinic.
Assignment of participants to treatment arms will be made based upon the status of the 
relevant molecular aberration in a participant's tumour. The strength of clinical hypothesis as 
well as the prevalence of each aberration will be considered when overlapping or co-occurring 
qualifying molecular criteria are encountered. Guidelines to inform cohort allocation for 
participants with overlapping aberrations or more than a single qualifying aberration will be 
detailed separately where applicable.
4.3
Justification for Dose
Please refer to individual modules for details.
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit or the last scheduled procedure shown for the individual 
module that they are included in.
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure for the last participant in the study.
5
STUDY POPULATION - CORE
The core study population requirements are described below, please refer to individual 
modules for further specific details.
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Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
The inclusion criteria that are applicable to all modules in the study are described in this 
section. Please also refer to the relevant module for specific criteria applicable to each cohort. 
Where criteria are more stringent in the module rather than the core, the investigator should 
adhere to the module criteria.
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
1
Capable of giving signed informed consent as described in Appendix B which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
2
Provision of written Optional Genetic Research Information informed consent prior to 
collection of samples for optional genetic research that supports Genomic Initiative.
Age
3
Participant must be at least 18 years of age inclusive, at the time of signing the informed 
consent.
Sex
4
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies (see 
Section 5.3.1).
Other
5
Participant is willing and able to comply with the study protocol for the duration of the 
study including undergoing treatment and scheduled visits and examinations. 
5.2
Exclusion Criteria
The exclusion criteria that are applicable to all modules in the study are described in this 
section. Please also refer to the relevant module for specific criteria applicable to each cohort. 
Where criteria are more stringent in the module rather than the core, the investigator should 
adhere to the module criteria.
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Persistent toxicities (> CTCAE Grade 2) caused by previous cancer therapy, excluding 
alopecia and CTCAE Grade 2 peripheral neuropathy.
2
History of another primary malignancy except for: 

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
Malignancy treated with curative intent and with no known active disease ≥2 years 
before the first dose of study drug and of low potential risk for recurrence 

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease 

Adequately treated carcinoma in situ without evidence of disease 

Localised non-invasive primary under surveillance
3
Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD, severe 
Parkinson’s disease, active inflammatory bowel disease) or psychiatric condition 
(screening for chronic disease is not required).
Prior/Concurrent Clinical Study Experience
4
Participants with a known hypersensitivity to study interventions or any of the excipients 
of the products.
Other Exclusions
5
Major surgery within 2 weeks of starting study intervention: participants must have 
recovered from any effects of any major surgery.
6
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
7
Judgement by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements.
8
Previous enrolment in the present study. 
9
Participants with gastrointestinal disorders likely to interfere with absorption of the study 
intervention.
10 Pregnant (confirmed with positive pregnancy test) or breast feeding women.
In addition, the following are considered criteria for exclusion from the optional 
exploratory host genetic research:
11 Previous allogenic bone marrow transplant.
12 Non-leukocyte depleted whole blood transfusion within 120 days of the date of the 
genetic sample collection.
5.3
Lifestyle Considerations
Please refer to the relevant modules. Where restrictions are more stringent in the individual 
module rather than the core module, the investigator should adhere to the individual module 
criteria.

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5.3.1
Contraception
Male participants: Must use a condom (with spermicide) during the study, and for 1 week 
after the last dose of study intervention, with all sexual partners. Where a sexual partner of a 
male participant is a ‘woman of childbearing potential’ who is not using effective 
contraception, male participants must use a condom during the study and for 6 months after 
the last dose of study intervention. Male participants must also not donate sperm for 6 months 
after the last dose of study intervention.
Female participants: Pregnancy tests on blood (screening) or urine (other time points) 
samples will be performed for women of childbearing potential prior to the start of study 
intervention, at the timepoints defined in the individual module SoA.
Women of childbearing potential must use enhanced contraception during the study, and for 
1 month after the last dose of study intervention, with all male sexual partners. Contraceptives 
that are prone to drug-drug interactions may not be effective due to a potential CYP3A4 
interaction with study intervention. Contraception used must therefore include a condom and 
one of:

Medroxyprogesterone injections (eg, Depo-provera)

Intrauterine device

Levonorgestrol Intrauterine System (eg, Mirena)

Tubal occlusion

Vasectomised partner
Women who are breast feeding are excluded from the study.
5.4
Screen Failures
Please refer to individual modules for screen failure definitions. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the CONSORT publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened following consultation with the sponsor. Rescreened participants should be 
assigned the same participant number as for the initial screening, and re-sign the ICF.
6
STUDY INTERVENTION - CORE
Please refer to the relevant module.

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6.1
Intervention after the Final DCO
After the final DCO and as long as the clinical development program is ongoing, AstraZeneca 
will continue to supply IP treatment to patients who, in the investigator’s opinion, continue to 
benefit from receiving IP treatment.
Depending on what is available at the time, the patients would be followed either:

Within the current study

Within a safety expansion study if available

Within a  drug supply program (commercial or compassionate use program) if 
applicable
In case of treatment continuation after the final DCO within the current study:

Patients will continue to attend site visits for safety assessments.

There will be no more data collection except SAE reporting, overdosing and 
pregnancies. The clinical study database will be closed.

SAEs, overdoses and pregnancies will be reported following a paper form process. All 
SAEs, overdose and pregnancies will be reported until 30 days after last dose and 
recorded in the safety database.

Drug dispensation and reconciliation will be handled by site at each patient’s visit.

Site will remain open until the last patient treatment discontinuation.
In case of treatment continuation after the final DCO within a safety extension study, if
available:

Safety extension study would have to be approved by Regulatory Authority and Ethics
Committee at the patient’s site.

Safety assessments would be performed as per the safety extension study protocol.

SAEs will be reported following a paper form process. All SAEs, overdose and
pregnancies will be reported until 30 days after last dose and recorded in the
safety database.

Patients would be proposed to transition to the safety study and sign a new consent
form.
If the study drug is marketed for use in the disease under study indication:

Patients may discontinue study and switch to marketed product.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL - CORE
7.1
Discontinuation of Study Intervention
Participants may be withdrawn from any aspect of the study at any time, without prejudice to 
further treatment. Procedures for withdrawal from the exploratory research on collected 
samples are outlined in Appendix I 2.

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Participants may be discontinued from study intervention in the following situations:

Participant or investigator decision. The participant is at any time free to withdraw his/her 
participation in the study.

AEs.

Severe non-compliance to this protocol (participants or investigator) as judged by the 
investigator and/or AstraZeneca.

Disease progression.

Participants incorrectly initiated on study intervention (Section 7.1.2).

When the reason does not impact safety consider the risk/benefit to the participant of 
stopping treatment.

Life-threatening or other unacceptable toxicity.

The discovery of an unexpected, significant, or unacceptable risk to the participants 
enrolled in the study.

Lack of evaluable and/or complete data.

Decision to modify the development plan of the drug.

A decision on the part of the sponsor to suspend or discontinue development of the drug.

Confirmed pregnancy in women of childbearing potential.
7.1.1
Temporary Discontinuation
Please refer to the relevant module.
7.1.2
Procedures for Handling Participants Incorrectly Initiated on Study 
Intervention
Participants who do not meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled or receive study intervention. There can be no exceptions to this 
rule.
When participants that do not meet the inclusion/exclusion criteria are enrolled in error or 
incorrectly started on study intervention, or when participants subsequently fail to meet the 
study criteria post initiation, the investigator should inform the sponsor Study Physician 
immediately and these participants will be documented as protocol violations.
Any participant who is found to have failed to comply with all of the selection criteria, but has 
not started study intervention, will be removed from the study following completion of safety 
follow-up activities.
Any participant started on study intervention in error, and he/she has subsequently been found 
to have failed to comply with all of the selection criteria, will undergo a risk/benefit 

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assessment by the investigator/sponsor; if the participant is judged to be receiving clinical 
benefit, the investigator may choose to continue to dose them with the study intervention.
Every effort should be made to keep all participants in the study until completion of safety 
follow-up activities.
The sponsor Study Physician is to ensure all such contacts are appropriately documented.
7.2
Participant Withdrawal from the Study

A participant 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.

If the participant 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 participant 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.
7.3
Lost to Follow-up
A participant 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 participant fails to return to the clinic for a required
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and,
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 

Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants enrolled. Public sources 
may be searched for vital status information. If vital status is determined as deceased, this 

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will be documented and the participant 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 B.
8
STUDY ASSESSMENTS AND PROCEDURES - CORE

Please refer to the relevant individual modules for study procedures and their timings. 
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 participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in individual 
module SoAs, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the individual module SoAs.
8.1
Efficacy Assessments
Please refer to individual modules for details.
8.2
Safety Assessments
Please refer to individual module SoAs for details on the timing/visits for safety assessments.
8.2.1
Physical Examinations

A complete physical examination with weight will be performed. Height will be recorded 
at screening only.

Examination will include general appearance, respiratory, cardiovascular, abdomen, skin, 
head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, 
musculoskeletal (including spine and extremities) and neurological systems. Investigators 
should pay special attention to clinical signs related to previous serious illnesses. 
Situations in which physical examination results should be reported as AEs are described 
in Section 8.3.5.
8.2.2
Vital Signs
8.2.2.1
Seated blood pressure and pulse rate
Blood pressure and pulse rate will be measured in the sitting position after at least 10 minutes 
rest.

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8.2.2.2
Body temperature
Body temperature will be measured in degrees Celsius.
Any changes in vital signs should be recorded as an AE if applicable.
8.2.3
Electrocardiograms
Resting 12-lead ECG
Twelve-lead ECGs will be obtained after the participant has been resting semi-supine for at 
least 5 minutes prior to times indicated. All ECGs should be recorded with the participant in 
the same physical position. A standardised ECG machine should be used that automatically 
calculates the heart rate and measures PR, QRS, and QT intervals, and the participant should 
be examined using the same machine throughout the study, where feasible.
For triplicate ECGs, 3 individual ECG tracings should be obtained in succession, no more 
than 2 minutes apart. The full set of triplicates should be completed within 5 minutes. Results 
from each replicate of the ECG should be recorded and an assessment of clinical significance 
recorded for each timepoint. Numerical values (eg, QT, QTcF, PR interval) should be assessed 
based on an average of the triplicate readings, whilst qualitative findings (eg rhythm and 
overall evaluation) from all replicates should be taken into account.
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 participant’s medical records. If an abnormal ECG finding at screening is 
considered to be clinically significant by the investigator, it should be reported as a concurrent 
condition. For all ECGs details of rhythm, PR, R-R, QRS and QTcF interval and an overall 
evaluation will be recorded.
8.2.4
Performance Status

Performance status will be assessed according to US ECOG criteria (Table 2).

These scales and criteria are used by doctors and researchers to assess how a patient’s 
disease is progressing, assess how the disease affects the daily living abilities of the 
patient, and determine appropriate treatment and prognosis (Oken et al, 1982). 
Table 2
Eastern Cooperative Oncology Group Performance Status
Grade
ECOG
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

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Grade
ECOG
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
5
Dead
8.2.5
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation,
and urinalysis will be taken as indicated in the individual specific module SoAs.
Laboratory assessments do not need to be repeated at baseline if the baseline visit is within 
3 days of the screening sample. The date of each collection will be recorded in the appropriate 
eCRF.
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.
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.
8.3
Adverse Events and Serious Adverse Events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section
The definitions of an AE or SAE can be found in Appendix H.
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’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 the time of the first dose of study intervention
throughout the treatment period and including the follow-up period till the last safety follow-
up visit or study termination.
SAEs will be recorded from the time of signing of the screening Part 1 ICF throughout the 
treatment period and including the follow-up period till the last safety follow-up visit.

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If an investigator learns of any SAEs, including death, at any time after last safety follow-up 
visit and he/she considers there is a reasonable possibility that the event is related to study 
intervention, the investigator should notify AstraZeneca.
If the investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a participant
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
Any AEs that are unresolved at the participant’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 participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE;

AE (verbatim)

CTCAEv5 grade

The date and time when the AE started and stopped

The date, time and new CTCAEv5 grade if this has changed

Whether the AE is serious or not

Investigator causality rating against the study intervention(s) (yes or no)

Action taken with regard to study intervention(s)

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication

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8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention 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 study intervention?’
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 H to the Clinical 
Study Protocol.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or care provider 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 Clinical Study Protocol-mandated laboratory tests, vital signs, and other 
safety assessments will be summarised in the CSR. 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs, and 
other safety assessments should therefore only be reported as AEs if they fulfil any of the SAE 
criteria, are the reason for concomitant therapy, and/or modification or discontinuation of 
treatment with the study intervention 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) unless clearly due to progression of disease under study (see 
Disease progression Section 8.3.7).
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).

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Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 x ULN together with total bilirubin ≥2 x 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.
8.3.7 Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the study intervention is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE. Events, which are unequivocally 
due to disease progression, should not be reported as an AE during the study.
8.3.7.1
New cancers
The development of a new cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study intervention and have been identified after the participant’s 
inclusion in this study. They do not include metastases of the original cancer.
8.3.7.2
Handling of deaths
All deaths that occur during the study, or within the follow-up period after the administration 
of the last dose of study intervention, should be reported as follows:

Death, which is unequivocally due to disease progression, should be communicated to the 
study monitor at the next monitoring visit and should be documented in the eCRF 
module, but should not be reported as a SAE during the study.

Where death is not clearly due to disease progression of the disease under study the AE 
causing the death should be reported to the study monitor as an SAE within 24 hours. The 
report should contain a comment regarding the co-involvement of progression of disease, 
if appropriate, and should assign a single primary cause of death together with any 
contributory causes.

Deaths with an unknown cause should always be reported as a SAE but every effort 
should be made to establish 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 

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(with translation of important parts into English) should be reported in an expedited 
fashion to an AstraZeneca representative within the usual timeframes.
8.3.8
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within one 
calendar day ie, immediately but no later than 24 hours of when he or she becomes aware of 
it.
Once the investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.
The reference document for definition of expectedness is Section 5 of the individual study 
intervention IB.
8.3.9
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study participant has received any study 
intervention
8.3.9.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately.

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Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/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 participant was discontinued from the study.
If any pregnancy occurs during exposure to study intervention or in the 1 month after 
discontinuing study intervention, 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 8.3.9) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.3.9.2
Paternal Exposure 
Pregnancy of the participant’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 abnormality), occurring from the date of the first dose until 16 weeks after 
dosing after the last dose and as indicated by previous studies (preclinical and clinical) should,
if possible, be followed up and documented in the Pregnancy Report Form. Consent from the 
partner must be obtained before the Pregnancy Report Form is completed. 
8.3.10
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 8.3.8) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Appendix H 4.

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8.4
Overdose
For this study, any dose of study intervention greater than those specified in the protocol is 
considered to be an overdose. This may include a higher dose of study intervention or study 
intervention taken at the correct dose but for longer duration.

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 intervention 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.
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 overdoses associated with an SAE (see Section 8.3.8) 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 
Sample see Appendix I.
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. 

PK samples will be disposed of after the Bioanalytical Report finalisation or 6 months 
after issuance of the draft Bioanalytical Report (whichever is earlier), unless consented 
for future analyses.

PK 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.
8.5.1
Pharmacokinetics
Please refer to individual modules for details.
8.5.2
Pharmacodynamics
Please refer to individual modules for details.

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8.6
Human Biological Sample Biomarkers
Please refer to individual modules for details.
8.7
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research during treatment of 
progression is also part of this study as specified in the SoA and is subject to agreement in the 
separate genetic research consent form.
Blood sample for DNA isolation and tissue samples will be collected from participants who 
have consented to participate in the genetic analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
Details on processes for collection and shipment and destruction of these samples can be 
found either in the appendices or in the Laboratory Manual. 
See Appendix J for further information regarding the Genomics Initiative genetic sample.
8.8
Health Economics or Medical Resource Utilisation and Health 
Economics
Health Economics/Medical Resource Utilisation and Health Economics parameters are not 
evaluated in this study.
9
STATISTICAL CONSIDERATIONS - CORE
Please refer to individual modules for details.

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REFERENCES - CORE
Bryant et al, 2005
Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of 
BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 
2005;434:913–917.
Coyne et al, 2017
Coyne GO, Takebe N, and Chen AP. Defining Precision: The Precision Medicine Initiative 
Trials NCI-MPACT and NCI-MATCH. Curr Probl Cancer. 2017;41(3):182-193.
Farmer et al, 2005
Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB, et al. (2005). 
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 
2005;434:917–921.
Feng et al, 2015
Feng X, Li H, Dean M, Wilson HE, Kornaga E, Enwere EK, et al. Low ATM protein 
expression in malignant tumor as well as cancer-associated stroma are independent prognostic 
factors in a retrospective study of early-stage hormone-negative breast cancer. Breast Cancer 
Res. 2015 May 3;17:65.
Golan et al, 2019
Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance 
Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N. Engl. J. Med. 2019; 
381:317–327.
Kaufman et al, 2015
Kaufman B, Sharpira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaňa J et 
al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 
mutation. J Clin Oncol 2015;33(3):244-251.
Kumar et al, 2016
Kumar A, Coleman I, Morrissey C, Zhang X, True LD, Gulati R et al. Substantial 
interindividual and limited intraindividual genomic diversity among tumors from men with 
metastatic prostate cancer. Nat Med. 2016 Apr;22(4):369-78.
Mateo et al, 2015
Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R et al. DNA-Repair 
Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015 Oct 
29;373(18):1697-708.

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Moore et al, 2018. 
Moore K, Colombo N, Scambia G, Kim B-G, Oaknin A, Friedlander M, et al. Maintenance 
Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N. Engl. J. Med. 2018; 
379: 2495–2505.
Oken et al, 1982
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982:5;649-655.
Robinson et al, 2015
Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM et al. Integrative
clinical genomics of advanced prostate cancer. Cell. 2015 May 21;161(5):1215-1228.
Robson et al, 2017
Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for Metastatic 
Breast Cancer in Patients with a Germline BRCA Mutation. N. Engl. J. Med. 2017;377:523–
533.
Tan et al, 2016
Tan W-L, Jain A, Takano A, Newell EW, Gopalakrishna Iyer N, Lim W-T, et al. Novel 
Therapeutic Targets on the Horizon for Lung Cancer. Lancet Oncol. 2016; 17(8):e347-e362.
Zimmer et al, 2019
Zimmer K, Kocher F, Spizzo G, Salem M, Gastl G, Seeber A. Treatment According to 
Molecular Profiling in Relapsed/Refractory Cancer Patients: A Review Focusing on Latest 
Profiling Studies. Comput Struct Biotechnol J. 2019;17:447-453.

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11
MODULE 1: CERALASERTIB MONOTHERAPY IN ATM 
ALTERED ADVANCED SOLID TUMOURS (AST) AND
PROSTATE CANCER
11.1
MODULE SUMMARY - MODULE 1
11.1.1
Synopsis
Rationale
Ataxia telangiectasia mutated (ATM) is a serine/threonine protein kinase that is recruited and 
activated by DNA double strand breaks and has both checkpoint and repair functions. Ataxia 
Telangiectasia and Rad3 Related (ATR) is an apical kinase with a critical role in the DNA-
damage response. During normal DNA replication, ATR is recruited at stalled replication 
forks which can progress to double strand breaks if left unrepaired. In normal cells, there is a 
significant interplay between ATR and ATM as stalled replication forks can be converted into 
double strand breaks through further DNA-damage and the resection of double strand breaks 
generates single stranded DNA.
Preclinical models have suggested that ATM-deficient cell lines are sensitised to DNA 
damaging agents, including platinum chemotherapy and ATR inhibitors. Ceralasertib is an 
oral inhibitor of the serine/threonine protein kinase ATR, a member of the phosphoinositide-3-
kinase related kinase (PIKK) family. There are emerging data which are demonstrating the 
anti-tumour activity of ATR inhibitors in patients with ATM mutation and/or protein loss.
In line with previous and ongoing studies, it is anticipated that patients with ATM altered aST 
and mCRPC would benefit from treatment with ceralasertib in this study.
Overall Design
Module 1 is investigating ceralasertib, previously known as AZD6738, monotherapy 
administered orally, to participants with advanced/metastatic solid malignancies with ATM 
mutation and/or protein loss.
Number of Participants
Cohort A (aST): A total of ~25 molecularly eligible and centrally confirmed participants will 
be enrolled into Cohort A.
Cohort B (mCRPC): A total of ~27 molecularly eligible and centrally confirmed participants 
will be enrolled into Cohort B. Unfavourable CTC count requirement may be introduced for 
all participants to ensure an adequate (approximately ≥50%) number of participants with CTC 
count ≥5/7.5 mL blood.

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At the time of protocol amendment 2, 8 participants had been dosed at 240 mg BID in 
Cohort A, and 1 participant had been dosed at 240 mg BID in Cohort B. Following the 
reduction of the starting dose from 240 mg BID to 160 mg BID in protocol amendment 2, the
intention is to enrol an additional total of ~25 and ~27 participants in Cohort A and B,
respectively, at the 160 mg BID.
In case of discordance between local and central testing, additional participants may be 
enrolled in order to satisfy the intended sample size of molecularly eligible and centrally 
confirmed participants.
Each Cohort A and Cohort B may be further expanded 
 
 This would occur in the event an efficacy signal is observed, and subject to a 
protocol amendment.
Statistical Methods
Data will be presented separately for each cohort of participants within Module 1. No formal 
statistical analyses will be carried out for this study and the data will be summarised using 
standard summary statistics.
Cohort A (aST)
Objective response rate is defined as the percentage of participants who have at least one 
response of CR or PR prior to any evidence of progression (as defined by RECIST 1.1) that is 
confirmed at least 4 weeks later. Percentage of participants will be accompanied with a 2-
sided 80% confidence interval as obtained from a Clopper-Pearson test.
Cohort B (mCRPC)
Composite response will be defined on the basis of the following outcomes; if any of these 
occur in the absence of radiological or PSA progression (according to RECIST 1.1 for soft 
tissue and visceral lesions, prostate cancer working group 3 (PCWG3) criteria for bone 
lesions, and PSA) participants will be considered to have responded:

Investigator assessed radiological objective response by RECIST 1.1 for soft tissue and 
visceral lesions and PCWG3 criteria for bone lesions. Response must be confirmed at 
least 4 weeks later. BICR assessment may be introduced if the cohort is expanded, subject 
to a protocol amendment.

Conversion of CTC count from ≥ 5/7.5 mL blood (unfavourable) at baseline to < 5/7.5 
mL blood (favourable) confirmed by a second consecutive value obtained 3 or more 
weeks later (as per PCWG3 criteria).

PSA decline of > 50% confirmed by a second consecutive measurement at least 3 weeks 
later (based on PCWG1 criteria).
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Percentage of participants will be accompanied with a 2-sided 80% confidence interval as 
obtained from a Clopper-Pearson test.
11.1.2
Schema
Figure 2
Module Design
1 All aST except NSCLC and prostate cancer.
2 Ceralasertib administered twice a day between Days 1 to 14 in 28 day cycles.
Abbreviations: aST=advanced solid tumours; ATM=ataxia telangiectasia mutated; BID=twice daily; 
IHC=immunohistochemistry; NSCLC=non-small-cell lung carcinoma.

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l
Study intervention administered twice a day between Day 1 and Day 14 in 28 day cycles. All safety assessments and laboratory results must be reviewed 
by the Investigator or physician designee prior to start of each study treatment dosing cycle.
m
Baseline contrast enhanced CT brain scan assessment (MRI where CT is contraindicated) applies to advanced solid tumour participants only (Cohort A 
[aST]). A CT brain scan will be performed if participant is not known to have brain metastases. If the participant has known brain metastases, a baseline 
MRI will be performed.
n
CT scans of the chest, abdomen, and pelvis (or MRI where CT is contraindicated) and bone scans (Cohort B [mCRPC] only) should be conducted every 
8 weeks (±1 week) after the start of treatment (Cycle 1 Day 1) up to 1 year, then every 12 weeks (±1 week) until objective disease progression as per 
RECIST 1.1 or PCWG3 criteria. In the event of treatment interruptions or delays, tumour assessments should proceed to schedule relative to Cycle 1 
Day 1. Bone progression observed by bone scan (Cohort B [mCRPC]) requires confirmation by bone scan at least 6 weeks later and preferably no later 
than the next scheduled scan (see Section 11.8.1.2). Soft tissue or visceral progression observed by CT or MRI, according to RECIST 1.1, does not 
require a confirmatory scan.
o
Clinical CTC counts and PSA levels (Cohort B [mCRPC] only) will be assessed every cycle up to Cycle 5 Day 1, then every 8 weeks (±1 week) up to 
1 year, then every 12 weeks (±1 week), aligned with tumour assessments (except those aligned with C1D1, C2D1, and C4D1), until radiographic 
objective disease progression as per RECIST 1.1 or PCWG3 criteria or off-study. CTC count conversion, PSA response by PCWG1 criteria, and PSA 
progression by PCWG3 criteria will need to be confirmed 4 weeks (±1 week) later unless a radiographic objective disease progression is registered
within 12 weeks of PSA progression in which case concurrent PSA progression will be regarded as confirmed. In the absence of radiographic 
progression, if confirmatory PSA sample is not taken in 4 weeks (±1 week), it should be taken as soon as possible before the next scheduled assessment.
Abbreviations: AE=adverse events; aST=advanced solid tumour; ATM=ataxia telangiectasia mutated; BP=blood pressure; CR=complete response; 
CSP=clinical study protocol; CT=computed tomography; CTC=circulating tumour cells; 
; ECG=electrocardiogram; d=day; 
DNA=deoxyribonucleic acid; ECOG=Eastern Cooperative Oncology Group; G3=grade 3; ICF=informed consent form; IHC=immunohistochemistry; 
mCRPC=metastatic castration-resistant prostate cancer; MRI=magnetic resonance imaging; NGS=next generation sequencing; PCWG3=the prostate cancer 
working group 3; PGx=pharmacogenetic; PK=pharmacokinetic; PR=partial response; PSA=prostate specific antigen; RECIST=response evaluation criteria in 
solid tumours; SAE=serious adverse event; SD=stable disease; SoC=standard of care; WOCBP=women of childbearing potential.
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11.2
INTRODUCTION - MODULE 1
Module 1 is testing ceralasertib, previously known as AZD6738, in 2 participant populations 
(Cohort A and Cohort B) whose tumours contain deleterious or suspected deleterious genetic 
alterations in the ATM gene. Cohort A is recruiting participants with ATM altered aST,
except participants with non-small-cell lung carcinoma and prostate cancer. Cohort B is 
recruiting participants with ATM altered mCRPC. Molecularly eligible participants in 
Module 1 will have tumours containing alterations in ATM. A molecularly eligible participant 
is defined as a participant with deleterious or suspected deleterious ATM mutation in tumour 
or blood (germline or ctDNA), tested in a locally accredited laboratory using a validated test 
in line with local regulations (eg, CAP/CLIA laboratory, where available). Definitions of 
qualifying ATM mutations include deleterious/suspected deleterious, pathogenic/likely 
pathogenic, disease, or cancer-associated variants. Variants of unknown significance or benign 
variants are not eligible for enrolment. Cohort A and Cohort B will each enrol participants 
with ATM IHC > 5% and ≤5%. Prospective selection of patients with ATM IHC ≤5% may 
be introduced in each cohort based on emerging ATM protein deficiency prevalence and 
ceralasertib clinical activity data.
11.2.1
Module Rationale
ATM is a serine/threonine protein kinase that is recruited and activated by DNA double strand 
breaks and has both checkpoint and repair functions. Ataxia telangiectasia and rad3 related 
protein (ATR) is an apical kinase with a critical role in the DNA-damage response. During 
normal DNA replication, ATR is recruited at stalled replication forks which can progress to 
double strand breaks if left unrepaired. In normal cells, there is a significant interplay between 
ATR and ATM as stalled replication forks can be converted into double strand breaks through 
further DNA-damage and the resection of double strand breaks generates single stranded 
DNA (Thuss et al, 2011, and Toledo et al, 2011).
Preclinical models have suggested that ATM-deficient cell lines are sensitised to DNA 
damaging agents, including platinum chemotherapy and ATR inhibitors (Reaper et al, 2011). 
Ataxia telangiectasia mutated protein loss of function has been described in various tumour 
groups: up to 22% of metastatic tumours from patients with gastric cancer might have low or 
undetectable ATM expression, (Kim et al, 2013), 8% in colorectal cancer. Synthetic lethality 
between ATR inhibition and ATM deficiency was recently demonstrated in gastric cancer 
warranting further clinical studies for ceralasertib in ATM deficiency tumours (Min et al, 
2017).
AstraZeneca internal data for the prevalence of ATM mutations and prevalence of ATM 
protein loss 
 is presented in Table 4. 
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Preclinically, ceralasertib has demonstrated anti-tumour activity in gastric cancer cells. In 
SNU-601 cells with dysfunctional ATM, ceralasertib treatment led to an accumulation of 
DNA-damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3 
whereas, SNU-484 cells with functional ATM were not sensitive to ceralasertib. In addition, 
in an in vivo tumour xenograft mouse model, ceralasertib significantly suppressed tumour 
growth and increased apoptosis. These findings suggest synthetic lethality between ATR 
inhibition and ATM deficiency in gastric cancer cells (Min et al, 2017).
Signs of preliminary efficacy (unpublished internal data) were observed in an ongoing study 
of ceralasertib combined with durvalumab in patients with NSCLC and ATM mutation or 
protein expression loss previously treated with immune checkpoint inhibitors 
(NCT03334617).
11.2.1.2
Prostate Cancer
The concept of synthetic lethality of DDR inhibitors in DDR-deficient backgrounds has been 
explored clinically in mCRPC: PARPi have been used in BRCA1/2 mutations and HRR 
mutations, including ATM mutations. The ongoing TRITON2 study of rucaparib in 
participants with DNA-Damage Repair-deficient mCRPC associated with HRR gene 
alterations demonstrated confirmed radiographic responses in 44.0% of participants with a 
deleterious BRCA1/2 alteration. In addition, male patients who had progressed on an 
androgen receptor directed therapy and chemotherapy demonstrated confirmed PSA responses 
in 51.1% of participants with a deleterious BRCA1/2 alteration. Based on this data, the US 
FDA granted breakthrough therapy designation for rucaparib as a monotherapy for patients 
with BRCA1/2-mutated mCRPC who have received ≥1 prior androgen receptor directed 
therapy and a taxane based chemotherapy (Wassim Abida et al, 2018).
Interim results from the TALAPRO-1 study of talazoparib monotherapy demonstrated anti-
tumour activity in mCRPC patients with DDR alterations who had previously received taxane 
therapy and NHT with confirmed overall ORR of 25.6%. 
Efficacy was most notable in patients whose tumours harboured BRCA1/2 alterations with a 
confirmed ORR of 50%. The composite response in patients with deleterious or suspected 
deleterious ATM mutations was reported to be 6.7% (1/15) and the PSA decline > 50% was 
reported in one patient out of 15 (De Bono et al, 2020). 
The GALAHAD study of niraparib in patients with mCRPC and DRD demonstrated CTC0 
and CTC conversion of 49% (45.5% in patients with measurable disease and 55.6% in patients 
with non-measurable disease) (Smith et al, 2020). The CTC conversion in patients with 
measurable disease was similar to ORR per RECIST 1.1, concluding that in patients with 
measurable and non-measurable disease, CTC is correlated with longer time on  treatment and 
prolongation of survival. Hence CTC conversion should be considered as a validated endpoint 
regardless of measurable or non-measurable diseases.

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Prostate cancer is recognised to have interpatient molecular heterogeneity and genomic 
aberrations that interfere with DNA repair which accounts for approximately 25 to 30% of all 
sporadic, castration-resistant prostate cancers (Grasso et al, 2012). For mCRPC, PCWG3 
strongly recommends incorporating molecular profiling of tumours into clinical study 
strategies for a better understanding of the disease biology to identify predictors of sensitivity 
to a specific therapy. In line with the afore mentioned, we could anticipate that patients with 
ATM altered aST and mCRPC would benefit from treatment with ceralasertib in this study.
A detailed description of the chemistry, pharmacology, efficacy, and safety of ceralasertib is 
provided in the IB.
11.2.2
Background
11.2.2.1
Role of ATR
During normal DNA replication, ATR is recruited at stalled replication forks which can 
progress to double strand breaks if left unrepaired. ATR is also recruited to single strand DNA 
coated with RPA following single strand DNA-damage or the resection of double strand 
breaks. Recruitment and activation of ATR leads to cell cycle arrest in the S phase while the 
DNA is repaired, and the stalled replication fork resolved, or nuclear fragmentation and entry 
into programmed cell death/apoptosis (Cimprich and Cortez 2008).
Loss of ATR function leads to the inability to resolve stalled replication forks, the 
accumulation of DNA-damage and rapid cell death exemplified by nuclear fragmentation. 
ATR deletion is embryonic lethal in mice, however severe ATR hypomorphism is tolerated in 
humans leading to Seckel Syndrome. Normal cells from patients with Seckel Syndrome have 
reduced ATR function and show extensive DNA breaks when subjected to replication stress 
(Ajani et al, 2007, and Alderton et al, 2004).
11.2.2.2
Disease Linkage
Humans with loss of ATM function, typically through homozygous mutation of ATM, suffer 
from ataxia telangiectasia and have a 37-fold increased risk of cancer. Ataxia telangiectasia 
patients have approximately a 10% risk of developing lymphoma or leukaemia (NCI 2006). 
There is also a substantial risk of breast cancer, especially in women less than 50 years of age 
(relative risk=4.94), and an excess risk of colorectal cancer (relative risk=2.54) and stomach 
cancer (relative risk=3.39) (Thompson et al, 2005). Patients with ataxia telangiectasia show 
hypersensitivity to radiation.
Sporadic ATM deficiency is reported in many tumour types, and ATM deficiency is expected 
to sensitise tumour cells to ATR inhibition through their complementary roles in DNA-
damage repair. Patients with ATM-deficient malignancies can be clinically identified and, in 
most cases, are known to have a poor prognosis with current therapies.

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During tumourigenesis, ATM can be inactivated or lost providing a selection advantage for 
the tumour cell through the increased potential for genome alteration, and an increased 
dependence on ATR function. Similarly, oncogene activation such as c-Myc leads to 
increased replication stress, an accumulation of stalled replication forks and dependence on 
ATR function (Murai et al, 2012 and Murga et al, 2011).
A full description of non-clinical and clinical studies are presented in the IB.
11.2.3
Benefit/Risk Assessment
11.2.3.1
Risk Assessment
Data from non-clinical studies and emerging data from the clinical development programme 
has not identified any risks that would preclude investigation of ceralasertib in advanced 
cancer setting and shows that ceralasertib has a manageable safety profile in an advanced 
cancer population. 
Effects on bone marrow, particularly anaemia and thrombocytopenia, are anticipated in the 
clinic and may occur in the second or third week of dosing. These events are deemed schedule 
limiting, rather than dose limiting toxicities as the main issue is a delayed recovery of the 
platelets. Myelosuppression has been successfully managed with dose interruptions, dose 
reductions (dose and schedule) and supportive measures such as blood transfusions in the 
ongoing studies. Routine monitoring of haematology and biochemistry blood counts is 
planned.
A number of other potential risks based on toxicology data for ceralasertib and clinical 
findings when it is used with various combinations are being monitored in ongoing clinical 
trials. For updates on the emerging safety data and a detailed description of all potential risks 
for ceralasertib please refer to the latest ceralasertib IB. 
11.2.3.2
Benefit Assessment
Ceralasertib is considered to have a positive benefit-risk profile for patients with advanced 
cancer. Preclinical data suggest that, where tumour cells are dependent upon ATR for DNA 
repair through defects in HR or other DNA repair pathways eg ATM or BRCA mutations, 
ceralasertib selectively increases tumour sensitivity to therapy in advance cancer patients.
Early proof of concept data from multiple studies has shown evidence of efficacy from ATR 
inhibition patients whose tumours contain ATM mutations and ATM protein loss (see 
Section 0). Participants in this study will benefit from the monitoring of all AEs arising during 
the clinical study, related or not related to the study intervention. In addition, they will be 
contributing to the development of new therapies for advanced cancer.

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Cohort A may be further expanded,
. This 
would occur in the event an efficacy signal is observed, and subject to a protocol amendment.
For timing of assessments refer to the SoA in Section 11.1.3.
Figure 3
Study Design – Cohort A
1All aST, excluding participants with NSCLC and prostate cancer.
2Ceralasertib administered twice a day between Days 1 to 14 in 28 day cycles.
Abbreviations: ATM=ataxia telangiectasia mutated; BID=twice daily; IHC=immunohistochemistry; 
NSCLC=non-small-cell lung carcinoma.
11.4.1.2
Cohort B
Cohort B is recruiting participants with ATM altered metastatic mCRPC (Figure 4). A total of 
~27 molecularly eligible and centrally confirmed participants dosed at ceralasertib 160mg 
BID will be enrolled into Cohort B. Unfavourable CTC count requirement may be introduced 
for all participants to ensure adequate (approximately ≥50%) number of participants with 
CTC count ≥5/7.5 mL blood.
Cohort B may be further expanded,
. This 
would occur in the event an efficacy signal is observed, and subject to a protocol amendment.
For timing of assessments refer to the SoA in Section 11.1.3.
Figure 4
Study Design – Cohort B
1 Unfavourable CTC count requirement may be introduced for all participants to ensure adequate (approximately 
≥ 50%) number of participants with CTC count ≥ 5/7.5 mL blood. ATM ‘deficient’ is defined as ATM IHC ≤ 5% 
ATM-positive tumour nuclei using the Ventana assay (VENTANA ATM (Y170) RPA Assay).
2 Ceralasertib administered twice a day between Days 1 to 14 in 28 day cycles.
Abbreviations: ATM=ataxia telangiectasia mutated; BID=twice daily; IHC=immunohistochemistry.
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11.4.1.3
Confirmation of ATM Protein Expression and ATM Mutation Status
Participants with deleterious or suspected deleterious ATM tumour mutations (mono or 
biallelic) will be identified by approved local pre-existing test results of mutations in tumour 
or blood (germline or ctDNA). Definitions of qualifying ATM alterations include 
deleterious/suspected deleterious, pathogenic/likely pathogenic, disease- or cancer-associated 
mutations/variants or equivalent wording. Variants of unknown significance or benign/likely 
benign variants are not eligible. To assist the sites, rules for determining qualifying ATM 
mutations are attached in Appendix K. Central prospective NGS testing to determine ATM 
mutation status for participant eligibility into the study may be introduced. Sites will be 
required to submit a blood sample and tumour tissue to confirm centrally ATM mutations 
from local pre-existing tests in blood/tumour and to assess tumour ATM IHC status. To ensure 
sufficient participants are recruited with ATM IHC deficiency, prospective testing for ATM 
status by IHC may be introduced.
For a pre-existing NGS ATM mutation test to be acceptable for assessment of eligibility, it 
should meet the following criteria:
1
Test is validated and conducted in a CLIA-certified (for the US sites) or with local 
accreditation laboratory (for sites outside of the US).
2
Meets the acceptance criteria specified by the study sponsor (details of proposed pre-
existing NGS test should be provided in the NGS testing laboratory questionnaire for 
sponsor approval).
3
Information from local test result is provided, including location where it was performed, 
methodology, specimen type and minimal data on the analytical performance. 
4
Site agrees to provide the minimum required tumour tissue samples for central 
confirmation of ATM status by central NGS and IHC testing as defined in the Central 
Laboratory Manual.
Provision of an FFPE tumour tissue sample or slides is mandatory. The definition of ATM-
deficient is staining of ATM protein of 0-5% of tumour nuclei by IHC using the VENTANA 
ATM (Y170) RPA Assay.
For participants with a local ATM mutation test when ATM IHC testing is retrospective, 
participants may proceed to Screening Part 2 following submission of the mutation test result. 
If the central test result is subsequently different to the local test result, the participant may 
continue treatment if it is considered in their best interests. 
Two-step consent procedure will be implemented for all participants. Part 1 consent 
(Screening Part 1) may be taken whilst the participant is receiving a prior line of treatment. 
However, if an ATM alteration is identified, this does not guarantee a reserved participant 
place in Part 2 (Screening Part 2). Test results (from Screening Part 1) will be disclosed after 

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11.5.1
Inclusion Criteria (Cohort A [aST] and Cohort B [mCRPC])
The screening will have 2 parts, Part 1 and Part 2, which apply for both Cohort A and 
Cohort B. Participant consent for Part 1 will allow the submission of a pre-specified local test 
report or tumour sample to confirm molecular eligibility. All participants must submit blood 
and FFPE tumour samples for central confirmation of ATM mutation and ATM IHC testing. 
Participants will then be asked to also consent for Part 2 allowing further assessments to 
confirm study eligibility.
11.5.1.1
Screening Part 1 (Molecular eligibility)
Screening Part 1 is for all participants in Module 1. For participants who have already 
undergone local ATM NGS testing, submission of the local test report is mandatory. If 
prospective IHC ATM testing is triggered, local ATM NGS test report must be provided prior 
to Screening Part 2. . All participants must submit a FFPE tumour sample for central 
confirmation (NGS and IHC).
Mandatory ATM IHC protein loss according to central testing may be introduced.
Screening Part 1 may be conducted whilst the participant is receiving a prior line of treatment. 
If an ATM alteration is identified, this does not guarantee a reserved participant place in 
Screening Part 2.
1
Participants must have a histologically confirmed diagnosis of aST (excluding NSCLC) 
or mCRPC tumour.
2
Participants must have a deleterious or suspected deleterious ATM mutation in tumour or 
blood (germline or ctDNA). Definitions of qualifying ATM mutations may include 
deleterious/suspected deleterious, pathogenic/likely pathogenic, disease- or cancer-
associated variants, or equivalent wording. Variants of unknown significance, benign or 
likely benign alterations are not qualifying. To assist the sites rules for qualifying ATM 
mutations are attached in the Appendix K. Testing must be performed in a locally 
accredited laboratory using a validated test in line with local regulations (eg, CAP/CLIA 
laboratory where available). Submission of a copy of local test result is mandatory for 
eligibility. 
3
All participants must submit a FFPE sample for central confirmation of ATM IHC and 
NGS status. If retrospective testing is used, Screening Part 1 and Part 2 can be done 
simultaneously with local NGS result. If prospective testing is enabled, then all 
participants must submit a FFPE tumour sample for central confirmation of ATM IHC 
and NGS status at Screening Part 1 and wait for the result before proceeding to Screening 
Part 2. For the specific tumour sample requirements please refer to the respective 
Screening Part 2 inclusion criteria.

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11.5.1.2
Screening Part 2 (Study eligibility)
Participants must meet the eligibility criteria described in the core module for all participants
(Section 5.1) and those listed below. 
Type of Participant and Disease Characteristics
1
Participants who have no standard treatment options available or in whom the standard 
treatment options are contraindicated.
2
Eastern Cooperative Oncology Group performance status of 0 to 2.
3
Life expectancy ≥16 weeks.
4
Normal organ and bone marrow function measured within 28 days prior to the first dose 
of study intervention as defined below: 
(a) Haemoglobin ≥9.0 g/dL with no blood transfusions (packed red blood cells) in the 
past 28 days. Participants already receiving erythropoietin at the time of screening for 
the study may continue it providing they have been receiving it for more than one 
month at the time study intervention is started.
(b) Absolute neutrophil count ≥1.5 × 109/L.
(c) Platelet count ≥100 × 109/L with no platelet transfusions in the past 28 days.
(d) Total bilirubin ≤1.5 × institutional ULN unless the participant has documented 
Gilbert’s Syndrome in which case it must be ≤ 3 × institutional ULN.
(e) Aspartate aminotransferase/alanine aminotransferase ≤2.5 × institutional ULN unless 
liver metastases are present in which case they must be ≤5 × ULN.
(f) Participants must have creatinine clearance of ≥45 mL/min estimated or measured 
using standard methodology at the investigating site (ie, Cockcroft-Gault, 
Modification of Diet in Renal Disease, chronic kidney disease Epidemiology 
Collaboration, ethylenediaminetetraacetic acid or 24 hour urine): 
Estimated CrCl=(140-age [years]) × weight (kg)(× 0.85)
serum creatinine (mg/dL) × 72
Other
5
Participant must be able to swallow tablets whole.
In addition, participants are eligible to be included in Cohort A and Cohort B only if all of the 
following criteria apply, respectively.
11.5.1.3
Cohort A – aST
1
Participants must fulfil all the core and Module 1 eligibility criteria.
2
Availability of archival or fresh tumour FFPE specimens for central testing of ATM 
protein loss using IHC and for confirmation of ATM mutation using NGS. Submission of 
the sample is mandatory for enrolment. If archival samples are submitted, they must have 

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been obtained within 3 years. If an archival specimen is not available fresh standard of 
care tumour sample may be provided. The site needs to refer to the pathology manual for 
acceptable sample types for testing. Fine needle aspirates are not acceptable.
3
Participants with histologically confirmed aST (excluding participants with NSCLC and 
prostate cancer). 
4
Measurable disease by RECIST 1.1 criteria.
5
Radiological evidence of disease progression on previous treatment prior to study entry.
11.5.1.4
Cohort B – mCRPC
1
Participants must fulfil all the core and Module 1 eligibility criteria.
2
Availability of archival or fresh tumour FFPE specimens for central testing of ATM 
protein loss using IHC and for confirmation of ATM mutation using NGS. Submission of 
the sample is mandatory for enrolment. If archival samples are submitted, they must have 
been obtained within 5 years. If an archival specimen is not available fresh standard of 
care tumour sample may be provided. The site needs to refer to the pathology manual for 
acceptable sample types for testing. Fine needle aspirates are not acceptable.
3
Previously received and progressed on at least one NHA (eg, abiraterone acetate, 
apalutamide, and/or enzalutamide) and at least one taxane regimen for the treatment of 
prostate cancer (unless the participant has contraindications to taxanes). 
4
Participants with histologically confirmed metastatic castrate resistant prostate cancer. 
Participants whose disease spread is limited to regional pelvic lymph nodes or local 
recurrence (eg, bladder, rectum) are not eligible.
5
Documented prostate cancer progression at study entry while on androgen deprivation or 
after bilateral orchiectomy as assessed by the investigator with one or both of the 
following:

Radiographic progression based on PCWG3 criteria.

PSA progression defined by a minimum of 3 rising PSA levels with an interval of ≥1 
week between each determination. The PSA value at the Screening Part 2 visit should 
be ≥2 ng/mL; participants receiving systemic glucocorticoids for control of 
symptoms must have documented progression while on systemic glucocorticoids 
prior to commencing Cycle 1 Day 1 of study intervention.
6
One or both of the following:

Measurable disease according to RECIST 1.1 (except bone lesions).

Unfavourable CTC count (≥5/7.5 mL blood) according to local or central test. 
Submission of a copy of the test result is mandatory for eligibility. [Unfavourable 
CTC count requirement for all participants by local or central testing may be 
introduced to ensure adequate (approximately ≥50%) number of participants with 

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CTC count ≥5/7.5 mL blood.]. If participant has no measurable disease, then 
prospective testing may be done in order for participant to enrol.
7
Serum testosterone levels ≤50 ng/dL (≤1.75 nmol/L) within (≤) 28 days before 
enrolment (not required for participants after bilateral orchiectomy).
8
Participants without prior surgical castration must be currently taking for at least 4 weeks 
and willing to continue LHRH analog (agonist or antagonist) therapy throughout the 
duration of study intervention period.
11.5.2
Exclusion Criteria (Cohort A [aST] and Cohort B [mCRPC])
Participants must meet the eligibility criteria described in the core module for all participants 
(Section 5.2) and those listed below.
Medical Conditions
1
Any of the following cardiac diseases currently or within the last 6 months:

Unstable angina pectoris.

Congestive heart failure > Class 2 as defined by the New York Heart Association 
(see Appendix C).

Acute myocardial infarction.

Significant ventricular or supraventricular arrhythmias (participants with chronic 
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are 
eligible).

Mean resting corrected QT interval (QTc) > 470 msec obtained from 
3 electrocardiograms (ECGs) in 24 hours using the Fredericia formula.

Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia, congenital long QT syndrome, immediate family 
history of long QT syndrome or unexplained sudden death under 40 years of age.

For Cohort B (mCRPC), surgery or local prostatic intervention (excluding a prostatic 
biopsy) within 28 days of Cycle 1 Day 1.
2
Participants with known active infections (ie, hepatitis B or C, tuberculosis, or COVID-
19).
3
Participants considered a poor medical risk due to a serious, uncontrolled medical 
disorder, non-malignant systemic disease or active, uncontrolled infection.

Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent 
(within 3 months) myocardial infarction, uncontrolled major seizure disorder, 
unstable spinal cord compression, superior vena cava syndrome, extensive interstitial 
bilateral lung disease on high resolution CT scan or any psychiatric disorder that 
prohibits obtaining informed consent, and any other medical condition that, in the 
opinion of the investigator, places the participant at unacceptable risk of toxicity.

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4
Participants with symptomatic and/or uncontrolled brain metastases.

A contrast enhanced CT brain scan (MRI where CT is contraindicated), to confirm 
the absence of brain metastases is part of baseline disease assessment for participants 
with aST. If new asymptomatic brain metastases are discovered, an interval scan 
(minimum 4 weeks) should be conducted to confirm the new brain lesions are not 
progressing and do not require local CNS-directed therapy. If local treatment is 
necessary, this should occur before study entry. 

Participants with spinal cord compression unless considered to have received 
definitive treatment for this and evidence of clinically SD for 28 days.

Participants who have experienced a seizure or seizures within 6 months of study 
intervention or who are currently being treated with cytochrome P450 enzyme 
inducing anti-epileptic drugs for seizures (use of anti-epileptic drugs to control pain 
is allowed in participants not suffering from seizures unless drug is excluded due to 
CYP3A4 induction - phenytoin, carbamazepine, phenobarbital).

Participants with a history of treated CNS metastases are eligible, provided they meet 
all of the following criteria: Disease outside the CNS is present. No clinical evidence 
of progression since completion of CNS-directed therapy. Minimum of 3 weeks 
between completion of radiotherapy and Cycle 1 Day 1 and recovery (Grade ≤1) 
from significant acute toxicity with no ongoing requirement for > 10 mg of 
prednisone per day or an equivalent dose of other corticosteroid. If on corticosteroids, 
the participant should be receiving a stable dose of corticosteroids, started at least 
4 weeks prior to study intervention.
4a
Participants with INR ≥1.5 (except those who receive vitamin K antagonists and direct 
factor Xa inhibitors) or with other evidence of impaired hepatic synthesis function.
Prior/Concomitant Therapy (see Appendix D)
5
Previous therapy with an ATR inhibitor.
6
Any systemic anti-cancer therapy within 14 days or 5 half-lives (whichever is longer) of 
Cycle 1 Day 1. For biological therapeutics, including monoclonal antibodies and vaccines 
(eg, Sipuleucel-T), the minimum washout period shall be 28 days. The participant can 
receive a stable dose of bisphosphonates or denosumab for bone metastases, before and 
during the study as long as these were started at least 5 days prior to study intervention.

Agents such as 5α-reductase inhibitors (finasteride, dutasteride), oestrogen 
compounds (including estramustine) and megesterol are considered as anti-cancer 
agent in prostate cancer and prohibited within 14 days or 5 half-lives (whichever is 
longer) prior to study intervention. Ongoing treatment with LHRH analogs for 
prostate cancer are required in absence of prior bilateral orchiectomy.
7
Exposure to a small molecule IP within 14 days or 5 half-lives (whichever is longer) prior 
to Cycle 1 Day 1.

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8
Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose 
of study intervention, with the exception of participants receiving radiation to more than 
30% of the bone marrow or with a wide field of radiation who should not start study 
intervention within 21 days after radiation.
9
Concomitant use of known strong CYP 3A inhibitors (eg itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) (Table 14). The required washout period 
prior to starting study intervention is 2 weeks. 
10 Concomitant use of known strong CYP 3A inducers (eg phenobarbital, enzalutamide, 
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s 
Wort) (Table 14). The required washout period prior to starting study intervention is 
5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
11.5.3
Lifestyle Considerations
11.5.3.1
Meals and Dietary Restrictions
Participants must fast (water to drink only) from at least 2 hours prior to taking a dose to at 
least 1 hour post-dose for all doses.
Participants should avoid concomitant drugs, herbal supplements and/or ingestion of foods 
known to modulate CYP3A4 activity (See Section 11.6.5 and Appendix D).
11.5.3.2
Skin
Study intervention may increase the skin’s sensitivity to sunlight, which may result in 
sunburn. Participants should therefore take appropriate precautions when out in the sun (eg 
limit exposure, wear appropriate clothing [hat and sunglasses] and use sunscreen).
11.5.3.3
Contraception
Please refer to the core protocol (Section 5.3.1).
11.5.4
Screen Failures
Screen failures are defined as participants who consent to participate in Screening Part 1 
(molecular eligibility) and who are not subsequently entered in Screening Part 2 (study 
eligibility) or participants who consent to participate in Screening Part 2 (study eligibility) but 
are not subsequently entered in the study.
Participants will only receive their central molecular test results (from Screening Part 1) after 
they have been confirmed ineligible at Screening Part 2 or have concluded their participation 
in the study.
Please refer to the core protocol for further details (Section 5.4).

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11.6
STUDY INTERVENTION - MODULE 1
Study intervention is defined as any investigational intervention(s) or marketed product(s) 
intended to be administered to a study participant according to the study protocol.
11.6.1
Study Intervention Administered
Eligible participants will receive study intervention as described in Table 7. For both Cohorts
A and B, study intervention will be administered by oral tablet twice a day between Day 1 and 
Day 14 in 28 day cycles. Study intervention will be dispensed and returned as shown in the 
SoA (Section 11.1.3).
Table 7
Investigational Products
ARM Name
AZD6738
Intervention Name
Ceralasertib
Type 
Drug
Dose Formulation
Tablet
Unit Dose 
Strength(s)
AZD6738 tablets 20 mg or 80 mg
Dosage Level(s)
160 mg twice daily*
Route of 
Administration
Oral
Use
Experimental
Sourcing
AstraZeneca R&D
Packaging and 
Labelling
Study intervention will be provided in high density polyethylene (HDPE) 
bottles. Each bottle will be labelled in accordance with Good Manufacturing 
Practice Annex 13 and per country regulatory requirements.
*AstraZeneca elected to reduce the starting dose of ceralasertib from 240 mg BID to 160 mg BID with protocol 
amendment 2. Participants who are receiving treatment and have completed Cycle 1 and Cycle 2 without severe 
haematological toxicity or SAEs and are deemed to be benefitting from treatment, may continue on the current 
dose of 240 mg BD 2 weeks on / 2 weeks off at the investigator’s discretion.
Abbreviations: BID=twice daily; SAE=serious adverse events.
11.6.2
Preparation/Handling/Storage/Accountability of Interventions
1
Study intervention will be supplied by AstraZeneca R&D supply chain as individual 
bottles of tablets. Additional information about study intervention may be found in the 
Investigator Brochure.
2
Labels will be prepared in accordance with Good Manufacturing Practice and local 
regulatory guidelines by AstraZeneca R&D supply chain. The labels will fulfil Good 

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Manufacturing Practice Annex 13 requirements for labelling. Label text will be translated 
into local language.
3
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
4
Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention (after instruction of medical team 
participants should not take their study intervention until authorised by study team). All 
study intervention 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.
5
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.
11.6.3
Measures to Minimise Bias: Randomisation and Blinding
This is a modular, open-label study. Module 1 is a non-randomised, monotherapy, 2 cohort 
design.
11.6.4
Study Intervention Compliance
When participants self-administer study intervention at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning 
and counting of 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 study intervention tablets dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the eCRF.
Overdose is described in Section 8.4.
11.6.5
Concomitant Therapy
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential 
enzyme inducer) or 5 half-lives (whichever is longer) before the start of study intervention 
until completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, 
the medication will not interfere with the study.

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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrolment or 
receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
If medically feasible participants taking regular medication, with the exception of potent 
inhibitors or inducers of CYP3A, should be maintained on it throughout the study period.
Pre-medication

Anti-emetic treatment: No primary prophylactic treatment with anti-emetics is advised. 
However, anti-emetic treatment may be administered as secondary prophylaxis or 
treatment according to the guidelines of the participating sites. Please note: aprepitant 
(Emend®) is a substrate, moderate inhibitor and inducer of CYP3A4 and also an inducer 
of CYP2C9.
Therefore, the use of aprepitant is NOT allowed in this study for the treatment of 
nausea and vomiting induced by the study intervention. In general, drugs that interfere 
with CYP3A4 are not allowed in this study, and aprepitant is NOT an exception. For 
further information about CYP3A4, CYP2C9 or prohibited/allowed medication in this 
study, see Appendix D.
Supportive care
Participants will be permitted to receive appropriate supportive care measures as deemed 
necessary by the treating physician including but not limited to the items outlined below:

Diarrhoea: Diarrhoea should be treated promptly with appropriate supportive care, 
including administration of an anti-diarrheal agent according to standard practice 
guidelines. Anti-diarrheal agents should not be taken prophylactically. Participants should
be instructed to begin taking anti-diarrheal medication at the first sign of: 1) poorly 
formed or loose stool, 2) occurrence of more bowel movements than usual in one day or 
3) unusually high volume of stool. Anti-diarrheal agents should be deferred if blood or 
mucus is present in the stool or if diarrhoea is accompanied by fever. In this setting, 
appropriate diagnostic microbiologic specimens should be obtained to exclude an 
infectious aetiology. Participants should also be advised to drink liberal quantities of clear 
fluids to help prevent dehydration.

Nausea/vomiting: Nausea and vomiting should be treated adequately, and strong 
consideration should be given to the administration of secondary prophylactic anti-emetic 

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therapy according to standard institutional practice. Participants should be strongly 
encouraged to maintain liberal oral fluid intake. Supportive care with aprepitant (a 
CYP3A4 inhibitor / inducer / substrate) according to institutional guidelines in the 
context of standard of care chemotherapy is NOT allowed. See Appendix D.

Anaemia: Transfusions and/or erythropoietin may be utilised as clinically indicated for 
the treatment of anaemia but should be clearly noted as concurrent medications. No blood 
transfusions in the 28 days prior to first dose is allowed.

Neutropaenia: Colony-stimulating factors including G-CSF, pegylated G-CSF or GM-
CSF according to Institutional Standards, following discussion with the Principal 
Investigator and AstraZeneca.
Blood transfusions are allowed at any time during the study.

Avoid concomitant medications, herbal supplements and/or ingestion of foods that 
significantly modulate CYP3A4 or Pgp activity (see Appendix D). Note these include 
common azole antifungals, macrolide antibiotics, etc. For participants receiving study 
intervention in the absence of discontinuation criteria, if the investigator feels that 
concomitant administration of medications, herbal supplements or foods that significantly 
modulate CYP3A4 activity is necessary based upon medical judgement, such products 
may be administered with caution following discussion between the investigator and the 
sponsor Study Physician.
Concomitant medication may be given as medically indicated with the following exceptions.
11.6.5.1
Therapy that may NOT be administered
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy [LHRH 
analogues in prostate cancer and hormone replacement therapy are acceptable], biological 
therapy or other novel agent) for the disease under study is to be permitted while the 
participant is receiving study intervention.
Live attenuated virus and bacterial vaccines should not be administered, eg yellow fever, 
measles, influenza, rubella, mumps, typhoid, mycobacterium tuberculosis (BCG), Yersinia 
pestis (EV). An increased risk of infection by the administration of these vaccines has been 
observed with conventional chemotherapy and the effects with ceralasertib are unknown. The 
administration of killed vaccines is allowed. Examples of killed vaccines are cholera, bubonic 
plague, polio vaccine, hepatitis A and rabies.
11.6.5.2
Drug-Drug Interaction Between Ceralasertib and Other Drugs
Ceralasertib is an investigational drug for which no data on in vivo interactions are currently 
available. Potential interaction and guidelines below are considered on the basis of preclinical 
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The lists of CYP and transporter inhibitors/inducers, and CYP and transporter substrates are 
available in Appendix D. They are not exhaustive and the absence of a drug from these lists 
does not imply that its combination with ceralasertib is safe. If ceralasertib is being 
administered in combination, potential interactions of the combination partner should also be 
considered.

Restrictions regarding drugs affecting CYP metabolism 
The principal enzyme for metabolising ceralasertib is CYP3A4. Participants should avoid 
concomitant drugs, herbal supplements, and/or ingestion of foods known to modulate 
CYP3A4 activity from the time they enter the screening period until 28 days after the last 
dose of study intervention.

Prior to study intervention, use of potent inducers or inhibitors of CYP3A are not 
permitted. For participants taking any of these drugs (examples provided in 
Appendix D) the required washout periods before starting ceralasertib is five 
half-lives; except for St. John’s wort, which is 3 weeks.

On study intervention, if there is no suitable alternative concomitant medication other 
than a potent inhibitor of CYP3A, the investigator must interrupt ceralasertib for the 
duration of the potent CYP3A inhibitor and wait for the required washout period 
(five half-lives) before dosing ceralasertib again. If potent CYP3A inducers are 
considered necessary for the participant’s safety and welfare, this may diminish the 
clinical efficacy of ceralasertib and the participant should be monitored carefully for 
any change in the efficacy of study intervention. Refer to Appendix D for additional 
guidance.

The use of any herbal supplements or ‘folk remedies’ (and medications and foods 
that significantly modulate CYP3A activity) should be discouraged. If deemed 
necessary, such products may be administered with caution and the reason for use 
documented in the eCRF.
In vitro data also suggest that ceralasertib may be metabolised by CYP2C8 but a lesser 
extent, therefore caution should be applied with co-administration of potent inhibitors or 
inducers of CYP2C8 (examples provided in Appendix D).

Drugs known to be inhibitors or inducers of Pgp and/or BCRP, undertake 
appropriate monitoring if co-administration is necessary 
-
Ceralasertib is also a P-gp substrate. Co-administration of P-gp inhibitors or inducers 
may affect exposure to ceralasertib and therefore should not be co-administered with 
ceralasertib. If the use of any inhibitors or inducers of P-gp are considered necessary 
for the participant’s safety and welfare, the investigator must contact the study office 
and a decision to allow the participant to continue in the study will be made on a case-
by-case basis.

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-
Ceralasertib is a substrate of BCRP. Co-administration of BCRP inhibitors or inducers 
may affect exposure to ceralasertib; therefore, it is recommended that the investigators 
must interrupt ceralasertib for the duration of the BCRP inhibitor or inducer and wait 
for the required washout period of the BCRP modulator (five half-lives) before dosing 
ceralasertib again. 

Drugs known to be substrates of CYP3A4 and/or CYP2B6, undertake appropriate 
monitoring if co-administration is necessary 
Ceralasertib is a potential inducer of CYP3A4 and CYP2B6. Caution should be applied 
with co-administration of drugs that are either completely metabolised by CYP3A4 and/or 
CYP2B6, or that are CYP3A4 and/or CYP2B6 substrates and also have a narrow 
therapeutic index. Investigators should be aware that the exposure of other drugs 
metabolised by CYP3A4 and/or CYP2B6 may be reduced.

Drugs known to be substrates of OATP1B1 and BCRP, undertake appropriate 
monitoring if co-administration is necessary 
Ceralasertib is an inhibitor of OATP1B1 and BCRP. Co-administration of substrates of 
OATP1B1 and/or BCRP may affect exposure to ceralasertib; therefore, it is 
recommended that caution should be applied when such drugs are to be administered with 
ceralasertib.

Anticoagulation therapy
Participants on warfarin may participate in this study but it is recommended that their INR 
is monitored more frequently.
11.6.6
Dose Modification
11.6.6.1
General Guidance
Any clinically significant and/or unacceptable toxicity observed during the course of the study 
should be managed by interruption of the dose of study intervention in the first instance, dose 
reductions if necessary, and administration of supportive therapy.
If the toxicity resolves or reverts to ≤ CTCAEv5 Grade 1 or 2 (depending on the toxicity, see 
Table 8) treatment with study intervention may be restarted using the rules in Table 8 and 
Table 9 for dose modifications. Participants who have their dose previously reduced to the 
lowest possible dose and who have demonstrated an acceptable response to the dose 
interruption may be permitted to restart at the lowest dose level at the discretion of the 
investigator.  
If the toxicity does not resolve to ≤ CTCAEv5 Grade 1 or 2 (depending on the toxicity) or the 
participant is not showing clinical benefit, then the participant should be discontinued from 
study intervention and observed until resolution of the toxicity.

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Repeat dose interruptions are allowed as required for a maximum of 28 days on each occasion 
as recommended in Table 8. If the duration of dose interruption is longer than 28 days, the 
case should be discussed with the AstraZeneca study physician.
Study intervention dose interruption for conditions other than toxicity resolution should be 
kept as short as possible. If a participant cannot restart study intervention within 28 days for 
resolution of intercurrent conditions not related to disease progression or toxicity, the case 
should be discussed with the AstraZeneca study physician.
Study intervention should be stopped at least 3 days prior to planned surgery and restarted 
10 days post-surgery if the wound has healed. If the wound has not healed well, a further 
14 days may be allowed and the participant can recommence ceralasertib if there is no 
evidence of disease progression based on the clinical judgement. No stoppage of study 
intervention is required for any biopsy procedure. Study intervention should be discontinued 
for a minimum of 3 days before a participant undergoes palliative radiation treatment.  Study 
intervention should be restarted within 4 weeks as long as any bone marrow toxicity has 
recovered.
The dose of study intervention must not be adjusted under any other circumstances unless 
prior agreement is given by the sponsor. 
All dose modifications and interruptions (including any missed doses) and the reasons for the 
modifications/interruptions are to be recorded in the eCRF.
11.6.6.2
Guidance for Dose Modification and Interruption
Refer to Table 8 and Table 9 for dose modification and stopping criteria. Once dose is 
reduced, escalation is not permitted.
Participants with ≥ G3 anaemia, neutropenia, thrombocytopenia during Cycle 1 and Cycle 2 
will be required to attend for additional Day 8 and Day 14 assessments until there is no 
evidence of ≥ G3 anaemia, neutropenia, thrombocytopenia for at least 2 cycles. Participants 
who develop a ≥ G3 anaemia, neutropenia, thrombocytopenia later in their treatment, will also 
need to have additional Day 8 and Day 14 assessments until there is no evidence of ≥ G3 
anaemia, neutropenia, thrombocytopenia for at least 2 cycles.
Table 8
Guidance for Dose Modifications, Interruptions and Discontinuations
for Ceralasertib
Event 
Action
Grade 1 neutropenia and/or thrombocytopenia
Ceralasertib dosing may continue if neutrophil count 
is ≥1500/mm3 and/or platelet count is ≥75,000/mm3. 

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Event 
Action
Grade 1-2 toxicities (except neutropenia and 
thrombocytopenia)
Investigator decision whether to interrupt ceralasertib 
(max 28 days) or continue treatment. Treatment may 
be resumed at the same dose level or with a dose 
reduction by 1 level. For prolonged (>2 weeks) or 
persistent Grade 2 toxicity (>28 days) that does not 
respond to supportive treatment, ceralasertib should 
be interrupted and restarted at lower dose.
Grade 2 neutropenia or 
Grade 3 anaemia
Interrupt ceralasertib (max 28 days) and give 
appropriate supportive treatment e.g. transfusion, 
until AE improves to at least neutrophil count 
≥1500/mm3 and haemoglobin ≥8.0 g/dL, then restart 
reducing the dose of ceralasertib by 1 level1.
If a further dose reduction is required after the level 2
dose reduction, the participant must stop treatment.
Grade 2-3 thrombocytopenia
First occurrence
Interrupt ceralasertib (max 28 days) and give 
appropriate supportive treatment until platelets 
improve to at least ≥100,000/mm3. At resolution, it 
is not mandatory to lower the dose as blood counts 
may recover during the “off period” on the 
intermittent schedule. If blood counts do not recover 
by the start of the next dosing period, ceralasertib 
should be restarted with a dose reduction by 1 level 
for ceralasertib.
Subsequent occurrences
Interrupt ceralasertib (max 28 days) and give 
appropriate supportive treatment. Treatment may be 
restarted with a reduced dose of ceralasertib when the 
toxicity is resolved or investigator discretion to stop 
treatment.
Grade 4 thrombocytopenia
Interrupt ceralasertib (max 28 days) and give 
appropriate supportive treatment; investigator 
discretion on whether to restart treatment with a dose 
reduction by 1 dose level ceralasertib when the 
platelet count has recovered to ≥100,000/mm3 or 
stop treatment.
If a second Grade 4 thrombocytopenia occurs and 
does not recover to baseline or Grade 1 within 
28 days treatment must be stopped.

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Event 
Action
Grade 3-4 toxicity
(including Grade 3-4 neutropenia or
Grade 4 anaemia)
Excludes Grade 3 anaemia or
Grade 3-4 thrombocytopenia (see above)
First occurrence
Interrupt ceralasertib (max 28 days) and give 
appropriate supportive treatment; restart treatment 
with a dose reduction by 1 level for ceralasertib when 
the toxicity is resolved (Grade 1 or 2 depending on 
the toxicity or returns to baseline).
Subsequent occurrences
In case of haematological toxicity or Grade 3 non 
haematological toxicity, investigator discretion on 
whether to interrupt ceralasertib (max 28 days) or to 
stop treatment. Restart treatment with a dose 
reduction by 1 or 2 levels for ceralasertib.
If a second Grade 4 haematological toxicity occurs 
and does not recover to baseline or Grade 1 within 
28 days, treatment must be stopped. 
If a second Grade 4 non-haematological toxicity 
occurs treatment must be stopped.
If a further dose reduction is required after the level 2
dose reduction, the participant must stop treatment.
Vomiting
If vomiting occurs shortly after study intervention is 
swallowed, the dose should only be replaced if all of 
the intact tablets can be counted. Resume with the 
following scheduled dose.
Missed dose
Allowed to take the scheduled dose up to 2 hours 
after the scheduled dose time. If greater than 2 hours, 
the missed dose should not be taken, and participant 
should continue with next dose at allotted time.
1 This table is for guidance. Therefore, for example, it may be deemed appropriate by the investigator to reduce 
the dose by more than one dose level depending on the individual participant circumstances.
Table 9
Dose Reduction Levels for Ceralasertib
Initial dose
160 mg BID days 1-14
Level 1 dose reduction
120 mg BID days 1-14
Level 2 dose reduction
80 mg BID days 1-14
Level 3 dose reduction
Stop treatment
*AstraZeneca elected to reduce the starting dose of ceralasertib from 240 mg BID to 160 mg BID with protocol 
amendment 2. For any participant continuing at 240 mg BID 2 weeks on / 2 weeks off at the investigator’s 
discretion), the ceralasertib dose should be reduced to 160 mg BID days 1-14 (‘initial dose’) and thereafter 
follow the dose reduction levels as tabulated.

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Abbreviations: BID=twice daily; SAE=serious adverse events.
11.6.6.3
Individual Stopping Criteria
Cardiovascular
Clinically significant hypotension defined as an asymptomatic decrease of more than 
20 mmHg in systolic BP to below 70 mmHg persisting for at least 10 minutes.
Symptomatic orthostatic fall in systolic BP of more than 20 mmHg compared to resting seated 
systolic BP.
Hepatic
ALT or AST or ALP* > 5 x ULN
ALT or AST or ALP* > 3 x ULN with the appearance of symptoms associated with a clinical 
diagnosis of hepatitis including right upper quadrant pain or tenderness, fever, rash or 
eosinophilia (> 5%).
[ALT or AST > 3 x ULN] and [total bilirubin > 2 x ULN or INR+ > 1.5 or other evidence of 
impairment to the synthesis function of the liver].
* In the presence of bone metastases bone specific isoform of raised ALP in the presence of a 
raised gamma-GT (to ensure the ALP change is specific to the liver).
+ Unless participant is receiving warfarin or other vitamin K antagonists, or direct factor Xa 
inhibitors.
Please refer to Appendix E “Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law.”
11.6.7
Intervention after the Final DCO
Patients still receiving IP at the time of final analysis DCO may continue to receive study
treatment within the study. Patients will continue to attend study visits as per SoA, section 
11.1.3,  Table 3, with a reduced number of assessments:

Physical Examination including weight

Vital signs

Complete blood count and other clinical safety laboratory assessments 

Pregnancy test (WOCBP only)

Dosing with Ceralasertib

Adverse events (AE)

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The Investigator will continue to monitor the patient’s safety laboratory results prior to and
periodically during treatment in order to manage AEs in accordance with the dose
modification and stopping guidelines (see section 11.6.6). 
All data from the safety assessments will be recorded in the patient’s medical records with the
following being reported to AstraZeneca, as applicable:

SAEs and AESIs

Pregnancy

Overdoses
For these patients ongoing at the time of final analysis DCO, tumour assessment and bone 
scans will be performed as per standard of care frequency, but as with safety assessments,
these data will not be reported to AstraZeneca.
11.7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL -
MODULE 1
Please refer to the core protocol (Section 6.1). 
Patients may receive study intervention until objective disease progression, or as long as they 
are continuing to show clinical benefit, as judged by the investigator, or treatment 
discontinuation criteria are met.
Any participant who permanently discontinues study intervention should be followed up till 
the safety follow-up visit (see follow-up Section 7.3) and until radiographic disease 
progression is registered and confirmed where necessary according to the protocol 
requirements.
The SoA (Section 11.1.3) details the data to be collected at the time of study intervention 
discontinuation, and for any further evaluations that need to be completed.
11.8
MODULE ASSESSMENTS AND PROCEDURES - MODULE 1
Study procedures and their timing are summarised in the SoA (Table 3).
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 300 mL (over a 1-
month period). Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples.
11.8.1
Efficacy Assessments
In Cohort A (aST) any tumour lesions will be assessed by RECIST 1.1 criteria.

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In Cohort B (prostate cancer) soft tissue and visceral lesions will be assessed by RECIST 1.1 
and bone lesions by PCWG3 criteria. Bone lesions will not be included in the RECIST 1.1
soft tissue assessment.
11.8.1.1
Tumour Assessments
RECIST 1.1 guidelines for measurable, non-measurable, TLs and NTLs and the objective 
tumour response criteria are presented in Appendix F of this Clinical Study Protocol.
Baseline tumour assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual participants. Baseline assessments should be 
performed no more than 28 days before the start of study intervention, and ideally should be 
performed as close as possible to the start of study intervention. The methods of assessment 
used at baseline should be used at each subsequent follow-up assessment. In Cohort A, at the 
baseline CT scan, assessment of the brain should be included. Follow-up assessments should 
be performed every 8 weeks (± 1 week) for 1 year and thereafter every 12 weeks (± 1 week) 
after the start of study intervention until objective disease progression by RECIST 1.1 (in 
Cohort B RECIST 1.1 for soft tissue and visceral lesions and by PCWG3 criteria for bone 
lesions) or withdrawal of consent.
If a participant discontinues study intervention (and/or receives a subsequent anti-cancer 
therapy) prior to objective radiographic disease progression registered according to the 
protocol requirements, then the participant should still continue to be followed until objective 
radiographic disease progression.
Any other sites at which new disease is suspected should also be appropriately imaged. If an 
unscheduled assessment is performed and the participant has not progressed, every attempt 
should be made to perform subsequent assessments at the scheduled visits whilst the 
participant remains on study intervention.
Categorisation of objective tumour response assessment will be based on the RECIST 1.1 
guidelines for response: CR, PR, SD, and PD.
For participants who only have non-measurable disease at baseline, categorisation of objective 
tumour response assessment will be based on the RECIST 1.1 guidelines for response for 
NTLs: CR, PD and Non-CR/Non-PD.
If the investigator is in doubt as to whether progression has occurred, particularly with 
response to NTLs or the appearance of a new lesion, it is advisable to continue study 
intervention and reassess the participant’s status at the next scheduled assessment or sooner if 
clinically indicated.

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To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more NTLs is usually not 
sufficient to qualify for unequivocal disease progression status.
Frequency will be adjusted after 56 weeks of treatment if the tumour is not changing in size 
(SD, PR or CR) and will occur every 12 weeks (±1 week). 
It is important to follow the assessment schedule as closely as possible. Please refer to the 
SoAs (Section 11.1.3) and Appendix F.
11.8.1.2
Cohort B
Bone lesions assessment in Cohort B (mCRPC) (Based on PCWG3 Criteria)
Objective tumour response criteria for bone lesions using PCWG3 criteria are presented in 
Appendix G of this Clinical Study Protocol.
Bone lesions will be assessed by bone scintigraphy commonly performed with Technetium-99 
(bone scans). Bone lesions will be assessed by bone scan and will not be part of the RECIST 
1.1 malignant soft tissue assessment. The definition for bone progression is based on PCWG3 
criteria. Positive hot spots on the bone scan should be considered significant and unequivocal 
sites of malignant disease to be recorded as metastatic bone lesions.
Progression on a bone scan is defined as:

At the 8-week scan:

If 2 or more new metastatic bone lesions are observed on the first 8-week scan, the 
confirmatory scan performed (at least 6 weeks later), must show 2 or more 
additional new metastatic bone lesions (for a total of 4 or more new metastatic bone 
lesions since the baseline assessment). 

Note - The first bone scan completed after baseline will be considered the ‘8-week 
scan’ regardless if taken at Week 8 or at an unscheduled assessment. 

After the 8-week scan:

For participants without progression at the 8-week scan, this scan now serves as 
new baseline for all subsequent scans, i.e., all bone scans after Week 8 are compared 
to the Week 8 scan. If 2 or more new metastatic bone lesions are observed on scans 
obtained after the first 8-week assessment (compared to Week 8 scan), a 
confirmatory scan performed at least 6 weeks later and preferably no later than the 
next scheduled scan must show the persistence of, or an increase in, the number of 
metastatic bone lesions compared to the prior scan.

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The date of progression is the date of the first scan documenting the 2 new lesions. If the 
investigator is in doubt as to whether progression has occurred, it is advisable to continue 
study intervention and reassess the bone lesion status at the next scheduled assessment, or 
sooner if clinically indicated.  
The requirements for determination and confirmation of radiographic progression by either 
bone scan (bone progression) or CT/MRI (soft tissue progression) are summarised in 
Table 10.
Table 10
Requirements for Documentation of Progression
Visit
Criteria for Bone Progression
Criteria for Soft Tissue 
Progression
Week 8 scan
2 or more new lesion compared to baseline 
bone scan.
Requires confirmation scan at least 
6 weeks later with 2 or more additional 
new lesions compared to Week 8 scan
Progressive disease on CT or MRI by 
RECIST 1.1.
No confirmation scan required.
Subsequent scans
2 or more new lesion compared to Week 8 
bone scan.
Requires confirmation scan at least 
6 weeks later for persistence or increase in 
number of lesions
Progressive disease on CT or MRI by 
RECIST 1.1.
No confirmation scan required.
Abbreviations: CT=computed tomography; MRI=magnetic resonance imaging; RECIST=Response Evaluation 
Criteria in Solid tumours.
It is important to follow the assessment schedule as closely as possible. Please refer to the 
SoA (Section 11.1.3) and Appendix G.
Prostate Specific Antigen
Blood sample will be taken as detailed in the SoA (Section 11.1.3). For information on sample 
processing, handling and shipment refer to the Laboratory Manual.
For storage, re-use and destruction of biomarker samples see Section 8.5.
Circulating Tumour Cell Clinical Samples
A whole blood sample will be taken as detailed in the SoA (Section 11.1.3). Circulating 
Tumour Cell Clinical samples will be shipped under ambient conditions on the day of 
acquisition so as to be received at an AstraZeneca approved laboratory within 72 hours of 
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subsequent testing for CTC count will be performed centrally. For information on sample 
processing, handling and shipment refer to the Laboratory Manual.
For storage, re-use and destruction of biomarker samples see Section 8.5.
11.8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 11.1.3).
For all participants, results of all safety assessments must be available and must be reviewed 
by the Investigator or their deputy prior to start of each dosing cycle. Samples can be collected 
the day before dosing cycle start.
Prior to discharge from each in-patient and clinic visit, the Investigator or their deputy will be 
responsible for reviewing all available safety data, including vital signs and ECGs.
11.8.2.1
Physical Examinations

A complete physical examination with weight will be performed at the visits as indicated 
in the SoA and clinically indicated (Section 11.1.3). Height will be recorded at screening 
only.

Please refer to the core protocol (Section 8.2.1).
11.8.2.2
Vital Signs
Seated blood pressure and pulse rate
Blood pressure and pulse rate will be measured in the sitting position after at least 10 minutes 
rest. Assessments will be performed at the visits as shown in the SoA (Section 11.1.3).
Body temperature
Body temperature will be measured in degrees Celsius at the visits indicated in the SoA 
(Section 11.1.3).
11.8.2.3
Electrocardiograms
Resting 12-lead ECG
Triplicate 12-lead ECGs will be performed as shown in the SoA (Section 11.1.3).
Please refer to the core protocol (Section 8.2.3).
11.8.2.4
Performance Status
Performance status will be assessed at the visits as indicated in the SoA (Section 11.1.3) 
according to US ECOG criteria.
Please refer to the core protocol (Section 8.2.4).

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11.8.2.5
Brain Scan
At baseline, the imaging modalities used for assessment should be contrast enhanced CT 
(MRI where CT is contraindicated) scans of the brain (Cohort A only), chest, abdomen and 
pelvis (including liver and adrenal glands) and should encompass all areas of known 
predilection for metastases in the disease under evaluation, and should additionally investigate 
areas that may be involved based on signs and symptoms of individual participants. Follow-up 
CT or MRI assessments will cover chest, abdomen and pelvis with any other regions imaged 
at baseline where disease was present. Any other sites at which new disease is suspected 
should also be appropriately imaged. A CT scan of the brain should be performed in all 
participants in Cohort A at baseline if the participant is not known to have brain metastases. If 
the participant is known to have brain metastases then an MRI will be performed.
A contrast enhanced CT brain scan (MRI where CT is contraindicated) forms part of the 
baseline disease assessment in Cohort A only as indicated in the SoA (Section 11.1.3).
11.8.2.6
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation,
and urinalysis will be taken at the visits indicated in the SoA (Section 11.1.3).
Please refer to the core protocol (Section 8.2.5).
The clinical chemistry, haematology and urinalysis will be performed at a local laboratory at 
or near to the investigator site. Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site.
The following laboratory variables will be measured.
Table 11
Laboratory safety variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
Blood (B)-Haemoglobin
Serum (S)/Plasma (P)-Albumin
B-Leukocyte count
S/P-Alanine transaminase (ALT)
B-Leukocyte differential count (absolute count)a
S/P-Aspartate transaminase (AST)
Neutrophils
S/P-Alkaline phosphatase
Lymphocytes
S/P-Bilirubin, total
Monocytes
S/P-Calcium, total
Basophils
S/P-Creatinine
Eosinophils
S/P-Glucose
B-Platelet count
S/P-Magnesium
B-Reticulocytesb
S/P-Phosphate
Coagulationc
S/P-Potassium

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Table 11
Laboratory safety variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-INR
S/P-Sodium
APTT
S/P-Urea nitrogen or Urea
Urinalysis (dipstick)c
S/P-C - reactive protein
U-Protein
S/P-Thyroid stimulating hormone (TSH)d
U-Glucose
U-Blood
Other screening tests
Serum (screening) and urine (other time points) human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)
a
If absolute differentials not available please provide % differentials
b
If absolute particle counts not available please provide relative particle count
c
Coagulation and urinalysis are only scheduled for baseline and as clinically indicated post-baseline
d
Free triiodothyronine (T3) or free thyroxine (T4) will only be measured if TSH is abnormal or if there is 
clinical suspicion of an AE related to the endocrine system.
NB. In case a participant shows an AST or ALT ≥3 x ULN together with total bilirubin 
≥2 x ULN please refer to Appendix E. Actions required in cases of increases in liver 
biochemistry and evaluation of Hy’s Law’, for further instructions.
Additionally, a serum (screening) or urine (other time points) sample will be collected from all 
women of childbearing potential at the visits indicated in the SoA (Section 11.1.3).
11.8.3
Adverse Events and Serious Adverse Events
Please refer to the core protocol (Section 8.3).
11.8.4
Overdose
Please refer to the core protocol (Section 8.4).
11.8.5
Human Biological Samples
11.8.5.1
Pharmacokinetics

Venous blood samples for determination of concentrations of study intervention in plasma 
will be taken at the times specified in the SoA (Section 11.1.3). The date and time of 
collection of each sample will be recorded.

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. The timing of 
sampling may be altered during the course of the study based on newly available data to 
ensure appropriate monitoring. The total volume of blood taken from each participant will 
not exceed that presented in Section 11.8.1.

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
Plasma blood samples will be used to analyse the PK of the study intervention. Samples 
collected for analyses of study intervention concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study.

Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual.
Determination of Drug Concentration
Samples for determination of study intervention 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.
11.8.5.2
Pharmacodynamics
 will be used to inform the extent and duration of ATR target 
inhibition following treatment with study intervention. 
 will also be 
used to obtain assessment of the ceralasertib
 relationship in participants and 
determine any retrospective correlations with ATM status and response to study intervention.
The collection of blood based 
 samples will provide assessment of downstream 
effects of ceralasertib administration in participants. Additional 
 
 may be assessed. 
 will be collected and processed as detailed in the 
SoA (Section 11.1.3). This sample may also be used to assess 
.
Additional details of blood, archival and fresh frozen tissue collection, shipping and storage of 
samples for biomarker assays can be found in the Laboratory Manual.
For storage, re-use and destruction of 
 see Section 8.5 and Appendix I.
11.8.6
Human Biological Sample Biomarkers
11.8.6.1
Collection of Archival Tumour Samples
Formalin fixed tumour tissue embedded in paraffin blocks are to be requested for all 
participants. Archival samples from either primary or metastatic tumour will be accepted but 
tissue from the primary tumour is preferred. However, tissue from the most recent biopsy 
would be preferred where a participant has archival tissue samples from multiple time points.
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Approximately 30 freshly cut (within 30 days) unstained sections from the archival tumour 
block are accepted if tumour blocks cannot be submitted, however tumour tissue blocks are 
preferred. Specimens with insufficient tumour content or fine needle aspirates are inadequate 
to establish participant eligibility. Where available, provision of a copy of the pathology report 
associated with the tumour sample is also required.
Details of sample collection, processing, shipping and storage will be described in the 
Laboratory Manual and/or the Pathology and Genomic Testing manual.
11.8.6.2
Collection of Plasma Samples for 
A peripheral blood sample will be collected to provide plasma for 
 
 
, 
 
Section 11.1.3).
 
 
.
Details of sample collection, processing, shipping and storage will be described in the 
Laboratory Manual.
11.8.6.3
Collection of
 
.
For storage, re-use and destruction of 
 see Section 8.5.
11.8.7
Optional Genomics Initiative Sample
Please refer to core module for details.
11.9
STATISTICAL CONSIDERATIONS - MODULE 1
11.9.1
Statistical Hypotheses
No formal statistical hypotheses are being conducted for this study.
11.9.2
Sample Size Determination
Cohort A (aST): A total of ~25 molecularly eligible and centrally confirmed participants 
dosed at ceralasertib 160mg BID will be enrolled into Cohort A.  
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Cohort B (prostate cancer): A total of ~27 molecularly eligible and centrally confirmed 
participants dosed at ceralasertib 160mg BID  will be enrolled into Cohort B. Unfavourable 
CTC count requirement may be introduced for all participants to ensure adequate 
(approximately ≥50%) number of participants with CTC count ≥5/7.5 mL blood.
At the time of protocol amendment 2, 1 participant had been dosed at 240 mg BID in 
Cohort A, and 8 participants had been dosed at 240 mg BID in Cohort B. Following the 
reduction of the starting dose from 240 mg BID to 160 mg BID in protocol amendment 2, the
intention is to enrol an additional total of ~25 and ~27 participants in Cohort A and B, 
respectively, at the 160 mg BID.
The primary objective of this study is to determine investigator assessed objective response 
rate (Cohort A) and composite response rate (Cohort B) of study intervention. The number of 
participants has been based on the desire to obtain adequate response, tolerability, safety, 
pharmacokinetic and PDc data while exposing as few participants as possible to study 
intervention and procedures. In Cohort A, the sample size of ~25 participants is expected to 
give adequate precision in the estimate of the ORR. 
 
 In Cohort B, the sample size of ~27 participants is 
expected to give adequate precision in the estimate of composite response. 
 
 
Please refer to Table 12 for the definition of a molecularly eligible participant. In case of 
discordance between local and central testing, additional participants may be enrolled in order 
to satisfy the intended sample size of molecularly eligible and centrally confirmed 
participants.
Each Cohort A and Cohort B may be further expanded 
 
, in case of an efficacy signal, subject to an approved protocol 
amendment.
11.9.3
Populations for Analyses
The following populations are defined:
Table 12
Populations for Analysis
Population/Analysis set
Description
Enrolled Analysis Set
All study participants who signed the ICF (including screening failures).
Evaluable for Response Set
Cohort A: All study participants with measurable baseline disease who 
received at least 1 dose of study intervention.
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Population/Analysis set
Description
Cohort B: All study participants with measurable disease and/or 
unfavourable CTC count at baseline who received at least 1 dose of study 
intervention.
'Molecularly Eligible Centrally 
Confirmeda Evaluable for 
Response Set
Cohort A: All molecularly eligible and centrally confirmed study 
participants with measurable baseline disease who received at least 1 dose 
of study intervention.
Cohort B: All molecularly eligible and centrally confirmed study 
participants with measurable disease and/or unfavourable CTC count at 
baseline who receive at least 1 dose of study intervention.
Please refer to protocol Section 11.2 for the definition of a molecularly 
eligible participant.
 
 
 
Safety Set
All participants who received at least 1 dose of study intervention.
Molecularly Eligible Centrally 
Confirmed Set
All molecularly eligible and centrally confirmed participants who received 
at least 1 dose of study intervention.
a
Participants with any or both of the following conditions will be considered molecularly eligible centrally 
confirmed:
1) Centrally confirmed deleterious or suspected deleterious ATM mutation by NGS.
2) Centrally confirmed ATM IHC ≤ 5%.
11.9.4
Statistical Analyses
The SAP will be finalised prior to database lock and 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 key secondary endpoints. Any deviations from the planned analysis will be described in 
an SAP addendum and justified in the final integrated CSR.
Data that will be analysed at each timepoint is presented Table 13.
Table 13
Summary of Analyses and Data Cut-off Triggers
Analysis 
Trigger
Data Type Included
Interim Cohort A
Approximately 4 months after 18 
molecularly eligible centrally 
confirmed evaluable for response 
participants are enrolled.
At a minimum, key efficacy and 
safety data for Cohort A, Details to 
be provided in the SAP
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Analysis 
Trigger
Data Type Included
Interim Cohort B
Approximately 6 months after 12 
molecularly eligible centrally 
confirmed evaluable for response
participants are enrolled.
At a minimum, key efficacy and 
safety data for Cohort B, Details to 
be provided in the SAP
Primary analysis Cohort A
Approximately 6 months after 25 
molecularly eligible centrally 
confirmed evaluable for response 
participants are enrolled.
All data for Cohort A
Primary analysis Cohort B
Approximately 6 months after 27 
molecularly eligible centrally 
confirmed evaluable for response 
participants are enrolled.
All data for Cohort B
Abbreviations: ATM=ataxia telangiectasia mutated; RECIST=response evaluation criteria in solid tumours. 
11.9.4.1
General Considerations
All statistical analysis will be performed by Parexel International Biostatistics or other 
designated third party providers, under the direction of the Biostatistics Group, AstraZeneca. 
Further detail will be provided in the SAP. All statistical analysis will be performed using the 
latest available version of SAS® (SAS Institute Inc., Cary, North Carolina, US), version 9.4 or 
higher. Exploratory analyses may be reported outside of the CSR.
Safety data will be presented separately by starting dose (and total) for each cohort of 
participants within Module 1. Summaries of efficacy data will only be presented for 
participants receiving 160 mg BID starting dose, however, listings will include all participants 
(240 mg BID and 160 mg BID starting dose).

Cohort A: aST except NSCLC and prostate cancer

Cohort B: Metastatic castration-resistant prostate cancer
No formal statistical analyses will be carried out for this study and the data will be 
summarised using standard summary statistics.
Deviations from the protocol will be assessed as “important” or “not-important”. Deviations 
will be defined before database lock to determine the impact on any planned analyses. 
Important deviations will be defined in a separate protocol deviation document.
All important protocol deviations will be listed by participant for all enrolled participants. 
Further details will be described in the SAP.
Demographic data

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Characteristics of the participants, including medical history and disease characteristics at 
baseline will be listed for each participant and summarised by cohort.
Reasons for discontinuation of study intervention will be listed including the study day of 
treatment discontinuation and will be summarised by cohort.
Exposure
Exposure to study intervention will be listed for all participants by cohort.
11.9.4.2
Safety
Safety and tolerability will be assessed in terms of AEs, laboratory data, vital signs, and 
physical examination. These will be collected for all participants. Appropriate summaries of 
these data will be presented.
During the evaluation of AE data, an AstraZeneca medically qualified expert will review the 
list of AEs that were not reported as SAEs and AEs leading to discontinuation of study 
intervention. Based on the expert’s judgement, AEs of particular clinical importance may, 
after consultation with the Global Safety Physician, be considered other significant adverse 
events and reported as such in the CSR. A similar review of laboratory values, vital signs, 
ECGs and other safety assessments will be performed for identification of other significant 
AEs.
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.
11.9.4.3
Pharmacokinetic Variables
A statistical summary of ceralasertib concentration per the nominal time point and a listing of 
individual concentrations of ceralasertib will be generated.
11.9.4.4
Pharmacodynamic Variables
, 
11.9.4.5
Efficacy
Cohort A
Primary Endpoint(s)
Determination of objective response rate is the primary objective. The primary analysis will 
occur approximately 6 months after all participants have been enrolled into the cohort. 
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Blinded independent central review assessment may be introduced if the cohort is expanded, 
subject to an approved protocol amendment.
Objective Response Rate
Objective response rate is defined as the percentage of participants who have at least one 
response of CR or PR prior to any evidence of progression (as defined by RECIST 1.1) that is 
confirmed at least 4 weeks later. The primary analysis of objective response rate will be based 
upon the ‘molecularly eligible centrally confirmed evaluable for response’ population. 
Additionally, objective response rate will also be provided for the 'evaluable for response' 
population. Percentage of participants will be accompanied with a 2-sided 80% confidence 
interval as obtained from a Clopper-Pearson test.
Secondary Endpoint(s)
Duration of Response
Duration of response will be defined as the time from the date of first documented response 
until date of documented progression or death in the absence of disease progression, the end 
of response should coincide with the date of progression or death from any cause used for the 
PFS endpoint. The time of the initial response will be defined as the latest of the dates 
contributing towards the first visit response of PR or CR.
If a participant does not progress following a response, then their duration of response will use 
the PFS censoring time.
Descriptive data will be provided for the duration of response in responding participants, 
including the associated Kaplan-Meier estimate of median duration of response, where there 
are sufficient number of responders.
Percentage Change in Tumour Size 
The percentage change in TL tumour size from baseline will be summarised using descriptive 
statistics by visit. Waterfall plots showing the best percentage change from baseline in sum of 
the diameters of TLs will be produced. Spider plots showing the percentage change from 
baseline in tumour size for each subject over time will be produced.
Progression Free Survival
Progression free survival is defined as the time from start of study intervention until the date 
of objective disease progression or death (by any cause in the absence of progression) 
regardless of whether the participant withdraws from therapy or receives another anti-cancer 
therapy prior to progression. Participants who have not progressed or died at the time of 

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analysis will be censored at the time of the latest date of assessment from their last evaluable 
RECIST assessment. However, if the participant progresses or dies after 2 or more missed 
visits, the participant will be censored at the time of the latest evaluable RECIST assessment. 
If the participant has no evaluable visits or does not have baseline data, they will be censored 
at 0 days unless they die within 2 visits of baseline.
The PFS time will always be derived based on scan/assessment dates not visit dates.
For further details see Appendix F of this Clinical Study Protocol.
Analyses of PFS will be based upon the 'molecularly eligible centrally confirmed' population. 
Kaplan-Meier plots of PFS will be presented. Summaries will include the median PFS with 
respective CIs calculated using the Kaplan-Meier technique. Summaries will also provide the 
number and percentage of participants experiencing a PFS event, and the type of event 
(progression or death).
Cohort B
Primary Endpoint(s)
Determination of composite response rate is the primary objective. The primary analysis will 
occur approximately 6 months after all participants have been enrolled into the cohort.
Composite Response Rate
Composite response will be defined on the basis of the following outcomes; if any of these 
occur in the absence of radiological or PSA progression (according to RECIST 1.1 for soft 
tissue and visceral lesions, prostate cancer working group 3 (PCWG3) criteria for bone 
lesions, and PSA) participants will be considered to have responded:

Investigator assessed radiological objective response by RECIST 1.1 for soft tissue and 
visceral lesions and PCWG3 criteria for bone lesions. Response must be confirmed at 
least 4 weeks later. BICR assessment may be introduced if the cohort is expanded, subject 
to a protocol amendment.

Conversion of CTC count from ≥5/7.5 mL blood (unfavourable) at baseline to 
< 5/7.5 mL blood (favourable) confirmed by a second consecutive value obtained 3 or 
more weeks later (as per PCWG3 criteria).

PSA decline of > 50% confirmed by a second consecutive measurement at least 3 weeks 
later (based on PCWG1 criteria).
Overall radiological visit assessment in prostate cancer is provided in Appendix G.
The primary analysis of composite response rate will be based upon the ‘molecularly eligible 
centrally confirmed evaluable for response’ population. Additionally, composite response rate 
will also be provided for the 'evaluable for response' population. Percentage of participants 

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will be accompanied with a 2-sided 80% confidence interval as obtained from a Clopper-
Pearson test.
Secondary Endpoint(s)
Radiological Objective Response Rate
Radiological ORR is defined as the percentage of participants with a confirmed response of 
CR or PR in their soft tissue and visceral lesions assessed by RECIST 1.1 in the absence of 
bone progression assessed by PCWG3. The denominator is the number of participants in the 
evaluable for response set. The soft tissue ORR and overall radiological ORR will be 
summarised descriptively.
Duration of Radiological Response
Similar to Cohort A, duration of radiological objective response is defined as the time from 
the date of first documented response until date of objective radiologic disease progression or 
death. Descriptive data will be provided for the duration of response in responding 
participants, including the associated Kaplan-Meier estimate of median duration of response, 
where there are sufficient number of responders.
Percentage change in tumour size
Percentage change in tumour size will be summarised descriptively, as described for 
Cohort A.
CTC Count conversion
Conversion of CTC count are defined as a conversion from unfavourable at baseline 
(≥5/7.5 mL blood) to favourable post-baseline (< 5/7.5 mL blood). Post-baseline result should 
be confirmed with a second consecutive value obtained 3 or more weeks later. The percentage 
of participants with CTC count conversion based on those with unfavourable CTC at baseline, 
will be presented for this study.
Confirmed PSA Decline
Proportion of participants with a PSA decline of > 50% confirmed by a second consecutive 
measurement at least 3 weeks later.
Radiological PFS (rPFS) 
rPFS is defined as the time from the start of treatment until the date of objective radiographic 
disease progression or death.

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Participants who have not progressed (ie, who have a CR, PR or SD by RECIST 1.1, and non-
progressive disease by PCWG-3) at the time of analysis will be censored at the time of the 
latest date of their last evaluable RECIST 1.1 assessment or bone scan assessment that showed 
fewer than 2 new lesions. However, if the 2 or more consecutive scheduled radiographic 
assessments immediately prior to progression or death were not evaluable, the participant will 
be censored at the time of the latest evaluable RECIST 1.1 and bone scan assessment prior to 
the 2 or more missed assessments. If the participant has no evaluable visits or does not have 
baseline data, he will be censored at Day 1 unless he dies within 2 visits of baseline (in which 
case the participant’s date of death will be used). The rPFS time will always be derived based 
on scan/assessment dates, not visit dates. When the investigator is in doubt as to whether 
progressive disease has occurred and therefore reassesses the patient at a later date, the date of 
the initial scan should be declared as the date of progression if the repeat scans confirm 
progression.
Analyses of rPFS will be based upon the 'molecularly eligible centrally confirmed' population. 
Kaplan-Meier plots of rPFS will be presented. Summaries will include the median rPFS with 
respective CIs calculated using the Kaplan-Meier technique. Summaries will also provide the 
number and percentage of participants experiencing a rPFS event, and the type of event 
(progression or death).
11.9.4.6
Biomarker Variables
The analyses of biomarker variables include, but are not limited to, 
. Change 
from baseline and percent change from baseline for biomarker variables will be calculated for 
all participants.
11.9.5
Interim Analyses 
11.9.5.1
Cohort A
An administrative interim analysis will be conducted approximately 4 months after 
approximately 18 molecularly eligible centrally confirmed evaluable for response participants 
dosed at ceralasertib 160mg BID have been enrolled. The assessment of key efficacy and 
safety will be performed. The purpose for administrative interim is to inform internal decision 
making only with no planned adaptions to the study.
11.9.5.2
Cohort B
A futility interim analysis will also be conducted approximately 6 months after at least 12 
molecularly eligible centrally confirmed evaluable for response participants have been 
enrolled dosed at ceralasertib 160mg BID. The futility stopping rule for the prostate cohort 
will be based on the primary endpoint, composite response. AstraZeneca may decide to cease 
recruitment for the prostrate cohort at the interim analysis if there are ≤2 responders out of 12 
molecularly eligible and centrally confirmed participants. This stopping rule is for guidance 
CCI

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only, and any decision to cease recruitment will be based on sponsor review of all safety and 
efficacy clinical data available. Further details will be provided in the SAP.

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11.10
REFERENCES - MODULE 1
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with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a 
phase III trial for advanced gastric or gastroesophageal adenocarcinoma: the V-325 study 
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Alderton et al, 2004
Alderton GK, Joenje H, Varon R, Børglum AD, Jeggo PA, and O’Driscoll M. Seckel 
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Cimprich and Cortez 2008
Cimprich KA, Cortez D. ART: an essential regulator of genome integrity. Nat Rev Mol Cell 
Biol 2008;9:616-27.
De Bono et al, 2020
TALAPRO-1: A Phase 2 Study of Talazoparib in Men With DNA Damage Repair Mutations 
and Metastatic Castration-resistant Prostatae Cancer – June 2019 Interim Analysis. ASCO GU 
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Dillon et al, 2017
A Phase I dose-escalation study of ATR inhibitor monotherapy with AZD6738 in advanced 
solid tumors (PATRIOT Part A). AACR 2017.
Dillon et al, 2019
A Phase I study of ATR inhibitor, AZD6738, as monotherapy in advanced solid tumours 
(PATRIOT Part A, B). ESMO 2019.
Eder et al, 2019
Abstract A080: Olaparib and the ATR inhibitor AZD6738 in relapsed, refractory cancer 
patients with homologous recombination (HR) repair mutations – OLAPCO; AACR-NCI-
EORTC International Conference on Molecular Targets and Cancer.
Grasso et al, 2012
Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The 
mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012 Jul 
12;487(7406):239-43.
Kim et al, 2013
Kim HS, Kim MA, Hodgson D, Harbron C, Wellings R, O'Connor MJ, et al. Concordance of 
ATM (ataxia telangiectasia mutated) immunohistochemistry between biopsy or metastatic 

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tumor samples and primary tumors in gastric cancer patients. Pathobiology. 2013;80(3):127-
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Min A, Im SA, Jang H, Kim S, Lee M, Kim DK, et al. AZD6738, A Novel Oral Inhibitor of 
ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells. Mol Cancer 
Ther. 2017 Apr;16(4):566-577.
Murai et al, 2012
Murai J, Huang SYN, Das BB, Renaud A, Zhang Y, Doroshow JH et al. Trapping of PARP1 
and PARP2 by clinical PARP inhibitors. Cancer Res 2012;72:5588-5599.
Murga et al, 2011
Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R, Montaña MF et al. 
Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven 
tumours. Nat Struct. Mol Biol 2011;18(12):1331-1335.
NCI 2006
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Prostate Cancer Treatment, 2020
Prostate Cancer Treatment (PDQ) – Health Professional Version. National Cancer Institute. 
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Prostate Cancer Treatment, 2019
Prostate Cancer Treatment (PDQ) – Patient Version. National Cancer Institute. 2002-2019 Jun 
12.
Reaper et al, 2011
Reaper PM, Griffiths MR, Long JM, Charrier JD, Maccormick S, Charlton PA et al. Selective 
killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol 
2011;7(7):428-30.
SEER Stats
SEER Stat Fact Sheets: Prostate Cancer. National Cancer Institute. 
https://seer.cancer.gov/statfacts/html/prost.html 
Smith et al, 2020
Niraparib in Patients With Metastatic Castration-resistant Prostate Cancer (mCRPC) and 
Biallelic DNA-repair Gene Defects (DRD): Correlative Measure of Tumor Response in the 
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Thompson et al, 2005
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Thuss et al, 2011
Thuss-Patience P C, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, et al. Survival 
advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric 
cancer – A randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie 
(AIO). European J Cancer 2011;47:2306-2314.
Toledo et al, 2011
Toledo LI, Murga M, Zur R, Soria R, Rodriguez A, Martinez S et al. A cell-based screen 
identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat 
Struct. Mol Biol 2011;18:721-727.
Wassim Abida et al, 2018
ESMO 2018, Preliminary results from triton2: a phase 2 study of rucaparib in patients (pts) 
with metastatic castration-resistant prostate cancer (MCRPC) associated with homologous 
recombination repair (HRR) gene alterations.
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12
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
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 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
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.
A 1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Section 11.1.3 and Sections 11.8.1 to 11.8.7. Local and regional regulations 
and/or guidelines regarding reconsent of study participants should be checked and followed. 
Reconsent may be verbal if allowed by local and regional guidelines (note, in the case of 
verbal reconsent the ICF should be signed at the participant’s next contact with the study site). 
Visiting the study sites for the sole purpose of obtaining reconsent should be avoided. 
A 2
Rescreening of Participants To Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
AstraZeneca study physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with IP. If this delay 
is outside the screening window specified in Section 11.1.3 the participant will need to be 
rescreened to reconfirm eligibility before commencing study procedures. This will provide 
another opportunity to rescreen a participant in addition to that detailed in Section 11.5.4. The 
procedures detailed in Section 11.5.1.1 must be undertaken to confirm eligibility using the 
same randomization number as for the participant.

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A 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified healthcare professional from the study site or third party vendor service will visit 
the participants home/or other remote location as per local standard of procedures, as 
applicable. Supplies will be provided for a safe and efficient visit. The qualified healthcare 
professional will be expected to collect information per the CSP.
A 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the participants 
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow adverse events, concomitant medication to be reported and 
documented.
A 5
At-home or Remote Location IP Administration Instructions
If a site visit is not possible, at-home or remote location administration of IP may be 
performed by a qualified healthcare professional, provided this is acceptable within local 
regulation/guidance, or by the participant or his/her caregiver. The option of at-home or 
remote location IP administration ensures participants safety in cases of a pandemic where 
participants may be at increased risk by traveling to the site/clinic. This will also minimize 
interruption of IP administration during other study disruptions, eg, site closures due to natural 
disaster.
A 5.1
At-home or Remote Location IP Administration by the Participant or 
His/Her Caregiver
Prior to at-home or remote location IP administration the investigator must assess the 
participant or his/her caregiver to determine whether they are appropriate for at-home or 
remote location administration of IP. Once the participant 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 IP 
administration will be provided. More information related to the visit can be obtained via a 
telemedicine or home / remote visit.
A 6
Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified
healthcare professional from the study site or third party vendor service, or by the participant
themselves.

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Appendix B
Regulatory, Ethical, and Study Oversight Considerations
B 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an Institutional Review Boards 
(IRB)/Independent Ethics Committees (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 participants.

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.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilising medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it and will notify the IRB/IEC, if appropriate according to local 
requirements.
B 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 

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are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
B 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.

Participants 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. Participants or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study centre.

The medical record must include a statement that written informed consent was obtained 
before the participant 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.

Participants 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 participant or the participant’s legally 
authorised representative.

Please refer to individual modules for specific details.

For Module 1, the screening will have 2 parts, Part 1 and Part 2. Part 1 will confirm 
molecular eligibility and Part 2 will confirm study eligibility.
Participants who are rescreened are required to sign a new 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 participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants 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. 
B 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant 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 participant in the informed consent 

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
The participant 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.
B 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators.
B 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the 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.
B 7
Data Quality Assurance

All participant 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 physically or 
electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

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, 
Contract Research Organisations).

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 participants 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 20 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 

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destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
B 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the eCRF or 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.

Source data may include, but is not limited to: medical history and physical examination 
notes, hospital discharge summary, autopsy report when available, results of relevant 
diagnostic tests completed.
B 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 
participants.
The first act of recruitment is the first participant enrolled 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 participants by the investigator

Discontinuation of further study intervention 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 participant 
and should assure appropriate participant therapy and/or follow-up.

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Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
B 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a co-ordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix C
New York Heart Association
C 1
New York Heart Association Functional Classification
NYHA
Symptoms 
I
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnoea (shortness of breath).
II
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnoea (shortness of breath).
III
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, or dyspnoea.
IV
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any 
physical activity is undertaken, discomfort increases.
Abbreviation: NYHA=New York Heart Association.
C 2
References
Criteria Committee of the New York Heart Association, 1994
The Criteria Committee of the New York Heart Association. (1994). Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels (9th ed.). Boston: Little, 
Brown & Co. pp. 253–256.

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Appendix D
Guidelines Regarding Potential Interactions of Ceralasertib 
with Concomitant Medications
Restrictions regarding drugs affection CYP3A metabolism
There are currently no data confirming that there is a pharmacokinetic (PK) interaction 
between these agents and ceralasertib; a potential interaction is considered on the basis of 
preclinical and in vitro data only. Ceralasertib is predominantly eliminated via CYP3A 
metabolism, therefore CYP3A inhibitors or inducers may increase or decrease exposure to 
ceralasertib, respectively. Potent inhibitors or inducers of CYP3A should not be combined 
with ceralasertib. In vitro data also suggest that ceralasertib may be metabolised by CYP2C8 
but a lesser extent, therefore caution should be applied with co-administration of potent 
inhibitors or inducers of CYP2C8.
These lists are not intended to be exhaustive, and similar restrictions will apply to other agents 
that are known to modulate CYP3A or CYP2C8 activity. Please contact AstraZeneca with any 
queries you have on this issue. Please refer to full prescribing information for all drugs prior to 
co-administration with ceralasertib. 

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Table 14
Drugs Known to be Inhibitors of CYP3A4
Potent CYP3A inhibitors
Potent CYP3A inducers
Boceprevir
Ceritinib
Clarithromycin
Cobicistat (GS-9350)
Conivaptan
Danoprevir / RIT
Elvitegravir / RIT
Grapefruit juicea
Idelalisib
Indinavir
Indinavir /RIT
Itraconazole
Ketoconazole
LCL161
Lopinavir / RIT
Mibefradil
Mifepristone
Nefazodone
Nelfinavir
Posaconazole
Ribociclib
Ritonavir
Saquinavir
Saquinavir / RIT
Telaprevir
Telithromycin
Tipranavir/RIT
Troleandomycin
VIEKIRA PAK2b
Voriconazole
Apalutamide
Avasimibe
Carbamazepine
Enzalutamide
Ivosidenib
Lumacaftor
Mitotane
Phenobarbital
Phenytoin
Rifampin
Rifapentine
St John's Wort extract
a
Double-strength grapefruit juice. Participants should abstain from eating large amounts of grapefruit and 
Seville oranges (and other products containing these fruits e.g., grapefruit juice or marmalade) during the 
study (e.g., no more than a small glass of grapefruit juice [120 mL] or half a grapefruit or 1-2 teaspoons 
[15 g] of Seville orange marmalade daily).
b
VIEKIRA PAK = 150/100 mg paritaprevir/ritonavir + 25 mg ombitasvir + 800 mg dasabuvir for 28 days. 
List created using the University of Washington Drug-Drug Interaction Database July 2019.  
RIT=Ritonivir. Ritonavir has dual effects of simultaneous CYP3A inhibition and induction, and the net 
pharmacokinetic outcome during chronic ritonavir therapy is inhibition of CYP3A activity 

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Table 15
Drugs Known to be Inhibitors and Inducers of CYP2C8
Potent CYP2C8 inhibitors
Potent CYP2C8 inducers
Gemfibrozil
Clopidogrel
None identified
List created using the University of Washington Drug-Drug Interaction Database Jan 2020.
Drugs known to be inhibitors or inducers of Pgp and/or BCRP, undertake appropriate 
monitoring if co-administration is necessary
Ceralasertib is a substrate of Pgp and BCRP. Co-administration of Pgp inhibitors/inducers or 
BCRP inhibitors/inducers may affect exposure to AZD6738 therefore it is recommended that 
these are not co-administered with ceralasertib.
These lists are not intended to be exhaustive, and similar restrictions will apply to other agents 
that are known to modulate Pgp activity or BCRP activity. Please contact AstraZeneca with 
any queries you have on this issue. Please refer to full prescribing information for all drugs 
prior to co-administration with ceralasertib.
Table 16
Drugs Known to be Inhibitors or Inducers of P-gp
Drugs Known to be Inhibitors of Pgp
Drugs Known to be Inducers of Pgp
Alogliptin
Amiodarone
Asian ginseng (Panax ginseng)
Asunaprevir
AZD5672
azithromycin
Canagliflozin
Captopril
Carvedilol
Clarithromycin
Clopidogrel
Cobicstat
Conivaptan
Cremophor EL
Cremophor RH
Curcumin
Daclatasvir
Daclatasvir/asunaprevir/beclabuvir
Diltiazem
Diosmin
Dronedarone
Apalutamide
Avasimibe
Carbamazepine
Danshen (Salvia miltiorrhiza)
Efavirenz
Genistein
Green tea
Phenytoin
Quercetin
Rifabutin
Rifampin
Ritonavir
St. John's wort extract 
Tivantinib

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Drugs Known to be Inhibitors of Pgp
Drugs Known to be Inducers of Pgp
Elagolix
Eliglustat
Erythromycin
Felodipine
Five-flavor berry (schisandra chinensis)
Flibanserin
Fluvoxamine
Fostamatinib
Ginkgo
Glecaprevir/pibrentasvir
Indinavir 
Indinavir/ritonavir
Isavuconazole
Itraconazole
Ivacaftor
Ketoconazole
Lapatinib
Lopinavir/ritonavir
Mibefradil
Mifepristone
Milk thistle
Mirabegron
Nelfinavir
Neratinib
Nifedipine
Nitrendipine
Osimertinib
Paritaprevir/ritonavir/ombitasvir
Paroxetine
Piperine
Propafenone
Quercetin
Quinidine
Quinine
Ranolazine
Rifampin
Ritonavir
Rolapitant
Rucaparib
Saquinavir/ritonavir
Sarecycline

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Drugs Known to be Inhibitors of Pgp
Drugs Known to be Inducers of Pgp
Simeprevir
Sofosbuvir/velpatasvir/voxilaprevir
St. John's wort extract
Surfactant TPGS
Suvorexant
Talinolol
Telithromycin
Telaprevir
Telmisartan
Tezacaftor/ivacaftor
Ticagrelor
Tipranavir/ritonavir
Tolvaptan
Valbenazine
Valspodar (PSC 833)
Vandetanib
Velpatasvir
Vemurafenib
Verapamil
Voclosporin
Vorapaxar
Table 17
Drugs Known to be Inhibitors or Inducers of BCRP
Drugs Known to be Inhibitors of BCRP
Drugs Known to be inducers of BCRP
Afatinib 
Aripiprazole 
Curcumin 
Cyclosporine 
Elacridar 
Erlotinib 
Fluvastatin 
Fumitremorgin 
Gefitinib 
Ivermectin 
Lapatinib 
Nilotinib 
Novobiocin 
Pantoprazole 
Pitavastatin 
Please check individual drugs on a case-by-case basis 

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Drugs Known to be Inhibitors of BCRP
Drugs Known to be inducers of BCRP
Ponatinib 
Quercetin 
Quizartinib 
Rabeprazole 
Regorafenib 
Rilpivirine 
Sulfasalazine 
Sunitinib 
Tacrolimus 
Teriflunomide 
Trametinib 
Trifluoperazine 
Vismodegib
eltrombopag
Atazanavir
Lopinavir
Ritonavir
Tipranavir
Omeprazole
Estrone
17b-estradiol
Imatinib mesylate
List created using http://dmd.aspetjournals.org/content/dmd/43/4/490 full.pdf
Note: Although BCRP is involved in a number of clinically relevant drug-drug interaction, none of the cited 
inhibitors above is truly specific for this transporter
Drugs known to be substrates of CYP3A4 and/or CYP2B6, undertake appropriate 
monitoring if co-administration is necessary 
Ceralasertib is a potential inducer of CYP3A4 and CYP2B6. Therefore, caution should be 
applied with co-administration of drugs that are either completely metabolised by CYP3A4 
and/or CYP2B6, or that are substrates of CYP3A4 and/or CYP2B6 and also have a narrow 
therapeutic index. Investigators should be aware that the exposure of other drugs metabolised 
by CYP3A4 and/or CYP2B6 may be reduced.
Table 18
Drugs Known to be Metabolised by CYP3A4 and/or CYP2B6 and Have 
a Narrow Therapeutic Index
Metabolised by CYP3A4
and with a narrow therapeutic index
Metabolised by CYP2B6
and with a narrow therapeutic index
Alfentanil 
Bupropion

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Metabolised by CYP3A4
and with a narrow therapeutic index
Metabolised by CYP2B6
and with a narrow therapeutic index
Astemizole
Cisapride
Cyclosporine 
Diergotamine 
Ergotamine 
Fentanyl
Pimozide 
Quinidine 
Sirolimus 
Tacrolimus 
Terfenadine
Efavirenz
List created using the University of Washington Drug-Drug Interaction Database October 2019.
Note: This is not an exhaustive list.
Drugs known to be substrates of OATP1B1 and BCRP, undertake appropriate 
monitoring if co-administration is necessary 
Ceralasertib is also an inhibitor of OATP1B1 and BCRP. Caution should be applied with 
co-administration of substrates of OATP1B1 and/or BCRP as ceralasertib may increase their 
exposure.
These lists are not intended to be exhaustive and appropriate medical judgement is required. 
Please contact AstraZeneca with any queries you have on this issue. Please refer to full 
prescribing information for all drugs prior to co-administration with ceralasertib.
Table 19
Drugs Known to be Substrates of OATP1B1
Docetaxel
Enalapril
Olmesartan 
Phalloidin
Repaglinide
Statins* 
Temocaprilat
Valsartan
* all statins 
List created using https://www.solvobiotech.com/transporters/OATP1B1, latest access Nov 2019
Table 20
Drugs known to be substrates of BCRP
Anthracyclines

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Chlorothiazide 
Daunorubicin
Doxorubicin
Imatinib
Irinotecan
Methotrexate
Mitoxantrone
Nucleoside analogs
Pantoprazole
Prazosin
SN-38
Topotecan
Teriflunomide 
Rosuvastatin
List created using https://www.solvobiotech.com/transporters/bcrp, latest access Nov 2019

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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 Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal Product 
(IMP). 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Serious Adverse Events (SAEs) and Adverse Events (AEs) according to the 
outcome of the review and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥2 x ULN at any point during the study 
following the start of study intervention irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥3 x ULN together with TBL ≥2 x ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 

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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
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 participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥3 x ULN

AST ≥3 x ULN

TBL ≥2 x ULN
Local laboratories being used:
The investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Determine whether the participant meets PHL criteria (see Section E 2 Definitions 
within this Appendix 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 participant does not meet PHL criteria the investigator will:

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 participant 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 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting

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
For participants that met PHL criteria prior to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the participant’s 
condition

The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data

Subsequent to this contact the investigator will:

Monitor the participant 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. For studies using a central laboratory add: This 
includes deciding which the tests available in the Hy’s Law lab kit should be used.

Complete the 3 Liver eCRF Modules as information becomes available 
#A ‘significant’ change in the participant’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms. The 
determination of whether there has been a significant change will be at the discretion of the 
investigator, this may be in consultation with the Study Physician if there is any uncertainty.
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 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met. The AstraZeneca Medical Science Director 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:

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
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

If the alternative explanation is an AE/SAE: update the previously submitted 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 IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to study 
intervention 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 Treatment 
This section is applicable to participants with liver metastases who meet PHL criteria on study 
treatment, having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment 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 participant 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 
treatment and at their first on study treatment visit as described in section 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 participant’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 participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation 
or in combination, or a clinically relevant change in associated symptoms. The determination 
of whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.
E 8
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.

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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
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST 1.1 (Response Evaluation Criteria in Solid 
Tumours)
Introduction
This appendix details the implementation of RECIST (Response Evaluation Criteria in Solid 
Tumours) 1.1 guidelines (Eisenhauer et al, 2009) for the study with regards to investigator 
assessment of tumour burden including protocol-specific requirements for this study.
Assessment of Disease using RECIST 1.1
Definition of Measurable, Non-measurable, Target and Non-target Lesions
Participants with at least one lesion (measurable and/or non-measurable) that can be 
accurately assessed at baseline by computerised tomography (CT), magnetic resonance 
imaging (MRI) or plain X-ray should be included in this study.
Measurable lesions
A lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in 
the longest diameter (except lymph nodes which must have a short axis ≥15 mm with CT or 
MRI and which is suitable for accurate repeated measurements).
Non-measurable lesions

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥10 mm to < 15 mm short axis at baseline). Nodes with < 10 mm short 
axis are considered non-pathological and should not be recorded as non-target lesions 
(NTLs)

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural / pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that are not measurable by CT or MRI

Previously irradiated lesions as localised post-radiation changes, which affect lesion sizes, 
may occur. Therefore, lesions that have been previously irradiated will not be considered 
measurable and should be selected as NTLs at baseline and followed up as part of the 
NTL assessment

Skin lesions assessed by clinical examination 

Brain metastasis

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Special cases

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
can be considered measurable if the soft tissue component meets the definition of 
measurability. Blastic lesions are considered non-measurable.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in the 
same participant, these non-cystic lesions should be selected as the target lesions (TLs).
Target lesions
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline.
Non-target lesions
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.
Methods of Measurement
The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up.
The methods to be used for RECIST assessment are summarised in Table 21 and those 
excluded for tumour assessments in this study are discussed below, with the rationale 
provided.
Table 21
Summary of Methods of Assessment
Target Lesions
Non-target Lesions
New Lesions
CT (preferred)
CT (preferred)
CT (preferred)
MRI
MRI
MRI
Plain X-ray (includes chest X-ray)
Plain X-ray (includes chest X-ray)
Clinical examination
Clinical examination
Ultrasound
Bone scan
FDG-PET

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CT and MRI
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TLs selected for response assessment and to assess NTLs and 
identification of new lesions.
In this study it is recommended that CT examinations will be used to assess tumour burden at 
baseline (including assessment of brain lesions at baseline in participants with no known brain 
metastases) and follow-up visits. CT examination with intravenous contrast media 
administration is the preferred method. MRI should be used where CT is not feasible, or it is 
medically contraindicated, for pre-existing brain metastases, and when there is a clinical 
suspicion of brain metastases.
Clinical examination
Clinical examination will not be used for assessment of TLs. Clinically detected lesions can be 
selected as TLs if they are then assessed by CT or MRI scans. Clinical examination can be 
used to assess NTLs in participants that also have other lesions assessable by CT, MRI or 
plain X-ray and to identify the presence of new lesions.
X-rays
Plain X-ray
Plain X-rays may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions.
Chest X-ray
Chest X-rays will not be used for assessment of TLs as they will be assessed by CT or MRI 
examination. Chest X-rays can, however, be used to assess NTLs and to identify the presence 
of new lesions.
Ultrasound
Ultrasound examination will not be used for assessment of TLs and NTLs as it is not a 
reproducible method, does not provide an accurate assessment of tumour size and it is 
subjective and operator dependent. Ultrasound examination can, however, be used to identify 
the presence of new lesions. If new clinical symptoms occur and an ultrasound is performed, 
then new lesions should be confirmed by CT or MRI examination.

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Endoscopy and laparoscopy
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour measurements.
Tumour markers
Tumour markers will not be used for tumour response assessments per RECIST 1.1.
Cytology and histology
Histology will not be used as part of the tumour response assessment per RECIST 1.1. 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease (SD). In such circumstances, the cytology is necessary to differentiate between 
response / SD (an effusion may be a side effect of the treatment) and progressive disease (if 
the neoplastic origin of the fluid is confirmed). Where cytology findings are not available, any 
effusion that significantly worsens (from trace to large) or the appearance of a clinically 
significant effusion (requiring change in drug therapy) during the study treatment will be 
considered to be progression of NTLs or disease progression due to new lesions.
Isotopic bone scan
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or 
X-ray at baseline should be recorded as NTLs and followed by the same method as per 
baseline assessment.
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. New lesions will be recorded where a positive hot-spot that 
was not present on the baseline bone scan assessment is identified on a bone scan performed 
at any time during the study. The investigator should consider the positive hot-spot to be a 
significant new site of malignant disease and represent true disease progression in order to 
record the new lesion. Confirmation by CT, MRI and X-ray is recommended where bone scan 
findings are equivocal.
FDG-PET scan
FDG-PET (fluorodeoxyglucose positron emission tomography) scans may be used as a 
method for identifying new lesions, according with the following algorithm: New lesions will 
be recorded where there is positive FDG uptake (defined as when an uptake greater than twice 
that of the surrounding tissue is observed) not present on baseline FDG-PET scan or in a 
location corresponding to a new lesion on CT/MRI at the same follow-up visit. If there is no 
baseline FDG-PET scan available, and no evidence of new lesions on CT/MRI scans then 

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follow-up CT/MRI assessments should be continued, scheduled as per protocol or clinical 
indicated, in order to confirm new lesions.
Tumour response evaluation
Schedule of evaluation
Baseline tumour assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual participants and should be performed according to 
the respective schedule of activities until objective radiographic disease progression is 
registered according to the protocol requirements or withdrawal of consent. Any other sites at 
which new disease is suspected should also be adequately imaged at follow-up.
Target lesions
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved, should be identified as TLs at baseline. 
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions) but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimetres. At baseline, the sum of the diameters for all TLs will be calculated and reported 
as the baseline sum of diameters. At follow-up visits the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.
Special cases:

For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis.

If the CT/MRI slice thickness used is > 5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 0 mm.

If a TL splits into 2 or more parts, then record the sum of the diameters of those parts.

If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for one of the lesions and 0 mm recorded for the other lesion(s).

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
If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion.

When a TL has had any intervention eg, radiotherapy, embolisation, surgery etc., during 
the study, the size of the TL should still be provided where possible.
Evaluation of target lesions
Table 22 provides the definitions of the criteria used to determine objective tumour visit 
response for TLs.
Table 22
Overall Visit Response for Target Lesions
Complete Response (CR) 
Disappearance of all TLs since baseline. Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to < 10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of diameters of TLs, taking as
reference the baseline sum of diameters.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD.
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as
reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 
5 mm.
Not Evaluable (NE)
Only relevant if any of the TLs were not assessed or not evaluable or 
had a lesion intervention at this visit.
Note: If the sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL response.
Non-Target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. At each visit, an overall assessment of the NTL response should be 
recorded by the investigator. Table 23 provides the definitions of the criteria used to determine 
and record overall response for NTLs at the investigational site at each visit.

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Table 23
Overall Visit Response for Non-Target Lesions
Complete Response (CR) 
Disappearance of all NTLs since baseline. All lymph nodes must be 
non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD
Persistence of one or more NTLs.
Progressive Disease (PD)
Unequivocal progression of existing NTLs. Unequivocal progression 
may be due to an important progression in one lesion only or in several 
lesions. In all cases the progression MUST clinically significant for the 
physician to consider changing or stopping therapy.
Not Evaluable (NE)
Only relevant when one or some of the NTLs were not assessed and in 
the investigator’s opinion they are not able to provide an evaluable 
overall NTL assessment at this visit.
Note: For participants without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression criteria 
have not been met.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.
New Lesions
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed. If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.

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Tumour response data for participants with ‘symptomatic deterioration’ which required 
discontinuation of study treatment and without objective radiographic disease progression 
according to the protocol requirements will be censored at the date of their last RECIST 
assessment.
Evaluation of Overall Visit Response and Best Overall Response
The overall visit response will be derived using the algorithm shown in Table 24.
Table 24
Overall Visit Response
Target Lesions
Non-target lesions
New Lesions
Overall response
CR 
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
NE
No
PR
PR
Non-PD or NE
No
PR
SD
Non-PD or NE
No
SD
NA
Non-CR/Non-PD
No
SD (Non-CR/Non-PD)
NE
Non-PD or NE
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR=complete response; IR=incomplete response; NA=not applicable (relevant when no 
TLs/NTLs at baseline); NE=not evaluable; PD=progressive disease; PR=partial response; SD=stable disease.
Specifications for Radiological Imaging
These notes are recommendations for use in clinical studies. The use of standardised protocols 
for CT and MRI allows comparability both within and between different studies, irrespective 
of where the examination has been undertaken.
CT Scan
CT scans of the chest, abdomen, and pelvis should be contiguous throughout all the 
anatomical regions of interest. 

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The most critical CT image acquisition parameters for optimal tumour evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
Anatomic coverage
Optimal anatomic coverage for most solid tumours is the chest, abdomen and pelvis.
Coverage should encompass all areas of known predilection for metastases in the disease 
under evaluation and should additionally investigate areas that may be involved based on 
signs and symptoms of individual participants. Because a lesion later identified in a body part 
not scanned at baseline would be considered as a new lesion representing disease progression, 
careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points. This will enable better consistency not only of tumour 
measurements but also identification of new disease.
Intravenous contrast administration
Optimal visualisation and measurement of metastases in solid tumours requires consistent 
administration (dose and rate) of intravenous contrast as well as timing of scanning. Typically, 
most abdominal imaging is performed during the portal venous phase and (optimally) about 
the same time frame after injection on each examination. An adequate volume of a suitable 
contrast agent should be given so that the metastases are demonstrated to best effect and a 
consistent method is used on subsequent examinations for any given participant. It is very 
important that the same technique be used at baseline and on follow- up examinations for a 
given participant. For participants who develop contraindications to contrast after baseline 
contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or non-
enhanced) should be performed should also be based on the tumour type, anatomic location of 
the disease and should be optimised to allow for comparison to the prior studies if possible. 
Each case should be discussed with the radiologist to determine if substitution of these other 
approaches is possible and, if not, the participant should be considered not evaluable from that 
point forward. Care must be taken in measurement of TLs on a different modality and 
interpretation of non-target disease or new lesions, since the same lesion may appear to have a 
different size using a new modality. Oral contrast is recommended to help visualise and 
differentiate structures in the abdomen.
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study, then the recommended methods are: CT thoracic examination without 
contrast and abdominal and pelvic MRI with contrast. If MRI cannot be performed then CT 
without intravenous contrast is an option for the thorax, abdomen and pelvic examinations. 

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Slice thickness and reconstruction material
It is recommended that CT scans be performed at 5 mm contiguous slice thickness and this 
guideline presumes a minimum 5 mm thickness in recommendations for the measurable lesion 
definition. Exceptionally, particular institutions may perform medically acceptable scans at 
slice thicknesses greater than 5 mm. If this occurs, the minimum size of measurable lesions at 
baseline should be twice the slice thickness of the baseline scans.
All window settings should be included in the assessment, particularly in the thorax where 
lung and soft tissue windows should be considered. When measuring lesions, the TLs should 
be measured on the same window setting for repeated examinations throughout the study. All 
images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion.
MRI Scan
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement. Furthermore, the availability of MRI is variable globally. The modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. Generally, axial imaging of the abdomen and 
pelvis with T1 and T2 weighted imaging along with gadolinium-enhanced imaging should be 
performed. The field of view, matrix, number of excitations, phase encode steps, use of fat 
suppression and fast sequences should be optimised for the specific body part being imaged as 
well as the scanner utilised. It is beyond the scope of this appendix to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts and diseases. Ideally, the same type of 
scanner should be used, and the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-hold scanning techniques 
if possible.
For these reasons, CT is the imaging modality of choice.
FDG-PET scans
FDG-PET has gained acceptance as a valuable tool for detecting, staging and restaging several 
malignancies. If FDG-PET scans are included in a protocol, an FDG uptake period of 60 min 
prior to imaging has been decided as the most appropriate for imaging of participants with 
malignancy. Whole-body acquisition is important since this allows for sampling of all areas of 
interest and can assess if new lesions have appeared thus determining the possibility of 
interval progression of disease. Images from the base of the skull to the level of the mid-thigh 
should be obtained 60 min post injection. PET camera specifications are variable and 
manufacturer specific, so every attempt should be made to use the same scanner, or the same 

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model scanner, for serial scans on the same participant. Whole-body acquisitions can be 
performed in either 2- or 3-dimensional mode with attenuation correction, but the method 
chosen should be consistent across all participants and serial scans in the clinical study.
PET/CT scans
At present, low dose or attenuation correction CT portions of a combined PET–CT are of 
limited use in anatomically based efficacy assessments and it is therefore suggested that they 
should not be substituted for dedicated diagnostic contrast enhanced CT scans for tumour 
measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
performed as part of a PET–CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast) then the CT portion of the PET–CT can be used for RECIST measurements. 
However, this is not recommended because the PET portion of the CT introduces additional 
data that may bias an investigator if it is not routinely or serially performed.
F 1
REFERENCES
Eisenhauer et al, 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European 
Journal of Cancer 2009;45:228-247.

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Appendix G
Guidelines for Evaluation of Objective Tumour Response 
Using PCWG3 (Prostate Cancer Working Group Criteria 3) 
in Bone Lesions
Introduction
This appendix details the implementation of PCWG3 guidelines (Scher et al 2016) for the 
study with regards to assessment of tumour burden including protocol-specific requirements 
for this study.
Assessment of Bone Lesions Progression Using PCWG3 Criteria
Bone lesions will be assessed by bone scan and will not be part of the RECIST v1.1 malignant 
soft tissue assessment.
Method of Assessment
Bone lesions identified on a whole-body isotopic bone scan at baseline should be recorded and 
followed by the same method as per baseline assessment.
In this study isotopic bone scans will be used as a method of assessment to identify the 
presence of new bone lesions at follow-up visits. New lesions will be recorded where a 
positive and unequivocal hot-spot that was not present on the baseline bone scan assessment is 
identified on a bone scan performed at any time during the study. The investigator should 
consider the positive hot-spot to be a significant new site of malignant disease and represent 
true disease progression in order to record the new lesion.
Tumour progression evaluation
Schedule of the evaluation
Baseline assessments should be performed no more than 28 days before the start of study 
intervention. Follow-up assessments will be performed according to the respective schedule of 
activities until objective radiographic disease progression as defined by RECIST 1.1 (soft 
tissue) or PCWG3 (bone). 
If an unscheduled assessment was performed and the participant has not progressed, every 
attempt should be made to perform the subsequent assessments at their originally scheduled 
visits. This schedule is to be followed in order to minimise any unintentional bias caused by 
some participants being assessed at a different frequency than other participants.

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Documentation of lesions
All bone lesions (or sites of disease) should be identified at baseline. Their status should be 
followed at subsequent visits. At each visit an overall assessment of the bone lesion 
progression should be recorded by the investigator. This section provides the definitions of the 
criteria used to determine and record bone progression at the investigational site at each visit.
Progression on a bone scan is identified using PCWG3 as follow:

At the 8 week scan:
2 or more new metastatic bone lesions are observed on the first 8-week scan compared to 
the baseline assessment. The confirmatory scan, performed at least 6 weeks later and 
preferably no later than the next scheduled visit for a bone scan (ie, Week 16), must show 
2 or more additional new metastatic bone lesions (for a total of 4 or more new metastatic 
bone lesions since the baseline assessment) for progression to be documented.
Note - The first bone scan completed after baseline will be considered the ‘8-week scan’ 
regardless if taken at week 8 or at an unscheduled assessment.

After the 8 week scan:
2 or more new metastatic bone lesions are observed compared to the 8week assessment. 
The confirmatory scan, performed at least 6 weeks later and preferably at the next 
scheduled visit for a bone scan, must show the persistence of or an increase in the number 
of metastatic bone lesions compared to the prior scan for progression to be documented.
The date of progression is the date of the scan that first documents the second lesion.
Evaluation of bone progression status
Table 25 provides the definitions for the visit bone progression status for bone lesions.
Table 25
Bone Progression Status
Non-Progressive Disease (Non-PD)
No evidence of progression, or appearance of one new bone lesion, 
or non-fulfilment of the progression criteria including new lesions 
without confirmation of progression.
Progressive Disease (PD)
Bone lesions fulfilling the requirements for at least 2 new lesions 
and confirmation of progression.
Not Evaluable (NE)
Only relevant if a follow-up bone scan is not performed.

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Overall radiological visit assessment in prostate cancer. 
Table 26 provides the definitions for how the visit responses for soft tissue (according to 
RECIST 1.1 criteria) and bone progression status (according to PCWG3 criteria) are 
combined to give an overall radiological objective visit response.
Table 26
Overall Radiological Visit Response
Overall visit soft 
tissue response 
(RECIST 1.1)
Bone progression 
status (PCWG3)
Bone lesions at visit 
Present/Absent
Overall radiological 
visit response
CR
Non-PD
Absent
CR
CR
Non-PD
Present
PR
CR
NE
-
PR
PR
Non-PD or NE
Any
PR
SD
Non-PD or NE
Any
SD
NED
Non-PD or NE
Any
Non-PD
NE
Non-PD or NE
Any
NE
PD 
Any
Any
PD
Any
PD
Any
PD
Abbreviations: CR=complete response; IR=incomplete response; NE=not evaluable (only relevant if a follow-up 
bone scan is not performed), NED=No Evidence of Disease (only relevant when there is no TL and NTL from 
baseline); PD=progressive disease; PR=partial response; SD=stable disease.
Confirmation of response
In this study, imaging for confirmation of response (CR or PR) should be performed at the 
next scheduled RECIST and PCWG3 assessment (and must not be less than 4 weeks later) 
following the date the criteria for response were first met.
Table 27
Best Overall Response When confirmation of CR and PR Required
Overall radiological 
response first time point
Overall radiological 
response subsequent time 
point
Best overall response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD or PD
CR
PD 
SD or PD
CR
NE
SD or NE 
PR
CR
PR

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Overall radiological 
response first time point
Overall radiological 
response subsequent time 
point
Best overall response
PR 
PR
PR
PR
SD
SD
PR
PD
SD or PD
PR
NE
SD or NE
NE
NE
NE
Abbreviations: CR=complete response; NE=not evaluable; PD=progressive disease; PR=partial response; 
SD=stable disease.
a
if a CR is truly met at first time point, then any disease seen at subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD was met. However, sometimes 
‘CR’ may be claimed when subsequent scan suggest small lesions were likely still present and in fact the 
participant had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR.
G 1
REFERENCES
Scher et al 2016
Scher HI, Morris MJ, Stadler WM et al. Trial design and objectives for castration-resistant 
prostate cancer: Updated recommendations from the Prostate Cancer Clinical Trials Working 
Group 3. J Clin Oncol 34 (2016).

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Appendix H
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
H 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a participant or 
clinical study participant 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.
H 2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-participant 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 participant or may require medical 
treatment to prevent one of the outcomes listed above
Adverse Events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed 
and reported as a Non-Serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
Serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalisation, may be assessed as Non-Serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy.

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The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 
is being treated by the IP 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 participant 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 
participant’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 a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant 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 and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse

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Intensity rating scale:
mild (awareness of sign or symptom, but easily tolerated)
moderate (discomfort sufficient to cause interference with normal activities)
severe (incapacitating, with inability to perform normal activities)
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 H 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 H 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 H 2.
The grading scales found in the revised National Cancer Institute CTCAE latest version will 
be utilised for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
H 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 participant 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.

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In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With 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.
H 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 intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

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Examples of events that do not require reporting as medication errors in clinical studies:

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open-label studies, even if an 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 I
Handling of Human Biological Samples
I 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 
participants 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 for the 
remainder of the sample life cycle.
I 2
Withdrawal of Informed Consent for donated biological samples 
If a participant withdraws study consent samples collected from the participant 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.
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, 
and the action documented and study site notified.
I 3
International Airline Transportation Association (IATA) 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 

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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 UN3373 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 J
Optional Genomics Initiative Sample
J 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 blood sample and tissue samples will be collected for DNA analysis from 
consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant´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.

The samples will be retained while research continues but no longer than 15 years or 
other period as per local requirements.
J 2
Genetic research plan and procedures
Selection of genetic research population

All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study.
Inclusion criteria
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol 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:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection

Healthy Volunteers and paediatric participant samples will not be collected for the 
Genomics Initiative.

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Withdrawal of consent for genetic research:  

Participants 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.
Collection of samples for genetic research

The blood sample for this genetic research will be obtained from the participants at on 
Cycle 1 Day 1. Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding participants who may withdraw due to an adverse 
event (AE). If for any reason the sample is not drawn on Cycle 1 Day 1, it may be taken 
at any visit until the last study visit. Only one sample should be collected per participant 
for genetics during the study.

Details of sample collection, processing, shipping and storage are described in the 
Laboratory Manual.
Coding and storage of DNA samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years, from the date of last participant 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 participant enrolment code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory 
audit, and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements

The principles for ethical and regulatory requirements for the study, including this 
genetics research component, are outlined in Appendix B.
Informed consent

The genetic component of this study is optional and the participant 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 participant must sign and date both 

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the consent form for the main study and the optional genetic research consent form. 
Copies of both signed and dated consent forms must be given to the participant and the 
original filed at the study centre. The Principal investigator(s) is responsible for ensuring 
that consent is given freely and that the participant understands that they may freely 
withdrawal from the genetic aspect of the study at any time.
Participant data protection

AstraZeneca will not provide individual genotype results to participants, 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 participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, an AstraZeneca Physician or an 
investigator might know a participant’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’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 
participant 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.

The results of this pharmacogenetic research will be reported separately and will not form 
part of the CSR.

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Appendix K
ATM Alterations Classification Guidance
ATM Classification Algorithm
for Definition of Qualifying Alterations
(based on Lynparza HRR Classification Algorithm v2)
K 1
Introduction
This appendix describes the genomic alterations in the ATM gene that will be classified 
qualifying for the PLANETTE study (“A Modular Phase 2a Multicenter Open-Label Study to 
Investigate DNA-damage Response Agents (or Combinations) in Patients With Advanced 
Cancer Whose Tumours Contain Molecular Alterations”). These rules are based on Lynparza 
HRR classification algorithm (used in AstraZeneca clinical trials).
The appendix is made available for information purposes only. Use of this guidance outside 
the PLANETTE study is entirely at the investigator’s discretion.
This document contains 3 sections.  

Section K 1.1 describes the generic rules for determining qualifying mutations in ATM 
(EntrezID 472; RefSeq NM_000051).

Section K 1.2 describes a look-up list of qualifying mutations that do not meet the generic 
rules in section K 1.1.

Section K 1.3 describes the rationale and process for arriving at the qualifying mutations 
listed in section K 1.2.
K 1.1
Instructions for generic eligibility criteria for ATM 

Classification of variants will be conducted in accordance with the principles published in 
the American College of Medical Genetics and Genomics (ACMG) standards and 
guidelines for the interpretation of sequence variants (Richards et al 2015).

For clarification, only patients with “deleterious” or “suspected deleterious” variants will 
be considered qualifying within the PLANETTE study. Patients with variants of uncertain 
significance (VUS) will not be eligible.
The following algorithm implements the criteria specified above. If the variant meets any of 
the following criteria the patient is considered eligible for the study:

Mutations that result in truncation of the protein product, including:

Any nonsense mutations

Any frameshift indels

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
Any mutations in the consensus splice donor and acceptor sequence (5’ 
GT……intron…..AG 3’) that disrupts the consensus, including insertions and 
deletions

Large-scale genomic deletions (affecting at least one whole exon), insertions or 
rearrangements

Any homozygous deletion

Any missense, splice, nonsense, or short in frame deletions not captured by above but 
specified as deleterious, pathogenic, clinically important, suspected deleterious or 
suspected pathogenic in the BIC or ClinVar database, or by a validated Dx device, or 
known to be founder mutations in a given local region.

Any mutations not captured above but specified in the lookup table from Section K 1.2.
K 1.2
Special instructions for eligibility criteria for mutations ATM gene 
Any variant which does not meet the above generic eligibility criteria in Section K 1.1 should 
be queried against the variant look-up lists for special variants. If the variant is present in the 
separate look-up lists, the alteration is considered qualifying.
The current resultant lists are given below as Table 28 and Table 29 with numbering based on 
NM_000051 (ATM) transcript.
Table 28
Look-up List for Missense and Synonymous Variants
Table 29
Look-up List for Deleterious Intronic Variants

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K 1.3
Procedures used to generate the look-up tables in Section K 1.2
The following procedures were used to generate the static look-up tables with information 
ClinVar to complement the generic rules from Section K 1.1. The tables were locked down on 
11 Jan 2016 (based on a November 2015 extract from ClinVar).

The ClinVar database for variants in ATM was used with the following inclusion criteria:

In “Clinical significance”, with entries “pathogenic” or “likely pathogenic”.

And variant specified as missense, or synonymous, or intronic.

And in “Review status”, with the entry “expert panel”, which corresponds to the 3 
star rating as discussed with AstraZeneca, or 2 star rating with multiple consistent 
submission. The 4 star rating is a category called ‘Practice guideline’ that wasn’t 
available for any missense mutations in these genes.
K 2
References
Richards et al 2015
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines 
for the interpretation of sequence variants: a joint consensus recommendation of the American 
College of Medical Genetics and Genomics and the Association for Molecular Pathology. 
Genet Med. 2015;17(5):405-24.

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Appendix L
Abbreviations
Abbreviation or special 
term
Explanation
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine transaminase
ANC
Absolute neutrophil count
ANSM
Agence Nationale de Sécurité du Médicament et des Produits de Santé (French 
National Agency for Medicines and Health Products Safety)
ARID1A
AT-Rich Interaction Domain 1A
aST
Advanced Solid Tumours
AST
Aspartate transaminase
ATM
Ataxia telangiectasia mutated
ATR
Ataxia telangiectasia and rad3 related protein
BCRP
Breast cancer resistance protein
BICR
Blinded independent central review
BID
Twice daily
BMI
Body mass index
BP
Blood pressure
BRCA1
BReast CAncer gene 1
BRCA2
BReast CAncer gene 2
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CLIA
Clinical Laboratory Improvement Amendments
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials

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COPD
Chronic obstructive pulmonary disease
COVID-19
Coronavirus disease 2019
CPT
Common Protocol Template
CR
Complete response
CrCl
Creatinine clearance
CRO
Clinical Research Organisation
CSF
Cerebrospinal fluid
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computerised tomography
CTA
Clinical Trial Applications
CTC
Circulating tumour cell
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P
DCO
Data Cut Off
DDR
DNA-damage response
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DoR
Duration of response
DRD
DNA-Repair gene Defects
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
CCI
CCI

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EMA
European Medicines Agency
ESR
Externally Sponsored Research 
EU
European Union
FAS
Full Analysis Set
FDA
The Food and Drug Administration
FDG
Fluorodeoxyglucose
FFPE
Formalin fixed and paraffin embedded
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HCV
Hepatitis C virus
HGSOC
High-grade serous ovarian cancer
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HL
Hy’s Law
HR
Homologous recombination
HRR
Homologous recombination repair
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
IND
Investigational New Drug

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INR
International normalized ratio
IRB
Institutional Review Board
IVRS
Interactive Voice/Web Response System
LHRH
Luteinizing hormone-releasing hormone
mCRPC
Metastatic castration-resistant prostate cancer
MRI
Magnetic resonance imaging
NE
Not evaluable
NGS
Next generation sequencing
NHA
Novel hormonal agent
NTRK
Neurotrophic tyrosine receptor kinase
ULN
Upper limit of normal
NSCLC
Non-small-cell lung carcinoma
NTL
Non-target lesions
OATP1B1
Organic anion transporter protein B1
ORR
Objective response rate
OS
Overall survival
PARP
Poly (ADP-ribose) polymerase
PCWG3
Prostate Cancer Working Group 3
PD
Progressive disease
PDc
Pharmacodynamic
PET
Positron emission tomography
PFS
Progression free survival
PHL
Potential Hy’s Law
Pgp
P-glycoprotein
PI
Principal investigator

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PIKK
Phosphoinositide-3-kinase related kinase
PK
Pharmacokinetic
PPS
Per Protocol Analysis Set
PR
Partial response
PR interval
The time from the onset of the P wave to the start of the QRS complex
PSA
Prostate specific antigen
QRS
A combination of the Q wave, R wave and S wave, the QRS complex
RECIST
Response Evaluation Criteria in Solid Tumours
RNA
Ribonucleic acid
RPA
Replication Protein A
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SCHNN
Squamous cell carcinoma of the head and neck
SD
Stable disease
SE
Standard error
SMPC
Summary of product characteristics
SoA
Schedule of activities
SoC
Standard of care
SUSAR
Suspected unexpected serious adverse reactions
TBL
Total bilirubin
TL
Target lesions
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
US
United States

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UV
Ultraviolet
QT interval
The time from the start of the Q wave to the end of the T wave
QTcF
The corrected QT interval (QTc) according to Fridericia's formula
WBDC
Web Based Data Capture
WHO
World Health Organization
WOCBP
Women of childbearing 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 3 (04-Apr-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:
Preliminary data (Yap et al. Cancer Discov. 2021;11(1):80-91.) showed that patients with 
either ATM mutation, or ATM protein loss, or both had benefit on an ATR inhibitor. In 
Module 1 we used an arbitrary 60% threshold for the minimum number of patients with ATM 
protein loss. However, there is no robust justification for this threshold, and it is impeding 
recruitment, therefore we propose to remove the 60% threshold for both cohorts A and B. This 
amendment will not impact the primary analysis, and the subgroup analysis will still be 
conducted and patients’ tumor samples tested retrospectively.
Section # and Name
Description of Change
Brief Rationale 
Substantial/Non-
Substantial
MODULE 1 (Section 11) 
Ceralasertib Monotherapy in ATM Altered Advanced Solid Tumours (aST) and Prostate Cancer
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE Information
Deletion of the text “a participant has 
completed the study” and addition of 
text “last safety follow up visit"
to clarify 
collection of 
SAEs 
discontinues 
after safety 
follow up visit.
Non-substantial
11.1.1 M1 Synopsis, 
Number of Participants 
Cohort A
Deletion of text “ensuring at least 60% 
of participants with ATM IHC ≤ 5%”
Please see 
overall rationale
Substantial 
11.1.1 M1 Synopsis, 
Number of Participants 
Cohort B
Deletion of text “ensuring at least 60% 
of participants with ATM IHC ≤ 5%”
Please see 
overall rationale
Substantial
11.1.2 M1 Study Design
Deletion of footnote 2 “2 A minimum 
of 60% participants will be ATM IHC 
≤ 5% (ie n=15) in addition to having a 
deleterious or suspected deleterious (or 
pathogenic/likely pathogenic) mutation 
in the ATM gene. ATM ‘deficient’ is 
Please see 
overall rationale
Substantial

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defined as ATM IHC ≤ 5% ATM-
positive tumour nuclei using the 
Ventana assay (VENTANA ATM 
(Y170) RPA Assay)”
11.1.3 Schedule of 
Activities (SoA) Table 3, 
Footnote A
Addition of the text “If prospective 
central ATM NGS testing is 
introduced” and “must submit a 
sample”
Clarification 
that this relates 
to prospective 
NGS testing 
only
Non-substantial
11.1.3 Schedule of 
Activities (SoA) Table 3, 
Footnote E
Addition of the text “scheduled”
Clarification 
that 
 is 
only taken at 
scheduled 
assessments and 
at progression
Non-substantial
11.1.3 Schedule of 
Activities (SoA) Table 3, 
Footnote L
Addition of the text “All safety 
assessments and laboratory results 
must be reviewed by the Investigator or 
physician designee prior to start of 
each study treatment dosing cycle”
Clarification
Non-substantial
11.2 M1 Introduction
Deletion of the text “ensuring at least 
60% of participants with ATM IHC ≤ 
5%” and addition of text “Prospective 
selection of patients with ATM IHC ≤ 
5% may be introduced in each cohort 
based on emerging ATM protein 
deficiency prevalence and ceralasertib 
clinical activity”
Please see 
overall rationale
Substantial
11.2.1.2 Module Rationale, 
Prostate Cancer
Deletion of text “evaluating rucaparib 
in patients”
Typo
Non-substantial
11.4.1.1 Study Design 
Cohort A
Addition of the text “dosed at 
ceralasertib 160mg BID”
Clarification
Non-substantial
11.4.1.1 Study Design 
Cohort A
Deletion of the text “with prospective 
selection, if necessary, to ensure at 
least 60% of participants with ATM 
IHC ≤ 5%”
Please see 
overall rationale
Substantial
11.4.1.1 Study Design 
Cohort A (Figure 3)
Deletion of foot note 2 “2A minimum 
of 60% participants will be ATM IHC 
≤ 5% (ie n=15) in addition to having a 
see overall 
rationale
Substantial
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deleterious or suspected deleterious (or 
pathogenic/likely pathogenic) mutation 
in the ATM gene. ATM ‘deficient’ is 
defined as ATM IHC ≤ 5% ATM-
positive tumour nuclei using the 
Ventana assay (VENTANA ATM 
(Y170) RPA Assay)”
11.4.1.2 M1 Design, Cohort 
B
Addition of the text “dosed at 
ceralasertib 160mg BID”
Clarification
Non-substantial
11.4.1.2 Study Design 
Cohort B
Deletion of the text “ensuring at least 
60% of participants with ATM IHC ≤ 
5%”
see overall 
rationale
Substantial
11.4.1.2 Study Design 
Cohort B (Figure 4)
Deletion of the text “A minimum of 
60% participants will be ATM IHC ≤ 
5% (ie n=16) in addition to having a 
deleterious or suspected deleterious (or 
pathogenic/likely pathogenic) mutation 
in the ATM gene”
see overall 
rationale
Substantial
11.4.1.3 Confirmation of 
ATM Protein Expression 
and ATM Mutation Status
Deletion of the text “To ensure that a 
minimum of 60% participants will be 
ATM IHC ≤ 5% for each disease 
cohort (ie n=15 aST and n=16 prostate) 
by the time of the interim and final 
analyses, an additional enrolment 
criteria of ATM loss may be 
implemented. To enable this”
Additional text added to clarify that 
prospective testing may be introduced. 
The decision to trigger prospective 
participant selection may be based on 
preliminary data from subgroup 
analysis”
see overall 
rationale
Substantial
11.5.1.1 Inclusion Criteria 
Screening Part 1 (Molecular 
Eligibility)
Deletion of the text “if required to 
ensure a minimum 60% enrolled 
participants are ATM IHC deficient 
(defined as ATM protein staining ≤ 5% 
of tumour nuclei) by the time of 
interim analysis and final analysis in 
addition to ATM genetic alteration.
Prospective selection by ATM IHC 
will only be triggered after a maximum 
number of participants with ATM 
see overall 
rationale
Substantial

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protein staining of > 5% by IHC have 
been enrolled”
11.5.1.1 Inclusion Criteria, 
Screening Part 1 (Molecular 
Eligibility)
Addition of the text “if prospective 
ICH ATM testing is triggered, local 
ATM NGS test report must be 
provided”
Deletion of the text “Prospective ATM 
NGS central testing may be 
introduced”
Correction 
around 
provision of 
local ATM 
NGS tests
Non-substantial
11.5.1.1 Inclusion Criteria, 
Screening Part 1 (Molecular 
Eligibility)
Inclusion criterion #2 – Addition of the 
text to clarify details around ATM 
mutation
Clarification
Non-substantial
11.5.1.2 Inclusion Criteria, 
Screening Part 2 (Study 
Eligibility), Type of 
Participant and Disease 
Characteristics
Inclusion criterion #4(a) - Addition of 
the text “Participants already receiving 
erythropoietin at the time of screening 
for the study may continue it providing 
they have been receiving it for more 
than one month at the time study 
intervention is started” This text was 
moved from 
Section, 11.6.5, Concomitant Therapy, 
Supportive Care
Clarification
Non-substantial
11.5.1.3 Inclusion Criteria, 
Other, Cohort A- aST
Inclusion criterion #2 – Deletion of text 
“Specimens from bone biopsies”
Details to be 
added to lab 
manual 
allowing bone 
biopsies post 
validation
Non-substantial
11.5.1.4 Inclusion Criteria, 
Other, Cohort B - mCRPC
Inclusion criterion #2 – Deletion of text 
“Specimens from bone biopsies”
Details to be 
added to lab 
manual 
allowing bone 
biopsies post 
validation
Non-substantial
11.5.2 Exclusion Criteria 
(Cohort A and Cohort B), 
Medical Conditions
Exclusion criterion #1, 7th bullet point 
- Addition of text “28 days”
Correction of 
typo in CSP 
Amendment 02. 
Correct wording 
was in CSP 
Amendment 01
Non-substantial

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11.5.2 Exclusion Criteria 
(Cohort A and Cohort B), 
Medical Conditions
Exclusion criterion #4 – Addition of 
the text “if new asymptomatic brain 
metastases are discovered, an interval 
scan (minimum 4 weeks) should be 
conducted to confirm the new brain 
lesions are not progressing and do not 
require local CNS-directed therapy. If 
local treatment is necessary, this should 
occur before study entry”
Clarification 
around 
identification 
and 
management of 
asymptomantic 
brain mets
Non-substantial
11.5.2 Exclusion Criteria 
(Cohort A and Cohort B), 
Medical Conditions
Exclusion criterion #4a- Addition of 
the text “and direct factor Xa 
inhibitors”
Addition of 
class of drugs 
that can lead to 
INR elevation
Non-substantial
11.6.5 Concomitant 
Therapy
Deletion of text 
“Paracetamol/Acetaminophen, at doses 
of ≤2 grams/day, is permitted for use 
anytime during the study. Other 
concomitant medication may be 
considered on a case by case basis by 
the investigator in consultation with the 
Medical Monitor if required”
Removal of text 
from protocol 
template left in 
error
Non-substantial
11.6.5.1 Concomitant 
Therapy, Supportive Care
Moving of the text “Participants 
already receiving erythropoietin at the 
time of screening for the study may 
continue it providing they have been 
receiving it for more than one month at 
the time study intervention is started” 
to Section 11.5.1.2 Inclusion Criteria, 
Screening Part 2 (Study Eligibility), 
Type of Participant and Disease 
Characteristics
Deletion of the text “Prophylactic 
erythropoietin should not be started 
during Cycle 1 of the study, but may be 
started during Cycle 2 and after, 
following discussions with the 
Principal Investigator and 
AstraZeneca”
Movement of 
text -
clarification
Deletion of text 
- correction
Non-substantial
11.6.6.3 Individual 
Stopping Criteria, Hepatic
Addition of text “or other vitamin K 
antagonists, or direct factor Xa 
inhibitors”
Addition of 
class of drugs 
that can lead to 
INR elevation
Non-substantial

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11.7 Discontinuation of 
study Intervention and 
Participant 
Discontinuation/Withdrawal 
– Module 1
Addition of text “Patients may receive 
study intervention until objective 
disease progression, or as long as they 
are continuing to show clinical benefit, 
as judged by the investigator, or 
treatment discontinuation criteria are 
met”
Clarification of 
length of study 
treatment
Non-substantial
11.8.2 Module Assessments 
and Procedures- Module 1, 
Safety Assessments
Addition of text “For all participants, 
results of all safety assessments must 
be available and must be reviewed by 
the Investigator or their deputy prior to 
start of each dosing cycle. Samples can 
be collected the day before dosing 
cycle start. Prior to discharge from 
each in-patient and clinic visit, the 
Investigator or their deputy will be 
responsible for reviewing all available 
safety data, including vital signs and 
ECGs”
Clarification
Non-substantial
11.8.6.1 Human Biological 
Sample Biomarkers, 
Collection of Archival 
Tumour Samples
Deletion of text “Bone samples are 
inadequate for central testing”
Details to be 
added to lab 
manual 
allowing bone 
biopsies post 
validation
Non-substantial
11.9.2 Sample Size 
Determination Cohort A
Deletion of text “ensuring at least 60% 
of participants with ATM IHC ≤ 5%”
Addition of text “dosed at ceralasertib 
160mg BID”
see overall 
rationale
Substantial
11.9.2 Sample Size 
Determination Cohort B
Deletion of text “ensuring at least 60% 
of participants with ATM IHC ≤ 5%”
Addition of text “dosed at ceralasertib 
160mg BID”
see overall 
rationale
Substantial
11.9.2 Sample Size 
Determination
Deletion of text “It is intended to 
ensure at least 60% of participants have 
ATM IHC ≤ 5%, in order to have an 
adequate number of participants for 
exploration of efficacy in this subset”
see overall 
rationale
Substantial
11.9.4 Summary of 
Analyses and Data Cut-off 
Deletion of text “with at least 60% 
ATM IHC ≤5%)”
Please see 
overall rationale
Substantial

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Triggers Cohort A (Table 
13)
11.9.4 Summary of 
Analyses and Data Cut-off 
Triggers Cohort B (Table 
13)
Deletion of text “with at least 60% 
ATM IHC ≤5%)”
Please see 
overall rationale
Substantial
11.9.5.1 Interim Analyses 
Cohort A
Deletion of text “with at least 60% 
ATM IHC ≤5%”
Addition of text “dosed at ceralasertib 
160mg BID”
Please see 
overall rationale
Substantial
11.9.5.1 Interim Analyses 
Cohort B
Deletion of text “with at least 60% 
ATM IHC ≤5%”
Addition of text “dosed at ceralasertib 
160mg BID”
Please see 
overall rationale
Substantial
Throughout
Minor administrative changes
To correct 
errors in format, 
typography or 
language
Non-substantial
Amendment 2 (27-May-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. 

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Overall Rationale for the Amendment:
Inclusion of updates made for Amendment FRA-1, a local protocol amendment applicable in 
France that was prepared in response to queries from the French National Agency for 
Medicines and Health Products Safety (ANSM), to implement urgent safety measures (adding 
extra safety visits and reducing dose to 160 mg BID), 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
2.2 Background
Deletion of the text “This modular 
study will investigate the 
efficiency and tolerability of 
ceralasertib in patients with 
various molecular alterations”.
Module 1 specific text is not 
required in the Core section.
Non-substantial
4.1.3 Study 
Conduct 
Mitigation During 
Study Disruptions 
Due to Cases of 
Civil Crisis, 
Natural Disaster, 
or Public Health 
Crisis
Addition of new section/text 
relating to study disruption.
To allow greater flexibility 
for study conduct during 
current COVID-19 pandemic 
or other similar situations.
Substantial
5.1 Inclusion 
Criteria
Inclusion criterion 6 regarding 
ability to swallow tablets was 
moved to Module 1, Section 
11.5.1.2.
Future modules may not 
include tablets.
Non-substantial
7.1 
Discontinuation of 
Study Intervention
Text additions clarifying the 
situations for study intervention 
discontinuation.
Template text update. 
Non-substantial
7.2 Participant 
Withdrawal from 
the Study
Text describing procedure for 
withdrawal of consent for 
disclosure of future information 
and use of existing samples has 
been added.
Template text update. 
Non-substantial
Text describing modified follow-
up options was deleted.
This is not applicable to this 
study.
Non-substantial
Text describing a study 
intervention discontinuation visit 
was deleted.
Visit deleted as there is no 
such visit in the study.
Non-substantial
8.2.3 
Electrocardiograms
Text describing triplicate ECG 
recordings was added from 
Module 1 Section 11.8.2.3.
Generic screening ECG 
details retained in the Core 
section.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
8.3.1 Time Period 
and Frequency for 
Collecting AE and 
SAE Information
Text was amended to clarify that 
AEs will be collected throughout 
treatment period.
Clarification that AEs will 
be collected from start of 
study treatment period and 
not from screening.
Non-substantial
8.3.9.1 Maternal 
Exposure
The text was changed from 
“congenital abnormalities” to 
“congenital anomaly”.
Template text update.
Non-substantial
Throughout
Minor administrative changes.
This revision was made to 
correct errors in format, 
typography or language.
Non-substantial
MODULE 1 (Section 11):
Ceralasertib Monotherapy in ATM Altered Advanced Solid Tumours (aST) and Prostate Cancer
11.1.1 Synopsis
Number of participants was 
updated to include “Addition of 
the text “At the time of protocol 
amendment 2, 1 participant had 
been dosed at 240 mg BID in 
Cohort A, and 8 participants had 
been dosed at 240 mg BID in 
Cohort B. Following the reduction 
of the starting dose from 240 mg 
BID to 160 mg BID in protocol 
amendment 2, the intention is to 
enrol an additional total of ~25 and 
~27 participants in Cohort A and 
B, respectively, at the 160 mg 
BID”.
Clarification of sample size 
following dose reduction to 
160 mg BID.
Substantial
11.2 Schema
Figure 2 Module Design was 
updated to reflect the updated dose 
of 160 mg BID.
Update following dose 
reduction to 160 mg BID.
Substantial
11.1.3 Schedule of 
Activities
In Table 3 (Schedule of 
Activities), the time window for 
Cycle 2 Day 1 and from Cycle 3 
Day 1 onwards updated to “-1/+3 
days”.
Update allows for any 
required assessment results 
to be received.
Non-substantial
In Table 3 (Schedule of 
Activities), the time window for 
last dose of study intervention was 
updated from “± 7 days” to “+ 7 
days”.
There is no possibility of a 
time window prior to last 
dose.
Non-substantial
In Table 3 (Schedule of 
Activities), “Provide copy of local 
NGS testing report” was added.
Clarification of this 
requirement at screening.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
In Table 3 (Schedule of 
Activities), “Optional tumour 
sample” was added as a separate 
row.
Clarification of tumour 
sampling in SoA. Mandatory 
at screening and optional at 
last dose and follow-up. 
Optional samplings are not 
archival or standard of care.
Non-substantial
In Table 3 (Schedule of 
Activities), “Peripheral blood for 
 was moved up in order of 
appearance in the table.
To group together 
assessments performed at 
screening.
Non-substantial
In Table 3 (Schedule of 
Activities), addition of “triplicate” 
in the ECG assessment row for 
screening. Deletion of assessment 
timepoints during the study period.
Clarification that triplicate 
ECGs would be collected at 
screening only.
Substantial
In Table 3 (Schedule of 
Activities), addition of assessment 
time points for Cycle 1 Day 14 and 
Cycle 2 Day 14.
To confirm vital signs 
assessment during the 
treatment period.
Substantial
In Table 3 (Schedule of 
Activities), “Clinical safety 
laboratory assessments” was 
changed to “Complete blood count 
and other clinical safety laboratory 
assessments”.
Clarification.
Non-substantial
In Table 3 (Schedule of 
Activities), “Serum testosterone 
(not required in participants after 
bilateral orchiectomy) and PSA (if 
no radiographic progression, local 
assessment” was added. 
Clarification of this 
requirement as per inclusion 
criteria for Cohort B.
Non-substantial
In Table 3 (Schedule of 
Activities), footnote d for ECG 
was deleted as no longer required. 
Subsequent footnote numbering 
was updated.
Footnote is no longer 
required.
Non-substantial
In Table 3 (Schedule of 
Activities), additional Day 8 visits 
were added for Cycle 1 and 
Cycle 2.
Precautionary monitoring of 
safety assessments related to 
≥ G3 thrombocytopenia or ≥ 
G3 neutropenia.
Substantial
Footnotes were updated, including 
re-numbering.
Clarification.
Non-substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
11.2 Introduction –
Module 1
Text was updated from “ATM 
IHC  ≥5%” to “ATM IHC  >5%”.
Definition should be more 
than 5% (not equal or more).
Non-substantial
Text was updated to include 
“Definitions of qualifying ATM 
mutations include 
deleterious/suspected deleterious, 
pathogenic/likely pathogenic, 
disease, or cancer-associated 
variants. Variants or unknown 
significance or benign variants are 
not eligible for enrolment”.
Clarify definition of ATM 
mutations.
Non-substantial
11.2.1 Module 
Rationale
Text was updated from “Ataxia 
telangiectasia and rad3 related 
protein…” to “Ataxia 
telangiectasia mutated protein 
loss..”.
Updated to reflect the 
description of ataxia 
telangiectasia.
Non-substantial
Text was added to describe further 
details of the first in human ATR 
inhibitor study.
IRB request.
Non-substantial
11.2.1.2 Prostate 
Cancer
Text was added “The concept of 
synthetic lethality of DDR 
inhibitors in DDR-deficient 
backgrounds has been explored 
clinically in mCRPC: PARPi have 
been used in BRCA1/2 mutations
and HRR mutations, including 
ATM mutations.” to replace the 
original text “Targeted next 
generation sequencing of advanced 
prostate cancer has identified an 
8% incidence of ATM mutations 
(Beltran et al, 2013 and Choi et al, 
2016).”
Clarity in the description of 
BRCA mutations.
Non-substantial
11.2.2.2 Disease 
Linkage
Text was deleted “...a rare, 
autosomal recessive disorder that 
leads to progressive 
neurodegeneration (cerebellar 
ataxia), orbital telangiectasia, 
immunodeficiency..”
To aid clarity and flow.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
11.3 Objectives 
and Endpoints –
Module 1
In Table 5 (Objectives and 
Endpoints – Cohort A), one of the 
secondary endpoints/variables was 
reworded to remove the details 
regarding the urinalysis and 
coagulation.
These parameters are not 
collected during the study. 
Non-substantial
In Table 5 (Objectives and 
Endpoints – Cohort A), one of the 
secondary endpoints/variables was 
reworded to remove the details 
regarding ECG.
ECG is not an 
endpoint/variable in the 
study.
Non-substantial
In Table 5 (Objectives and 
Endpoints – Cohort A), the 
exploratory objective for
 
 
”.
Clarification.
Non-substantial
In Table 6 (Objectives and 
Endpoints – Cohort B), the 
primary objective was reworded to 
remove the details regarding the 
previous treatments of participants.
To align objectives with the 
revised Inclusion Criterion 3 
for Cohort B. 
Non-substantial
In Table 6 (Objectives and 
Endpoints – Cohort B), addition of 
a secondary endpoint//variable 
“Duration of radiological 
response”.
Consistency since it is also 
listed in the statistics section.
Non-substantial
In Table 6 (Objectives and 
Endpoints – Cohort B), one of the 
secondary endpoints/variables was 
reworded to remove the details 
regarding the urinalysis and 
coagulation.
These parameters are not 
collected during the study. 
Non-substantial
In Table 6 (Objectives and 
Endpoints – Cohort B), one of the 
secondary endpoints/variables was 
reworded to remove the details 
regarding ECG.
ECG is not an 
endpoint/variable in the 
study.
Non-substantial
CCI
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
In Table 6 (Objectives and 
Endpoints – Cohort B), addition of 
the exploratory endpoints/variables 
“
 
 
 
 
 
 
”.
For consistency since it is 
also listed in the statistics 
section.
Non-substantial
In Table 6 (Objectives and 
Endpoints – Cohort B), the 
exploratory endpoint/variable for 
 
 
 
Non-substantial
In Table 6 (Objectives and 
Endpoints – Cohort B), the 
exploratory objective for 
 
 
Clarification.
Non-substantial
In Table 6 (Objectives and 
Endpoints – Cohort B), the 
exploratory endpoint/variable for 
 
 was added. 
Clarification to be consistent 
with the objective.
Non-substantial
11.4.1.1 Cohort A
Figure 3 Study Design was 
updated to reflect the updated dose 
of 160 mg BID.
Update following dose 
reduction to 160 mg BID.
Substantial
11.4.1.2 Cohort B
For Figure 4 (Study Design –
Cohort B) the footnote was 
updated with “in addition to 
having a deleterious or suspected 
deleterious mutation in the ATM 
gene”.
For consistency with the 
footnote for Figure 3 (Study 
Design – Cohort A).
Non-substantial
Figure 4 Study Design was 
updated to reflect the updated dose 
of 160 mg BID.
Update following dose 
reduction to 160 mg BID.
Substantial
11.4.1.3 
Confirmation of 
ATM Protein 
Expression and 
Section 11.8.3.3 was moved from 
“Human biological samples” to 
“Study design” as a new 
subsection.
To aid clarity since the 
description of ATM 
expression and mutation 
confirmation is part of the 
study design.
Non-substantial
CCI
CCI
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
ATM Mutation 
Status
The text description was updated 
to better describe the process for 
confirming ATM protein 
expression and ATM mutation 
status. Text was also updated to 
define qualifying ATM mutations.
Clarification.
Non-substantial
The text “This may only be 
implemented in the study after the 
7th participant in the aST cohort or 
the 4th participant in prostate 
cancer cohort has been enrolled 
and is positive for ATM protein 
staining of > 5% by IHC” was 
deleted.
To allow flexibility for study 
conduct.
Non-substantial
11.4.3 Justification 
for Dose
The whole section was updated to 
include a description of the change 
in dose from 240 mg BID to 
160 mg BID.
To implement urgent safety 
measures including reducing 
dose to 160 mg BID.
Substantial
11.5.1 Inclusion 
Criteria
Addition of the text “All 
participants must submit blood and 
FFPE tumour samples for central 
confirmation of ATM mutation 
and ATM IHC testing”.
Clarification that submission 
of a tumour sample is 
required for central 
confirmation even if the 
participant has a local NGS 
report available.
Non-substantial
11.5.1.1 Screening 
Part 1 (Molecular 
eligibility)
Addition of text describing 
requirements for local ATM NGS 
testing. Also confirming that all 
participants must submit a FFPE 
tumour sample for central NGS 
and IHC confirmation. Prospective 
ATM NGS testing may be 
introduced.
Clarification of the 
requirements for Screening 
Part 1.
Non-substantial
Screening Part 1 Inclusion 
Criterion 2 was revised to specify 
that eligible participants have 
deleterious or suspected 
deleterious ATM mutation in 
tumour or blood.
To allow participants with 
germline mutations to avoid 
local testing of the tumour.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Screening Part 1 Inclusion 
Criterion 2 was revised to include 
“Definitions of qualifying ATM 
mutations include 
deleterious/suspected deleterious, 
pathogenic/likely pathogenic, 
disease, or cancer-associated 
variants. Variants or unknown 
significance or benign variants are 
not eligible for enrolment”.
Clarify definition of ATM 
mutations.
Non-substantial
Screening Part 1 Addition of a new 
inclusion criterion regarding 
tumour sample for central 
confirmation of ATM mutation 
and ATM IHC testing.
For clarity, existing text in 
the section was moved 
down/edited and added to 
the list of criteria.
Substantial
11.5.1.2 Screening 
Part 1 (Study 
eligibility)
Screening Part 2 Inclusion 
Criterion 1 was revised to specify 
that eligible patients should have 
no standard treatment available.
Revision was requested by 
ANSM because early phase 
clinical trials should enrol 
participants without 
therapeutic alternatives.
Substantial
11.5.1.3 Cohort A -
aST
Cohort A – aST Inclusion 
Criterion 2 was revised to include 
“The site needs to refer to the 
pathology manual for acceptable 
tissue types for testing. Specimens 
from bone biopsies and fine needle 
aspirates are not acceptable.”
For clarity in terms of 
acceptable tissue types for 
testing.
Non-substantial
11.5.1.4 Cohort B -
mCRPC
Cohort B – mCRPC Inclusion 
Criterion 2 was revised to include 
“The site needs to refer to the 
pathology manual for acceptable 
tissue types for testing. Specimens 
from bone biopsies and fine needle 
aspirates are not acceptable.”
For clarity in terms of 
acceptable tissue types for 
testing.
Non-substantial
Cohort B – mCRPC Inclusion 
Criterion 3 was revised to specify 
that eligible patients should have 
received at least one taxane 
regimen (unless the participant has 
contraindications to taxanes).
Requested by ANSM.
Substantial
Cohort B – mCRPC Inclusion 
Criterion 7 was revised to add 
“(not required for participants after 
bilateral orchiectomy)”.
For clarity.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
11.5.2 Exclusion 
Criteria
Exclusion Criterion was added 
under medical conditions to 
exclude participants with INR 
≥1.5 (except those who receive 
vitamin K antagonists) or with 
other evidence of impaired hepatic
synthesis function. 
Requested by ANSM for 
consistency with Individual 
Stopping Criteria.
Substantial
11.6.1 Study 
Intervention 
Administered
Table 7 Investigational Products 
was updated to include the change 
for dose from 240 mg twice daily 
to 160 mg twice daily. A footnote 
was also added to clarify the 
change and additional information.
To implement urgent safety 
measures including reducing 
dose to 160 mg BID.
Substantial
11.6.5 
Concomitant 
Therapy
Text was added to detail anti-
cancer therapies not allowed 
during the study.
To specify in more detail the 
allowed anti-cancer 
treatments during the study.
Non-substantial
11.6.6.2 Guidance 
for Dose 
Modification and 
Interruption
Additional test was added 
“Participants with ≥ G3 anaemia, 
neutropenia, thrombocytopenia 
during Cycle 1 and Cycle 2 will be 
required to attend for additional 
Day 8 and Day 14 assessments 
until there is no evidence of ≥ G3 
anaemia, neutropenia, 
thrombocytopenia for at least 2 
cycles. Participants who develop a 
≥ G3 anaemia, neutropenia, 
thrombocytopenia later in their 
treatment, will also need to have 
additional Day 8 and Day 14 
assessments until there is no 
evidence of ≥ G3 anaemia, 
neutropenia, thrombocytopenia for 
at least 2 cycles”. 
Precautionary monitoring of 
safety assessments related to 
≥ G3 anaemia, neutropenia, 
and thrombocytopenia.
Substantial
Table 8 was updated to include 
instructions to specify that 
treatment must be stopped after 
2 occurrences of Grade 4 non-
haematological toxicities. 
Requested by ANSM.
Substantial

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Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Table 9 Dose Reduction Levels for 
Ceralasertib was updated to 
include the change for dose from 
240 mg twice daily to 160 mg 
twice daily. A footnote was also 
added to clarify the change and 
additional information.
To implement urgent safety 
measures including reducing 
dose to 160 mg BID.
Substantial
11.6.6.3 Individual 
Stopping Criteria
This sub-heading was moved up to 
include the “Cardiovascular” 
subheading under it.
For clarity of text.
Non-substantial
11.6.7 Intervention 
after the End of the 
Study
Possibility to continue treatment 
after the end of the study was 
added.
Requested by ANSM.
Substantial
Additional detail describing the 
possibility of an extension study 
was added.
Template text update.
Non-substantial
11.8.1.2 Bone 
lesions assessment 
in Cohort B 
(mCRPC) (Based 
on PCWG3 
Criteria)
In Table 10 (Requirements for 
Documentation of Progression), 
the “Week 8 scan” and 
“Subsequent scans” visit time 
windows were updated. Minor 
updates for criteria for bone 
progression definitions.
Clarification of time 
windows for assessments.
Non-substantial
Text describing
 
 
was added from Section 
11.8.6 “Human Biological Sample 
Biomarkers” to Section 11.8.1.2.
For clarity since both are 
efficacy assessments and to 
clarify between clinical and 
.
Non-substantial
11.8.2.3 
Electrocardiograms
Text describing triplicate ECG 
recordings at Screening Part 2 was 
moved to Core Section 8.2.3.
To keep the generic 
screening ECG details in the 
Core section.
Non-substantial
11.8.2.5 Brain 
Scan
Text describing the brain scan 
process was re-ordered. 
To aid clarity and flow.
Non-substantial
11.8.2.6 Clinical 
Safety Laboratory 
Assessments
In Table 11 (Laboratory safety 
variables), footnote c was added to 
confirm that “Coagulation and 
urinalysis are only scheduled for 
baseline and as clinically indicated 
post-baseline”.
To clarify collection of 
coagulation and urinalysis at 
baseline only.
Non-substantial
11.8.5.2 
Pharmacodynamics
Addition of the text “This sample 
may also be used to assess 
.”
Clarification.
Non-substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
11.8.6.1 Collection 
of Archival 
Tumour Samples
Collection of archival tumour 
samples was moved under Section 
11.8.6 Human Biological Sample 
Biomarkers and updated to remove 
“decalcified samples” and add 
“Bone samples are inadequate for 
central testing”.
Bone biopsies are not 
suitable for IHC.
Non-substantial
11.8.6.3 Collection 
of Exploratory 
 
 
Text was added to differentiate 
that these are exploratory 
 
samples.
To clarify the clinical 
 
samples (efficacy) and these 
exploratory 
 samples.
Non-substantial
11.9.2 Sample Size 
Determination
Addition of the text “At the time 
of protocol amendment 2, 1 
participant had been dosed at 240 
mg BID in Cohort A, and 8 
participants had been dosed at 240 
mg BID in Cohort B. Following 
the reduction of the starting dose 
from 240 mg BID to 160 mg BID 
in protocol amendment 2, the 
intention is to enrol an additional 
total of ~25 and ~27 participants in 
Cohort A and B, respectively, at 
the 160 mg BID”.
Clarification of sample size 
following dose reduction to 
160 mg BID.
Substantial
11.9.3 Population 
for Analyses
In Table 12 (Population for 
Analysis) updates to description 
text for CTC count and inclusion 
of a footnote defining molecularly 
eligible centrally confirmed.
To clarify the description of 
population sets regarding 
CTC count and to clarify 
what is considered 
molecularly eligible 
centrally confirmed.
Non-substantial
11.9.4 Statistical 
Analyses
In Table 13 (Summary of Analyses 
and Data Cut-off Triggers) 
addition of “evaluable for 
response” when describing 
molecularly eligible participants.
To clarify the definition of 
participants as molecularly 
eligible centrally confirmed 
evaluable for response 
participants.
Non-substantial
11.9.4.1 General 
Considerations
Text was updated to confirm data 
presentation for safety and efficacy 
data.
To clarify that only 160 mg 
BID data will be presented 
in summary efficacy tables. 
All other information will be 
included in the listings.
Non-substantial
CCI
CCI
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Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
11.9.4.2 Safety
Text was updated to removed 
“ECG changes” from safety 
analysis.
ECG is not an 
endpoint/variable in the 
study.
Non-substantial
11.9.4.3 
Pharmacokinetic 
Variables
Text was updated to delete 
“Pharmacokinetic analysis of the 
plasma concentration data for 
study intervention will be the 
responsibility of Covance.” 
To remove specific details of 
laboratories which will be 
documented separately.
Non-substantial
11.9.4.5 Efficacy
Addition of text description under 
secondary endpoints for 
“Percentage Change in Tumour 
Size”.
For consistency between 
listed endpoints/variables in 
Section and the statistical 
Section 11.3.
Non-substantial
Throughout.
Clarifying the description of the 
mutation in the ATM gene 
throughout from “deleterious 
mutation” to “deleterious or 
suspected deleterious mutation”.
To include participants with 
suspected deleterious 
mutations in addition to 
participants with deleterious 
mutations.
Non-substantial
Update of “AST” to “aST” for 
advanced solid tumours.
To clarify the abbreviations 
for advanced solid tumour 
(aST) and aspartate 
transaminase (AST).
Non-substantial
Minor administrative changes.
To correct errors in format, 
typography or language.
Non-substantial
Appendix A 
Changes Related to 
Mitigation of 
Study Disruptions 
Due to Cases of 
Civil Crisis, 
Natural Disaster, 
or Public Health 
Crisis
Addition of appendix relating to 
study disruption.
To describe processes during 
the current COVID-19 
pandemic or other similar 
situations.
Substantial
Appendix H 
Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, 
Follow-up, and 
Reporting
Under Section H2, the text was 
changed from “congenital 
abnormalities” to “congenital 
anomaly”.
Template text update.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Appendix G 
Guidelines for 
Evaluation of 
Objective Tumour 
Response Using 
PCWG3 (Prostate 
Cancer Working 
Group Criteria 3) 
in Bone Lesions
Minor update of Table 27 title 
from “Best Overall Response 
When confirmation of CR and TR 
Required” to “Best Overall 
Response When confirmation of 
CR and PR Required”.
Typographical correction.
Non-substantial
Appendix K ATM 
Alterations 
Classification 
Guidance
An appendix was created to 
provide details on the rules for 
qualifying ATM mutations.
To provide clarification for 
ATM  mutation definitions.
Substantial 
Appendix M
Protocol 
Amendment 
History
An appendix was created to 
include summary of changes of 
previous amendments.
This appendix is required per 
template when amending the 
protocol more than once.
Non-substantial
Amendment 1 (12-August-2020)
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:
Table 8 has been updated to add clarity on the management of neutropenia, anaemia and 
prolonged or intolerable Grade 2 toxicity.
Section # 
and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
11.6.6.2, 
Guidance for 
Dose 
Modification 
and 
Interruption, 
Table 8.
Addition of 
“discontinuations” to table 
title.
To clarify that that the table provides 
guidance for dose modifications, 
interruption and discontinuations for 
ceralasertib.
Substantial
Addition of definition for 
prolonged Grade 2 toxicity.
To provide greater clarification for the 
management of Grade 2 toxicity.
Substantial
Addition of “Grade 2” for 
thrombocytopenia” under 
Grade 2 events.
To provide greater clarification for the 
management of Grade 2 neutropenia and 
Grade 2 thrombocytopenia.
Substantial
Addition of “Grade 3-4 
neutropenia or Grade 4 
anaemia” under Grade 3-4 
toxicity 
To provide greater clarification for the 
management of Grade 3 neutropenia and 
anaemia.
Substantial

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D5339C00001 Clinical Study Protocol Amendment 4
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