A Randomised, Open-Label, Phase 2 Study of Ceralasertib Monotherapy and Ceralasertib Plus Durvalumab in Patients With Unresectable or Advanced Melanoma and Primary or Secondary Resistance to PD-(L)1 Inhibition
Phase: PHASE2
Conditions: Melanoma
Sponsor: AstraZeneca

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Clinical Study Protocol - Amendment 3 
Ceralasertib, Durvalumab - D533AC00001 
AstraZeneca 
CONFIDENTIAL AND PROPRIETARY 

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Clinical Study Protocol 
Study Treatment
Ceralasertib, Durvalumab
Study Code
D533AC00001
Version
Amendment 3
Date
17 December 2024
EudraCT Number
2021-001722-21
EU CT Number
2024-512378-91
MONETTE: A Randomised, Open-Label, Phase 2 Study of 
Ceralasertib Monotherapy and Ceralasertib plus Durvalumab in 
Patients with Unresectable or Advanced Melanoma and Primary 
or Secondary Resistance to PD-(L)1 Inhibition 
Sponsor Name: AstraZeneca AB
Legal Registered Address: AstraZeneca AB, S-151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s):
European Union Clinical Trials (EU CT) Number: 2024-512378-91
European Clinical Trials Database (EudraCT) Number: 2021-001722-21
Investigational New Drug Number: 152571
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: D533AC00001
Amendment Number: Amendment 3
Study Treatment: Ceralasertib monotherapy or ceralasertib plus durvalumab
Study Phase: 2
Version Scope: Global
Short Title: MONETTE: A Phase 2 Study of Ceralasertib Monotherapy and Ceralasertib Plus 
Durvalumab in Patients with Unresectable or Advanced Melanoma and Resistance to PD-(L)1
Inhibition

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Acronym: MONETTE
Study clinical lead: AstraZeneca study physician name and contact information will be 
provided separately
International co-ordinating investigator: PPD
PPD
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 3
17-December-2024
Amendment 2
14-March-2022
Amendment 1
01-July-2021
Original Protocol
13-May-2021
Amendment 3
This modification is considered to be substantial based on the criteria set forth in Regulation 
(EU) No 536/2014 of the European Parliament.
Overall Rationale for the Amendment:
The clinical study protocol (CSP) Amendment 2, dated 14-March-2022, has been updated to 
include new Reference Safety Information in line with the Investigator’s Brochure (IB) update 
and clarification has been added for the planned safety data collection in the Post-trial Access 
Program. Further, the duration of contraception after the last dose of study treatment was 
updated to align with the Sponsor’s drug safety recommendations. In addition, requirements 
from the EU Regulation No 536/2014 were consolidated into the global protocol to create a 
single, unified document. Minor formatting and editorial corrections are not presented in this 
summary.
Summary of Changes:
List of Substantial Modifications 
Section Number and Name
Description of Change
Brief Rationale
Section 2.3.1 Risk Assessment
Table 4 Risk Assessment 
In the description of risks 
associated with ceralasertib 
treatment, fatigue/asthenia were 
added to the list of identified risks 
and MDS/AML were added to the 
list of potential risks. 
To align with ceralasertib IB, 
edition 13, dated 
18 September 2024. 
Selection criteria were not 
required to be updated in the 
context of these risks because the 
study is no longer recruiting 
patients.
AML = acute myeloid leukaemia; IB = Investigator’s Brochure; MDS = myelodysplastic syndrome.

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List of Non-Substantial Modifications 
Section Number and Name 
Description of Change 
Brief Rationale 
Cover Page 
EU CT Number added on the 
CSP cover page. 
To comply with EU-CTR 
requirement. 
Section 1.1 Synopsis;  
Section 1.3 Schedule of Activities;  
Section 5.1.1 Inclusion Criteria;  
Section 5.2.1 Exclusion Criteria;  
Section 5.3.1 Contraception;  
Section 7.1.2 Follow-up of Patients 
Post Discontinuation of Study 
Treatment;  
Section 8.3.13.2 Paternal Exposure 
The new appendix, 
Appendix K1.1, was 
cross-referenced to indicate 
country-specific requirements 
for Belgium. 
For document navigation. 
Section 1.1 Synopsis;  
Section 1.3 Schedule of Activities;  
Section 4.1 Overall Design; 
Section 5.1.1 Inclusion Criteria; 
Section 5.2.1 Exclusion Criteria; 
Section 5.3.1 Contraception; 
Section 6.6 Dose Modification; 
Section 7.1 Discontinuation of 
Study Treatment;  
Section 7.1.2 Follow-up of Patients 
Post Discontinuation of Study 
Treatment; 
Section 8.3.13.2 Paternal Exposure 
The new appendix, 
Appendix K1.2, was 
cross-referenced to indicate 
country-specific requirements 
for France. 
For document navigation. 
Section 1.1 Synopsis;  
Section 4.1 Overall Design; 
Section 8.3 Adverse Events and 
Serious Adverse Events;  
Section 9.2.1 Sample Size 
Determination;  
Appendix A3 Informed Consent 
Process;  
Appendix G Guidelines for 
Evaluation of Objective Tumour 
Response Using RECIST 1.1 
(Response Evaluation Criteria in 
Solid Tumours) 
The new appendix, 
Appendix K1.3, was 
cross-referenced to indicate 
country-specific requirements 
for Germany. 
For document navigation. 
Section 1.1 Synopsis 
Section 7.1.2 Follow-up of Patients 
Post Discontinuation of Study 
Treatment 
Corrected time period of 
follow-up for safety 
assessments post treatment 
discontinuation from “90 days” 
to “180 days” after last dose of 
study treatment for ceralasertib 
and durvalumab combination. 
Correction. 

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Section Number and Name
Description of Change
Brief Rationale
Section 4.4 End of Study Definition
Clarified definition of the end 
of study according to EU and 
FDA requirements.
For consistency and alignment in 
terms of posting study results.
Section 5.1.1 Inclusion Criteria, 
Main Study and Biopsy Sub-Study;
Section 5.3.1 Contraception
Updated the contraception 
period after the last dose of 
study intervention for female 
patients from 1 month to 
6 months.
Added a restriction that female 
patients must not breastfeed and 
must not donate or retrieve ova 
from signing the ICF to 
approximately 6 months after 
the last dose of study treatment.
To align with the latest safety 
outcomes and recommendations 
for contraception. 
Section 6.5.2 Drug-Drug 
Interaction Between Ceralasertib 
and Other Drugs;
Appendix F Guidelines Regarding 
Potential Interactions of 
Ceralasertib with Concomitant 
Medications, including the table 
listing drugs known to be 
metabolised by 
Addition of ceralasertib as a 
potential inducer of 
.
To align with the current 
ceralasertib IB, edition 13, dated 
18 September 2024.
Section 6.6.1 Management of 
Toxicities 
Added guidance on 
management of prolonged 
haematological toxicities
To align with Sponsor’s guidance 
ceralasertib toxicity management 
updated consequence to including 
MDS/AML as potential risks. 
Section 6.7 Treatment After the 
End of the Study;
Section 8.3.1 Time Period and 
Frequency for Collecting AE and 
SAE information
Added wording related to 
PTAP.
To clarify the planned safety data 
collection and reporting during the 
PTAP.
Section 8.3.7 Disease Progression
Added text on reporting of 
disease progression as a safety 
event in applicable cases.
For clarification.
Section 8.3.11 Safety Data to be 
Collected Following the Final Data 
Cutoff of the Study
Updated wording for safety data 
reporting.
For clarifying procedure for data 
collection.
Section 8.3.12 Reporting of Serious 
Adverse Events
Addition of wording to describe 
reporting of SUSARs to the 
EudraVigilance Database, in 
accordance with EU-CTR 
536/2014.
Update required to comply with 
regulatory requirement (eg, 
EU-CTR).
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Section Number and Name 
Description of Change 
Brief Rationale 
Section 8.3.12 Reporting of Serious 
Adverse Events 
Added wording for SAE 
reporting.  
For clarifying procedure for data 
collection. 
Section 8.3.13.1 Maternal exposure 
Added wording for pregnancy 
related reporting. 
 For clarifying procedure for data 
collection. 
Section 8.3.14 Medication Error, 
Drug Abuse, and Drug Misuse 
Updated common wording for 
reporting standards. 
To align with the latest CSP 
template. 
Section 8.3.14 Medication Error 
Added Drug Abuse and Drug 
Misuse definition. The level 3 
heading was changed to 
“Medication Error, Drug Abuse, 
and Drug Misuse”. 
 To comply with EU guidance on 
the collection, verification, and 
presentation of safety data from 
clinical trials and with Sponsor’s 
corporate safety standards. 
Section 8.4 Overdose 
Added wording regarding 
AE/SAE reporting in case of 
overdose. 
To align with the latest CSP 
template.  
Section A 1 Regulatory and Ethical 
Considerations  
Updated regulatory reporting 
Requirements for SAEs. 
To comply with EU Regulation 
No. 536/2014. 
Appendix A1 
Added sub-heading “Regulatory 
Reporting Requirements for 
Serious Breaches of Protocol or 
GCP”. 
To comply with regulatory 
requirement (eg, EU-CTR) and 
global company requirement. 
Appendix A4 
Updated Data Protection 
information and added 
sub-heading “Personal Data 
Breaches”. 
To comply with EU-CTR. 
Appendix A6 
Updated information about 
timelines for submission of 
study results summaries to 
EMA. 
To comply with EU-CTR. 
Appendix A7 
Updated template wording and 
added information about 
retention timelines of records 
and documents to “25 years 
after study archiving or as 
required by local regulations”. 
To comply with EU-CTR and to 
align with Sponsor’s company 
policy. 
Appendix B4 
Added detailed Drug Abuse and 
Drug Misuse definition and 
examples. 
To comply with EU guidance on 
the collection, verification and 
presentation of safety data from 
clinical trials and with Sponsor’s 
corporate safety standards. 
Appendix J Abbreviations 
List of abbreviations updated. 
To define newly added 
abbreviations. 

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Section Number and Name 
Description of Change 
Brief Rationale 
Appendix K Country-specific 
Requirements 
Added new Appendix to allow 
for consolidation of 
country-specific CSPs. 
To consolidate local CSP 
amendments for Belgium, France, 
and Germany into a single, as 
required per EU-CTR. 
AE = adverse event; CSP = clinical study protocol; CTR = Clinical Trials Regulation; EMA = European 
Medicines Agency; EU = European Union; EU-CTR = European Union Clinical Trials Regulation; 
FDA = Food and Drug Administration; GCP = good clinical practice; IB = Investigator’s Brochure; 
ICF = Informed Consent Form; PTAP = Post-trial Access Program; SAE = serious adverse event; 
SUSAR = suspected unexpected serious adverse reaction. 
 
 
 

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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
TABLE OF CONTENTS .......................................................................................................... 8 
1 
PROTOCOL SUMMARY.................................................................................... 14 
1.1 
Synopsis ................................................................................................................ 14 
1.2 
Schema .................................................................................................................. 23 
1.3 
Schedule of Activities ........................................................................................... 24 
2 
INTRODUCTION ................................................................................................ 50 
2.1 
Study Rationale ..................................................................................................... 50 
2.2 
Background ........................................................................................................... 50 
2.2.1 
Immunotherapies .................................................................................................. 50 
2.2.2 
Melanoma ............................................................................................................. 52 
2.2.3 
Ceralasertib ........................................................................................................... 53 
2.2.4 
Durvalumab .......................................................................................................... 54 
2.2.5 
Ceralasertib in Combination with Durvalumab .................................................... 55 
2.2.6 
Biopsy Sub-Study ................................................................................................. 55 
2.3 
Benefit/Risk Assessment ...................................................................................... 56 
2.3.1 
Risk Assessment ................................................................................................... 56 
2.3.1.1 
Ceralasertib ........................................................................................................... 57 
2.3.1.2 
Durvalumab .......................................................................................................... 57 
2.3.2 
Benefit Assessment ............................................................................................... 59 
2.3.3 
Overall Benefit: Risk Conclusion ......................................................................... 60 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 61 
4 
STUDY DESIGN ................................................................................................. 69 
4.1 
Overall Design ...................................................................................................... 69 
4.1.1 
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................. 71 
4.2 
Scientific Rationale for Study Design .................................................................. 72 
4.3 
Justification for Dose ............................................................................................ 73 
4.3.1 
Ceralasertib Monotherapy Dose Rationale ........................................................... 73 
4.3.2 
Ceralasertib and Durvalumab Combination Therapy Dose Rationale ................. 74 
4.3.2.1 
Dose Rationale for Durvalumab 1500 mg Q28D ................................................. 76 
4.4 
End of Study Definition ........................................................................................ 77 
5 
STUDY POPULATION ....................................................................................... 78 
5.1 
Inclusion Criteria .................................................................................................. 78 
5.1.1 
Main Study and Biopsy Sub-Study....................................................................... 78 
5.1.2 
Biopsy Sub-Study ................................................................................................. 80 
5.2 
Exclusion Criteria ................................................................................................. 81 
5.2.1 
Main Study and Biopsy Sub-Study....................................................................... 81 

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5.2.2 
Biopsy Sub-Study ................................................................................................. 84 
5.3 
Lifestyle Considerations ....................................................................................... 84 
5.3.1 
Contraception ........................................................................................................ 84 
5.3.2 
Meals and Dietary Restrictions ............................................................................. 86 
5.3.3 
Skin ....................................................................................................................... 87 
5.3.4 
Blood Donation ..................................................................................................... 87 
5.4 
Screen Failures...................................................................................................... 87 
6 
STUDY TREATMENT ........................................................................................ 87 
6.1 
Study Treatments Administered ........................................................................... 88 
6.1.1 
Study Treatments .................................................................................................. 88 
6.1.1.1 
Ceralasertib ........................................................................................................... 88 
6.1.1.2 
Durvalumab .......................................................................................................... 88 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 89 
6.2.1 
Durvalumab Storage, Infusion Preparation and Administration .......................... 89 
6.2.1.1 
Durvalumab Storage ............................................................................................. 89 
6.2.1.2 
Durvalumab Infusion Preparation ........................................................................ 90 
6.2.1.3 
Durvalumab Administration ................................................................................. 90 
6.2.2 
Ceralasertib Storage and Administration .............................................................. 91 
6.2.2.1 
Ceralasertib Storage .............................................................................................. 91 
6.2.2.2 
Ceralasertib Administration .................................................................................. 91 
6.3 
Measures to Minimise Bias: Randomisation and Blinding .................................. 91 
6.3.1 
Main Study ........................................................................................................... 91 
6.3.1.1 
Screening Procedures............................................................................................ 92 
6.3.1.2 
Methods for Assigning Treatment Groups ........................................................... 93 
6.3.1.3 
Procedures for Handling Incorrectly Enrolled or Randomised Patients ............... 93 
6.3.2 
Biopsy Sub-Study ................................................................................................. 94 
6.4 
Treatment Compliance.......................................................................................... 94 
6.5 
Concomitant Therapy ........................................................................................... 95 
6.5.1 
Restricted, Prohibited, and Permitted Concomitant Medications/Therapies ........ 95 
6.5.2 
Drug-Drug Interaction Between Ceralasertib and Other Drugs ........................... 99 
6.5.3 
Drug-Drug interactions Between Durvalumab and Other Drugs ....................... 101 
6.5.4 
Rescue Medication.............................................................................................. 101 
6.6 
Dose Modification .............................................................................................. 102 
6.6.1 
Management of Toxicities .................................................................................. 105 
6.7 
Treatment After the End of the Study................................................................. 107 
7 
DISCONTINUATION OF STUDY TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL .......................................................... 108 
7.1 
Discontinuation of Study Treatment ................................................................... 108 
7.1.1 
Temporary Discontinuation/Rechallenge ........................................................... 109 
7.1.2 
Follow-up of Patients Post Discontinuation of Study Treatment ....................... 109 
7.1.3 
Follow-up for Survival ....................................................................................... 109 
7.2 
Patient Withdrawal from the Study .................................................................... 110 
7.3 
Lost to Follow up ................................................................................................ 110 

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8 
STUDY ASSESSMENTS AND PROCEDURES.............................................. 111 
8.1 
Efficacy Assessments ......................................................................................... 112 
8.1.1 
Tumour Assessments .......................................................................................... 112 
8.1.1.1 
Investigator’s Assessment of Tumour Response Per RECIST 1.1 ..................... 113 
8.1.1.2 
Blinded Independent Central Review of Tumour Assessments ......................... 114 
8.1.1.3 
Screening Assessments ....................................................................................... 114 
8.1.2 
Survival follow-up .............................................................................................. 115 
8.1.3 
Clinical Outcome Assessments........................................................................... 115 
8.1.3.1 
Patient Reported Outcomes ................................................................................ 115 
8.2 
Safety Assessments ............................................................................................. 120 
8.2.1 
Physical Examinations ........................................................................................ 120 
8.2.2 
Vital Signs .......................................................................................................... 120 
8.2.3 
Electrocardiograms ............................................................................................. 122 
8.2.4 
Eastern Cooperative Oncology Group Performance Status................................ 122 
8.2.5 
Clinical Safety Laboratory Assessments ............................................................ 122 
8.2.6 
Other Safety Assessments................................................................................... 125 
8.2.6.1 
Echocardiogram/Multigated Acquisition Scan ................................................... 125 
8.2.6.2 
Pneumonitis (Interstitial Lung Disease) Investigation ....................................... 125 
8.3 
Adverse Events and Serious Adverse Events ..................................................... 126 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ............... 126 
8.3.2 
Follow-up of AEs and SAEs............................................................................... 126 
8.3.3 
Causality Collection............................................................................................ 128 
8.3.4 
Adverse Events Based on Signs and Symptoms ................................................ 128 
8.3.5 
Adverse Events Based on Examinations and Tests ............................................ 128 
8.3.6 
Hy’s Law ............................................................................................................ 129 
8.3.7 
Disease Progression ............................................................................................ 129 
8.3.8 
New Cancers ....................................................................................................... 129 
8.3.9 
Deaths ................................................................................................................. 129 
8.3.10 
Adverse Events of Special Interest ..................................................................... 130 
8.3.11 
Safety Data to be Collected Following the Final Data Cut Off of the Study ..... 131 
8.3.12 
Reporting of Serious Adverse Events ................................................................. 131 
8.3.13 
Pregnancy ........................................................................................................... 132 
8.3.13.1 
Maternal Exposure .............................................................................................. 133 
8.3.13.2 
Paternal Exposure ............................................................................................... 133 
8.3.14 
Medication Error, Drug Abuse, and Drug Misuse .............................................. 134 
8.3.14.1 
Timelines ............................................................................................................ 134 
8.3.14.2 
Medication Error ................................................................................................. 134 
8.3.14.3 
Drug Abuse ......................................................................................................... 134 
8.3.14.4 
Drug Misuse........................................................................................................ 134 
8.4 
Overdose ............................................................................................................. 135 
8.5 
Human Biological Samples ................................................................................ 135 
8.5.1 
Pharmacokinetics ................................................................................................ 136 
8.5.1.1 
Determination of Drug Concentration ................................................................ 137 
8.5.2 
Immunogenicity Assessments ............................................................................ 137 
8.5.3 
Pharmacodynamics ............................................................................................. 137 

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8.5.3.1
Collection of Samples.........................................................................................137
8.6
Human Biological Sample Biomarkers ..............................................................137
8.6.1
Collection of Mandatory Samples for Biomarker Analysis ...............................137
8.6.1.1
Mandatory Archival Tumour Samples ...............................................................138
8.6.1.2
Tumour Biopsies for Main and Biopsy Sub-Study.............................................138
8.6.1.3
Blood Samples for Exploratory Biomarker Assessments...................................140
8.6.2
Collection of Optional Biomarker Samples........................................................141
8.6.2.1
Optional Biopsies................................................................................................141
8.6.3
Other Study Related Biomarker Research..........................................................142
8.6.4
Optional Future Scientific Research...................................................................142
8.7
.................................................................142
8.8
Health Economics OR Medical Resource Utilization and Health Economics...143
9
STATISTICAL CONSIDERATIONS ...............................................................143
9.1
Statistical Hypotheses.........................................................................................143
9.2
Sample Size Determination ................................................................................143
9.2.1
Main Study .........................................................................................................143
9.2.2
Biopsy Sub-Study...............................................................................................144
9.3
Populations for Analyses....................................................................................145
9.4
Statistical Analyses.............................................................................................146
9.4.1
General Considerations.......................................................................................146
9.4.2
Efficacy...............................................................................................................147
9.4.2.1
Primary Endpoint(s)............................................................................................147
9.4.2.2
Secondary Endpoints ..........................................................................................148
9.4.2.3
Subgroup Analysis..............................................................................................151
9.4.2.4
Exploratory Endpoint(s) .....................................................................................151
9.4.3
Safety..................................................................................................................152
9.4.3.1
Adverse Events...................................................................................................152
9.4.3.2
Other Safety Endpoint(s) ....................................................................................153
9.4.4
Other Analyses....................................................................................................153
9.5
Interim Analyses.................................................................................................153
9.6
Independent Data Monitoring Committee..........................................................155
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................156
11
REFERENCES ...................................................................................................253
LIST OF FIGURES
Figure 1
Study Design ...............................................................................................23
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LIST OF TABLES
Table 1
Ceralasertib Plus Durvalumab (Main Study) ..............................................24
Table 2
Ceralasertib Monotherapy (Main Study) ....................................................33
Table 3
Biopsy Sub-study ........................................................................................41
Table 4
Risk Assessment..........................................................................................59
Table 5
Objectives and Endpoints for Main Study ..................................................61
Table 6
Objectives and Endpoints for the Biopsy Sub-Study..................................67
Table 7
Highly Effective Methods of Contraception (< 1% Failure Rate) ..............86
Table 8
Investigational Products..............................................................................88
Table 9
Restricted Medications/Therapies...............................................................96
Table 10
Prohibited Concomitant Medications..........................................................96
Table 11
Guidance for Dose Modifications, Interruptions, and Discontinuations 
for Ceralasertib (all treatment arm) and Ceralasertib plus Durvalumab...103
Table 12
Dose Reduction Levels for Ceralasertib....................................................104
Table 13
Eastern Cooperative Oncology Group Performance Status......................122
Table 14
Laboratory Safety Variables .....................................................................123
Table 15
Expected 
% CI for CD8 T-cells Fold Change from Baseline with a 
Standard Deviation of 
) and 30 Evaluable Patients .............145
Table 16
Populations for Analysis ...........................................................................145
Table 17
RECIST 1.1 Evaluation of Target Lesions ...............................................198
Table 18
RECIST 1.1 Evaluation of Non-Target Lesions .......................................199
Table 19
RECIST 1.1 Overall Visit Response.........................................................200
Table 20
Summary of Methods of Assessment........................................................201
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations........................156
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .........................................................................165
Appendix C
Handling of Human Biological Samples...................................................171
Appendix D
.......................................................174
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ............................................................................178
Appendix F
Guidelines Regarding Potential Interactions of Ceralasertib with 
Concomitant Medications .........................................................................185
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Appendix G 
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 (Response Evaluation Criteria in Solid Tumours) ............... 195 
Appendix H 
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis, including COVID 
19 Outbreak ............................................................................................... 207 
Appendix I 
Patient Reported Outcomes ....................................................................... 212 
Appendix J 
Abbreviations ............................................................................................ 224 
Appendix K 
Country-specific Requirements ................................................................. 229 
Appendix L 
Protocol Amendment History ................................................................... 245 
 

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1 
PROTOCOL SUMMARY  
1.1 
Synopsis  
Protocol Title: MONETTE: A Randomised, Open-Label, Phase 2 Study of Ceralasertib 
Monotherapy and Ceralasertib plus Durvalumab in Patients with Unresectable or Advanced 
Melanoma and Primary or Secondary Resistance to PD-(L)1 inhibition 
Short Title: MONETTE: A Phase 2 Study of Ceralasertib Monotherapy and Ceralasertib Plus 
Durvalumab in Patients with Unresectable or Advanced Melanoma and Resistance to PD-(L)1 
Inhibition 
Rationale: This Phase 2 study aims to evaluate the efficacy and safety/tolerability of 
ceralasertib, when administered as monotherapy and in combination with durvalumab in 
patients with unresectable or advanced melanoma and primary or secondary resistance to 
PD-(L)1 inhibition. The rationale for conducting the study is supported by clinical data from 
ongoing studies, unmet need, and the evidence of ceralasertib modulating the immune 
environment. 
An open-label, non-randomised, biopsy sub-study is also planned in patients suitable for 
3 mandatory biopsies. The rationale for conducting the biopsy sub-study is to understand the 
mechanism of action of ceralasertib plus durvalumab and investigate ceralasertib as an 
immune modulator. 
 
 

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Objectives and Endpoints 
Objectives 
Endpoints 
Main Study 
Primary 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of objective response rate (ORR) 
in patients with unresectable or advanced 
melanoma and primary or secondary resistance 
to a PD-(L)1 inhibitor 
x 
The primary measure is the estimate of ORR for 
each experimental treatment arm, and a 
secondary measure of interest is the odds ratio 
of the ORR comparing the 2 treatment arms 
Secondary 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of Duration of Response (DoR) 
in patients with unresectable or advanced 
melanoma and primary or secondary resistance 
to a PD-(L)1 inhibitor 
x 
Median and landmark DoR estimates at 6, 9, 12, 
15, and 18 months 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of time to objective response 
(TTR) in patients with unresectable or advanced 
melanoma and primary or secondary resistance 
to a PD-(L)1 inhibitor 
x 
Median TTR and proportion of patients with 
response at the first scheduled tumour 
assessment 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of change in target lesion (TL) 
tumour size in patients with unresectable or 
advanced melanoma and primary or secondary 
resistance to a PD-(L)1 inhibitor 
x 
Percentage change from baseline in TL tumour 
size at week 16 and best percentage changes 
from baseline 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of progression free survival 
(PFS) in patients with unresectable or advanced 
melanoma and primary or secondary resistance 
to a PD-(L)1 inhibitor 
x 
Median and landmark PFS at 3, 6, 9, 12 months, 
and the hazard ratio comparing the 2 treatment 
arms 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of overall survival (OS) in 
patients with unresectable or advanced 
melanoma and primary or secondary resistance 
to a PD-(L)1 inhibitor 
x 
Median and landmark OS at 6, 9, 12, and 
18 months, and the hazard ratio comparing the 
2 treatment arms 
x 
To assess the PK of ceralasertib alone and when 
in combination with durvalumab 
x 
Concentration of ceralasertib in plasma (peak 
and trough concentrations, as data allow; sparse 
sampling) 
Safety 
x 
To assess the safety and tolerability of 
ceralasertib monotherapy and ceralasertib plus 
durvalumab in patients with unresectable or 
advanced melanoma and primary or secondary 
resistance to a PD-(L)1 inhibitor 
x 
Safety and tolerability will be evaluated in terms 
of adverse events (AEs), vital signs, and clinical 
laboratory assessments. 
 

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Objectives
Endpoints
Exploratory objectives
x
x
x
x
x
x
x
x
x
x
x
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Objectives
Endpoints
x
x
x
x
x
 
x
Biopsy Sub-Study
Primary
x
To assess changes in CD8+ T-cell infiltration of 
tumours induced by ceralasertib monotherapy
x
CD8+ T-cells tumour infiltration assessed in 
baseline, on-treatment and off-treatment tumour 
biopsies
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Objectives
Endpoints
Secondary
x
To estimate the effectiveness of ceralasertib plus 
durvalumab by assessment of ORR, DoR, TTR, 
change in tumour size, PFS, and OS
x
As described for the main study
x
To collect tumour tissue samples, or utilise 
residual samples, for the analysis of tumoural 
biomarkers that change following treatment 
with ceralasertib
x
Pre-treatment presence and/or on-treatment 
and/or off-treatment changes in PD-L1 and 
pRAD50
x
To assess changes in the proliferation of 
carcinoma and/or immune cells within tumours 
induced by ceralasertib monotherapy
x
Proliferation (using Ki67+ marker) of carcinoma 
and/or immune cells (including CD8+ T cells) 
will be assessed in baseline, on-treatment and 
off-treatment tumour biopsies.
Safety
x
To assess the safety and tolerability of 
ceralasertib plus durvalumab in patients with 
unresectable or advanced melanoma and 
primary or secondary resistance to a PD-(L)1 
inhibitor
x
As described for the main study
Exploratory
x
x
x
x
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Objectives
Endpoints
x
x
x
 
x
Overall Design
This is a Phase 2, randomised, open-label study of ceralasertib monotherapy and ceralasertib 
plus durvalumab in patients with unresectable or advanced melanoma and primary or 
secondary resistance to PD-(L)1 inhibition. Patients will be recruited from multiple centres 
with a global footprint that is expected to include North America, Europe, and Asia.
An open-label, non-randomised, biopsy sub-study is planned in patients suitable for 
3 mandatory biopsies. Patients recruited into the biopsy sub-study will receive 1 cycle of 
ceralasertib monotherapy (Cycle 0) followed by ceralasertib plus durvalumab from Cycle 1.
Disclosure Statement:
This is a Phase 2, randomised, open-label, multicentre, international study assessing the 
efficacy and safety of ceralasertib monotherapy and ceralasertib plus durvalumab in patients 
with unresectable or advanced melanoma with resistance to PD-(L)1 inhibition.
Patient Population:
The target population of interest in this study is patients with unresectable or advanced 
melanoma, measurable by RECIST 1.1, with confirmed progression during treatment with a 
PD-(L)1 inhibitor +/- a CTLA-4 inhibitor, eg, nivolumab, pembrolizumab, or atezolizumab, or 
the combination of nivolumab and ipilimumab, and with availability of a mandatory fresh 
tumour biopsy (if medically feasible) and a mandatory archival tumour sample of up to 
5 years, at screening.
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Number of Patients:
Main study: Approximately 150 patients are expected to be randomised in total, at a 2:1 
randomisation ratio, such that there will be approximately 100 evaluable patients in the 
ceralasertib and durvalumab combination therapy arm and approximately 50 patients in the 
ceralasertib monotherapy arm. However, fewer patients may be randomised to any given 
treatment arm following a recommendation by the Independent Data Monitoring Committee 
(IDMC) to terminate recruitment to an arm based on safety or lack of efficacy.
Enrolled
Estimated 
 patients
Randomly assigned
Estimated 150 patients
Evaluable patients
Estimated 150 patients
Biopsy sub-study:
The estimated number of patients in the biopsy sub-study is as follows:
Enrolled
Estimated 
 patients
Evaluable tumour biopsy patients
Estimated 30 patients
Note: “Enrolled” means a patient’s, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process. Potential 
patients who are screened for the purpose of determining eligibility for the study, but are not
randomised/assigned in the study, are considered “screen failures”, unless otherwise specified 
by the protocol. For country-specific requirements for Germany see Appendix K 1.3.
Treatment Groups and Duration:
Main study: The treatment arms are as follows:
x
Arm 1: Ceralasertib 240 mg BD, oral tablets, from Days 1 to 7, plus durvalumab 
1500 mg Day 8, IV infusion, Q28D, until progressive disease (confirmed 
RECIST 1.1-defined radiological progression), unacceptable toxicity, withdrawal of 
consent, or if a study treatment discontinuation criterion is met.
x
Arm 2: Ceralasertib 240 mg BD, oral tablets, from Days 1 to 7, Q28D, until progressive 
disease (confirmed RECIST 1.1-defined radiological progression), unacceptable toxicity, 
withdrawal of consent, or if a study treatment discontinuation criterion is met.
There is no defined maximum treatment duration for the treatment arms as the patients will 
receive study treatment until progressive disease (confirmed RECIST 1.1-defined radiological 
progression), unacceptable toxicity, withdrawal of consent, or if a study treatment 
discontinuation criterion is met.
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Randomization into the treatment arms will be stratified by: 
x 
Resistance to prior immune-oncology treatment (primary/early relapse in adjuvant setting 
vs secondary resistance). 
x 
Baseline lactate dehydrogenase expression (below and equal to the upper limit of normal 
vs above upper limit of normal). 
 
Biopsy sub-study: During Cycle 0, patients will be treated with ceralasertib 240 mg BD, as 
oral tablets, from Days 1 to 7, Q28D, followed by an off-treatment period between 
Days 8 to 28. From Cycle 1, patients will be treated with the combination of ceralasertib 
240 mg BD, oral tablets, from Days 1 to 7, plus durvalumab 1500 mg Day 8, as an IV 
infusion, Q28D, until progressive disease (confirmed RECIST 1.1-defined radiological 
progression), unacceptable toxicity, withdrawal of consent, or if a study treatment 
discontinuation criterion is met. 
Follow-up of patients post discontinuation of study treatment for main and biopsy 
sub-study: After study treatment discontinuation, all patients will be followed up for safety 
assessments 30 days after their last dose of study treatment for ceralasertib monotherapy or 
180 days after last dose of study treatment for ceralasertib and durvalumab combination (ie, 
the safety follow-up visit). All randomised patients in the main study and all patients in the 
biopsy sub-study will be followed for survival status and post discontinuation anti-cancer 
therapies. For country-specific requirements for Belgium and France see Appendices K 1.1 
and K 1.2 respectively. 
Patients who have discontinued study treatment in the absence of Response Evaluation 
Criteria in Solid Tumours (RECIST) 1.1-defined (per investigator assessment) radiological 
progression will be followed up with tumour assessments according to the Schedule of 
Activities (SoA) until RECIST 1.1-defined disease progression or death (whichever comes 
first) regardless of whether or not the patient started a subsequent anti-cancer therapy, unless 
they have withdrawn all consent to study related assessments. 
Independent Data Monitoring Committee: 
An IDMC comprised of independent experts will be convened to review the unblinded safety 
and tolerability data and the unblinded efficacy data from the interim analyses, in order to 
recommend to the sponsor whether or not to limit recruitment to any treatment arm. 
Following the reviews, the IDMC will recommend whether the study should continue 
unchanged, be stopped, or be modified in any way. 
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
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 analyses of efficacy data will be conducted during the study, the 
 
when approximately 
patients have been enrolled (approximately 
 patients in the
ceralasertib and durvalumab combination therapy arm and approximately 
 patients in the 
ceralasertib monotherapy arm) with approximately 
 follow up and the 
 when
approximately 
patients have been enrolled (approximately 
 patients in the ceralasertib 
and durvalumab combination therapy arm and approximately 
 patients in the ceralasertib 
monotherapy arm) with approximately 
weeks follow up.
Statistical Methods
Main study: Each treatment arm is experimental and thus will be analysed separately for 
objective response rate (ORR). The study will recruit approximately 100 patients in the
ceralasertib and durvalumab combination therapy arm. With 100 patients the expected 
 
width of the 
% confidence interval (CI) for ORR will be up to approximately 
% when the 
proportion of patients with an objective response is in the range % to 
%. A secondary 
objective is to compare the ORR between the two treatment arms. With 150 patients 
(100 patients randomised to the ceralasertib and durvalumab combination therapy arm and 
50 patients randomised to the ceralasertib monotherapy arm), there will be at least 
% power 
at a 
 of 
 to detect a difference in ORR, assuming an ORR for ceralasertib 
plus durvalumab of 
% and an ORR for ceralasertib monotherapy of 
%.
The primary analysis will be conducted once all randomised patients have had a minimum of 
 of follow-up after start of study treatment or have discontinued from the study, 
whichever occurs first. The primary analysis of ORR will be based on blinded independent 
central review (BICR) according to RECIST 1.1 using the safety analysis set. As primary 
analysis, ORR will be summarised for each treatment arm with 95% CI (Clopper-Pearson). As 
a secondary objective ORR will be compared between the treatment arms using logistic 
regression adjusting for PD-(L)1 resistance type and lactate dehydrogenase (LDH) per 
randomisation stratification as covariates. The odds ratio with corresponding 95% CI and 
p-value will be estimated. This comparative analysis will be provided using the full analysis 
set. Time to event endpoints of duration of response (DoR), progression free survival (PFS), 
and overall survival (OS) will be summarised descriptively by Kaplan-Meier method, 
including the medians, and landmark estimates with corresponding 95% CI. Comparison 
between the treatment arms will be conducted using a log rank test stratified by PD-(L)1
resistance type and LDH per randomisation stratification. The hazard ratio with corresponding 
95% CI will be estimated using a Cox proportional hazards model stratified by PD-(L)1
resistance type and LDH. Time to response (TTR) will be summarised descriptively. The 
percentage change in target lesion tumour size from baseline at 16 weeks and best percentage 
change will be summarised visually by waterfall and spider plots. No adjustments for 
multiplicity are planned.
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Safety data will be summarised descriptively and will not be formally analysed unless 
otherwise specified. 
Biopsy sub-study: The sample size of approximately 30 patients with evaluable tumour 
biopsies at baseline and ceralasertib off-treatment period is designed to give adequate 
precision in CD8+ T-cells tumour infiltration fold change from baseline. Data will be 
transformed as appropriate eg, log2-transformation, and analysed by mixed effect model 
repeated measures (MMRM) with fixed effect for timepoint and an unstructured 
variance-covariance matrix to account for repeated measures within a patient. The least 
squares means for each timepoint will be presented, together with the difference to baseline 
visit and 95% CI. Association of biomarkers to clinical outcomes will be presented visually, 
eg, boxplots by Best Overall Response (BOR). 
1.2 
Schema  
Figure 1 
Study Design  
 
BD = twice daily; CTLA-4 = cytotoxic T-lymphocyte-associated protein-4; Q28D = every 28 days; BRAFi = BRAF 
inhibitor; MEKi = MEK inhibitor; min = minimum; PD-(L)1 = programmed death ligand 1; R = randomisation. 
 

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1.3 
Schedule of Activities  
The procedures for this study are presented in the SoA for ceralasertib and durvalumab combination therapy in Table 1, for the 
ceralasertib monotherapy in Table 2, and for the biopsy sub-study in Table 3. 
Table 1 
Ceralasertib Plus Durvalumab (Main Study)  
Procedure 
Screening a  
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in 
CSP section 
 or appendix 
Cycles 1-2 
Cycle 3 
C4-onwards 
Study Treatment Discontinued 
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-21 
to 
 -1 
Day 1 
Day 7 
Day 8 
Day 15 
Day 1 
Day 7 
Day 8 
Day 1 
Day 8 
30 days 
60 days 
90 days 
180 days  
(6 months) 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
± 3 
± 1 
± 3 
± 7 
± 7 
± 7 
 
Informed consent: 
main study b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5 and 
Appendix 
A 3 
Informed consent: 
genetic sample and 
analysis (optional) b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
and 
Appendix A 3 
Archival tumour 
sample, mandatory c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.6.1 
Fresh tumour biopsy 
d 
X 
 
 
 
X 
(C2 
only) 
 
 
 
 
 
X  
(PD) 
 
 
 
 
 
Section 8.6.1 
Inclusion and 
exclusion criteria e, f 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sections 5.1, 
5.2 and 5.4 
Demography g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Procedure 
Screening a  
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in 
CSP section 
 or appendix 
Cycles 1-2 
Cycle 3 
C4-onwards 
Study Treatment Discontinued 
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-21 
to 
 -1 
Day 1 
Day 7 
Day 8 
Day 15 
Day 1 
Day 7 
Day 8 
Day 1 
Day 8 
30 days 
60 days 
90 days 
180 days  
(6 months) 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
± 3 
± 1 
± 3 
± 7 
± 7 
± 7 
 
Prior anti-cancer 
therapy h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
Full physical 
examination a 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
Section 8.2.1 
Targeted physical 
examination i 
 
 
 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Section 8.2.1 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1 
Weight a 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 8.2.1 
Past and current 
medical conditions 
X 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sections 
5.1 and 5.2 
12-lead ECG j, k 
X 
(Tri
plic
ate) 
As clinically indicated; single ECGs 
 
 
 
 
 
 
Section 8.2.3 
Echocardiogram/MU
GA 
X 
As clinically indicated 
X 
 
 
 
 
 
Section 
8.2.6.1 
Vital signs k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Procedure 
Screening a  
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in 
CSP section 
 or appendix 
Cycles 1-2 
Cycle 3 
C4-onwards 
Study Treatment Discontinued 
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-21 
to 
 -1 
Day 1 
Day 7 
Day 8 
Day 15 
Day 1 
Day 7 
Day 8 
Day 1 
Day 8 
30 days 
60 days 
90 days 
180 days  
(6 months) 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
± 3 
± 1 
± 3 
± 7 
± 7 
± 7 
 
ECOG performance 
status l 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Section 
8.2.4 
Hepatitis B and C 
and HIV screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sections 
5.1 and 
8.2.5 
Safety laboratory 
assessments (clinical 
chemistry including 
TSH, haematology, 
urinalysis f, k, m) 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Section 
8.2.5 
Coagulation 
parameters n 
X 
X 
Section 
8.2.5 
Pregnancy test 
(WOCBP only) o 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
Section 
8.2.5 
AE 
X 
Å============                                  X                          ===============Æ 
At every visit and may be conducted by phone if not tied to a visit. 
 
 
Section 8.3 
Concomitant 
medications 
X 
Å============                                  X                          ===============Æ 
At every visit and may be conducted by phone if not tied to a visit.
 
 
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Procedure
Screening a
Intervention period (28-day cycles)
Post-intervention follow-up period
Details in 
CSP section
or appendix
Cycles 1-2
Cycle 3
C4-onwards
Study Treatment Discontinued 
(last dose of study treatment)
Safety follow-up
(# of days after last dose)
Progression/Survival 
Follow-up (Q8W until 
18 months, then Q12W)
Cycle Day 
-21
to
-1
Day 1
Day 7
Day 8
Day 15
Day 1
Day 7
Day 8
Day 1
Day 8
30 days
60 days
90 days
180 days 
(6 months)
Visit window 
(± days) 
-
-
-
-
± 1
± 3
-
± 1
± 3
± 1
± 3
± 7
± 7
± 7
Tumour imaging 
(RECIST 1.1;
CT/MRI including 
brain scan at 
baseline) p, s
X q
X
Tumour assessments will be conducted every 8 weeks (±1 week) after start of treatment 
(C1D1) up to 18 months, then every 12 weeks (±1 week) until objective disease 
progression per RECIST 1.1. If a patient discontinues without disease progression, 
RECIST tumour assessments will be performed every 8 weeks for 18 months, then every 
12 weeks, thereafter. 
Section 
8.1.1
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Procedure
Screening a
Intervention period (28-day cycles)
Post-intervention follow-up period
Details in 
CSP section
or appendix
Cycles 1-2
Cycle 3
C4-onwards
Study Treatment Discontinued 
(last dose of study treatment)
Safety follow-up
(# of days after last dose)
Progression/Survival 
Follow-up (Q8W until 
18 months, then Q12W)
Cycle Day 
-21
to
-1
Day 1
Day 7
Day 8
Day 15
Day 1
Day 7
Day 8
Day 1
Day 8
30 days
60 days
90 days
180 days 
(6 months)
Visit window 
(± days) 
-
-
-
-
± 1
± 3
-
± 1
± 3
± 1
± 3
± 7
± 7
± 7
Blood sample for 
ceralasertib PK 
testing u
X
X
Section 
8.5.1
Blood sample for 
durvalumab PK 
testing u
X
X
X
Section 
8.5.1
Blood sample for 
durvalumab 
immunogenicity 
testing v
X
X
X
X
Every 
4
cycles
X
X
X
Section
8.5.2
Randomisation w
X
Section 6.3
Ceralasertib study 
treatment (dispensed 
or returned)
X
X
X
X
(returned
)
Sections
6.2.2.2 and 
6.4
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Procedure
Screening a
Intervention period (28-day cycles)
Post-intervention follow-up period
Details in 
CSP section
or appendix
Cycles 1-2
Cycle 3
C4-onwards
Study Treatment Discontinued 
(last dose of study treatment)
Safety follow-up
(# of days after last dose)
Progression/Survival 
Follow-up (Q8W until 
18 months, then Q12W)
Cycle Day 
-21
to
-1
Day 1
Day 7
Day 8
Day 15
Day 1
Day 7
Day 8
Day 1
Day 8
30 days
60 days
90 days
180 days 
(6 months)
Visit window 
(± days) 
-
-
-
-
± 1
± 3
-
± 1
± 3
± 1
± 3
± 7
± 7
± 7
Dosing with 
ceralasertib 
(self-administered) x
X (Days 1 to 
7)
X (Days 1 to 
7)
X
(Days 
1 to 7)
Sections
6.2.2.2 and 
6.4
Dosing with 
durvalumab (IV 
infusion) x
X
X
X
Sections
6.2.1.2 and 
6.2.1.3
Dosing diary y, aa
X
(Days 1 to 7 of every cycle)
Section 6.4
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Procedure
Screening a
Intervention period (28-day cycles)
Post-intervention follow-up period
Details in 
CSP section
or appendix
Cycles 1-2
Cycle 3
C4-onwards
Study Treatment Discontinued 
(last dose of study treatment)
Safety follow-up
(# of days after last dose)
Progression/Survival 
Follow-up (Q8W until 
18 months, then Q12W)
Cycle Day 
-21
to
-1
Day 1
Day 7
Day 8
Day 15
Day 1
Day 7
Day 8
Day 1
Day 8
30 days
60 days
90 days
180 days 
(6 months)
Visit window 
(± days) 
-
-
-
-
± 1
± 3
-
± 1
± 3
± 1
± 3
± 7
± 7
± 7
PRO training/set up
aa
X
X
Section
8.1.3.1
Survival status bb
X
X
X
X
X
Sections 
7.1.3 and 
8.1.2
Subsequent 
anticancer therapy cc
Xc
Xc
Xc
Xc
Xc
Xc
Section 
7.1.2
a
If screening assessments have been performed within 3 days prior to starting study intervention, they do not have to be repeated at Cycle 1 Day 1 if the 
patient’s condition has not changed.
b
Written informed consent and any locally required privacy act document authorisation must be obtained prior to performing any protocol-specific 
procedures, including screening/baseline evaluations.
c
Submission of archival tumour tissue is mandatory for all patients. A minimum of 20 freshly cut unstained sections from the archival tumour block are 
accepted if tumour blocks cannot be submitted, however tumour tissue blocks are preferred.
d
Fresh tumour biopsies are mandatory, if medically feasible, in all patients with biopsiable disease at screening. However, if patients do not have disease 
suitable for biopsy, they are required to provide a tumour sample collected within 5 years prior to study entry. Optional on-treatment biopsies will be 
collected at Cycle 2 between Day 15 and Day 28 and at disease progression, only if a fresh tumour sample was provided at screening. Optional on-treatment 
biopsies are not required if a fresh tumour sample was not collected at screening. For sample collection details refer to Section 8.6 of the protocol.
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e
Submission of the cytological or histological report, and molecular report confirming BRAF mutation status is mandatory at screening. In addition, the 
investigator must confirm the type of PD-(L)1 resistance at screening and whether the LDH is normal or above upper limit of normal, in order to stratify the 
patients accordingly. Other genomic characteristics will be collected where known eg, NRAS, c-kit, PD-(L)1, NF1, MSI.
f
Clinical laboratory assessment parameters are to be assessed at baseline on Day 1 (unless all screening laboratory assessments are performed within 3 days 
prior to Day 1) and full blood count result should be checked prior to dosing when assessed on a dosing day. Serum or plasma clinical chemistry (including 
LFT monitoring) and haematology may be performed more frequently if clinically indicated. Urinalysis should be performed at baseline (screening) and 
then as clinically indicated. Thyroid stimulating hormone testing is to be done at the timepoints indicated and also when clinically indicated (clinically 
suspecting immune-related hypo/hyper thyroidism). Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE 
related to the endocrine system.
g
Baseline demographics will include all prior treatments (start/stop dates, best response, treatment line, reason for treatment discontinuation and, if due to 
RECIST 1.1-defined disease progression, how progression was determined and dates of radiographic scans indicating disease progression) and disease stage 
at diagnosis and at study entry. Other genomic characteristics will be collected where known eg, NRAS, c-kit, PD-(L)1, NF1, MSI.
h
Collect data on prior anti-cancer therapies, including best response, setting (eg, adjuvant/metastatic), prior radiotherapy, and prior surgery. For the prior 
anti-PD-(L)1 regimen, also collect reason for discontinuation and details of scans indicating RECIST 1.1-defined disease progression, including 
anonymised copies of the scan reports.
i
Additional physical examination will be performed, if clinically indicated.
j
Triplicate ECGs at screening only. Subsequent ECGs should only be taken if clinically indicated.
k
Whenever ECG, vital signs and blood draws are scheduled on the same day, it is recommended that the assessments occur in the following order: vital 
signs, ECG, and then blood draws. The timing of the ECG and vital signs assessments must allow for the blood draw (eg, PK blood sample) to occur at the 
scheduled time points.
l
ECOG assessment also to be performed at initiation of subsequent anticancer therapy, where possible. In addition, ECOG performance status should be 
collected at initiation of subsequent anticancer therapy, if appropriate site staff are available to collect such information. Additional ECOG assessments may 
be performed (eg, on Day 15), if clinically indicated.
m
Patients who develop a ≥ Grade 3 of anaemia, neutropenia, or thrombocytopenia during the treatment period will also need to have additional assessments
on Day 15 (for combination of ceralasertib and durvalumab) until there is no evidence of ≥ Grade 3 anaemia, neutropenia, or thrombocytopenia for at least 
2 cycles.
n
Coagulation will be performed at screening and as clinically indicated during subsequent visits.
o
Women of childbearing potential only. Serum pregnancy test at screening, urine test at other time points up to 90 days after the last dose of study treatment.
For country-specific requirements for Belgium and France see Appendices K 1.1 and K 1.2, respectively.
p
CT scans of the chest, abdomen, and pelvis (or MRI where CT is contraindicated) should be conducted every 8 weeks (±1 week) after the start of study 
treatment (Cycle 1 Day 1) up to 18 months, then every 12 weeks (±1 week) until objective disease progression as per RECIST 1.1, irrespective of treatment 
decisions. In the event of study treatment interruptions or delays, tumour assessments should proceed to schedule relative to Cycle 1 Day 1. Soft tissue or 
visceral progression observed by CT or MRI, according to RECIST 1.1, does not require a confirmatory scan. To confirm progression based on non-target 
lesions, additional scans or images/photographs may be required for submission for BICR.
q
Baseline contrast enhanced MRI brain scan assessment (or CT if MRI is contraindicated) for all patients at screening.
r
s
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t
u
For ceralasertib, PK sample will be collected in all patients at pre-dose (up to 1 hour prior) and 1 hour (± 30 min) post-dose on Day 7 of each cycle, for the 
first 3 cycles. For durvalumab, PK sample will be collected in all patients at pre-dose (up to 1 hour prior) and 1 hour (± 30 min) post-dose on Day 8 of each 
cycle, for the first 3 cycles. For non-dosing days, PK sample will be collected at similar times as dosing day.
v
Immunogenicity sample for durvalumab to be collected at screening, then pre-dose on Day 8 of Cycles 1, 2, 3, and 4, then every 4 cycles, end of treatment, 
90 days and 6 months (± 7 days) after last dose.
w
Every effort should be made to minimise the time between randomisation and starting treatment (ie, within 3 business days of randomisation).
x
Ceralasertib administered twice daily from Days 1 to 7 of each cycle. Durvalumab administered on Day 8 of each cycle.
y
For ceralasertib, patients will be required to complete a dosing diary (e-diary) from Day 1 to Day 7 of each cycle, using an electronic device. The dosing 
diary must be reviewed by the designated study personnel on Day 1 of each cycle.
z
aa
The device/e-diary should be fully charged, and checked that it is fully functioning, prior to the patient’s first dosing visit. The site should ensure the patient 
is trained and understands how to use the PRO device/doing diary prior to the first use.
bb
Survival status collected 8 weekly reducing to 12 weekly after 18 months.
cc
Other anti-cancer therapies collected 8 weekly reducing to 12 weekly after 18 months. Off study treatment follow-up: subsequent anti-cancer therapies to be 
collected.
AE = adverse events; ATM = ataxia telangiectasia mutated; BICR = Blinded independent central review; BRAF = B-Rapidly Accelerated Fibrosarcoma gene; 
C = cycle; CR = complete response; CSP = clinical study protocol; CT = computed tomography; 
; d = day;
; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; 
; IL = Item Library; IV = intravenous; MRI = magnetic resonance imaging; 
MSI = microsatellite instability; MUGA = multigated acquisition; NF1 = neurofibromatosis type 1; 
;
PD-(L)1 = programmed death ligand 1; 
; PK = pharmacokinetic; PRO = patient-reported outcomes; 
; RECIST = Response Evaluation Criteria in Solid Tumours; 
; SAE = serious adverse event; SD = stable disease; SoC = standard of care; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid 
stimulating hormone; WOCBP = women of childbearing potential.
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Table 2 
Ceralasertib Monotherapy (Main Study)  
Procedure 
Screening a 
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in CSP section 
 or appendix 
Cycles 1-2 
Cycle 3 
C4-onwards 
Study Treatment  
Discontinued  
(Last dose of study treatment) 
Safety follow-up  
 
Progression/Survival 
Follow-up  
 
(Q8W until  
18 months, then 
Q12W) 
 
Cycle Day  
-21 
to 
 -1 
Day 1 
Day 7 
Day 15 
Day 1 
Day 7 
Day 15 
Day 1 
Day 15 
 
30 days after  
last dose 
 
 
Visit window 
(± days)  
- 
- 
- 
± 1 
± 3 
- 
± 1 
± 3 
± 1 
± 3 
± 7 
 
Informed consent: 
main study b 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 5 and 
Appendix A 3 
Informed consent: 
genetic sample and 
analysis (optional) b 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 and 
Appendix A 3 
 
Archival tumour 
sample, mandatory c 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 8.6.1 
Fresh tumour biopsy 
d 
X 
 
 
X 
(C2 
only) 
 
 
 
 
 
X (PD) 
 
 
Section 8.6.1 
Inclusion and 
exclusion criteria e, f 
X 
X 
 
 
 
 
 
 
 
 
 
 
Sections 5.1, 5.2 and 
5.4 
Demography g 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
Prior anti-cancer 
therapy h 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
Full physical 
examination a 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
Section 8.2.1 
Targeted physical 
examination i 
 
 
X 
X 
 
X 
X 
 
X 
 
 
 
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Procedure 
Screening a 
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in CSP section 
 or appendix 
Cycles 1-2 
Cycle 3 
C4-onwards 
Study Treatment  
Discontinued  
(Last dose of study treatment) 
Safety follow-up  
 
Progression/Survival 
Follow-up  
 
(Q8W until  
18 months, then 
Q12W) 
 
Cycle Day  
-21 
to 
 -1 
Day 1 
Day 7 
Day 15 
Day 1 
Day 7 
Day 15 
Day 1 
Day 15 
 
30 days after  
last dose 
 
 
Visit window 
(± days)  
- 
- 
- 
± 1 
± 3 
- 
± 1 
± 3 
± 1 
± 3 
± 7 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1 
Weight a 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Section 8.2.1 
Past and current 
medical conditions 
X 
X a 
 
 
 
 
 
 
 
 
 
 
Sections 5.1 and 5.2 
12-lead ECG j, k 
X 
(Trip
licat
e) 
As clinically indicated; single ECGs 
 
 
 
Section 8.2.3 
Echocardiogram/MU
GA 
X 
As clinically indicated 
X 
 
 
Section 8.2.6.1 
Vital signs k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 8.2.2 
ECOG performance 
status l 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
Section 8.2.4 
Hepatitis B and C 
and HIV screening 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 and 8.2.5 
Safety laboratory 
assessments (clinical 
chemistry including 
TSH, haematology, 
urinalysis) f, k, m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Procedure
Screening a
Intervention period (28-day cycles)
Post-intervention follow-up period
Details in CSP section
or appendix
Cycles 1-2
Cycle 3
C4-onwards
Study Treatment 
Discontinued 
(Last dose of study treatment)
Safety follow-up Progression/Survival 
Follow-up
(Q8W until 
18 months, then 
Q12W)
Cycle Day 
-21
to
-1
Day 1
Day 7
Day 15
Day 1
Day 7
Day 15
Day 1
Day 15
30 days after 
last dose
Visit window 
(± days) 
-
-
-
± 1
± 3
-
± 1
± 3
± 1
± 3
± 7
Coagulation 
parameters n
X
X
Section 8.2.5
Pregnancy test 
(WOCBP only) o
X
X
X
X
X
Section 8.2.5
AE
X
Å============                                  X                          ===============Æ
At every visit and may be conducted by phone if not tied to a visit.
Section 8.3
Concomitant 
medications
X
Å============                                  X                          ===============Æ
At every visit and may be conducted by phone if not tied to a visit.
Section 6.5
Tumour imaging 
(RECIST 1.1; 
CT/MRI including 
brain scan at 
baseline) p, s
X q
X
Tumour assessments will be conducted every 8 weeks (±1 week) after start of 
treatment (C1D1) up to 18 months, then every 12 weeks (±1 week) until 
objective disease progression per RECIST 1.1. If a patient discontinues without 
disease progression, RECIST tumour assessments will be performed every 8 weeks for 
18 months, then every 12 weeks, thereafter.
Section 8.1.1
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Procedure
Screening a
Intervention period (28-day cycles)
Post-intervention follow-up period
Details in CSP section
or appendix
Cycles 1-2
Cycle 3
C4-onwards
Study Treatment 
Discontinued 
(Last dose of study treatment)
Safety follow-up Progression/Survival 
Follow-up
(Q8W until 
18 months, then 
Q12W)
Cycle Day 
-21
to
-1
Day 1
Day 7
Day 15
Day 1
Day 7
Day 15
Day 1
Day 15
30 days after 
last dose
Visit window 
(± days) 
-
-
-
± 1
± 3
-
± 1
± 3
± 1
± 3
± 7
Blood sample for 
ceralasertib PK 
testing u
X
X
Section 8.5.1
Randomisation v
X
Section 6.3
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Procedure
Screening a
Intervention period (28-day cycles)
Post-intervention follow-up period
Details in CSP section
or appendix
Cycles 1-2
Cycle 3
C4-onwards
Study Treatment 
Discontinued 
(Last dose of study treatment)
Safety follow-up Progression/Survival 
Follow-up
(Q8W until 
18 months, then 
Q12W)
Cycle Day 
-21
to
-1
Day 1
Day 7
Day 15
Day 1
Day 7
Day 15
Day 1
Day 15
30 days after 
last dose
Visit window 
(± days) 
-
-
-
± 1
± 3
-
± 1
± 3
± 1
± 3
± 7
Ceralasertib study 
treatment (dispensed 
or returned)
X
X
X
X
(returned)
Sections 6.2.2.2 and 
6.4
Dosing with 
ceralasertib (self-
administered) w
X (Days 1 to 
7 of every 
cycle)
X (Days 1 to 
7 of every 
cycle)
X
(Days 1 
to 7 of 
every 
cycle)
Sections 6.2.2.2 and 
6.4
Dosing diary x, z
X
(Days 1 to 7 of every cycle)
Section 6.4
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Procedure
Screening a
Intervention period (28-day cycles)
Post-intervention follow-up period
Details in CSP section
or appendix
Cycles 1-2
Cycle 3
C4-onwards
Study Treatment 
Discontinued 
(Last dose of study treatment)
Safety follow-up Progression/Survival 
Follow-up
(Q8W until 
18 months, then 
Q12W)
Cycle Day 
-21
to
-1
Day 1
Day 7
Day 15
Day 1
Day 7
Day 15
Day 1
Day 15
30 days after 
last dose
Visit window 
(± days) 
-
-
-
± 1
± 3
-
± 1
± 3
± 1
± 3
± 7
PRO training/set up z
X
X
Section 8.1.3.1
Survival status aa
X
X
Sections 7.1.3 and 
8.1.2
Subsequent 
anticancer therapy bb
X
X
X
Section 7.1.2
a
If screening assessments have been performed within 3 days prior to starting study intervention, they do not have to be repeated at Cycle 1 Day 1 if the 
patient’s condition has not changed.
b
Written informed consent and any locally required privacy act document authorisation must be obtained prior to performing any protocol-specific 
procedures, including screening/baseline evaluations.
c
Submission of archival tumour tissue is mandatory for all patients. A minimum of 20 freshly cut unstained sections from the archival tumour block are 
accepted if tumour blocks cannot be submitted, however tumour tissue blocks are preferred.
d
Fresh tumour biopsies are mandatory in all patients with biopsiable disease at screening. However, if patients do not have disease suitable for biopsy, they 
are required to provide a tumour sample collected within 5 years prior to study entry. Optional on-treatment biopsies will be collected at Cycle 2 between 
Day 15 and Day 28 for ceralasertib monotherapy and at disease progression, only if a fresh tumour sample was provided at screening. Optional on-treatment 
biopsies are not required if a fresh tumour sample was not collected at screening. For sample collection details refer to Section 8.6 of the protocol.
e
Submission of the cytological or histological report, and molecular report confirming BRAF mutation status is mandatory at screening. In addition, the 
investigator must confirm the type of PD-(L)1 resistance at screening and whether the LDH is normal or above upper limit of normal, in order to stratify the 
patients accordingly. Other genomic characteristics will be collected where known eg, NRAS, c-kit, PD-(L)1, NF1, MSI.
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f
Clinical laboratory assessment parameters are to be assessed at baseline on Day 1 (unless all screening laboratory assessments are performed within 3 days 
prior to Day 1) and full blood count result should be checked prior to dosing when assessed on a dosing day. Serum or plasma clinical chemistry (including 
LFT monitoring) and haematology may be performed more frequently if clinically indicated. Urinalysis should be performed at baseline (screening) and 
then as clinically indicated. Thyroid stimulating hormone testing is to be done at the timepoints indicated and also when clinically indicated (clinically 
suspecting immune-related hypo/hyper thyroidism). Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE 
related to the endocrine system.
g
Baseline demographics will include all prior treatments (start/stop dates, best response, treatment line, reason for treatment discontinuation and, if due to 
RECIST 1.1-defined disease progression, how progression was determined and dates of radiographic scans indicating disease progression per RECIST 1.1)
and disease stage at diagnosis and at study entry. Other genomic characteristics will be collected where known eg, NRAS, c-kit, PD-(L)1, NF1, MSI.
h
Collect prior anti-cancer therapies, including best response, setting (eg, adjuvant/metastatic), prior radiotherapy, and prior surgery. For the prior anti-PD-
(L)1 regimen, also collect reason for discontinuation and details of scans indicating RECIST 1.1 disease progression, including anonymised copies of the 
scan reports.
i
Additional physical examination will be performed, if clinically indicated.
j
Triplicate ECGs at screening only. Subsequent ECGs should only be taken if clinically indicated.
k
Whenever ECG, vital signs and blood draws are scheduled on the same day, it is recommended that the assessments occur in the following order: vital 
signs, ECG, and then blood draws. The timing of the ECG and vital signs assessments must allow for the blood draw (eg, PK blood sample) to occur at the 
scheduled time points.
l
ECOG assessment also to be performed at initiation of subsequent anticancer therapy, where possible. In addition, ECOG performance status should be 
collected at initiation of subsequent anticancer therapy, if appropriate site staff are available to collect such information. Additional ECOG assessments may 
be performed (eg, on Day 15), if clinically indicated.
m
Patients who develop a ≥Grade 3 of anaemia, neutropenia, or thrombocytopenia during the treatment period will also need to have additional assessments 
on Day 7 (for ceralasertib monotherapy) until there is no evidence of ≥ Grade 3 anaemia, neutropenia, or thrombocytopenia for at least 2 cycles.
n
Coagulation will be performed at screening and as clinically indicated during subsequent visits. For country-specific requirements for Belgium see 
Appendix K 1.1.
o
Women of childbearing potential only. Serum pregnancy test at screening, urine test at other time points up to 30 days after the last dose of study treatment.
For country-specific requirements for Belgium and France see Appendices K 1.1 and K 1.2, respectively.
p
Computed tomography scans of the chest, abdomen, and pelvis (or MRI where CT is contraindicated) should be conducted every 8 weeks (±1 week) after 
the start of treatment (Cycle 1 Day 1) up to 18 months, then every 12 weeks (±1 week) until objective disease progression as per RECIST 1.1, irrespective 
of treatment decisions. In the event of treatment interruptions or delays, tumour assessments should proceed to schedule relative to Cycle 1 Day 1. Soft 
tissue or visceral progression observed by CT or MRI, according to RECIST 1.1, does not require a confirmatory scan. To confirm progression based on 
non-target lesions, additional scans or images/photographs may be required for submission for BICR.
q
Baseline contrast enhanced MRI brain scan assessment (or CT if MRI is contraindicated) for all patients at screening.
r
s
t
u
PK samples will be collected in all patients at pre-dose (up to 1 hour prior) and 1 hour (± 30 min) post-dose on D7 of each cycle, for the first 3 cycles.
v
Every effort should be made to minimise the time between randomisation and starting treatment (ie, within 3 business days of randomisation).
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w
Ceralasertib administered twice daily from Days 1 to 7 of each cycle.
x
For ceralasertib, patients will be required to complete a dosing diary (e-diary) from Day 1 to Day 7 of each cycle, using an electronic device. The dosing 
diary must be reviewed by the designation study personnel on Day 1 of each cycle.
y
z
The device/e-diary should be fully charged, and checked that it is fully functioning, prior to the patient’s first dosing visit. The site should ensure the patient 
is trained and understands how to use the PRO device/dosing diary prior to the first use.
aa
Survival status collected 8 weekly, reducing to 12 weekly after 18 months.
bb
Other anti-cancer therapies collected 8 weekly, reducing to 12 weekly after 18 months. Off study treatment follow-up: subsequent anti-cancer therapies to 
be collected.
AE = adverse events; ATM = ataxia telangiectasia mutated; BICR = Blinded independent central review; BRAF = B-Rapidly Accelerated Fibrosarcoma gene; 
C = cycle; CR = complete response; CSP = clinical study protocol; CT = computed tomography; 
; d = day;
; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; 
; HIV = human immunodeficiency virus;
; MRI = magnetic resonance 
imaging; MSI = microsatellite instability; MUGA = multigated acquisition; NF1 = neurofibromatosis type 1;
;
PD-(L)1 = programmed death ligand 1; 
; PK = pharmacokinetic; 
; RECIST = Response Evaluation Criteria in Solid Tumours; 
; SAE = serious adverse event; 
SD = stable disease; SoC = standard of care; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; WOCBP = women of childbearing 
potential.
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Table 3 
Biopsy Sub-study  
Procedure 
Screening a  
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in 
CSP section 
 or 
appendix 
Cycle 0 
Cycle 1 
C2-
onwards 
Study Treatment Discontinued
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-21 to 
 -1 
Day 1 
Day 7 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
30 days 
60 days 
90 days 
180 days  
(6 months) 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
 
± 3 
± 1 
± 3 
± 7 
± 7 
± 7 
 
Informed consent: 
main study b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5 
and 
Appendix 
A 3 
Informed consent: 
genetic sample and 
analysis (optional) b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
and 
Appendix A 3
 
Archival tumour 
sample, mandatory c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.6.1 
Fresh tumour biopsy d 
X 
 
X 
X (between 
D15 and 
D28) 
 
 
 
 
 
 
X (PD; 
optional
) 
 
 
 
 
 
Section 8.6.1 
Inclusion and 
exclusion criteria e, f 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sections 
5.1, 5.2 and 
5.4 
Demography g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Procedure 
Screening a  
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in 
CSP section 
 or 
appendix 
Cycle 0 
Cycle 1 
C2-
onwards 
Study Treatment Discontinued
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-21 to 
 -1 
Day 1 
Day 7 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
30 days 
60 days 
90 days 
180 days  
(6 months) 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
 
± 3 
± 1 
± 3 
± 7 
± 7 
± 7 
 
Prior anti-cancer 
therapy h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 
5.1 
Full physical 
examination a 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
Section 
8.2.1 
Targeted physical 
examination i 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
Section 
8.2.1 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 
8.2.1 
Weight a 
X 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Section 
8.2.1 
Past and current 
medical conditions 
X 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sections 
5.1 and 
5.2 
12-lead ECG j, k 
X 
(Triplicat
e) 
As clinically indicated; single ECGs 
 
 
 
 
 
 
Section 
8.2.3 
Echocardiogram/MU
GA 
X 
As clinically indicated 
X 
 
 
 
 
 
Section 
8.2.6.1 

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Procedure 
Screening a  
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in 
CSP section 
 or 
appendix 
Cycle 0 
Cycle 1 
C2-
onwards 
Study Treatment Discontinued
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-21 to 
 -1 
Day 1 
Day 7 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
30 days 
60 days 
90 days 
180 days  
(6 months) 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
 
± 3 
± 1 
± 3 
± 7 
± 7 
± 7 
 
Vital signs k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 
8.2.2 
ECOG performance 
status l 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Section 
8.2.4 
Hepatitis B and C 
and HIV screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sections 
5.1 and 
8.2.5 
Safety laboratory 
assessments (clinical 
chemistry including 
TSH, haematology, 
urinalysis) f, k, m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 
8.2.5 
Coagulation 
parameters n 
X 
X 
Section 
8.2.5 
Pregnancy test 
(WOCBP only) o 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
 
 
Section 
8.2.5 
AE 
X 
Å============                                  X                          ===============Æ 
At every visit and may be conducted by phone if not tied to a visit. 
 
 
Section 8.
3 

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Procedure
Screening a
Intervention period (28-day cycles)
Post-intervention follow-up period
Details in 
CSP section
or 
appendix
Cycle 0
Cycle 1
C2-
onwards
Study Treatment Discontinued
(last dose of study treatment)
Safety follow-up
(# of days after last dose)
Progression/Survival 
Follow-up (Q8W until 
18 months, then Q12W)
Cycle Day 
-21 to
-1
Day 1
Day 7
Day 15
Day 22
Day 1
Day 8
Day 15
Day 22
Day 1
Day 8
30 days
60 days
90 days
180 days 
(6 months)
Visit window 
(± days) 
-
-
-
-
± 1
± 3
-
± 1
± 3
± 1
± 3
± 7
± 7
± 7
Concomitant 
medications
X
Å============                                  X                          ===============Æ
At every visit and may be conducted by phone if not tied to a visit.
Section 6.
5
Tumour imaging 
(RECIST 1.1; 
CT/MRI including 
brain scan at 
baseline) p
X q
X
Tumour assessments will be conducted every 8 weeks (±1 week) after start of 
treatment (C1D1) up to 18 months, then every 12 weeks (±1 week) until objective 
disease progression per RECIST 1.1. If a patient discontinues without disease 
progression, RECIST tumour assessments will be performed 8 weekly for 18 
months, then 12 weekly, thereafter.
Section 
8.1.1
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Procedure
Screening a
Intervention period (28-day cycles)
Post-intervention follow-up period
Details in 
CSP section
or 
appendix
Cycle 0
Cycle 1
C2-
onwards
Study Treatment Discontinued
(last dose of study treatment)
Safety follow-up
(# of days after last dose)
Progression/Survival 
Follow-up (Q8W until 
18 months, then Q12W)
Cycle Day 
-21 to
-1
Day 1
Day 7
Day 15
Day 22
Day 1
Day 8
Day 15
Day 22
Day 1
Day 8
30 days
60 days
90 days
180 days 
(6 months)
Visit window 
(± days) 
-
-
-
-
± 1
± 3
-
± 1
± 3
± 1
± 3
± 7
± 7
± 7
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Procedure 
Screening a  
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in 
CSP section 
 or 
appendix 
Cycle 0 
Cycle 1 
C2-
onwards 
Study Treatment Discontinued
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-21 to 
 -1 
Day 1 
Day 7 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
30 days 
60 days 
90 days 
180 days  
(6 months) 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
 
± 3 
± 1 
± 3 
± 7 
± 7 
± 7 
 
Blood sample for 
ceralasertib PK 
testing u 
 
X 
X 
 
 
 
 
 
 
 
 
X 
(optiona
l if 
biopsy 
is 
collecte
d) 
 
 
 
 
 
Section 
8.5.1 
Blood sample for 
durvalumab PK 
testing u 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Section 
8.5.1 
Blood sample for 
durvalumab 
immunogenicity 
testing v 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
Section 
8.5.2 
Ceralasertib study 
treatment (dispensed 
or returned) 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
(returne
d) 
 
 
 
 
 
Sections 
6.2.2.2 
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Procedure 
Screening a  
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in 
CSP section 
 or 
appendix 
Cycle 0 
Cycle 1 
C2-
onwards 
Study Treatment Discontinued
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-21 to 
 -1 
Day 1 
Day 7 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
30 days 
60 days 
90 days 
180 days  
(6 months) 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
 
± 3 
± 1 
± 3 
± 7 
± 7 
± 7 
 
Dosing with 
ceralasertib 
(self-administered) w 
 
X x (Days 
1 to 7) 
 
 
X 
(Day
s 1 
to 7 
of 
ever
y 
cycle
) 
 
 
 
X 
(Day
s 1 
to 7 
of 
ever
y 
cycle
) 
 
 
 
 
 
 
 
Sections 
6.2.2.2 
and 6.4 
Dosing with 
durvalumab (IV 
infusion) w 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Sections 
6.2.1.2 
and 
6.2.1.3 
Dosing diary y, z 
 
X (Days 1 to 7 of every cycle) 
 
 
 
 
 
 
Section 
6.4 
Survival status aa 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Sections 
7.1.3 and 
8.1.2 
Subsequent 
anticancer therapy bb 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Section 
7.1.2 
a 
If screening assessments have been performed within 3 days prior to starting study intervention, they do not have to be repeated at Cycle 1 Day 1 if the 
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b 
Written informed consent and any locally required privacy act document authorisation must be obtained prior to performing any protocol-specific 
procedures, including screening/baseline evaluations. 
c 
Submission of archival tumour tissue is mandatory for all patients. A minimum of 20 freshly cut unstained sections from the archival tumour block are 
accepted if tumour blocks cannot be submitted, however tumour tissue blocks are preferred. 
d 
All study patients in the biopsy substudy are required to provide 3 mandatory fresh tumour biopsy samples for testing at Screening (Days -21 to -1), 
on-ceralasertib treatment, Cycle 0 (on Day 7) of ceralasertib monotherapy, and off-ceralasertib treatment, Cycle 0 (between Days 15 to 28). For sample 
collection details refer to Section 8.6 of the protocol. 
e 
Submission of the cytological or histological report, and molecular report confirming BRAF mutation status is mandatory at screening. In addition, the 
investigator must confirm the type of PD-(L)1 resistance at screening and whether the LDH is normal or above upper limit of normal, in order to stratify the 
patients accordingly. Other genomic characteristics will be collected where known eg, NRAS, c-kit, PD-(L)1, NF1, MSI. 
f 
Clinical laboratory assessment parameters are to be assessed at baseline on Day 1 (unless all screening laboratory assessments are performed within 3 days 
prior to Day 1) and full blood count result should be checked prior to dosing when assessed on a dosing day. Serum or plasma clinical chemistry (including 
LFT monitoring) and haematology may be performed more frequently if clinically indicated. Urinalysis should be performed at baseline (screening) and 
then as clinically indicated. Thyroid stimulating hormone testing is to be done at the timepoints indicated and also when clinically indicated (clinically 
suspecting immune-related hypo/hyper thyroidism). Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE 
related to the endocrine system. 
g 
Baseline demographics will include all prior treatments (start/stop dates, best response, treatment line, reason for treatment discontinuation and, if due to 
RECIST 1.1-defined disease progression, how progression was determined and dates of radiographic scans indicating disease progression) and disease stage 
at diagnosis and at study entry. Other genomic characteristics will be collected where known eg, NRAS, c-kit, PD-(L)1, NF1, MSI. 
h 
Collect data on prior anti-cancer therapies, including best response, setting (eg, adjuvant/metastatic), prior radiotherapy, and prior surgery. For the prior 
anti-PD-(L)1 regimen, also collect reason for discontinuation and details of scans indicating RECIST 1.1-defined disease progression, including 
anonymised copies of the scan reports. 
i 
Additional physical examination will be performed, if clinically indicated. 
j 
Triplicate ECGs at screening only. Subsequent ECGs should only be taken if clinically indicated. 
k 
Whenever ECG, vital signs and blood draws are scheduled on the same day, it is recommended that the assessments occur in the following order: vital 
signs, ECG, and then blood draws. The timing of the ECG and vital signs assessments must allow for the blood draw (eg, PK blood sample) to occur at the 
scheduled time points. 
l 
ECOG assessment also to be performed at initiation of subsequent anticancer therapy, where possible. In addition, ECOG performance status should be 
collected at initiation of subsequent anticancer therapy, if appropriate site staff are available to collect such information. Additional ECOG assessments may 
be performed (eg, on Day 15), if clinically indicated. 
m 
Patients who develop a ≥ Grade 3 of anaemia, neutropenia, or thrombocytopenia during the treatment period will also need to have additional assessments 
also on Day 15 until there is no evidence of ≥ Grade 3 anaemia, neutropenia, or thrombocytopenia for at least 2 cycles. 
n 
Coagulation will be performed at screening and as clinically indicated during subsequent visits. 
o 
Women of childbearing potential only. Serum pregnancy test at screening, urine test at other time points up to 90 days after the last dose of study treatment. 
For country-specific requirements for Belgium and France see Appendices K 1.1 and K 1.2, respectively. 

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p
CT scans of the chest, abdomen, and pelvis (or MRI where CT is contraindicated) should be conducted every 8 weeks (±1 week) after the start of study 
treatment (Cycle 1 Day 1) up to 18 months, then every 12 weeks (±1 week) until objective disease progression as per RECIST 1.1, irrespective of treatment 
decisions. In the event of study treatment interruptions or delays, tumour assessments should proceed to schedule relative to Cycle 1 Day 1. Soft tissue or 
visceral progression observed by CT or MRI, according to RECIST 1.1, does not require a confirmatory scan. To confirm progression based on non-target 
lesions, additional scans or images / photographs may be required for submission for BICR.
q
Baseline contrast enhanced MRI brain scan assessment (or CT if MRI is contraindicated) for all patients at screening.
r
s
t
u
For ceralasertib, PK sample will be collected in all patients at pre-dose (up to 1 hour prior) and 1 hour (± 30 min) post-dose on Day 1 and Day 7 of Cycle 0.
For durvalumab, PK sample will be collected in all patients at study treatment discontinuation and at 90 days after last dose of the study treatment. For 
non-dosing days, PK sample will be collected at similar times as dosing day.
v
Immunogenicity sample for durvalumab to be collected at screening, end of treatment, 90 days and 6 months (± 7 days) after last dose.
w
Ceralasertib administered twice daily from Days 1 to 7 at Cycle 0 (a 28-day cycle) and at each cycle, Cycle 1 onwards. Durvalumab administered on Day 8
of each cycle, from Cycle 1 onwards.
x
Cycle 1 may start after the off-treatment biopsy is collected ie, between Cycle 0, Days 15 to 28, and if blood parameters are within limits. For 
country-specific requirements for Belgium see Appendix K 1.1.
y
For ceralasertib, patients will be required to complete a dosing diary (e-diary) from Day 1 to Day 7 of each cycle, using an electronic device. The dosing 
diary must be reviewed by the designated study personnel at Day 1 of each cycle.
z
The device/e-diary should be fully charged, and checked that it is fully functioning, prior to the patient’s first dosing visit. The site should ensure the patient 
is trained and understands how to use the dosing diary prior to the first use.
aa
Survival status collected 8 weekly reducing to 12 weekly after 18 months.
bb
Other anti-cancer therapies collected 8 weekly reducing to 12 weekly after 18 months. Off study treatment follow-up: subsequent anti-cancer therapies to be 
collected.
AE = adverse events; ATM = ataxia telangiectasia mutated; BICR = Blinded independent central review; BRAF = B-Rapidly Accelerated Fibrosarcoma gene; 
C = cycle; CR = complete response; CSP = clinical study protocol; CT = computed tomography; 
; d = day;
; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HIV = human 
immunodeficiency virus; MRI = magnetic resonance imaging; MSI = microsatellite instability; MUGA = multigated acquisition; NF1 = neurofibromatosis type 
1; 
; PD-(L)1 = programmed death ligand 1; 
; PK = pharmacokinetic; RECIST = Response 
Evaluation Criteria in Solid Tumours; 
; SAE = serious adverse event; SD = stable disease; SoC = standard of care; T3 = triiodothyronine; 
T4 = thyroxine; TSH = thyroid stimulating hormone; WOCBP = women of childbearing potential.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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2 
INTRODUCTION  
2.1 
Study Rationale  
This Phase 2 study aims to evaluate the efficacy and safety/tolerability of ceralasertib 
(AZD6738), when administered as monotherapy and in combination with durvalumab in 
patients with unresectable or advanced melanoma and primary or secondary resistance to 
PD-(L)1 inhibition. The rationale for conducting the main study is supported by clinical data 
from ongoing studies, unmet need, and the evidence of ceralasertib modulating the immune 
environment. 
An open-label, non-randomised, biopsy sub-study is also planned in patients suitable for 
3 mandatory biopsies. The rationale for conducting the biopsy sub-study is to understand the 
MoA of ceralasertib plus durvalumab and investigate ceralasertib as an immune modulator. 
The background to the study rationale is summarised in Section 2.2 and Section 2.3. The 
rationale for study design summarised in Section 4.2 and justification for study treatment dose 
summarised in Section 4.3. 
2.2 
Background  
2.2.1 
Immunotherapies  
It is increasingly understood that cancers are recognised by the immune system, and under 
some circumstances, the immune system may control or even eliminate tumours (Dunn et al 
2004). 
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling 
T‑cell activation. The PD‑1 receptor (cluster of differentiation [CD]279) is expressed on the 
surface of activated T-cells (Keir et al 2008). It has 2 known ligands: PD‑L1 (B7‑H1; CD274) 
and programmed death‑ligand 2 (PD‑L2) (B7‑DC; CD273) (Okazaki and Honjo 2007). PD‑1 
and PD‑L1/PD‑L2 belong to a family of immune checkpoint proteins that act as co‑inhibitory 
factors, which can halt or limit the development of T-cell response. When PD‑L1 binds to 
PD-1, an inhibitory signal is transmitted into the T-cell, which reduces cytokine production 
and suppresses T‑cell proliferation. Tumour cells exploit this immune checkpoint pathway as 
a mechanism to evade detection and inhibit immune response. 
PD‑L1 is constitutively expressed by B‑cells, dendritic cells, and macrophages (Qin et al 
2016). Importantly, PD‑L1 is commonly over‑expressed on tumour cells or on 
non‑transformed cells in the tumour microenvironment (Pardoll 2012). PD‑L1 expressed on 
the tumour cells binds to PD‑1 receptors on the activated T-cells, leading to the inhibition of 
cytotoxic T-cells. These deactivated T-cells remain inhibited in the tumour microenvironment. 

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The PD‑1/PD‑L1 pathway represents an adaptive immune resistance mechanism that is 
exerted by tumour cells in response to endogenous antitumour activity. 
The inhibitory mechanism described above is co-opted by tumours that express PD-L1 as a 
way of evading immune detection and elimination. The binding of an anti-PD-L1 agent to the 
PD‑L1 receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed 
on immune cells. This activity overcomes PD-L1-mediated inhibition of antitumour 
immunity. While functional blockade of PD-L1 results in T-cell reactivation, this mechanism 
of action is different from direct agonism of a stimulatory receptor such as CD28. 
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance antitumour immune responses in 
participants with cancer. Results of pre-clinical and clinical studies of monoclonal antibodies 
(mAbs) targeting the PD‑L1/PD-1 pathway have shown evidence of clinical activity and a 
manageable safety profile, supporting the hypothesis that an anti-PD-L1 antibody could be 
used to therapeutically enhance antitumour immune response in participants with cancer 
(Brahmer et al 2012, Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009, Topalian et al 
2012, Zhang et al 2008) with responses that tend to be more pronounced in participants with 
tumours that express PD-L1 (Powles et al 2014, Rizvi et al 2015, Segal et al 2015). In 
addition, high mutational burden (eg, in bladder carcinoma; Alexandrov et al 2013) may 
contribute to the responses seen with immune therapy. 
In contrast, CTLA-4 is constitutively expressed by regulatory T-cells and upregulated on 
activated T-cells. CTLA-4 delivers a negative regulatory signal to T-cells upon binding of 
CD80 (B7.1) or CD86 (B7.2) ligands on antigen-presenting cells (Fife and Bluestone 2008). 
Blockade of CTLA-4 binding to CD80/86 by anti‑CTLA-4 antibodies results in markedly 
enhanced T-cell activation and antitumour activity in animal models, including killing of 
established murine solid tumours and induction of protective antitumour immunity. Therefore, 
it is expected that treatment with an anti‑CTLA-4 antibody will lead to increased activation of 
the human immune system, increasing antitumour activity in participants with solid tumours. 
Pre-clinical data have now been added to a wealth of clinical data showing that blockade of 
negative regulatory signals to T-cells such as CTLA-4 and PD-L1 has promising clinical 
activity. Ipilimumab was first granted United States (US) FDA approval for the treatment of 
metastatic melanoma and is currently under investigation for several other malignancies. 
Nivolumab and pembrolizumab, 2 anti-PD-1 agents, and atezolizumab, an anti‑PD-L1 agent, 
have been granted approvals by agencies for the treatment of a number of malignancies 
including metastatic melanoma, squamous and non-squamous cell non-small-cell lung cancer, 
squamous cell carcinoma of the head and neck, and urothelial carcinoma. In addition, there are 
data from agents in the anti-PD-1/PD-L1 class showing clinical activity in a wide range of 
tumour types. 

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2.2.2 
Melanoma  
Melanoma is the most serious form of skin cancer and the fifth most frequently diagnosed 
cancer in the US, with 100,350 new cases estimated to occur in 2020, representing 6% of all 
new cancer diagnoses. The incidence of melanoma is increasing each year. Five-year survival 
rates depend on the stage of disease at the time of diagnosis. For those with localised disease, 
5-year relative survival is estimated at 92%. However, in the US, approximately 4% of 
patients present with metastatic melanoma, the main cause of melanoma deaths (Zbytek B et 
al, 2008), and the 5-year relative survival rate is approximately 25%. In 2020, it is anticipated 
that there will be an estimated 6,850 deaths from melanoma (Siegel RL et al, 2020). 
In the US, since 2011, mortality rates for melanoma have declined rapidly, decreasing by an 
average of approximately 7% per year between 2013 and 2017. This decline in mortality for 
metastatic disease has been attributed to the approval of immunotherapies such as CPIs and 
targeted treatments such as BRAF and MEK inhibitors (Siegel RL et al, 2020). Whilst 
approximately 50% of patients may be suitable for targeted therapy, immunotherapy is the 
mainstay of treatment, due to the fact that durable CRs and long-term clinical benefit are 
observed. However, the majority of patients treated with CPI would exhibit either primary 
resistance (defined as treatment duration ≥ 6 weeks and best response of progressive disease 
or stable disease for < 6 months), or secondary resistance (defined as treatment duration 
≥ 6 months and best response of CR, PR, or stable disease for > 6 months), according to 
Society for Immunotherapy of Cancer consensus definition (Kluger HM et al, 2020). 
However, when resistance to CPI occurs on treatment, there are no standards of care and the 
available treatment recommendation options are limited and provide minimal clinical benefit. 
Chemotherapy may be an option for these patients but has not been proven to increase 
survival and is associated with a short-lasting objective response in a minority of patients, as 
reported in few retrospective studies. The majority of these studies pre-date the use of CPI. 
However, there are retrospective studies which have reported anecdotal activity of 
chemotherapy in immunotherapy-resistant patients, with varying magnitudes of benefit 
(Goldinger DS et al, 2018). 
Among the promising treatments for CPI-resistant advanced melanoma there is a cellular 
therapy with cryopreserved autologous tumour infiltrating lymphocytes (lifileucel or LN144). 
Preliminary data from a Phase 2 study in patients with unresectable or metastatic melanoma 
treated with at least 1 systemic prior therapy including a PD-(L)1 blocking antibody and if 
BRAF V600 mutation positive, a BRAF or BRAF/MEK inhibitor, were recently presented. 
Sixty-six patients were pre-treated with anti-PD-(L)1, 80% with anti-CTLA-4, and 23% with a 
combination of BRAF/MEK inhibitor. Common Terminology Criteria for Adverse Events 
Grade 3/4 thrombocytopenia, anaemia, febrile neutropenia, and neutropenia were reported in 
54 (82%), 31 (47%), 36 (55%), and 26 (39%) of the patients respectively. Objective responses 
were demonstrated in 24 (36.4%) patients and median DoR was not yet reached after 
18.7 months of follow-up (Sarnaik A et al, 2020). Considering the proportion of patients with 

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CTCAE Grade 3/4 events and that patients must have one lesion of > 1.5 cm resectable for 
tumour-infiltrating lymphocyte generation, it could be anticipated that few patients would be 
eligible for the treatment with lifileucel. Therefore, patients with advanced unresectable 
melanoma with primary and secondary resistance to PD-(L)1 inhibition, according to Society 
for Immunotherapy of Cancer consensus definition (Kluger HM et al, 2020), should be still 
considered as a population of unmet medical need.
2.2.3
Ceralasertib
Ceralasertib (AZD6738) is being developed as an oral anti-tumour agent in patients with DNA 
Damage Response (DDR)-deficient tumours, including (but not limited to) breast cancer 
susceptibility gene (BRCA) mutant and ATM gene or protein deficiency, or in combination 
with durvalumab, chemotherapy or poly-adenosine 5’‑diphosphate-ribose polymerase (PARP) 
inhibitors. Activity may not be restricted to these patient populations and there is preclinical 
evidence of activity as monotherapy or combinations across broader malignant disease types 
and molecular aberrations.
Ceralasertib is an inhibitor of the serine/threonine protein kinase, ATR, a member of the 
phosphatidylinositol 3 kinase-related kinase family (Foote et al 2018). ATR is the apical 
kinase in the replication stress response DNA damage induced checkpoint pathway (Cimprich 
and Cortez 2008, Forment and O’Connor 2018) and during normal DNA replication is 
recruited at stalled replication forks, which can progress to double strand breaks (DSBs) if left 
unrepaired. Following resection of DSBs, ATR is recruited to single-strand DNA coated with 
Replication Protein A following single-strand DNA damage. Recruitment and activation of 
ATR leads to cell cycle arrest in S-phase while the DNA is repaired, and the stalled replication 
fork resolved. 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.
In addition, there is evidence that ATR can modulate the tumour immune environment and 
inhibition of ATR can potentiate the effects of treatment by modulation of T-cells. 
Ceralasertib is being developed as monotherapy in patients whose tumours have potentially 
sensitising genotypes that include but are not limited to biomarkers such as ATM-deficiency, 
high replication stress or immune signatures - combining with the PARP inhibitor, olaparib, or 
chemotherapy where ATR inhibition exacerbates the effects of DNA damaging treatments and 
in combination with durvalumab where inhibition of ATR is postulated to enhance antitumour 
activity.
As of the cut-off of 13 June 2021, ceralasertib has been administered to 1173 patients either as 
monotherapy or in combination with other agents. This includes 506 patients in AstraZeneca 
sponsored studies (comprising 46 patients treated with monotherapy and 460 patients treated 
in combination with other agents), 12 patients in AstraZeneca/Acerta sponsored studies and 
667 patients in ESR studies.

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A detailed description of the chemistry, pharmacology, efficacy, and safety of ceralasertib is 
provided in the IB.
2.2.4
Durvalumab
Durvalumab is a human monoclonal antibody of the IgG 1 kappa subclass that blocks the 
interaction of PD-(L)1 (but not programmed cell death ligand-2) with PD-1 on T-cells and 
CD80 (B7.1) on immune cells. It is being developed by AstraZeneca for use in the treatment 
of cancer. The proposed MoA for durvalumab is interference in the interaction of PD-(L)1
with PD-1 and CD80 (B7.1). Blockade of PD-(L)1/PD-1 and PD-(L)1/CD80 interactions 
releases the inhibition of immune responses, including those that may result in tumour 
elimination. In vitro studies demonstrate that durvalumab antagonises the inhibitory effect of 
PD-(L)1 on primary human T-cells resulting in the restored production of IFN-γ (Stewart et al, 
2015). In vivo studies have shown that durvalumab inhibits tumour growth in xenograft 
models via a T-cell-dependent mechanism (Stewart et al, 2015). Based on these data, 
durvalumab is expected to stimulate the patient’s antitumour immune response by binding to 
PD-(L)1 and shifting the balance toward an antitumour response. Durvalumab has been 
engineered to reduce antibody-dependent cellular cytotoxicity and complement-dependent 
cytotoxicity.
As of the DCO date of 12 July 2021, an estimated 12874 patients have received durvalumab in 
AstraZeneca sponsored interventional studies in multiple tumour types, stages of disease and 
lines of therapy. Of these, 5136 patients received durvalumab monotherapy. An estimated 
13113 patients have been randomised and treated to the various treatment/comparator arms in 
sponsor-blinded and/or double-blinded studies. In addition, >
patients have participated 
in the durvalumab EAP (Study D4194C00002) for patients with locally advanced, 
unresectable NSCLC whose disease has not progressed following platinum-based 
chemoradiation therapy, and >
patients in the EAP for durvalumab in combination with 
platinum and etoposide (Study D419QR00007) for the first-line treatment of extensive-stage 
small-cell lung carcinoma. The cumulative world-wide post-approval patient exposure since 
launch is estimated to be approximately 52006 patient-years.
Details on the safety profile of durvalumab monotherapy in Section 2.3.1.2.
Refer to the current durvalumab IB for a complete summary of preclinical and clinical 
information including safety, efficacy, and PK.
Durvalumab has been approved to treat unresectable stage III non-small cell lung cancer, and 
extensive-stage small cell lung cancer (administered in combination with chemotherapy). 
Refer to the package insert (or label) for your specific country, as applicable.
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2.2.5
Ceralasertib in Combination with Durvalumab
The underpinning hypothesis for combining durvalumab and ceralasertib is that the 
combination will result in induction of immune memory, leading to more durable control of 
tumour growth than is achievable with either modality alone. Molecularly targeted therapies 
may serve as “cancer vaccines” inducing the killing of tumour cells and resulting in the 
release of tumour antigens and neoantigens, which can then be presented by APCs to 
tumour-specific T-cells. These T-cells become activated but also upregulate inhibitory 
checkpoints such as CTLA-4 and PD-1, which can be blocked with antibodies to permit 
enhanced anti-tumour T-cell responses, including memory T-cell responses, to enable 
long-term control of disease and possible cure. In addition, the use of targeted agents to 
directly kill tumour cells, with release of tumour antigens, may focus the activated immune 
response generated by immunotherapy agents on tumour antigens rather than self-antigens 
expressed on normal tissues, resulting in fewer AEs.
Clinical experience of the combination of ceralasertib and durvalumab is summarised in the 
ceralasertib IB.
Refer to Section 4.3.2 for details.
2.2.6
Biopsy Sub-Study
Emerging studies of DNA damage, genomic instability, and DNA damage repair-deficiencies 
have been associated with activation of the innate immune response leading to the priming of
the adaptive immune system, which may help drive enhanced anti-tumour responses. 
Pre-clinical evidence suggests that ATR inhibition (such as through ceralasertib treatment) 
may modulate PD-(L)1 expression and the consequences of the failure to repair S-phase DNA 
damage (DNA fragmentation, cytosolic DNA/RNA, chromosome mis-segregation, 
micronuclei, etc) can activate an innate immune response through antiviral nucleic acid 
sensing pathways. Here, activation of cGAS-STING dependent cytosolic DNA and/or 
RIG-I-MAVS dependent RNA sensing pathways induce type I IFN signalling and present the 
cancer cell for T-cell mediated immune destruction, with potential for further enhancement of 
activity in combination with immune checkpoint inhibition (Sato et al, 2017, Parkes et al, 
2017, Sun et al, 2018, Sheng et al, 2020, Feng et al, 2020, AZ unpublished data). In addition 
to direct activity on cancer cells, ceralasertib shows significant decreases in proliferating 
CD8+ effector T-cell populations whilst on drug treatment but recovers when treatment is 
stopped (Krebs et al, 2018) which suggests the importance of sufficient time off drug and 
utilisation of intermittent dosing schedules to elicit optimal immune-mediated anti-tumour 
responses.
In pre-clinical studies using mouse tumour models (
) in immunocompetent 
mice where ceralasertib and anti-PD-(L)1 show moderate anti-tumour responses as 
monotherapy, the combination improves anti-tumour activity using an intermittent 1-week 
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on/1-week off dosing of ceralasertib (See ceralasertib IB primary pharmacodynamics 
section 2.2.5). Analysis of peripheral blood and tumour immune biomarker profiling (
model) of immunocompetent mice dosed with ceralasertib showed marked depletion of 
proliferating CD8+ T-cells when on-drug (1 week on, compared to baseline) which recovered 
when off-drug (1 week off), mimicking the impact seen in human clinical trials (Krebs et al, 
2018, AZ unpublished data). Moreover, flow cytometry analysis of TILs during the off-drug 
recovery phase showed re-population of tumour CD8+ T-cells with a significantly increased 
number with a PD1-/GzmB+ phenotype compared to the vehicle control group, suggesting an 
increased population of effective T-cells in the tumour following ceralasertib treatment using 
this regimen.
Mechanistic studies in
 tumour model indicates ceralasertib activity was driven primarily 
through
 and 
-mediated mechanism as anti-tumour responses were 
suppressed when ceralasertib was co-administered with either anti-
 or anti-
 receptor 
 antibodies in immunocompetent mice. Similarly, no anti-tumour activity is 
observed for this model in immunocompromised nude mice which lack T-cells. The 
 
cells treated with ceralasertib also demonstrated 
 and secretion of 
and 
 genes such as CXCL10/IP10, further supporting ceralasertib 
induced 
 signalling as potential 
 for immune-mediated cell killing.
Preclinical data suggest that ceralasertib modulates T-cells to immune-effective phenotype, 
which would sensitise tumour to IO/durvalumab. Evidence of ceralasertib modulating the 
immune environment is also available from patient data. In an AZ Phase I and Window of 
opportunity trial, ceralasertib decreased proliferating CD8+ T-cells on-treatment in the tumour
and periphery (blood), whereas in the off-drug period the peripheral proliferating T-cells 
increase to levels higher than baseline. In addition, ceralasertib led to initial decrease of 
IL12-p40 cytokine followed by a subsequent increase of IL12-p40 subunit in the off-drug
period. We have also observed ceralasertib modulating gene expression associated with 
immune cell subtypes in the tumour. Altogether, the data suggest that ceralasertib modulates 
the immune environment, which would increase sensitivity of tumour to durvalumab. 
However, the MoA of ATRi + durvalumab combination is not well understood in patients. 
The biopsy sub-study will enable understanding of MoA of ATRi + durvalumab and patient 
selection.
2.3
Benefit/Risk Assessment
2.3.1
Risk Assessment
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-(L)1 as well 
as those directed against PD-1 or CTLA-4, aim to boost endogenous immune responses 
directed against tumour cells. By stimulating the immune system, however, there is the 
potential for adverse effects on normal tissues.
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2.3.1.1 
Ceralasertib  
Data from non-clinical studies and emerging data from the clinical development programme 
of ceralasertib shows that ceralasertib as monotherapy or in combination with durvalumab has 
a manageable safety profile in an advanced cancer population. There were no risks identified 
that would preclude investigation of ceralasertib as monotherapy or in combination with 
durvalumab in advanced unresectable melanoma. 
Identified risks for ceralasertib include anaemia, neutropenia (including febrile neutropenia), 
thrombocytopenia, nausea, vomiting, diarrhoea, and fatigue/asthenia which have been 
reported during the clinical use of ceralasertib as monotherapy or in combination with olaparib 
or durvalumab. Potential risks include myelodysplastic syndrome (MDS)/acute myeloid 
leukaemia (AML). The emerging safety profile of ceralasertib either as monotherapy or in 
combination with either olaparib or durvalumab is consistent with preclinical findings and/or 
the safety profile of the respective combination agent. 
Detailed information on the identified and potential risks, including the most commonly 
observed AEs, for ceralasertib when used alone or in combination are provided in the 
ceralasertib IB. 
2.3.1.2 
Durvalumab  
Risks with durvalumab include, but are not limited to, diarrhoea/colitis, 
pneumonitis/interstitial lung disease, endocrinopathies (ie, events of 
hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and hypo-thyroidism, type I 
diabetes mellitus and diabetes insipidus), hepatitis/increases in transaminases, 
nephritis/increases in creatinine, rash/dermatitis (including pemphigoid), myocarditis, 
myositis/polymyositis, immune thrombocytopenia, infusion-related reactions, hypersensitivity 
reactions, pancreatitis, encephalitis, serious infections, and other rare or less frequent 
inflammatory events including neuromuscular toxicities (eg, Guillain-Barré syndrome, 
myasthenia gravis). 
In monotherapy clinical studies, AEs at an incidence of ≥ 20% include events such as fatigue 
and decreased appetite. Approximately 10% of patients discontinued the drug due to an AE. 
The majority of treatment-related AEs were manageable, with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity. 
Please see the current version of the IB for a detailed summary of the monotherapy data 
including AEs, SAEs, and CTCAE Grade 3 to 5 events reported across the durvalumab 
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For information on all identified and potential risks with durvalumab or for a detailed 
summary of durvalumab monotherapy AE data, refer to the current version of the durvalumab 
IB. 

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Table 4 
Risk Assessment  
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Ceralasertib 
Currently identified risks for 
ceralasertib treatment include 
anaemia, neutropenia 
thrombocytopenia, nausea, 
vomiting, diarrhoea, and 
fatigue/asthenia. Potential risks for 
ceralasertib include MDS/AML. 
Based on available non-clinical 
and clinical data and individual 
case reviews for ceralasertib. For 
updates on the emerging safety 
data and a detailed description of 
all identified and potential risks for 
ceralasertib please refer to the 
latest ceralasertib IB (Sections 5.4 
to 5.6). 
Routine monitoring of 
haematology and biochemistry 
blood counts is planned. 
Dose interruptions and reductions 
of ceralasertib will be permitted 
(Section 6.6). 
 
Durvalumab 
Risks with durvalumab include, 
but are not limited to, 
diarrhoea/colitis, 
pneumonitis/ILD, 
endocrinopathies (ie, events of 
hypophysitis/hypopituitarism, 
adrenal insufficiency, hyper- and 
hypothyroidism, type I diabetes 
mellitus and diabetes insipidus), 
hepatitis/increases in 
transaminases, nephritis/increases 
in creatinine, rash/dermatitis 
(including pemphigoid), 
myocarditis, 
myositis/polymyositis, immune 
thrombocytopenia, 
infusion-related reactions, 
hypersensitivity reactions, 
pancreatitis, encephalitis, serious 
infections, and other rare or less 
frequent inflammatory events 
including neuromuscular toxicities 
(eg, Guillain-Barré syndrome, 
myasthenia gravis). 
In monotherapy clinical studies, 
AEs at an incidence of ≥ 20% 
include events such as fatigue and 
decreased appetite. Approximately 
10% of patients discontinued the 
drug due to an AE. 
Please see the current version of 
the IB for a detailed summary of 
the monotherapy data including 
AEs, SAEs, and CTCAE Grade 3 
to 5 events reported across the 
durvalumab programme. 
Refer to “Dosing Modification and 
Toxicity Management Guidelines 
for Durvalumab Monotherapy or 
in Combination with Other 
Products” as provided to the 
investigative site as an Annex 
document, which is maintained 
within the Site Master File. 
AE = adverse event; AML = acute myeloid leukaemia; CTCAE = Common Terminology Criteria for Adverse 
Events; IB = Investigator’s Brochure; ILD = interstitial lung disease; MDS = Myelodysplastic syndrome; 
SAE = serious adverse event. 
2.3.2 
Benefit Assessment  
Ceralasertib is considered to have a positive benefit-risk profile for patients with advanced 
cancer. There are encouraging clinical data of benefit for post-immuno-oncology melanoma 
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suggest ceralasertib affects tumour microenvironment, which might make tumour more 
responsive to durvalumab. Refer to Sections 4.2 and 4.3 for ceralasertib and durvalumab data. 
Patients in this study will benefit from the monitoring of all AEs arising during the clinical 
study, related or not related to the study treatment. In addition, they will be contributing to the 
development of new therapies for advanced cancer. 
The study rationale and dose justification are summarised in Section 2.1 and Section 4.3, 
respectively. 
2.3.3 Overall Benefit: Risk Conclusion  
Taking into account the measures taken to minimise risk to patients enrolling in this study, the 
potential risks identified in association with ceralasertib as monotherapy or in combination 
with durvalumab are justified by the anticipated benefits that may be afforded to patients with 
advanced unresectable melanoma. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 5 
Objectives and Endpoints for Main Study  
Objectives 
Endpoints 
Primary 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of objective response rate (ORR) 
in patients with unresectable or advanced 
melanoma and primary or secondary resistance 
to a PD-(L)1 inhibitor 
x 
ORR is defined as the proportion of patients 
who have a confirmed complete response, (CR) 
or confirmed partial response (PR), as 
determined by Blinded Independent Central 
Review (BICR) per Response Evaluation 
Criteria in Solid Tumours (RECIST 1.1) 
The analysis will include all dosed patients as dosed. 
 
Data obtained from randomisation up until 
progression, or the last evaluable assessment in the 
absence of progression, will be included in the 
assessment of ORR, regardless of whether the patient 
withdraws from therapy. Patients who go off study 
treatment without a response or progression, receive a 
subsequent therapy, and then respond will not be 
included as responders in the ORR. 
 
The primary measure is the estimate of ORR for each 
experimental treatment arm, and a secondary measure 
of interest is the odds ratio of the ORR comparing the 
2 treatment arms. 
 
Additionally, ORR will be analysed using the 
investigator assessment per RECIST 1.1 as a 
sensitivity analysis. 
Secondary 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of Duration of Response (DoR) 
in patients with unresectable or advanced 
melanoma and primary or secondary resistance 
to a PD-(L)1 inhibitor 
x 
DoR will be defined as the time from the date of 
first documented confirmed response until date 
of documented progression per RECIST 1.1 as 
assessed by BICR or death due to any cause 
The analysis will include all dosed patients as dosed 
who have a confirmed response, regardless of 
whether the patient withdraws from study treatment, 
receives another anti-cancer therapy or clinically 
progresses prior to RECIST 1.1 progression. 
 
The measure of interest is the median and landmark 
estimates at 6, 9, 12, 15, and 18 months of DoR. 
 
Additionally, DoR will be analysed using the 
investigator assessment per RECIST 1.1 as a 
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Objectives 
Endpoints 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of time to objective response 
(TTR) in patients with unresectable or advanced 
melanoma and primary or secondary resistance 
to a PD-(L)1 inhibitor 
x 
Time to response is defined as the time from 
randomisation until the date of first documented 
objective response, which is subsequently 
confirmed per RECIST 1.1 as assessed by 
BICR. The analysis will include all dosed 
patients as dosed who have a confirmed 
response. 
Data obtained from randomisation up until 
progression, or the last evaluable assessment in the 
absence of progression, will be included in the 
assessment of TTR. Patients who go off treatment 
without a response or progression, receive a 
subsequent therapy, and then respond will not be 
included. 
The measure of interest is the median TTR and the 
proportion of patients with response at the first 
scheduled tumour assessment. 
 
Additionally, TTR will be analysed using the 
investigator assessment per RECIST 1.1 as a 
sensitivity analysis. 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of change in target lesion (TL) 
tumour size in patients with unresectable or 
advanced melanoma and primary or secondary 
resistance to a PD-(L)1 inhibitor 
x 
Percentage change from baseline in TL tumour 
size is based on the RECIST 1.1 TL 
measurements as assessed by BICR 
Tumour size is the sum of the longest diameters of 
the TLs. The percentage change from baseline in TL 
tumour size at post-baseline assessment (week 16) is 
obtained for each patient taking the difference 
between the sum of the TLs at post-baseline 
assessment and the sum of the TLs at baseline 
divided by the sum of the TLs at baseline times 100. 
 
Patients who progress before week 16 should have 
had a tumour assessment performed at the time of 
progression prior to study treatment discontinuation. 
The tumour size from their latest progression 
assessment will be used instead of the week 16 
assessment for these patients. 
 
The analysis will include all dosed patients as dosed. 
 
Additionally, best percentage changes from baseline 
in TL tumour size will be derived. Change in TL 
tumour size will also be analysed using the 
investigator assessment per RECIST 1.1 as a 
sensitivity analysis. 

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Objectives 
Endpoints 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of progression free survival 
(PFS) in patients with unresectable or advanced 
melanoma and primary or secondary resistance 
to a PD-(L)1 inhibitor 
x 
PFS is defined as time from randomisation until 
progression per RECIST 1.1 as assessed by 
BICR or death due to any cause 
The analysis will include all randomised patients as 
randomised, regardless of whether the patient 
withdraws from study treatment, receives another 
anti-cancer therapy or clinically progresses prior to 
RECIST 1.1 progression. 
However, if the patient progresses or dies 
immediately after 2 or more consecutive missed 
visits, the patient will be censored at the time of the 
latest evaluable assessment prior to the 2 missed 
visits. 
The measure of interest is the median and landmark 
estimates at 3, 6, 9, 12 months of PFS, and the hazard 
ratio comparing the 2 treatment arms. 
Additionally, PFS will be analysed using the 
investigator assessment per RECIST 1.1 as a 
sensitivity analysis. 
x 
To estimate the effectiveness of ceralasertib 
monotherapy and ceralasertib plus durvalumab 
by assessment of overall survival (OS) in 
patients with unresectable or advanced 
melanoma and primary or secondary resistance 
to a PD-(L)1 inhibitor 
x 
OS is defined as time from randomisation until 
the date of death due to any cause 
The analysis will include all randomised patients as 
randomised, regardless of whether a patient 
withdraws from study treatment or receives another 
anti-cancer therapy. 
The measure of interest is the median of OS and 
landmark estimates at 6, 9, 12, and 18 months, and 
the hazard ratio comparing the 2 treatment arms. 
x 
To assess the PK of ceralasertib alone and when 
in combination with durvalumab 
x 
Concentration of ceralasertib in plasma (peak 
and trough concentrations, as data allow; sparse 
sampling) 

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Objectives 
Endpoints 
Safety 
x 
To assess the safety and tolerability of 
ceralasertib monotherapy and ceralasertib plus 
durvalumab in patients with unresectable or 
advanced melanoma and primary or secondary 
resistance to a PD-(L)1 inhibitor 
Safety and tolerability will be evaluated in terms of 
adverse events (AEs), vital signs, and clinical 
laboratory assessments. Assessments related to AEs 
cover: 
x 
Occurrence/Frequency 
x 
Relationship to study treatment as assessed by 
investigator 
x 
Common Terminology Criteria for Adverse 
Events (CTCAE) grade 
x 
Seriousness 
x 
Death 
x 
AEs leading to discontinuation of study 
treatment 
x 
AEs leading to dose reduction of ceralasertib 
x 
AEs leading to dose reduction of durvalumab 
x 
AEs leading to dose interruption of ceralasertib 
x 
AEs leading to dose interruption of durvalumab 
Vital signs parameters include systolic and diastolic 
blood pressure, and pulse. Assessments cover: 
x 
Observed value 
x 
Absolute change from baseline values over time 
x 
Vital sign status including change in 
abnormality (eg, abnormal-clinically significant, 
abnormal-clinically not significant) from 
baseline 
Laboratory parameters include clinical chemistry and 
haematology parameters as well as urinalysis. 
Assessments cover: 
x 
Observed value 
x 
Absolute and percentage change from baseline 
values over time 
x 
Laboratory parameter status including change in 
abnormality (eg, low, normal, high) from 
baseline to maximum post-baseline value. 
Assessments cover: 
x 
Urinalysis categorisation as collected on the 
database including change in categorisation 
from baseline to maximum on-treatment value 
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Objectives
Endpoints
x
x
x
x
x
x
x
x
x
x
x
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Objectives
Endpoints
x
x
x
x
x
 
x
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The objectives and endpoints for the biopsy sub-study are as follows:
Table 6
Objectives and Endpoints for the Biopsy Sub-Study
Objectives
Endpoints
Primary
x
To assess changes in CD8+ T-cell infiltration of 
tumours induced by ceralasertib monotherapy
x
CD8+ T-cells tumour infiltration assessed in 
baseline, on-treatment and off-treatment tumour 
biopsies
Assessments cover:
x
Observed log2-transformed value in baseline, 
on-treatment and off-treatment
x
Absolute change from baseline in log2- scale 
in on-treatment and off-treatment samples
x
Fold change from baseline for on-treatment 
and off-treatment samples
Secondary
x
To estimate the effectiveness of ceralasertib plus 
durvalumab by assessment of ORR, DoR, TTR, 
change in tumour size, PFS and OS
x
As described for the main study, using the 
investigator assessment of tumour response per 
RECIST 1.1
The analysis will include all dosed patients as dosed, 
with endpoints to be derived using date of first dose 
instead of date of randomisation where applicable. 
x
To collect tumour tissue samples, or utilise 
residual samples, for the analysis of tumoural 
biomarkers that change following treatment with 
ceralasertib
x
Pre-treatment presence and/or on-treatment 
and/or off-treatment changes in PD-L1 and 
pRAD50
x
To assess changes in the proliferation of 
carcinoma and/or immune cells within tumours 
induced by ceralasertib monotherapy
x
Proliferation (using Ki67+ marker) of carcinoma 
and/or immune cells (including CD8+ T cells) 
will be assessed in baseline, on-treatment and 
off-treatment tumour biopsies.
Safety
x
To assess the safety and tolerability of 
ceralasertib plus durvalumab in patients with 
unresectable or advanced melanoma and 
primary or secondary resistance to a PD-(L)1
inhibitor
x
As described for the main study
Exploratory
x
x
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Table 6
Objectives and Endpoints for the Biopsy Sub-Study
Objectives
Endpoints
x
x
x
.
x
x
 
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4 
STUDY DESIGN  
4.1 
Overall Design  
Main study: This is a Phase 2, randomised, open-label, multicentre, international study 
assessing the efficacy and safety of ceralasertib and ceralasertib plus durvalumab in patients 
with unresectable or advanced melanoma and primary or secondary resistance to PD-(L)1 
inhibition. Patients will be recruited from multiple centres with a global footprint that is 
expected to include North America, Europe, and Asia. 
Approximately 150 patients will be randomised, at a 2:1 randomisation ratio (approximately 
100 patients in Arm 1 and approximately 50 patients in Arm 2) to the following intervention 
groups: 
1 
Arm 1: Ceralasertib 240 mg BD Days 1 to 7 plus durvalumab 1500 mg Day 8, Q28D, 
until progressive disease, unacceptable toxicity, withdrawal of consent, or if a study 
treatment discontinuation criterion is met. 
2 
Arm 2: Ceralasertib 240 mg BD Days 1 to 7, Q28D, until progressive disease, 
unacceptable toxicity, withdrawal of consent, or if a study treatment discontinuation 
criterion is met. 
Randomisation will be stratified by resistance to prior immune-oncology treatment and 
baseline LDH expression. At enrolment, investigators will confirm the PD-(L)1 resistance 
type and whether LDH is normal or above upper limit of normal in order to stratify the 
patients accordingly. For further details on randomization, refer to Section 6.3.1. 
Crossover between treatment arms is not permitted. 
Patients must have received at least 1 line of treatment for metastatic disease including an 
anti-PD1 or anti-PD-(L)1 therapy, or combination of anti-PD1/L1 and anti-CTLA4 and no 
more than 2 prior regimens in the metastatic setting. All patients must have demonstrated 
disease progression on anti-PD-(L)1 while on treatment and must have confirmatory scan for 
progression disease per RECIST 1.1 unless progression is accompanied with clinical 
deterioration. Patients who progress on adjuvant immunotherapy are also permitted to enrol 
provided that they progressed on therapy or within 12 weeks after completion of the treatment. 
Patients with BRAF mutations may have received a BRAF or BRAF plus MEK inhibitor if 
eligible to do so. All patients must demonstrate disease progression prior to study entry and 
there must be no intervening therapy eg, investigational agents after completion of prior 
immunotherapy, except for approved targeted agents for patients with eligible BRAF or c-Kit 
mutations. For country-specific requirements for France see Appendix K 1.2. 

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Due to the different schedules of administration of the study treatment options, neither 
patients nor investigators will be blinded to study treatment assignment. Measures to limit bias 
are detailed in Section 6.3.
An IDMC comprised of independent experts will be convened to review the unblinded safety 
and tolerability data and the unblinded efficacy data from the interim analyses and will 
recommend to the sponsor whether the study should continue unchanged, be stopped, or be 
modified in any way. Further details on the IDMC are present in Section 9.6.
Number of Patients
Approximately 150 patients are expected to be randomised in total, at a 2:1 randomisation 
ratio, such that there will be approximately 100 evaluable patients in the ceralasertib and 
durvalumab combination therapy arm and approximately 50 patients in the ceralasertib 
monotherapy arm. However, fewer patients may be randomised to any given treatment arm 
following a recommendation by the IDMC to terminate recruitment to an arm based on safety 
or lack of efficacy.
Enrolled
Estimated 
patients
Randomly assigned
Estimated 150 patients
Evaluable patients
Estimated 150 patients
Biopsy sub-study: An open-label, non-randomised, biopsy sub-study is planned in patients 
suitable for 3 mandatory biopsies. Patients recruited into the biopsy sub-study will receive 
1 cycle of ceralasertib monotherapy (Cycle 0) followed by ceralasertib plus durvalumab from 
Cycle 1.
The biopsy sub-study is anticipated to recruit patients from pre-defined/selected subset of sites 
and the estimated number of patients in the biopsy sub-study is as follows:
Enrolled
Estimated 
 patients
Evaluable tumour biopsy patients
Estimated 30 patients
Note: “Enrolled” means a patient’s, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process. Potential 
patients who are screened for the purpose of determining eligibility for the study, but are not 
randomised/assigned in the study, are considered “screen failures”, unless otherwise specified 
by the protocol. For country-specific requirements for Germany see Appendix K 1.3.
Serial tumour biopsies are mandated in the patients recruited into the biopsy sub-study and 
will be taken at baseline during the screening period, during treatment with ceralasertib 
monotherapy and during the off-treatment period of ceralasertib monotherapy.
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During the Cycle 0 treatment period, patients will be treated with ceralasertib 240 mg BD 
Days 1 to 7, followed by an off-treatment period between Days 8 to 28. From Cycle 1 
onwards, patients will be treated with the combination of ceralasertib 240 mg BD Days 1 to 7 
plus durvalumab 1500 mg Day 8, Q28D, until progressive disease, unacceptable toxicity, 
withdrawal of consent, or if a study treatment discontinuation criterion is met. 
For dose modification recommendation, stopping rules and discontinuation for ceralasertib 
monotherapy or in combination with durvalumab, please refer guidance for the main study 
(Section 6.6). 
4.1.1 
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis  
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions and considerations if 
site personnel or study patients become infected with severe acute respiratory syndrome 
coronavirus 2 [SARS-CoV-2] or similar pandemic infection), which would prevent the 
conduct of study-related activities at study sites, thereby compromising the study site staff’s 
ability to conduct the study or the patient’s ability to participate in the study. The investigator 
or designee should contact the study sponsor to discuss whether the mitigation plans below 
should be implemented. 
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain 
compliance with GCP, and minimise risks to study integrity. 
Where allowable by local health authorities, ethics committees, health care provider 
guidelines (eg, hospital policies) or local government, these changes may include the 
following options: 
x 
Obtaining consent for the mitigation procedures (note, in the case of verbal consent, the 
ICF should be signed at the patient’s next contact with the study site). 
x 
Rescreening: Additional rescreening for screen failures and to confirm eligibility to 
participate in the clinical study can be performed in previously screened patients. The 
investigator should confirm this with the designated AstraZeneca clinical lead. 
x 
Home or Remote visit: Performed by a site-qualified HCP or HCP provided by a TPV. 
x 
Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 
 
If a site visit is not possible, at home delivery and administration of study treatment may be 
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For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix H. 
4.2 
Scientific Rationale for Study Design  
Two separate investigator-initiated collaborative studies support the investigation of 
ceralasertib in advanced unresectable malignant melanoma. The first study was the 
combination with weekly paclitaxel in 33 PD-1 resistant advanced melanoma patients which 
showed an ORR of 33% median PFS of 3.6 months and median OS of 7.4 months. Seven out 
of 11 patients had a duration of response of more than 6 months (Lee J et al, 2020). The 
second study, a combination of ceralasertib with durvalumab in 30 post PD-1 patients with 
advanced melanoma, showed a ORR of 30%, six of nine patients with a PR maintained a 
response for > 6 months (66.7%), median DoR 8.8 months, median PFS 7.1 months and 
median OS 14.2 months (Kim R et al, 2022) (Section 4.3). The patient population in both of 
these studies was patients with advanced unresectable malignant melanoma with primary or 
secondary resistance to anti-PD-(L)1 inhibition, who demonstrated anti-tumour activity and 
were a population with unmet medical need, similar to patients with early relapse following 
adjuvant therapy. AstraZeneca aims to confirm the efficacy signals in a multicentre 
company-sponsored trial. 
Secondly, given that there is no single agent data for ceralasertib in advanced unresectable 
malignant melanoma and activity was demonstrated for 2 separate ceralasertib combinations, 
AstraZeneca aims to test the activity of monotherapy ceralasertib to understand the 
contribution of ceralasertib to the combination with durvalumab. Thus, a 2-arm trial is 
proposed comprising ceralasertib plus durvalumab and ceralasertib monotherapy. 
In this study, durvalumab is not proposed to be tested as a single agent as it is not the standard 
of care in the treatment of advanced melanoma. Durvalumab (10 mg/kg) has been evaluated in 
a Phase 1 study (unpublished data on file) in 21 stage IV PD-(L)1 naïve patients with 
advanced cutaneous melanoma; 6 out the 21 patients were previously treated with 
immunotherapy and in this study, 3 (14%) patients achieved a PR and 9 patients had stable 
disease as best response. The proportion of patients with DoR ≥ 6 months was 3 (100%); 
≥ 9 months, 2 (67%); and ≥ 12 months, 1 (33%). Among the 3 patients with PR, 2 were 
previously treated with only ipilimumab monotherapy, one in the adjuvant setting with 
progressive disease as best response and the second in the setting of advanced unresectable 
metastatic melanoma. 
Therefore, due to the available evidence, durvalumab monotherapy is anticipated to have low 
clinical efficacy in patients with confirmed progression on prior anti-PD-(L)1 regimens in a 
patient population in need of an effective disease controlling regimen. 

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4.3
Justification for Dose
The ceralasertib and durvalumab combination therapy doses and regimen selected for this 
study are based on the goal of selecting an optimal combination dose that would demonstrate 
promising efficacy and have an acceptable safety profile.
The rationale is based on the emerging efficacy data and improved tolerability from Module 3
of HUDSON study (D6185C00001), which included patients with NSCLC who previously 
progressed on chemotherapy and immune checkpoint inhibitors. In HUDSON study, 
ceralasertib 240 mg BD was administered using a 7-day schedule, Days 22 to 28, combined 
with durvalumab 1500 mg on Day 1, in a 28-day cycle. The combination was more effective 
than other durvalumab combinations in patients within the same study, with superior PFS and 
OS data. Furthermore, emerging pre-clinical data and preliminary peripheral blood biomarker 
data from PKPD modelling in Study 4 (D5330C00004) are more supportive for the 7 days 
schedule, showing that a longer time off ceralasertib treatment allows for a more immune 
permissive environment and reduced haematological toxicity.
4.3.1
Ceralasertib Monotherapy Dose Rationale
The dose of ceralasertib selected for this study (240 mg BD) is primarily based on the clinical 
results observed in the HUDSON study (D6185C00001), with supportive data on preclinical, 
translational and clinical pharmacology data/modelling from Study 4 (D5330C00004).
Preliminary PK observations from Study 4 (D5330C00004) showed 
 
dose-proportional increase in exposure, where the plasma concentrations following a single 
dose at 320 mg QD were 
 to that observed at 240 mg QD
% overlap in 
AUC), suggesting the need to change to BD schedules in order to increase ceralasertib 
exposure beyond the dose of 240 mg QD.
The dose of ceralasertib as monotherapy 240 mg BD for 7 days in 28-day cycles is based on 
clinical safety and tolerability (mainly bone marrow safety outcomes) and clinical PK/PD
data. The dose level of 240 mg BD is predicted to maintain ceralasertib concentrations above 
the estimated concentration of an inhibitor where ATR catalytic activity is reduced by 90% 
(IC90) threshold for 
 hours in 
% of the patients based on simulations from a 
preliminary population PK model, and hence, it achieves maximum IC90 daily coverage. In 
addition, 1-week ceralasertib dosing maximises cytotoxic T-cell (CD8+/Ki67+) proliferative 
burst (by minimising the time in which proliferative T-cells are depleted) during the three-
week off-treatment period, potentially promoting upregulation of PD-(L)1 which can be 
subsequently blocked with durvalumab to enhance anti-tumour T-cell responses.
Considering emerging PK data from ongoing studies, there is no evidence to indicate any 
ethnic sensitivity in Asian patients compared to Western patients.
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The choice of ceralasertib schedule is supported by preclinical data in syngeneic mouse 
tumour models in which an intermittent dosing schedule for ceralasertib is most efficacious in 
terms of balancing the direct anti-tumour effects, the potential for priming an IFN-mediated 
immune response and dynamic modulation of the tumour immune microenvironment (see 
ceralasertib IB). An intermittent schedule is also supported by a population PK-PD model 
describing ceralasertib-induced thrombocytopenia and neutropenia, which showed that at least 
two-week off-treatment period is needed for platelet/neutrophil recovery. This same model 
also demonstrated that haematological toxicity is reduced with a 7-day schedule compared to 
14-day schedule of ceralasertib. 
The immunomodulatory effects of ceralasertib have been evaluated in multiple clinical 
studies. Longitudinal peripheral blood analysis from Study 4 (D5330C00004) and Study 7 
(D5330C00007) demonstrated on-drug suppression of peripheral proliferating cytotoxic 
T-cells (CD8+/Ki67+) during ceralasertib treatment, followed by off-drug rebound above 
pre-treatment levels. Similar changes were not seen in total T-cells (proliferating cytotoxic 
T-cells comprise a subset of the total T-cells), suggesting that these effects are primarily 
restricted to proliferating cells. In addition, 1-week ceralasertib dosing maximises cytotoxic 
T-cell (CD8+/Ki67+) proliferative burst (by minimising the time in which proliferative T-cells 
are depleted) during the three-week off-treatment period, potentially promoting upregulation 
of PD-L1 which can be subsequently blocked with durvalumab to enhance anti-tumour T-cell 
responses. 
Ceralasertib has been tested as monotherapy in the investigator-initiated collaborative 
study-PATRIOT (D533OC00002, Study NCT02223923), which showed that the tolerable 
schedule is 2 weeks on/2 weeks off in a 28-day cycle (Dillon et al, 2017; Dillon et al, 2019). 
Ceralasertib is also being tested as monotherapy in patients with ATM gene or protein altered 
advanced solid tumours and prostate cancer in the modular Phase 2A study PLANETTE 
(Study D5339C00001). 
Refer to the current ceralasertib IB for further information. 
4.3.2 
Ceralasertib and Durvalumab Combination Therapy Dose Rationale  
The ceralasertib and durvalumab combination therapy doses and regimen selected for this 
study are based on the goal of selecting an optimal combination dose that would demonstrate 
promising efficacy and have an acceptable safety profile. 
To date, ceralasertib has been tested at different dose levels (80 mg to 240 mg BD) in 
combination with durvalumab in two ongoing AZ-sponsored clinical studies and seven 
externally sponsored studies, across multiple therapy indications. Ceralasertib 240 mg 14-day 
regimen (Days 15 to 28) in combination with durvalumab 1500 mg on Day 1, of a Q28D cycle 
is being tested in Module 3 of the ongoing Study 4 (D5330C00004) where 27 patients with 

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NSCLC and squamous cell cancer of the head and neck have been treated. The ceralasertib 
and duvalumab combination is also being tested in the HUDSON study (D6185C00001) in 
NSCLC with 2 various schedules of ceralasertib 7 days or 14 days. In HUDSON the 7 days 
schedule was well tolerated and demonstrated encouraging efficacy data in 66 patients. 
Longitudinal peripheral gene expression data from the HUDSON study (D6185C00001) 
indicate increases in gene expression signatures associated with Tumour Necrosis Factor α 
(TNFα) signalling and CD56dim Natural Killer (NK) cells upon treatment with ceralasertib, 
which return to baseline during the off-drug period. T-cell receptor sequencing, assessed using 
Adaptive Biotechnologies' immunoSEQ assay, revealed increases in peripheral richness 
following treatment with the combination of ceralasertib and durvalumab. Taken together, 
these data support a mechanism of immune modulation by ceralasertib in combination with 
durvalumab in this patient population. 
Clinical data has emerged that supports the 7-day schedule of ceralasertib in NSCLC. The 
HUDSON study is exploring ceralasertib 240 mg BD in both a 7-day schedule (in Module 3) 
and a 14-day schedule (in Module 9) combined with durvalumab 1500 mg QD, Day 1 in a 
Q28D cycle. The 240 mg BD 14-day schedule of ceralasertib was also explored in 
Study 4 Module 3 (D5330C00004C). Safety information from HUDSON Module 3 and 
Module 9 and Study 4 (D5330C00004) indicate that a 7-day schedule has better tolerability in 
NSCLC patients than a 14-day schedule. The 14-day schedule is associated with increased 
dose reductions (n=9/25 [36%]; compared to HUDSON patients on the 7-day schedule, 
n=9/65 [14%]) and increased dose discontinuations due to AEs (n = 6/25 [24%] in Study 4; 
compared to HUDSON patients on the 7-day schedule, n=3/65 [5%]). The combination of 
ceralasertib and durvalumab showed OS benefit in patients on the 7-day schedule. In 
Module 3 of HUDSON, ceralasertib 240 mg BD was administered Days 1 to 7 at Cycle 0, and 
from Cycle 1 durvalumab 1500 mg Day 1 was combined with ceralasertib 240 mg BD 
Days 22 to 28. This dose and schedule were well tolerated. The efficacy data from HUDSON 
Module 3 showed ORRs of 28.6% (ATM deficient cohort [A.3.ATM]), 8.0% (acquired 
resistance cohort [B.3.ACQ]), and 15.0% (primary resistance cohort [B.3.PRI]). Six-month 
mPFS was 69.64% (A.3.ATM), 35.19% (B.3.ACQ) and 45.59% (B.3.PRI). The 6-month 
median OS was 95.24% (A.3.ATM), 76.0% (B.3.ACQ) and 70.0% (B.3.PRI). Efficacy data 
for the dose-expansion cohort in Study 4 (D5330C00004) is immature as the study is ongoing. 
However, there is preliminary evidence of efficacy for the combination of ceralasertib and 
durvalumab in 4 patients in the dose-escalation part of the study; these 4 patients achieved a 
confirmed RECIST response (n=1 confirmed complete response and n=3 partial responses) 
A recent study (D6183C00003, NCT03780608) conducted in a single centre in South Korea 
investigated the activity of ceralasertib plus durvalumab in a Phase 2 study in patients with 
advanced unresectable melanoma resistant to prior anti-PD-(L)1 treatment. The dose of 
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Day 1, Q28D. The data indicated there were 9 patients (30%, 95% CI 13.6% - 46.4%) with 
ORR, and a DCR of 63.3% (95% CI 28% 46.1% - 80.6%) patients with DoR > 6 months, 
median DoR 8.8 months (range, 3.8 to 11.7 months). After 18 PFS events, median PFS 7.1 
months (95% CI 3.6 - 10.6; 67% mature), and median OS 14.2 months (95% CI 9.3-19.1 
months). Responses were seen across the melanoma subtypes suggesting that this combination 
has broad activity in malignant melanoma. In terms of safety, TEAEs led to dose reduction of 
ceralasertib in 14 patients (46.7%). The most common causes of ceralasertib dose reduction 
were thrombocytopenia (Grade > 3) and neutropenia (Grade > 3). None of the patients 
discontinued durvalumab or ceralasertib due to AEs (Kim R et al, 2022). 
In the proposed Phase II melanoma study, a 7-day dosing schedule for the ceralasertib dose of 
240 mg BD, in combination with 1500 mg durvalumab on Day 8 of a 28-day cycle will be 
used, based on supportive preclinical, translational, clinical pharmacology, and clinical data. 
4.3.2.1 
Dose Rationale for Durvalumab 1500 mg Q28D  
A population PK model was developed for durvalumab using monotherapy data Study 1108 
(N = 292; doses = 0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid tumours). Population PK 
analysis indicated only minor impact of body weight on the PK of durvalumab (coefficient of 
≤ 0.5). The impact of body weight-based (10 mg/kg q2w) and fixed dosing (750 mg q2w) of 
durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, 
median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was 
selected to approximate 10 mg/kg (based on median body weight of ~75 kg). A total of 
1000 patients were simulated using body weight distribution of 40 to 120 kg. Simulation 
results demonstrate that body weight-based and fixed dosing regimens yield similar median 
steady state PK concentrations with slightly less overall between-patient variability with fixed 
dosing regimen. 
A comparison of the observed durvalumab peak and trough concentrations following an initial 
dose of 10 mg/kg, 20 mg/kg and a fixed dose of 1500 mg revealed the geometric mean peak 
concentration at 1500 mg was 13% higher than at 20 mg/kg and 149% higher than that of 
10 mg/kg. The fixed dose of 1500 mg Q4W is predicted to result in a similar AUC with only a 
modest difference in median peak and trough levels at steady state compared to 10 mg/kg 
q2w, based on population PK simulations. Complete PD-(L)1 suppression is anticipated 
following a 1500 mg Q4W dose, given its equivalent PK exposure (AUC, maximum observed 
concentration [Cmax], and trough) at steady state compared to the 20 mg/kg Q4W dose. 
Therefore, the fixed dose of 1500 mg Q4W has been selected as the dosing regimen 
investigated in multiple ongoing studies of durvalumab across different cancer types. 
Similar findings have been reported by others (Narwal et al 2013; Ng et al 2006, Wang 
et al 2009, Zhang et al 2012). Wang and colleagues investigated 12 mAbs and found that fixed 
and body size-based dosing perform similarly, with fixed dosing being better for 7 of 12 

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antibodies (Wang et al 2009). In addition, they investigated 18 therapeutic proteins and 
peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-patient variability in PK/pharmacodynamic parameters (Zhang et al 2012). 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given the expectation of similar PK exposure and variability, 
AstraZeneca considered it feasible to switch to fixed dosing regimens. 
A fixed dose of 1500 mg durvalumab administered Q28D is to be used for all patients with a 
body weight greater than 30 kg. 
Currently, the use of a fixed dose of 1500 mg durvalumab, administered both in combination 
with chemotherapy and as monotherapy, is approved for treatment of extensive stage small 
cell lung cancer; additionally, the 1500 mg fixed dose is approved in some countries as 
monotherapy for unresectable stage III non-small cell lung cancer. Refer to the local package 
insert (or label) for current approved regional dosing regimens, as applicable. 
4.4 
End of Study Definition  
For the purpose of Clinical Trial Transparency, the definition of the end of the study differs 
under FDA and EU regulatory requirements: 
European Union requirements define study completion as the last visit of the last subject for 
any protocol related activity. 
Food and Drug Administration requirements define two completion dates: 
Primary Completion Date – the date that the final patient is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure with 
different completion dates, this term refers to the date on which data collection is completed 
for all of the primary outcomes. 
Study Completion Date – the date the final patient is examined or receives an intervention for 
purposes of final collection of data for the primary and secondary outcome measures and AEs 
(for example, last patient’s last visit), whether the clinical study concludes according to the 
pre-specified protocol or is terminated. 
A patient is considered to have completed the study if they have completed all phases of the 
study including the last visit or the last scheduled procedure shown in the SoA (Section 1.3). 
The study may be stopped if, in the judgement of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings. 

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The end of the study is defined as the date of the last visit of the last patient in the study 
globally.
See Section 6.7 for details on patient management following final DCO as well as following 
study completion.
5
STUDY POPULATION
The target population of interest in this study is patients with unresectable or advanced 
melanoma with resistance to PD-(L)1 inhibition.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Patients who do not meet the eligibility criteria requirements are screen failures; refer to 
Section 5.4.
5.1
Inclusion Criteria
5.1.1
Main Study and Biopsy Sub-Study
Patients 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 A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
2
Provision of signed and dated written 
 informed 
consent prior to collection of samples for 
 that supports 
 
Age
3
Patient must be ≥18 years of age inclusive, at the time of signing the informed consent.
Type of Patient and Disease Characteristics
4
Patient must have a histologically or cytologically confirmed diagnosis of unresectable or 
metastatic melanoma of cutaneous, acral or mucosal subtype.
5
Availability of an archival tumour sample and a fresh tumour biopsy taken at screening, if 
medically feasible as per investigator assessment. If a mandatory fresh biopsy is not 
feasible, the patient is permitted to enrol if they have an archival sample up to 5 years.
6
Patient must have received at least 1 prior immunotherapy (anti-PD-(L)1 ± anti-CTLA-4)
for a minimum of 6 weeks and no more than 2 prior regimens in the metastatic setting.
Patients must have confirmed progression during treatment with a PD-(L)1 inhibitor +/- a
CTLA-4 inhibitor, eg, nivolumab, pembrolizumab, or atezolizumab, or the combination 
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of nivolumab and ipilimumab. Confirmed progression is defined as radiologic progression 
confirmed by a second scan at 4 to 12 weeks after the initial scan showing disease 
progression or, a single scan showing radiological progression accompanied by 
correlative symptoms suggestive to disease progression. Patients who received adjuvant 
therapy for previously resected disease with PD-(L)1 agents may also be eligible if 
disease recurrence occurred while still receiving the anti-PD-(L)1 therapy or < 12 weeks 
from the last dose of the anti-PD-(L)1 therapy. 
7 
No intervening treatment eg, investigational therapy is permitted between the 
anti-PD-(L)1 therapy and study treatment. However, patients with BRAF or c-Kit 
mutations that are eligible for targeted treatment, may receive the targeted treatment 
before or after licensed anti-PD-(L)1 therapy and prior to study entry. For 
country-specific requirements for France see Appendix K 1.2. 
8 
The interval between the last dose of anti-PD-(L)1, BRAF/MEK inhibitor and the first 
dose of the study regimen must be a minimum of 14 days. 
9 
BRAF V600E or V600K mutation status must be known at screening. Patients with 
BRAF mutant melanoma may have had a prior treatment regimen that included 
vemurafenib, dabrafenib, or an approved BRAF and approved MEK inhibitor. For 
country-specific requirements for France see Appendix K 1.2. 
10 May have received a TKI (eg, imatinib) if c-kit mutant and available, or declined therapy. 
11 Eastern Cooperative Oncology Group performance status 0 or 1, with no deterioration 
over the previous 2 weeks prior to baseline or day of first dosing. 
12 Measurable disease by RECIST 1.1. At least 1 lesion, not previously irradiated, that 
qualifies as a RECIST 1.1 target lesion (TL) at baseline and can be accurately measured 
at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have 
short axis ≥ 15 mm) with CT or MRI and is suitable for accurate repeated measurements. 
Tumour assessment by CT scan or MRI must be performed within 28 days prior to 
randomisation. Cutaneous lesions and other superficial lesions are not considered 
measurable disease lesions but may be considered as non-target lesions. For patients in 
the main study: if the patient has only 1 measurable lesion per RECIST 1.1, the biopsy 
specimen should be obtained from the non-target lesion or archival tissue. 
13 Patients with known CNS lesions should be asymptomatic, adequately treated with 
stereotactic radiation therapy, craniotomy, gamma knife therapy, or whole brain 
radiotherapy, with no subsequent evidence of CNS progression; patients must not require 
steroid exceeding > 10 mg prednisone or equivalent; patients with a history of central 
nervous system metastases must have MRI of the brain at screening. All AEs while 
receiving prior immunotherapy must have completely resolved, be medically controlled, 
or resolved to baseline prior to screening for this study. 
14 Patients must have a life expectancy ≥ 3 months from proposed first dose date. 

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Weight 
15 Body weight above 30 kg (> 30 kg). 
Sex/Reproduction 
16 Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies (Section 5.3.1). 
(a) Male patients: Male patients who intend to be sexually active with a female partner 
of childbearing potential must be surgically sterile or using an acceptable method of 
contraception (see Section 5.3.1) from the time of screening throughout the total 
duration of the study and for 6 months after the last dose of the study treatment, in 
order to prevent pregnancy in a partner. Male patients must not donate or bank sperm 
during this same time period. For country-specific requirements for Belgium and 
France see Appendices K 1.1 and K 1.2, respectively. 
(b) Female patients:  
(i) Negative pregnancy test (serum) for women of childbearing potential. 
(ii) Women of childbearing potential must agree to use one highly effective method 
of birth control (Table 7) from enrolment throughout the study until 6 months 
after the last dose of study treatment. Non sterilised male partners of a woman of 
childbearing potential must use a male condom plus spermicide (condom alone 
in countries where spermicides are not approved) throughout this period. For 
country-specific requirements for Belgium and France see Appendices K 1.1 and 
K 1.2, respectively. 
(iii) Female patients must not breastfeed and must not donate or retrieve ova from 
signing ICF to approximately 6 months after the last dose of study treatment. 
 
 
5.1.2 
Biopsy Sub-Study  
Patients are eligible to be included in the biopsy sub-study only if they meet all of the 
inclusion/exclusion criteria of the main study and all of the following criteria: 
1 
Consent to the provision of 3 mandatory tumour biopsies. 
2 
Have at least 1 tumour lesion medically accessible for 3 biopsies at baseline, on 
ceralasertib treatment and off ceralasertib treatment. 
Accessible lesions are defined as tumour lesions which are amenable to biopsy, unless 
clinically contraindicated or the patient has withdrawn consent. It is preferable that the 
same lesion is used for each biopsy, but if this is not possible, a patient may enrol if they 
have more than 1 lesion that is suitable for biopsy from the same tissue type 
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3 
Lesions used for biopsy should be different from those used as RECIST lesions, unless 
there are no other lesions suitable for biopsy. 
4 
Lesions used for biopsy may have received prior radiation therapy only if there is 
documented evidence of progression in the lesion after radiation treatment. 
 
5.2 
Exclusion Criteria  
5.2.1 
Main Study and Biopsy Sub-Study  
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1 
Patients must not have experienced a toxicity that led to permanent discontinuation of 
prior CPI treatment. Patients with unresolved ≥ Grade 2 toxicity from prior treatment 
(except alopecia and vitiligo) or ≥ Grade 1 for anti-PD-(L)1 antibody-related 
immune-mediated toxicities are excluded. Patients with irreversible toxicity that is not 
reasonably expected to be exacerbated by treatment with durvalumab or ceralasertib may 
be included (eg, hearing loss) after consultation with the AstraZeneca study clinical lead. 
2 
As judged by the investigator, any evidence of diseases (such as severe or uncontrolled 
systemic diseases, including uncontrolled hypertension, active bleeding diseases, active 
infection, active interstitial lung disease/pneumonitis, serious chronic gastrointestinal 
conditions associated with diarrhoea, psychiatric illness/social situations), history of 
allogenic organ transplant, which, in the investigator’s opinion, makes it undesirable for 
the patient to participate in the study or that would jeopardise compliance with the 
protocol. 
3 
Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow a 
formulated product, or previous significant bowel resection that would preclude adequate 
absorption, distribution, metabolism, or excretion of study treatment. 
4 
History of another primary malignancy except for malignancy treated with curative intent 
with no known active disease ≥ 3 years before the first dose of study treatment and of low 
potential risk for recurrence, basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin or lentigo maligna that has undergone potentially curative therapy or adequately 
treated carcinoma in situ without evidence of disease. 
5 
Uveal melanoma (eg, choroidal, iris, and ciliary body). 
6 
Must not have experienced a Grade ≥ 3 immune-related AE or an immune-related 
neurologic or ocular AE of any grade while receiving prior immunotherapy. Note: 
Patients with an endocrine AE of Grade ≤ 2 are permitted to enrol if they are stably 
maintained on appropriate replacement therapy and are asymptomatic. 
7 
History of symptomatic congestive heart failure, unstable angina pectoris, uncontrolled 
cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, 

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ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), 
symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic 
sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication 
or arrhythmias controlled by pacemakers may be permitted upon discussion with the 
study clinical lead. 
8 
Investigator judgment of 1 or more of the following: 
(a) Mean resting corrected QT interval of > 470 ms. 
(b) History of QT prolongation associated with other medications that required 
discontinuation of that medication, or any current concomitant medication known to 
prolong the QT interval and cause Torsades de Pointes (TdP). 
(c) Congenital long QT syndrome, family history of long QT syndrome, or unexplained 
sudden cardiac death under 40 years of age in first-degree relatives. 
9 
Must not have required the use of additional immunosuppression other than 
corticosteroids, infliximab or Cellcept for the management of an AE, not have 
experienced recurrence of an AE if re-challenged, and not currently requiring 
maintenance doses of > 10 mg prednisone or equivalent per day. 
10 Active or prior documented autoimmune or inflammatory disorders (including, but not 
limited to inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with 
the exception of diverticulosis], celiac disease, irritable bowel disease, Wegner syndrome, 
Hashimoto syndrome, hyperthyroidism, Sjogren’s syndrome, glomerulonephritis, 
multiple sclerosis, vasculitis, rheumatoid arthritis, idiopathic pulmonary fibrosis, 
pneumonitis, organising pneumonia, hepatitis, sarcoidosis, active tuberculosis) within the 
past 3 years. 
11 History of organ transplant that requires use of immunosuppressive medications 
including, but not limited to systemic corticosteroids at doses beyond 10 mg/day of 
prednisone or equivalent, methotrexate, azathioprine and tumour necrosis factor alpha 
blockers. Use of immunosuppressive medications for the management of study 
treatment-related AEs is acceptable. In addition, use of inhaled, topical and intranasal 
steroids, and local steroid injections (eg, intra-articular injection) is permitted. Steroids as 
premedications for hypersensitivity reactions or as an anti-emetic (eg, CT scan 
premedication) are also permitted. 
12 Inadequate bone marrow and impaired hepatic or renal function as demonstrated by any 
of the following laboratory values: 
 
Haemoglobin < 9.0 g/dL (no transfusions within the last 28 days). 
 
Absolute neutrophil count < 1.5 x 109/L. 
 
White blood cells ≤ 3 x 109/L. 
 
Platelet count < 100 x 109/L. 
 
Albumin < 33 g/L. 

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 
Total bilirubin ≥ 1.5 × the ULN or ≥ 3 × ULN in the presence of documented 
Gilbert’s syndrome (unconjugated hyperbilirubinemia). 
 
Aspartate aminotransferase/transaminase (SGOT)/Alanine 
aminotransferase/transaminase (ALT) (SGPT) ≥ 2.5 x institutional ULN unless liver 
metastases are present in which case it must be ≥ 5 x ULN. 
 
Serum creatinine > 1.5 x institutional ULN. 
 
Calculated creatinine clearance (CrCL) < 45 mL/min as determined by 
Cockcroft-Gault (using actual body weight).  
Males: 
CrCL =  
 
Weight (kg) × (140 - Age) 
(mL/min) 
 
72 × serum creatinine (mg/dL) 
Females: 
CrCL =  
 
Weight (kg) × (140 - Age)    
× 0.85 
(mL/min) 
 
72 × serum creatinine (mg/dL) 
 
International normalised ratio ≥ 1.5 or other evidence of impaired hepatic synthesis 
function. Patients on warfarin may participate in this study but it is recommended 
that their INR is monitored more frequently. 
13 Known active infection requiring systemic therapy, active hepatitis infection, positive 
hepatitis C virus antibody, hepatitis B virus surface antigen or HBV core antibody 
(anti-HBc), at screening. Patients with a past or resolved HBV infection (defined as the 
presence of anti-HBc and absence of HBsAg) are eligible. Patients positive for HCV 
antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 
14 Patients with confirmed COVID-19 infection by PCR test who have not made a full 
recovery. 
15 Known history of testing positive for human immunodeficiency virus (positive HIV 1/2 
antibodies) or known acquired immunodeficiency syndrome. 
16 Known history of drug or alcohol abuse within 21 days of screening. 
Prior/Concomitant Therapy 
17 Patients who have received prior chemotherapy for advanced melanoma are excluded. 
18 Any concurrent anticancer treatment. Concurrent use of hormonal therapy for 
non-cancer-related conditions (eg, hormone replacement therapy) is allowed. 
19 Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field 
of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose 
of study treatment. 
20 Major surgical procedure or significant traumatic injury within 4 weeks of the first dose 
of study treatment or an anticipated need for major surgery during the study. Note: Local 
surgery of isolated lesions for palliative intent is acceptable. 

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21 Receipt of: 
(a) Live or live attenuated vaccine within 30 days prior to the first dose of study 
treatment 
(b) COVID-19 vaccine (regardless of vaccine delivery platform, eg, vector, lipid 
nanoparticle) 30 days prior to the date of randomisation (from last vaccination or 
booster dose). 
Prior/Concurrent Clinical Study Experience 
23 Patients with a known hypersensitivity to ceralasertib or durvalumab or any of the 
excipients of the study treatment. 
24 Patients who have received prior durvalumab, regardless of the tumour type that is being 
treated, are excluded. 
25 Patients who have received Chk1 or ATR inhibitor are excluded. 
26 Participation in another clinical study with an investigational product administered in the 
last 28 days or 5 half-lives, whichever is shorter. 
Other Exclusions 
27 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
28 Judgement by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions, and requirements. 
29 Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 1 month after the last dose of ceralasertib (for ceralasertib monotherapy) and 
3 months after the last dose of study treatment for durvalumab and ceralasertib 
combination therapy. For country-specific requirements for Belgium and France see 
Appendices K 1.1 and K 1.2, respectively. 
 
5.2.2 
Biopsy Sub-Study  
1 
Patients must comply with the exclusion criteria described for the main study. 
2 
Patients with evidence of bleeding disease deemed unsafe for serial biopsies. 
 
5.3 
Lifestyle Considerations  
5.3.1 
Contraception  
Male patients: 
Non-sterilised male patients (including males sterilised by a method other than bilateral 
orchidectomy, eg, vasectomy) who intend to be sexually active with male partners and women 
of non-child bearing potential must be using an acceptable method of contraception such as 

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male condom plus spermicide (condom alone in countries where spermicides are not 
approved) from the time of screening throughout the total duration of the study and for 1 week 
after the last dose of study treatment to prevent exposure to ceralasertib via the semen. Where 
a sexual partner of a male patient is a ‘woman of childbearing potential’ who is not using 
effective contraception, or who is already pregnant, then the male patient must use a condom 
plus spermicide (where approved), during the study and for a further 6 months after the last 
dose of study treatment to prevent pregnancy in a partner. Male patients should refrain from 
fathering a child or donating sperm from the start of dosing until 6 months after the last dose 
of study treatment, if there is a concern about damaging the developing foetus from drug in 
ejaculate. For country-specific requirements for Belgium and France see Appendices K 1.1 
and K 1.2, respectively. 
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. 
Vasectomised males are considered fertile and should still use a male condom plus spermicide 
as indicated above during the clinical study. 
Female partners (of childbearing potential) of male patients must also use a highly effective 
method of contraception throughout this period (Table 7). 
Female patients:  
x 
Women not of childbearing potential are defined as women who are surgically sterile (ie, 
complete hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are 
postmenopausal. 
x 
Women will be considered postmenopausal if they have been amenorrhoeic for 
12 months prior to the planned date of randomisation without an alternative medical 
cause. The following age-specific requirements apply: 
 
Women < 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy and if they have luteinising hormone and follicle-stimulating hormone levels 
in the post-menopausal range for the institution. 
 
Women ≥ 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy, or had radiation-induced menopause with last menses > 1 year ago, or had 
chemotherapy-induced menopause with last menses > 1 year ago. 
x 
Women of childbearing potential must use highly effective form of birth control, as 
defined in Table 7, from the time of signing the informed consent and for 6 months after 
the last dose of study treatment. For all women of childbearing potential, cessation of 
contraception after the above defined time point should be discussed with a responsible 

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physician. For country-specific requirements for Belgium and France see 
Appendices K 1.1 and K 1.2, respectively.
A highly effective method of contraception is defined as one that can achieve a failure 
rate of less than 1% per year when used consistently and correctly. Note that some 
contraception methods are not considered highly effective (eg, male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action 
[excluding Cerazette/desogestrel which is considered highly effective]; and triphasic 
combined oral contraceptive pills). Female condom and male condom should not be used 
together. All women of child-bearing potential must have a negative serum pregnancy test 
result at Visit 1.
Table 7
Highly Effective Methods of Contraception (< 1% Failure Rate)
Non-hormonal methods
Hormonal methods
x
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of the 
patient)
x
Vasectomised sexual partner (with patient
assurance that partner received post-vasectomy 
confirmation of azoospermia)
x
Tubal occlusion
x
Intrauterine device (provided coils are 
copper-banded)
x
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®) aa
x
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®) aa
x
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®)
x
Intravaginal devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®)
x
Combined pill: Normal and low dose combined 
oral contraceptive pill
x
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®)
x
Mini pill: Progesterone based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based pill
a
Hormonal methods not prone to drug-drug interactions.
5.3.2
Meals and Dietary Restrictions
Patients must fast (water to drink only) from at least 2 hours prior to taking a dose of 
ceralasertib to at least 1-hour post-dose for all doses.
Patients should avoid concomitant drugs, energy drinks, herbal supplements and/or ingestion 
of foods known to modulate 
 activity (Appendix F).
CCI

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5.3.3 
Skin  
During study treatment and for 4 weeks after the last dose of study treatment, patients should 
be advised to avoid prolonged exposure to the sun, wear protective clothing including a hat, 
sunglasses, and seek shade from the sun as much as possible; in addition, SP30+ sunscreen 
should be used. Exposure to other sources of ultraviolet light including sun beds and tanning 
booths, etc, should be avoided. 
5.3.4 
Blood Donation  
Patients should not donate blood or blood components while participating in this study and 
through 90 days after receipt of the final dose of study treatment or until alternate anti-cancer 
therapy is started. 
5.4 
Screen Failures  
Screen failures are defined as patients who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure patients to meet the CONSORT publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened following consultation with the sponsor. Rescreened patients should be assigned 
the same patient number (ie, E-code) as for the initial screening. However, rescreening should 
be documented so that its effect on study results, if any, can be assessed. All assessments must 
be repeated for rescreening unless they are within 21 days of randomisation (> 28 days may be 
required for biopsy collection) or as applicable as some screening assessments could be valid 
for more than 21 days. 
If a patient is screened initially for the biopsy sub-study and is considered ineligible and is 
subsequently rescreened for the main study, the patient number will change. 
These patients should have the reason for study withdrawal recorded in eCRF as “eligibility 
criteria not fulfilled” (ie, patient does not meet the required inclusion/exclusion criteria). This 
reason for study withdrawal is only valid for screen failures (ie, patients who are not 
randomised/entered in the study). 
Patient enrolment and randomisation are described in Section 6.3. 
6 
STUDY TREATMENT  
Study treatment is defined as any investigational treatment(s), marketed product(s) or placebo 
intended to be administered to a study patient according to the study protocol. 

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6.1 
Study Treatments Administered  
6.1.1 
Study Treatments  
AstraZeneca will supply ceralasertib and durvalumab as study treatment. 
Table 8 
Investigational Products  
Treatment name 
Ceralasertib 
Durvalumab 
Type  
Synthetic 
Biologic 
Dosage form 
Tablet 
Concentrate solution for infusion 
Unit dose 
strength(s) 
Tablets in either 120 mg or 80 mg 
500 mg (50 mg/mL)  
Dosage regimen 
240 mg BD for 7 consecutive days 
(Days 1 to 7); Q28D 
1500 mg on Day 8 of each 28-day 
cycle; 20 mg/kg in patients who weigh 
≤ 30 kg 
Route of 
administration 
Oral 
IV infusion 
Use 
Experimental 
Experimental 
IMP and NIMP 
IMP 
IMP 
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and 
labelling 
High-density polyethylene bottles with 
child-resistant closures. 
Labels will be prepared in accordance 
with GMP and local regulatory 
guidelines. The labels will fulfil GMP 
Annex 13 requirements for labelling. 
Label text will be translated into local 
language, as required. 
Vials. Each vial will be labelled in 
accordance with GMP Annex 13 and 
per country regulatory requirement. 
Labels will be prepared in accordance 
with GMP and local regulatory 
guidelines. The labels will fulfil GMP 
Annex 13 requirements for labelling. 
Label text will be translated into local 
language, as required. 
Note: Label text prepared for durvalumab will show the product name as “MEDI4736” or “durvalumab” 
depending upon the agreed product name used in the approved study master label document. All naming 
conventions are correct during this transitional period. 
BD = twice daily; IMP = investigational medicinal product; IV = intravenous; NIMP = non-investigational 
medicinal product; Q28D = every 28 days. 
 
6.1.1.1 
Ceralasertib  
Ceralasertib tablets will be supplied by AstraZeneca. 
For storage and administration of ceralasertib, see Section 6.2.2. 
6.1.1.2 
Durvalumab  
Durvalumab will be supplied by AstraZeneca as a concentrate for solution for infusion. 
Durvalumab 500 mg will be supplied in a vial containing 50 mg/mL durvalumab, 26 mM 
histidine/histidine hydrochloride, 275 mM trehalose dihydrate and 0.02% weight/volume 

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(w/v) polysorbate 80; the solution has a pH of 6.0 and density of 1.05 g/mL. The label-claim 
volume for durvalumab is 10 mL. 
Durvalumab is a sterile, clear to opalescent, colourless to slightly yellow solution, free from 
visible particles. 
6.2 
Preparation/Handling/Storage/Accountability  
1 
The investigator or designee (eg, pharmacist) must confirm appropriate temperature 
conditions have been maintained during transit for all study treatment received at the site 
and throughout the entire study duration until authorisation is provided for on-site 
destruction or removal of the study treatment, reflecting completion of the study. In the 
event of a temperature excursion detected at any time during the study, sites will follow 
the reporting procedures for notifying the sponsor (or designated party); release of study 
treatment for clinical use can only occur once the event has been reviewed and approval is 
provided by the sponsor (or designated party). 
2 
Only patients enrolled in the study may receive study treatment and only authorised site 
staff may prepare, supply or administer study treatment. All study treatment must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff. 
3 
The investigator is responsible for study treatment accountability, reconciliation, and 
record maintenance (ie, receipt, reconciliation, and final disposition records reflecting 
destruction or return of all unused study treatment); this task may be delegated to study 
staff members identified on the site delegation log. The investigator (or designee) is also 
responsible for ensuring that the patient has returned all unused study treatment. 
4 
Further guidance and information for the final disposition of unused study treatments are 
provided in the Study Reference Manual. 
 
6.2.1 
Durvalumab Storage, Infusion Preparation and Administration  
6.2.1.1 
Durvalumab Storage  
Durvalumab vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. The 
investigator, or an approved representative (eg, pharmacist), will ensure that all study 
treatment is stored in a secured area, in refrigerated temperatures (2°C to 8°C; 36°F to 46°F) 
and in accordance with applicable regulatory requirements. A temperature log will be used to 
record the temperature of the storage area. Temperature excursions outside the permissible 
range listed in the clinical supply packaging are to be reported to the monitor upon detection. 
A calibrated temperature monitoring device will be used to record the temperature conditions 
in the drug storage facility. Storage conditions stated in the IB may be superseded by the label 
storage. 

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Study treatment must be kept in original packaging until time of preparation to prevent 
prolonged light exposure. 
The dose of durvalumab must be prepared by the investigator’s or site’s designated study 
treatment manager using aseptic techniques. Total time from needle puncture of the study 
treatment vial to the start of administration must not exceed: 
x 
24 hours at 2°C to 8°C (36°F to 46°F) 
x 
4 hours at room temperature 
 
If the final product is stored at both refrigerated and ambient temperatures, the total time must 
not exceed 24 hours otherwise a new dose must be prepared from new vials. Durvalumab vials 
do not contain preservatives; any unused portion of the vial must be discarded immediately 
after use. 
6.2.1.2 
Durvalumab Infusion Preparation  
A dose of 1500 mg for patients > 30 kg in weight will be prepared using an IV bag containing 
0.9% sodium chloride for injection or 5% dextrose for injection, with a final durvalumab 
concentration ranging from 1 to 15 mg/mL. Add 30 mL (ie, 1500 mg) of durvalumab to the IV 
bag. The IV bag size should be selected such that the final concentration is within 1 to 
15 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
If a patient’s weight falls to 30 kg or below (≤ 30 kg) the patient should receive weight-based 
dosing equivalent to 20 mg/kg of durvalumab Q28D (IV bag size selected is such that the final 
concentration is within 1 to 15 mg/mL) after consultation between investigator and study 
clinical lead, until the weight improves to > 30 kg, at which point the patient should start 
receiving the fixed dosing of durvalumab 1500 mg Q28D. 
6.2.1.3 
Durvalumab Administration  
Durvalumab infusions are to be administered through an IV administration set with a 0.2 or 
0.22 μm filter; acceptable configurations include an IV set containing an in-line filter or the 
attachment of a separate filter to the distal end of the IV tubing. 
The durvalumab infusion time is 1 hour ± 10 minutes; however, if there are interruptions, the 
total allowed time must not exceed 8 hours with the infusion bag maintained at room 
temperature, otherwise a new dose must be prepared from new vials. 
Do not co-administer other drugs through the same infusion line. 
The IV line will be flushed according to local practices to ensure the full dose is administered. 
Infusion time does not include the final flush time. 

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6.2.2 
Ceralasertib Storage and Administration  
6.2.2.1 
Ceralasertib Storage  
Ceralasertib product label on the bottle specifies the appropriate storage. It must be stored in 
the original outer container and under conditions specified on the label. 
6.2.2.2 
Ceralasertib Administration  
Ceralasertib tablets should be taken with a glass of water. When ceralasertib is administered, 
patients must fast (water permitted) for at least 2 hours prior to taking a dose, to at least 1 hour 
post-dose for all doses. 
Ceralasertib will be administered orally 240 mg twice daily, approximately 12 ± 2 hours apart, 
starting on Day 1 until Day 7, in each treatment cycle of both the treatment arms in the main 
study. In the biopsy sub-study, patients will self-administer ceralasertib tablets from Day 1 
until Day 7 of Cycle 0, followed by no study treatment between Day 8 and Day 28, and from 
Day 1 until Day 7 Cycle 1 onwards. 
Patients must receive ceralasertib for 7 days within each 28-day cycle. A cycle must not be 
< 28 days. Ceralasertib must not be given on any other days of the cycle, and dosing days 
must stay relative to Day 1 of each cycle. In case of drug interruption within the planned 
Days 1 to 7 dosing window (for any reason), resumption of treatment can only take place 
within the planned dosing window and not beyond, even if this means the patient receives less 
than the specified 7 days of ceralasertib dosing in the particular cycle. Dosing after Cycle 
Day 7 is not permitted and the planned 21 days off treatment should not be reduced. 
Patients are allowed to take the scheduled dose up to 2 hours after the scheduled dose time. If 
the interval between two doses is more than 14 hours, then the missed dose should not be 
taken and the patient should continue with the next dose at the allotted time. If the patient 
wishes to bring forward the time of their scheduled dose, the dose can be taken up to a 
maximum of 2 hours prior to the scheduled time, ie, ± 2-hour window. 
6.3 
Measures to Minimise Bias: Randomisation and Blinding  
6.3.1 
Main Study  
This is an open-label study; potential bias will be reduced by the following steps: central 
randomisation, use of BICR for tumour assessments and use of IDMC (Section 9.6). 
For the main study, patients will be randomly allocated to receive 1 of the study treatments, at 
a 2:1 randomisation ratio, such that there will be approximately 100 evaluable patients in the 
ceralasertib and durvalumab combination therapy arm and approximately 50 patients in the 
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At enrolment, Investigators will confirm PD-(L)1 resistance type and whether the LDH is 
normal or above upper limit of normal in order to stratify the patients accordingly. 
Stratification factors include: 
1 
Resistance to prior immune-oncology treatment (primary/early relapse in adjuvant setting 
vs secondary resistance). Based on SITC (Kluger HM et al, 2020) definitions of resistance 
to PD-(L)1 therapy:  
Primary resistance: patients with a drug exposure of ≥ 6 weeks who had PD or stable 
disease for < 6 months. 
Secondary resistance: patients with a drug exposure of ≥ 6 months who had confirmed 
CR or PR, or SD for > 6 months  
Early relapse in adjuvant setting: patients with PD within 12 weeks of the last dose 
2 
Baseline lactate dehydrogenase expression (below and equal to the upper limit of normal 
vs above upper limit of normal). Lactate dehydrogenase will be determined by a local test 
and values can vary depending on the lab. Therefore, patients will be stratified for LDH 
normal or above upper limit of normal, according to local lab reference ranges. 
 
Patients will be randomised as they become eligible. Once the eligibility of a patient has been 
confirmed, the investigator (or designee) will notify the centralised IWRS (all patients). The 
IWRS will then provide the randomisation identification code. Randomisation should take 
place as close to the start of study treatment as possible (randomisation does not apply to 
patients in the biopsy sub-study). 
Due to the different schedules of administration of the treatment options, neither patients nor 
investigators will be blinded to treatment assignment. However, to limit bias to study conduct, 
data quality, data analyses and data interpretation, appropriate key personnel and certain 
functions at AstraZeneca will remain blinded to treatment allocation until the database lock at 
primary analysis. Separate unblinded counterparts eg, biostatisticians and statistical 
programmers will do all necessary unblinded work during the course of the study, including 
interaction with the IDMC. Detailed procedures for maintenance of the blind will be described 
in the IDMC Charter and the study integrity plan. 
Study treatment details are summarised in Section 6. 
6.3.1.1 
Screening Procedures  
If a patient withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. Withdrawn patients will not be replaced. 
Investigators should keep a record (ie, the patient screening log) of patients who entered 
screening. 

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At screening/baseline (Days -21 to -1), the investigators or suitably trained delegate will: 
x 
Obtain signed informed consent before any study-specific procedures are performed. If 
laboratory or imaging procedures were performed for alternate reasons prior to signing 
consent, these can be used for screening purposes with consent of the patient. However, 
all screening imaging results must have been obtained within 28 days of randomisation 
and all screening laboratory results within 21 days of randomisation. 
x 
Identify patients to the IWRS per country regulations. Obtain a unique 7-digit enrolment 
number (E-code), through the IWRS in the following format (ECCNNXXX: CC being the 
country code, NN being the centre number, and XXX being the patient enrolment code at 
the centre). This number is the patient’s unique identifier and is used to identify the 
patient on the eCRFs. 
x 
Determine patient eligibility (see Sections 5.1 and 5.2). 
x 
Obtain signed informed consent for genetic research study (optional). Patients who decide 
not to sign the specific genetic ICF but the general study ICF are eligible for study 
enrolment and all other study procedures. 
 
If the patient is ineligible and not randomised, the IWRS should be accessed to terminate the 
patient in the system. 
Patients will begin treatment on Day 1. Treatment should start no more than 3 working days 
after being randomised. Patients must not be randomised and treated unless all eligibility 
criteria have been met. 
6.3.1.2 
Methods for Assigning Treatment Groups  
The actual treatment given to patients will be determined by the randomisation scheme in the 
IWRS. The randomisation scheme will be produced by a computer software programme that 
incorporates a standard procedure for generating randomisation numbers. One randomisation 
list will be produced for each of the randomisation strata. A blocked randomisation will be 
generated, and randomisation will be balanced within the IWRS at the 
site/country/region/central level. All centres will use the same list in order to minimise any 
imbalance in the number of patients assigned to each treatment group. 
Randomisation codes will be assigned strictly sequentially, within each stratum and 
site/country/region, as patients become eligible for randomisation. The IWRS will provide the 
kit identification number to be allocated to the patient at the randomisation visit and 
subsequent treatment visits. 
6.3.1.3 
Procedures for Handling Incorrectly Enrolled or Randomised Patients  
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
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enrolled but subsequently found not to meet all the eligibility criteria must not be randomised 
or started on study treatment and must be withdrawn from the study. 
Where a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the investigator should inform the AstraZeneca study clinical 
lead immediately, and a discussion should occur between the AstraZeneca study clinical lead 
and the investigator regarding whether to continue or discontinue the patient from treatment. 
The AstraZeneca study clinical lead must ensure all decisions are appropriately documented 
and that the potential benefit/risk profile remains positive for the patient. 
6.3.2 
Biopsy Sub-Study  
Enrolment to the biopsy sub-study will be open at selected sites only. At these sites, when 
enrolment to the biopsy sub-study is open, patients who are eligible for the biopsy sub-study 
should be enrolled to the biopsy sub-study part and not be randomised into the main study. 
6.4 
Treatment Compliance  
Sites will follow local practices for verification of study treatment doses, prepared and 
administered to study patients. 
When the individual dose for a patient is prepared from a bulk supply, the preparation of the 
dose will be confirmed by a second member of the study site staff. 
When patients are dosed at the site, they will have study treatment prepared, dispensed and 
administered by the investigator or designee, under medical supervision. The date, and time if 
applicable, of dose administered in the clinic will be recorded in the source documents and 
recorded in the eCRF. The dose of study treatment and study patient identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study treatment. 
When patients self-administer study treatments at home, compliance with study treatment will 
be assessed once per cycle and per local institutional policy. Compliance will be assessed by 
direct questioning, counting returned study treatments, etc 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. 
For ceralasertib, dosing compliance will be reviewed with the patient at the beginning of each 
new treatment cycle when study treatment is dispensed. All patients will be required to 
complete a dosing diary using an electronic device. The dosing diary must be reviewed once 
per each cycle and per local institutional policy. The patient must be instructed to record each 
date and time the dose(s) were taken in the dosing diary. If a dose is missed, the reason must 
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A record of the number of ceralasertib tablets dispensed to and taken by each patient must be 
maintained and reconciled with study treatment and compliance records. Study treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be 
recorded in the eCRF.
The investigator is responsible for ensuring that the patient has returned all unused study 
treatment.
6.5
Concomitant Therapy
Any concomitant treatment, procedure, or other medication considered necessary by the 
investigator for the patient’s safety and wellbeing, or vaccine (including over-the-counter or 
prescription medicines, vitamins, and/or natural/herbal products, other “folk remedies”, etc) or 
other specific categories of interest that the patient is receiving at the time of enrolment or 
receives during the study, including the follow-up period following the last dose of study
treatment must be recorded in the eCRF along with:
x
Reason for use
x
Dates of administration including start and end dates
x
Dosage information including dose and frequency
If medically feasible, patients 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 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator and 
sponsor, the medication will not interfere with the study.
Paracetamol/Acetaminophen, at doses of d 2 grams/day, is permitted for use any time 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.
6.5.1
Restricted, Prohibited, and Permitted Concomitant 
Medications/Therapies
Restricted, prohibited, and permitted concomitant medications/therapies are described below. 
Refer also to the dose modification guidelines for management of study treatment-related 
toxicities in the Annex document to this CSP.
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Table 9 
Restricted Medications/Therapies    
Medication/class of drug/Therapy 
Usage (including limits for duration permitted and 
special situations in which it’s allowed 
Hormonal therapy 
For non-cancer-related conditions (eg, insulin for 
diabetes and hormone replacement therapy) only. 
Bisphosphonates 
For the treatment of bone metastases and osteoporosis. 
Corticosteroids 
For the treatment of specific adverse drug reactions 
(refer to Toxicity Management Guidelines document). 
 
Table 10 
Prohibited Concomitant Medications    
Prohibited medication/class of drug 
Usage 
Any investigational therapy including anti-cancer 
therapy other than those under investigation in this 
study 
Must not be given concomitantly while the patient is 
on study treatment 
mAbs against CTLA-4, PD-1, or PD-(L)1 other than 
those under investigation in this study 
Must not be given concomitantly while the patient is 
on study treatment 
Any concurrent treatment including chemotherapy, 
radiotherapy, immunotherapy, or biologic or 
hormonal therapy for cancer treatment other than 
those under investigation in this study, except for 
those medications identified as “restricted”, as listed 
above.  
Must not be given concomitantly while the patient is 
on study treatment. (Concurrent use of hormones for 
non-cancer-related conditions [eg, insulin for diabetes 
and hormone replacement therapy] is acceptable. 
Local treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable [eg, by local 
surgery or radiotherapy]) 
Live attenuated vaccines  
Must not be given while receiving study treatment and 
up to 30 days after the last dose of durvalumab or 
ceralasertib. Local guidance should be consulted to 
determine the acceptable timeframe for vaccine 
administration following chemotherapy study 
treatment. 
Immunosuppressive medications including, but not 
limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumour necrosis 
factor-α blockers 
Must not be given concomitantly or used for 
premedication prior to the IO infusions. The following 
are allowed exceptions: 
x 
Use of immunosuppressive medications for the 
management of study treatment-related AEs  
x 
Short-term premedication for patients receiving 
combination agent where the prescribing 
information for the agent requires the use of 
steroids for documented hypersensitivity 
reactions 
x 
Use in patients with contrast allergies 
x 
In addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted 
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy related events 
experienced by the patient (eg, chronic obstructive 
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Table 10
Prohibited Concomitant Medications
Prohibited medication/class of drug
Usage
with study clinical lead for prolonged therapy or need 
for a slow taper.
Herbal and natural remedies that may have immune-
modulating effects and interfere with interpretation 
of study results
Must not be given concomitantly unless agreed by the 
sponsor.
Sunitinib
Must not be given concomitantly or through 90 days 
after the last dose of durvalumab.
EGFR TKIs 
Must not be given concomitantly. 
Must be used with caution in the 90 days post last 
dose of durvalumab. 
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with first generation EGFR 
TKIs) has been reported when durvalumab has been 
given concomitantly.
AE = adverse event; CTLA-4 = cytotoxic T-lymphocyte associated antigen; EGFR = epidermal growth factor 
receptor; IO = immune-oncology; mAbs = monoclonal antibodies; PD-1 = programmed cell death-1; 
PD-(L)1 = programmed cell death ligand-1; TKI = tyrosine kinase inhibitor.
Premedication
x
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 
 of 
 and also an 
 
of 
.
Therefore, the use of aprepitant is NOT allowed in this study for the treatment of nausea 
and vomiting induced by the study treatment. In general, drugs that interfere with 
 
are not allowed in this study, and aprepitant is NOT an exception.
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Supportive care
Patients may receive concomitant medications or treatments (eg, acetaminophen or 
diphenhydramine), except for those medications identified as “prohibited,” as listed above, if 
the investigator deems it necessary to provide adequate AE management.
Patient may receive vaccines limited only to non-live attenuated preparations (eg, influenza 
vaccine).
Patients will be permitted to receive appropriate supportive care measures (including 
antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control, 
and pain management [including palliative radiotherapy, etc]) as deemed necessary by the 
treating physician, including but not limited to the items outlined below:
x
Diarrhoea: Diarrhoea should be treated promptly with appropriate supportive care, 
including administration of an anti-diarrhoeal agent according to standard practice 
guidelines. Anti-diarrhoeal agents should not be taken prophylactically. Patients should 
be instructed to begin taking anti-diarrhoeal 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-diarrhoeal 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. Patients should also be advised to drink liberal quantities of clear 
fluids to help prevent dehydration.
x
Nausea/vomiting: Nausea and vomiting should be treated adequately, and strong 
consideration should be given to the administration of secondary prophylactic anti-emetic 
therapy according to standard institutional practice. Patients should be strongly 
encouraged to maintain liberal oral fluid intake. Supportive care with aprepitant (a 
) according to institutional guidelines in the context 
of standard of care chemotherapy is NOT allowed.
x
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.
x
Neutropenia: Colony-stimulating factors including G-CSF, pegylated G-CSF or 
GM-CSF according to Institutional Standards, following discussion with the Principal 
Investigator and AstraZeneca.
Avoid concomitant medications, herbal supplements and/or ingestion of foods that 
significantly modulate 
 activity. Note these include common azole 
antifungals, macrolide antibiotics, etc. For patients receiving study treatment in the absence of 
discontinuation criteria, if the investigator feels that concomitant administration of 
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medications, herbal supplements or foods that significantly modulate 
 activity is 
necessary based upon medical judgement, such products may be administered with caution 
following discussion between the investigator and the sponsor Study Physician.
The AstraZeneca study clinical lead should be contacted if there are any questions regarding 
concomitant or prior therapy.
If any concomitant therapy is administered due to new or unresolved AE, it should be 
recorded.
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
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 
in vitro data only.
The lists of 
 and transporter inhibitors/inducers, and 
 and transporter substrates are 
available in Appendix F. 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 
 metabolism 
The principal enzyme for metabolising ceralasertib is 
. Patients should avoid 
concomitant drugs, herbal supplements, and/or ingestion of foods known to modulate 
 activity from the time they enter the screening period until 28 days after the last dose 
of study treatment.
x
Prior to study treatment, use of potent inducers or inhibitors of 
 are not permitted.
For patients taking any of these drugs (examples provided in Appendix F) the required 
washout periods before starting ceralasertib is 
 half-lives; except for 
,
which is 3 weeks.
x
On study treatment, if there is no suitable alternative concomitant medication other than a 
potent inhibitor of 
, the investigator must interrupt ceralasertib for the duration of 
the potent 
 inhibitor and wait for the required washout period (
 half-lives) 
before dosing ceralasertib again. If potent 
 inducers are considered necessary for 
the patient’s safety and welfare, this may diminish the clinical efficacy of ceralasertib and 
the patient should be monitored carefully for any change in the efficacy of study 
treatment. Refer to Appendix F for additional guidance.
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x
The use of any herbal supplements or ‘folk remedies’ (and medications and foods that 
significantly modulate 
 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 
 but a lesser extent, 
therefore caution should be applied with co-administration of potent inhibitors or inducers of 
 (examples provided in Appendix F).
Drugs known to be inhibitors or inducers of 
 and/or 
, undertake appropriate 
monitoring if co-administration is necessary 
x
Ceralasertib is also a 
 substrate. Co-administration of 
 inhibitors or inducers may 
affect exposure to ceralasertib and therefore, they should not be co-administered with 
ceralasertib. If the use of any inhibitors or inducers of 
 are considered necessary for 
the patient’s safety and welfare, the investigator must interrupt ceralasertib for the 
duration of the 
 inhibitor or inducer and wait for the required wash-out period of the 
 modulator (
 half-lives) before dosing ceralasertib again. Refer to Appendix F for 
additional guidance.
x
Ceralasertib is a substrate of 
. Co-administration of strong
 inhibitors or 
inducers may affect exposure to ceralasertib; therefore, it is recommended that the 
investigators must interrupt ceralasertib for the duration of the strong
 inhibitor or 
inducer and wait for the required washout period of the 
 modulator (
 half-lives) 
before dosing ceralasertib again.
Drugs known to be substrates of 
, and/or 
, undertake appropriate monitoring if co-administration is necessary 
Based on in vitro data, ceralasertib is a potential inhibitor of 
as well as an inducer of 
. Caution should be applied with 
co-administration of drugs that are either completely metabolised by 
 or that are substrates of 
 and also have a narrow therapeutic index. Investigators should be 
aware that the exposure of other drugs metabolised by 
may be increased, and exposure of other drugs metabolised by
may be reduced.
Drugs known to be substrates of 
 and 
, undertake appropriate 
monitoring if co-administration is necessary 
Ceralasertib is an inhibitor of 
 and 
. Caution should be applied with 
co-administration of substrates of 
and/or 
 as ceralasertib may increase their 
exposure.
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 therapy 
Patients on 
 may participate in this study but it is recommended that their INR is 
monitored more frequently.
Refer to Appendix F for further details regarding prohibited concomitant medications with
ceralasertib.
6.5.3
Drug-Drug interactions Between Durvalumab and Other Drugs
There is no information to date on drug-drug interactions with durvalumab either 
pre-clinically or in patients.
As durvalumab is a mAb and therefore a protein, it will be degraded to small peptides and 
amino acids and will be eliminated by renal and reticuloendothelial clearance (CL). It is 
therefore not expected that durvalumab will induce or inhibit the major drug metabolising 
 pathways. As a result, there are no expected PK drug-drug interactions. The mechanism 
of action of durvalumab involves binding to PD-(L)1, and therefore significant 
pharmacodynamic drug interactions with commonly administered concomitant medications 
are not expected.
6.5.4
Rescue Medication
The study site will supply the required rescue medication and it will be obtained locally. The 
following rescue medications are required to be available at the site:
1
Infliximab/infliximab biosimilar (eg, for colitis).
2
Mycophenolate (eg, for hepatitis).
Under certain circumstances when local sourcing by the study site is not feasible or local 
regulations prevent the use of infliximab or mycophenolate for this use (as they are considered 
off-label for management of immunotherapy related toxicities), AstraZeneca will centrally 
supply the required rescue medications, which will be labelled and accompanied by 
Prescribing Information with local language translated text in accordance with regulatory 
guidelines. Accountability and storage requirements, as specified in Section 6.2, apply for any 
study treatment supplied by AstraZeneca. If required to manage an imAE, then the 
IVRS/IWRS will allocate the specific medication either by a kit or another identification 
number, to the pharmacist for a specific patient at the time of the event.
The date of rescue medication administration as well as the name and dosage regimen of the 
rescue medication must be recorded.
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As a result of imAEs that could potentially be experienced by patients on durvalumab and 
ceralasertib, appropriate treatment (eg, steroids and specific immunosuppressant rescue 
medications) must be made readily available to this patient population.
6.6
Dose Modification
Patients may delay durvalumab dosing under certain circumstances.
x
Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines, due to either an immune or a non-immune-related AE.
x
If dosing must be delayed for reasons other than treatment-related toxicity, dosing will 
resume as soon as feasible.
x
Dosing intervals of subsequent cycles may be shortened as clinically feasible in order to 
gradually align treatment cycles with the schedule of tumour efficacy (RECIST) and PRO 
assessments.
Any clinically significant and/or unacceptable toxicity observed during the course of the study 
should be managed in the first instance by interruption of the dose of study treatment, 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) 
treatment with study treatment may be restarted using the rules in Table 11 and Table 12 for 
dose modifications for ceralasertib plus durvalumab and ceralasertib monotherapy, 
respectively. Patients 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.
Patients who develop a ≥ Grade 3 of anaemia, neutropenia, or thrombocytopenia during the
treatment period will also need to have additional assessments on Day 7 (for ceralasertib 
monotherapy) and on Day 15 (for combination of ceralasertib and durvalumab and for those in 
the biopsy sub-study) until there is no evidence of ≥ Grade 3 anaemia, neutropenia, or 
thrombocytopenia for at least 2 cycles.
If the toxicity does not resolve to ≤CTCAEv5 Grade 1 or 2 (depending on the toxicity) or the 
patient is not showing clinical benefit, then the patient should be discontinued from study 
treatment and observed until resolution of the toxicity.
For simultaneous toxicities (for example, anaemia and neutropenia), the event should be 
considered singular, and 
 further dose modification should be made providing that both 
 resolve within 
. However, sequential toxicities (for example, anaemia 
followed by neutropenia) should follow the guidance as show in Table 11 and Table 12; if a 
recent dose reduction has been made, a second modification may be required before beginning 
the next cycle.
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 dose interruptions are allowed as required for a maximum of 
 on each occasion 
as recommended in Table 11. If the duration of ceralasertib dose interruption is longer than 
, the case should be discussed with the AstraZeneca study physician.
Once dose is reduced, escalation is not permitted.
Study treatment dose interruption for conditions other than 
 resolution should be kept 
as 
 as possible. If a patient cannot restart study treatment within 
 for resolution of 
intercurrent conditions not related to disease progression or 
, the case should be 
discussed with the AstraZeneca Study Physician.
No 
 of study treatment is required for any 
 procedure unless deemed necessary 
by the physician. Study treatment should be 
 for a minimum of 
 before a 
patient undergoes palliative radiation treatment or planned surgery. Study treatment should be 
 within 
 as long as any bone marrow toxicity has recovered. Radiotherapy 
should not involve 
 and progressive disease should be 
.
The dose of study treatment 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.
Table 11
Guidance for Dose Modifications, Interruptions, and Discontinuations 
for Ceralasertib (all treatment arm) and Ceralasertib plus 
Durvalumab
Event
Action
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Table 11
Guidance for Dose Modifications, Interruptions, and Discontinuations 
for Ceralasertib (all treatment arm) and Ceralasertib plus 
Durvalumab
Event
Action
Table 12
Dose Reduction Levels for Ceralasertib
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6.6.1 
Management of Toxicities  
The following general guidance should be followed for management of toxicities: 
x 
Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity if required). 
x 
If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of the assigned study treatment along with appropriate 
continuing supportive care. If medically appropriate, dose modifications are permitted. 
x 
All dose modifications should be documented with clear reasoning and documentation of 
the approach taken. 
 
All toxicities will be graded according to National Cancer Institute CTCAE, version 5.0. 
Comprehensive TMG have been developed to assist investigators with the recognition and 
management of toxicities associated with use of the immune-checkpoint inhibitor, 
durvalumab, PD-(L)1 inhibitor. These guidelines are applicable when durvalumab is used in 
combination with other anticancer drugs (ie, antineoplastic chemotherapy, targeted agents) 
administered concurrently or sequentially as part of a protocol-specific treatment regimen. 
The TMGs provide information for the management of immune-mediated reactions, 
infusion-related reactions, and non-immune-mediated reactions that may be observed with 
checkpoint inhibitor monotherapy or combination checkpoint inhibitor regimens, with specific 
instructions for checkpoint inhibitor-specific dose modifications (including discontinuation) 
and treatment interventions. Investigators are advised however to use local practice guidelines 
and consult local references for the management of toxicities observed with other anti-cancer 
treatment. 
The most current version of the TMGs is provided to the investigative site as an Annex to 
Protocol document entitled, “Dosing Modification and Toxicity Management Guidelines 
(TMGs) for Durvalumab Monotherapy or in Combination with Other Products” and is 
maintained within the Site Master File. 
Patients should be thoroughly evaluated, and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAEs. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an 
immune-related adverse events diagnosis. In the absence of a clear alternative aetiology, 
events should be considered potentially immune-related. In addition, there are certain 
circumstances in which durvalumab and ceralasertib should be permanently discontinued (see 
Section 7.1 for discontinuation criteria and the Dosing Modification and Toxicity 
Management Guidelines). Following the first dose of study treatment, subsequent 
administration of durvalumab can be modified based on toxicities observed as described in the 
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the investigator in the exercise of his/her clinical judgement in treating these types of 
toxicities. These guidelines apply to AEs considered causally related to durvalumab 
monotherapy and durvalumab with ceralasertib regimen by the reporting investigator. 
For patients who weigh > 30 kg, the dose of durvalumab cannot be modified. In case of doubt, 
the investigator should consult with the Study Physician. If a patient’s body weight falls to 
30 kg or below (≤ 30 kg) during the study, (s)he will be withdrawn from the study treatment 
unless (s)he derives some clinical benefit according to the treating physician. In this case, and 
following agreement between the treating physician and the sponsor, the patient may continue 
treatment at a body weight adapted dose of 20 mg/kg actual body weight. 
Durvalumab dosing can be interrupted in the event of treatment-related toxicity. All toxicities 
will be graded according to CTCAE version 5.0. Dose reductions of durvalumab are not 
permitted. In case of doubt, the investigator should consult with the Study Physician. 
Management of prolonged haematological toxicities  
Patient should be referred to a haematologist for further investigations and management in the 
event of prolonged haematological toxicity such as:  
x 
≥ 2-week interruption/delay in study intervention due to CTCAE Grade 3 or worse 
anaemia and/or development of blood transfusion dependence  
x 
≥ 2-week interruption/delay in study intervention due to CTCAE Grade 3 or worse 
neutropenia (ANC < 1 × 109/L)  
x 
≥ 2-week interruption/delay in study intervention due to CTCAE Grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence 
(Platelets < 50 × 109/L) 
 
Consider checking weekly differential blood counts including reticulocytes and peripheral 
blood smear. Bone marrow analysis and/or blood cytogenetic analysis should be considered at 
this stage according to standard haematological practice.  
Study intervention should be discontinued if blood counts do not recover to CTC Grade 1 or 
better within 4 weeks of dose interruption.  
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should 
be reported as an SAE and full reports must be provided by the investigator to AstraZeneca 
Patient Safety. Study intervention should be discontinued if patient’s diagnosis of MDS and/or 
AML is confirmed. 
The dose reduction levels for ceralasertib are summarised in Table 12. 

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6.7 
Treatment After the End of the Study  
As described in Section 4.4, the study will remain open until all patients have discontinued 
study treatment and completed their last expected visit/contact. 
After the final DCO for this study, AstraZeneca will continue to supply open-label ceralasertib 
or ceralasertib plus durvalumab to patients in the continued access phase of the study (PTAP) 
until disease progression occurs as judged by the investigator or until meeting any other 
discontinuation criteria as defined in Section 7.1. Patients should be followed according to the 
institution's Medical Standard of Care and as deemed appropriate by the investigators. No 
further data collection is required, except for SAEs and AEs, if applicable. Refer to 
Section 8.3.11 for safety reporting during PTAP. 
For patients continuing in the PTAP, it is recommended that the patients continue the 
scheduled site visits and investigators continue to observe ongoing patients at the frequency 
employed prior to the primary DCO. Investigators will monitor the patients’ safety laboratory 
results prior to and periodically during treatment with durvalumab and ceralasertib in order to 
manage AEs in accordance with the durvalumab and ceralasertib Dosing Modification and 
Toxicity Management Guidelines (see the Annex document to this CSP). 
During the PTAP, while a patient is receiving ceralasertib or ceralasertib plus durvalumab, 
dose modification and stopping criteria should generally follow the approach as described in 
this protocol. A change in the dose/schedule of ceralasertib or ceralasertib plus durvalumab 
should only occur for safety reasons, based on the investigator’s judgement. 
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving treatment with ceralasertib or ceralasertib 
plus durvalumab may be transitioned to such a study, and the current study would reach its 
end. The roll-over or extension study would ensure treatment continuation with visit 
assessments per its protocol, as applicable. Any patients who would be eligible to move to 
such a study would be given a new informed consent, as applicable. 
In the event that product development reaches a point where alternative product supply 
options become available, then these alternative product supply options will be discussed by 
AstraZeneca with the investigator. AstraZeneca will work with the investigator to transition 
the patient(s) to alternative supply, where possible. 

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7 
DISCONTINUATION OF STUDY TREATMENT AND 
PATIENT DISCONTINUATION/WITHDRAWAL  
7.1 
Discontinuation of Study Treatment  
It may be necessary for a patient to permanently discontinue (definitive discontinuation) study 
treatment. Patients may be withdrawn from any aspect of the study at any time, without 
prejudice to further treatment. If study treatment is permanently discontinued, the investigator 
should instruct the patient to contact the site before or at the time if study treatment is stopped. 
A patient that decides to discontinue study treatment will always be asked about the reason(s) 
and the presence of any AEs. The reason for discontinuation should be documented in the 
source document and the appropriate section of the eCRF. See the SoA (Section 1.3) for data 
to be collected at the time of discontinuation of study treatment and follow-up and for any 
further evaluations that need to be completed. 
Patients who have permanently discontinued from further receipt of study treatment will need 
to be discontinued from the IVRS/IWRS. All study treatment should be returned by the patient 
at their next on-site study visit or unscheduled visit. 
Patients will be discontinued from study treatment in the following situations: 
x 
Clinical or RECIST 1.1-defined radiological progression (refer to Section 8.1.1 and 
Appendix G).  
x 
Investigator determination that the patient is no longer benefiting from study treatment. 
x 
An AE that, in the opinion of the investigator or AstraZeneca: 
- 
Contraindicates further dosing. 
- 
Meets criteria for discontinuation defined in the dose modification guidelines for 
management of study treatment-related toxicities (see the Annex document to this 
CSP). 
- 
Presents life-threatening circumstances or causes unacceptable toxicity to the patient. 
x 
Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment. A patient who discontinues treatment is normally expected 
to continue to participate in the study (eg, for safety and survival follow-up) unless they 
specifically withdraw their consent to all further participation in any study procedures and 
assessments (see Section 7.2). 
x 
Severe non-compliance with the CSP as judged by the investigator or AstraZeneca. 
x 
Pregnancy or intent to become pregnant. 
x 
Initiation of subsequent anticancer therapy, including another investigational agent. 

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x 
Patients incorrectly initiated on study treatment. 
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When the reason does not impact safety consider the risk/benefit to the patient of 
stopping study treatment. 
x 
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study. 
x 
A decision on the part of the sponsor to suspend or discontinue development of the drug 
for reasons including but not limited to unfavourable risk/benefit or change in drug 
development plan. 
 
Note that discontinuation from study treatment is NOT the same thing as a withdrawal from 
the study. 
For country-specific requirements for France see Appendix K 1.2. 
7.1.1 
Temporary Discontinuation/Rechallenge  
The rules for restarting study treatment are summarised in Section 6.6. 
7.1.2 
Follow-up of Patients Post Discontinuation of Study Treatment  
After study treatment discontinuation, all patients will be followed up for safety assessments 
30 days after their last dose of study treatment for ceralasertib monotherapy or 180 days after 
last dose of study treatment for ceralasertib and durvalumab combination (ie, the safety 
follow-up visit). Patients will also be followed for survival status and post discontinuation 
anti-cancer therapies. Additional assessments to be performed at the time of the safety 
follow-up are detailed in the SoA (Section 1.3). For country-specific requirements for 
Belgium and France see Appendices K 1.1 and K 1.2, respectively. 
Patients who have discontinued study treatment prior to objective RECIST 1.1-defined 
radiological progression will be followed up with tumour assessments according to the SoA 
until RECIST 1.1 defined disease progression or death regardless of whether or not the patient 
started a subsequent anti-cancer therapy, unless they have withdrawn all consent to study 
related assessments. 
7.1.3 
Follow-up for Survival  
Patients will be followed up for survival status, as indicated in the SoA (Section 1.3), starting 
at an 8-weekly time interval, reducing to 12 weekly after 18 months. Survival information will 
be obtained via telephone contact with the patient or the patient’s family, or by contact with 
the patient’s current physician. 

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7.2 
Patient Withdrawal from the Study  
x 
A patient may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon. 
x 
A patient who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options to ensure the collection of endpoints and safety 
information including new AEs and follow-up on any ongoing AEs and concomitant 
medications (eg, telephone contact at 30 days (+7 days) after study treatment is 
discontinued, a contact with a relative or treating physician, or information from medical 
records). 
x 
At the time of withdrawal from the study, if possible, early study treatment 
discontinuation procedures should be conducted, as shown in the SoA (Section 1.3). See 
SoA for data to be collected at the time of study withdrawal and follow-up and for any 
further evaluations that need to be completed. 
 
The patient will discontinue the study treatment and be withdrawn from the study at 
that time. 
x 
If the patient withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
x 
If a patient withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation. The 
investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team. 
 
7.3 
Lost to Follow up  
A patient will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and no contact has been established by the time the study is completed (see 
Section 4.4), such that there is insufficient information to determine the patient’s status at that 
time. 
Patients who decline to continue participation in the study, including telephone contact, 
should be documented as “withdrawal of consent” rather than “lost to follow-up.” 
Investigators should document attempts to re-establish contact with missing patients 
throughout the study period. If contact with a missing patient is re-established, the patient 
should not be considered lost to follow-up and evaluations should resume according to the 
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The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
x 
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
study. 
x 
Before a patient is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record. 
x 
Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn or been lost to follow-up from the study. 
x 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
patient within legal and ethical boundaries for all patients randomised, including those 
who did not get study treatment. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented and the 
patient will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A. 
In order to support key efficacy endpoints of PFS and OS analyses, the survival status of all 
patients in the full analysis set and the safety analysis set should be re-checked; this includes 
those patients who withdrew consent or are classified as “lost to follow-up.” 
x 
Lost to follow-up – Site personnel should check hospital records and a publicly available 
death registry (if available), as well as checking with the patient’s current physician, to 
obtain the current survival status (the applicable eCRF modules will be updated). 
x 
In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarised in the SoA (Section 1.3). Data collection 
following study analysis until the end of the study is described below. 
x 
Protocol waivers or exemptions are not allowed. 

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x
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment.
x
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
x
All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
x
Procedures conducted as part of the patient’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
x
The maximum amount of blood collected from each patient over the duration of the study, 
including any extra assessments that may be required, will not exceed 300 mL (over a 
1-month). Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
For details on follow-up of patients after discontinuation of study treatment, see Section 7.1.2.
For SAE and AE reporting and laboratory assessment collection after 
 analysis, see 
Section 8.3.2.
8.1
Efficacy Assessments
8.1.1
Tumour Assessments
Tumour response will be evaluated by the investigator and by BICR (main study only) 
according to RECIST 1.1. All treatment decisions will be based on on-site assessment of 
scans. Patients who are determined to have progressed according to RECIST 1.1 criteria by 
the investigator will have scans centrally reviewed for confirmation of objective disease 
progression. If disease progression is not confirmed at central review an additional 
RECIST 1.1 assessment may be requested preferably at the next scheduled RECIST 1.1 visit.
Baseline tumour assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual patients. Baseline assessments should be 
performed no more than 21 days before randomisation, and ideally should be performed as 
close as possible to the start of study treatment. The methods of assessment used at baseline 
should be used at each subsequent follow-up assessment.
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Tumour assessment will be conducted every 8 weeks (±1 week) after the start of treatment 
(Cycle 1 Day 1) up to 18 months, then every 12 weeks (±1 week) until objective disease 
progression as per RECIST 1.1, irrespective of treatment decisions. In the event of treatment 
interruptions or delays, tumour assessments should proceed to schedule relative to Cycle 1 
Day 1. Tumour assessments (RECIST 1.1) are to continue according to schedule in patients 
who discontinue treatment for reasons other than disease progression. 
Any other sites at which new disease is suspected should also be appropriately imaged. If an 
unscheduled assessment is performed (eg, to investigate clinical signs and symptoms of 
progression) and the patient has not progressed, every attempt should be made to perform 
subsequent assessments at the scheduled visits whilst the patient remains on study treatment. 
Digital colour photographs documenting measurable lesions including a ruler to estimate the 
size of the lesion, should be obtained if the cutaneous lesion is included as part of the 
non-target lesions for disease assessment according to RECIST 1.1. Copies of the photograph 
should be forwarded to the central imaging vendor for potential retrospective analysis. The 
timing for capturing cutaneous lesion photographs should follow the same schedule as the 
imaging scans. 
Clinically stable patients will continue on study treatment following RECIST 1.1 progression 
after a favourable benefit-risk by the investigator and the Study Physician. Patients who 
continue treatment beyond radiographic disease progression will be closely monitored. If the 
follow-up scans do not confirm disease progression per RECIST 1.1, the patient may continue 
on study treatment. 
Categorisation of objective tumour response assessment will be based on the RECIST 1.1 
guidelines for response: CR, PR, stable disease, disease progression, and not evaluable. 
The RECIST 1.1 guidelines for measurable, non-measurable, TLs and NTLs and the objective 
tumour response criteria are presented in Appendix G of this protocol. 
8.1.1.1 
Investigator’s Assessment of Tumour Response Per RECIST 1.1  
Tumour response will be assessed by the investigators per RECIST 1.1 (Eisenhauer et al, 
2009). Guidelines for the evaluation of measurable, non-measurable, TLs, and NTLs and the 
objective tumour response per RECIST 1.1 are presented in Appendix G. 
From the investigator’s review of the imaging scans (and photographs if required), the 
evaluation of TLs, NTLs and new lesions will be used to determine the overall visit response 
for each patient. Overall visit responses for each visit will then be used to determine if and 
when a patient has progressed in accordance with RECIST and their best objective response to 
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8.1.1.2 
Blinded Independent Central Review of Tumour Assessments  
Coded copies of all imaging assessments (regardless of modality and including unscheduled 
visit scans) will be collected on an ongoing basis and sent to an AstraZeneca appointed iCRO 
for quality control, storage, and for BICR. Guidelines for image acquisition, de-identification, 
storage of digital copies at the investigative site (as source documents), and transfer to the 
iCRO will be provided in the imaging acquisition guideline handling document. Digital copies 
of all original scans should be stored at the investigator site as source documents. Electronic 
image transfer from the sites to the iCRO is strongly encouraged. A BICR of images will be 
performed at the discretion of AstraZeneca. Results of this independent review will not be 
communicated to investigators and results of the investigative tumour assessments will not be 
shared with the central reviewers. Management of the patients will be based solely upon the 
results of the RECIST assessment conducted by the investigator. 
The imaging scans will be reviewed by 2 independent radiologists using RECIST 1.1 and will 
be adjudicated, if required (ie, 2 reviewers will review the scans and, in case of a 
disagreement, adjudication is performed by a separate reviewer). The independent reviewers 
will be blinded to study treatment. 
The BICR will be conducted on an ongoing basis throughout the study. Where possible scans 
will be batched, and an in-patient series of assessments read together. 
For each patient, the BICR will define the overall visit response (ie, the response obtained 
overall at each visit by assessing TLs, NTLs, and new lesions) and no programmatic 
derivation of overall visit response is necessary. 
Further details of the BICR will be documented in the BICR Charter. 
For the biopsy sub-study, all CT/MRI scans and all imaging assessments performed for 
RECIST 1.1 tumour assessment will be reviewed at site. Duplicates must be available at the 
site in readiness to be sent for retrospective independent central RECIST 1.1 review, if 
deemed appropriate. 
8.1.1.3 
Screening Assessments  
All eligible patients must have confirmed progression during treatment with a PD-(L)1 
inhibitor +/- a CTLA-4 inhibitor (eg, nivolumab, pembrolizumab, or atezolizumab, or the 
combination of nivolumab and ipilimumab) prior to enrolment. Confirmed progression is 
defined as radiologic progression confirmed by a second scan at 4 to 12 weeks after the initial 
scan showing disease progression per RECIST 1.1 or, a single scan showing radiological 
progression accompanied by correlative symptoms suggestive to disease progression. 
As part of medical history, copies of the radiological scan reports stating progression will be 
collected and the investigator asked to confirm whether the patient had 2 scans showing 

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radiologic progression or a single scan accompanied by correlative symptoms. In the case of 
patients who have received intervening treatment prior to study entry, a copy of the scan 
report showing disease progression per RECIST 1.1 prior to study entry will be collected.
8.1.2
Survival follow-up
After discontinuation of study treatment, the survival status of the patients will continue to be 
collected 8-weekly, reducing to 12-weekly after 18 months, via phone.
Other anti-cancer therapies will be collected 8-weekly, reducing to 12-weekly after 
18 months.
8.1.3
Clinical Outcome Assessments
A COA is any assessment that may be influenced by human choices, judgment, or motivation 
and may support either direct or indirect evidence of treatment benefit.
8.1.3.1
Patient Reported Outcomes
Patient-reported outcome (PRO) assessment is one type of COA and is a general term 
referring to all outcomes and symptoms that are directly reported by the patient. 
Patient-reported outcomes have become important in evaluating the efficacy and tolerability 
of study treatments in clinical studies and will aid in understanding of the benefit/risk 
evaluation (Kluetz et al 2018).
The PRO measures will be self-administered by patients using an electronic device, at the 
timepoints indicated in the SoA (Section 1.3). The PRO measures will be provided in the 
language of the country in which they will be administered.
Each centre must allocate the responsibility for the administration of the questionnaires to a 
specific individual (eg, a research nurse, study coordinator) and, if possible, assign a back-up
to cover absence.
A web back-up may be available to answer the questionnaires if there are technical problems 
with the device.
Approximately 5 minutes are required on most weeks for patients to complete the 
questionnaires, and, once a month it will take about 15 minutes to answer the questions.
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The below instructions should be followed: 
x 
The research nurse or appointed site staff must explain to the patient the value and 
importance of completing PRO questionnaires, so they are motivated to comply with 
questionnaire completion. The patient should be informed that these questions are being 
asked to find out directly from them how they feel. 
x 
It is vital that the ePRO reporting is initiated at the baseline visit (Cycle 1, Day 1), as 
specified in the study plan to capture the effect of study treatment. The electronic device 
must be charged and fully functional at the beginning of the baseline visit to ensure that 
the PROs can be completed at the start of the visit. 
x 
The patient should bring the ePRO device to each site visit so the research nurse or 
appointed site staff can check if there are available PRO questionnaires to be completed 
and that the device is functioning properly. 
x 
PRO questionnaires completed at sites must be completed prior to study treatment 
administration and ideally before any discussions of health status, to avoid biasing the 
patient’s responses to the questions. As feasible, site staff should also ensure PRO 
questionnaires are completed prior to other study procedures such as collection of 
laboratory samples, to further minimise bias. 
x 
On completion of the questionnaire at the site, the device should be handed back to the 
research nurse or appointed staff nurse, who should check that all questionnaires were 
completed. 
x 
PRO questionnaires should be completed by the patient in a quiet and private location. 
The patient should be given the time they need to complete the questionnaires at their 
own speed. 
x 
The research nurse or appointed site staff should stress that the information is not 
routinely shared with study staff. Therefore, if the patient has any medical problems, they 
should discuss them with the doctor or research nurse separately from the PRO 
assessment. 
x 
The research nurse or appointed site staff must train the patient on how to use the ePRO 
device, using the materials and training provided by the ePRO vendor. 
x 
The research nurse or appointed site staff must provide guidance on whom to call if there 
are problems with the device when the patient is completing the ePRO at home. 
x 
All PRO questionnaires must be completed using the ePRO device; paper questionnaires 
are not allowed in this study. If technical or other device-related issues prohibit 
completion on the device, an appropriate back-up option may be considered with prior 
approval from AstraZeneca. 
x 
The research nurse or appointed site staff must remind the patient that there are no right 
or wrong answers and avoid introducing bias by not clarifying questions for the patient. If 

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the patient is uncertain about the meaning of a question, the site staff should ask the 
patient to answer based on what they think the item means. 
x 
The patient should not receive help from relatives, friends, or clinic staff in choosing 
answers on the PRO questionnaires. The responses are the patient’s alone. 
x 
Patients should be reminded to bring visual aids (eg, glasses or contact lenses) for reading 
to the initial clinic visit. If a patient uses visual aids for reading and does not have them 
when attending the clinic, the patient will be exempted from completing the PRO 
questionnaires at that clinic visit but should be asked to complete them at home. 
x 
Site staff must not read or complete the PRO questionnaires on behalf of the patient. If the 
patient is unable to read the questionnaire (eg, is blind, illiterate or not fluent in the 
available language), the patient is exempted from completing PRO questionnaires but 
may still participate in the study. If the patient cannot complete the PRO questionnaires 
due to reasons other than being blind, illiterate, or fluent in language, the AstraZeneca 
study team must be contacted to determine if they can be exempted. Patient exempted in 
this regard should be flagged appropriately by the site staff in the source documents and 
eCRF. 
x 
Questions must not be translated from an available language in the device into the 
language the patient speaks. 
x 
Reminders should be provided to patients, as needed, to ensure compliance with the 
assessment schedules. 
x 
The research nurse or appointed site staff must monitor compliance since minimising 
missing data is a key aspect of study success. 
x 
Finally, the research nurse or appointed site staff will review the completion status of 
questionnaires during site visits, and document the reason(s) why a patient could not 
complete assessments, in the source documents and in the designated eCRF. If the site 
receives an email notification regarding the patient’s compliance, appropriate action will 
be taken (eg, discussion with patient to improve compliance, a check in call from the site 
to ask the patient if they have any difficulties in completing questionnaires on schedule, 
etc). A solution to enhance/resolve compliance should be discussed with the patient. 
Discussions and compliance review should be reflected in source documents. 
 
A short description of each questionnaire is provided below and sample questionnaires are 
included in Appendix I. 

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8.1.3.1.1
 
 
 
8.1.3.1.2
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8.1.3.1.3
 
 
8.1.3.1.4
8.1.3.1.5
 
8.1.3.1.6
 
8.1.3.1.7
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8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations
Physical examinations, with weight, will be performed regularly at Day 1 of every cycle, at 
the end of treatment and during the safety follow-up visits, as indicated in the SoA 
(Section 1.3). Height will be recorded at screening only.
A complete physical examination will be performed and include assessments of the following: 
general appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, 
eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal (including spine and 
extremities), urogenital, dermatological, gastrointestinal, endocrine, haematologic/lymphatic, 
neurological systems, height, and weight. Targeted physical examinations are to be used by
the investigator on the basis of clinical observations and symptomatology.
Physical examination, as well as assessment of height and weight, will be performed at 
timelines as specified in the SoA.
Investigators should pay special attention to clinical signs related to previous serious illnesses, 
new or worsening abnormalities may qualify as AEs; see Section 8.3.5 for details.
8.2.2
Vital Signs
Vital signs (body temperature, BP, respiratory rate, and heart [pulse] rate) will be performed at 
timelines as specified in the SoA. Any changes in vital signs should be recorded as an AE if 
applicable.
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For patients taking ceralasertib monotherapy: Blood pressure and pulse measurements will 
be assessed with a completely automated device. Manual techniques will be used only if an 
automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the patient in a quiet setting without distractions (eg, television, cell phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute). The average of the 3 blood pressure readings will be recorded 
on the eCRF. 
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.5. 
For patients receiving ceralasertib plus durvalumab: On the first infusion day (Day 8 of 
each treatment cycle except for the patients in the ceralasertib monotherapy arm in the main 
study), patients in the ceralasertib plus durvalumab arm will be monitored and vital signs 
collected/recorded in the eCRF prior to, during, and after infusion of study treatment as 
presented in the bulleted list below. 
Blood pressure and pulse will be collected from patients in the IO arms before, during, and 
after each infusion at the following times (based on a 60-minute infusion): 
x 
Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [ie, the beginning of the infusion]) 
x 
Approximately 30 minutes during the infusion (halfway through infusion) 
x 
At the end of the infusion (approximately 60 minutes ± 5 minutes) 
If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements 
should follow the principles as described above or be taken more frequently if clinically 
indicated. A 1-hour observation period is recommended after the first infusion of durvalumab. 
Vital signs at subsequent infusions (ceralasertib plus durvalumab) 
Blood pressure, pulse and other vital signs should be measured, collected/recorded in eCRF 
prior to the start of the infusion. Patients should be carefully monitored and blood pressure 
and other vital signs should be measured during and post infusion as per institution standard 
and as clinically indicated. Any clinically significant changes in vital signs should be entered 
onto an unscheduled vital signs CRF page. If no infusion reaction has occurred with the initial 
infusion, and at the discretion of the investigator, the 1-hour observation period may be 
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8.2.3 
Electrocardiograms  
An electrocardiogram will be performed at timepoints as specified in the SoA (Section 1.3). 
Resting 12-lead ECG 
Triplicate 12-lead ECGs will be done at screening, and single ECG readings will be collected 
at other visits as clinically indicated. The patient should rest in a semi-supine position for at 
least 5 minutes before and also during the recording. The ECG machine will automatically 
calculate the heart rate and measures PR, QRS, QT, and QTcF intervals. 
All ECGs should be assessed by the investigator as to whether they are clinically significantly 
abnormal. Any clinically significant abnormalities detected including a QTcF value > 470 ms 
require triplicate ECG results. 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 (5 to 15 minutes window period). 
8.2.4 
Eastern Cooperative Oncology Group Performance Status  
Performance status will be assessed at the visits indicated in the SoA, according to ECOG 
criteria as follows: 
Table 13 
Eastern Cooperative Oncology Group Performance Status    
Grade 
Eastern Cooperative Oncology Group 
0 
Fully active, able to carry out all pre-disease activities without restrictions 
1 
Restricted in strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature eg, light housework, office work 
2 
Ambulatory and capable of self-care, but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled, cannot carry out self-care, totally confined to bed or chair 
5 
Dead 
 
Any significant change from baseline or screening in the ECOG performance status must be 
reported as an AE. 
8.2.5 
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 1.3). 

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Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF. 
The clinical chemistry, haematology including coagulation and urinalysis will be performed at 
a local laboratory at or near to the investigator site. Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site. 
Other safety laboratory tests include assessment for pregnancy (serum at screening or urine at 
other time points), HBsAg, HCV antibodies, and HIV antibodies. Pregnancy tests may be 
performed at the site using a licensed test (urine or serum pregnancy test). Women of 
childbearing potential are required to have a pregnancy test on Day 1 of every cycle and then 
as clinically indicated for studies with no suspected teratogenicity/foetotoxicity. Pregnancy 
test may occur on Day 1, but results must be available and reviewed by the treating physician 
or investigator prior to commencing study treatment. Abnormal clinically significant 
laboratory results should be repeated as soon as possible (preferably within 24 to 48 hours). 
The following laboratory variables will be measured: 
Table 14 
Laboratory Safety Variables    
Haematology/Haemostasis (whole blood) 
Clinical chemistry (serum or plasma) 
Hb 
Albumin 
Leukocyte count (total white cell count) a 
ALPc 
Haematocrit 
ALTc 
Red blood cell count 
ASTc 
Leukocyte differential count (absolute count) 
Amylased 
Neutrophilsa 
Bicarbonateb 
Lymphocytesa 
Calcium, total or calcium corrected (for albumin) 
Monocytes 
Chlorideb 
Basophils 
Conjugated bilirubinc 
Eosinophils 
Creatinine and CrCLb 
Platelet count 
C-reactive protein 
 
Gamma-glutamyl transferase 
Coagulation parameters 
Glucose (random) 
PTT and INRb 
Lactate dehydrogenase 
Urinalysis (dipstick) 
Lipased 
Glucose 
Magnesiumb 
Protein 
Phosphate 
Blood 
Potassium 

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Table 14 
Laboratory Safety Variables    
Colour and appearance 
Protein, total 
pH and specific gravity 
Sodium 
Bilirubin 
TBLc 
Ketones 
TSH 
 
T3 free (reflex)e 
Virology (serum): HBsAg, HCV and HIV antibodies f 
T4 free (reflex)e 
Pregnancy β-hCG in serum (pre-/screening) or urine 
(all other visits); only in WOCBP 
Unconjugated bilirubin 
 
Urea nitrogen/blood urea nitrogen, depending on 
local practice 
a 
Can be recorded as absolute counts or as percentages. Total white cell count therefore has to be provided. 
b 
Bicarbonate (where available), chloride, creatinine clearance, INR, magnesium and PTT testing are to be 
performed at baseline, on Day 1 (unless all screening laboratory clinical chemistry and haematology 
assessments are performed within 3 days prior to Day 1), and if clinically indicated. Creatinine clearance to 
be calculated using Cockcroft and Gault equation (Cockcroft and Gault 1976). 
c 
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. 
If total bilirubin is ≥ 2 × upper limit of normal (and no evidence of Gilbert’s syndrome), then fractionate 
into direct and indirect bilirubin. 
d 
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these 
parameters is routinely measured, either lipase or amylase is acceptable. 
e 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE 
related to the endocrine system. 
f 
If patient is HCV-Ag positive, then he/she should be checked for HCV RNA. 
NB. In case a patient shows an AST or ALT ≥ 3×ULN together with total bilirubin ≥ 2×ULN please refer to 
Appendix E ‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s law’, for further 
instructions. 
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; CK = creatinine kinase; CrCL = creatinine clearance; HB = haemoglobin; INR = international 
normalised ratio; aPTT = activated partial thromboplastin time T3 = triiodothyronine; T4 = thyroxine; 
TBL = total bilirubin; TSH = thyroid-stimulating hormone; ULN=upper limit of normal. 
 
Additionally, a serum (screening) or urine (other time points) sample will be collected for 
pregnancy testing from all women of childbearing potential at the visits indicated in the SoA 
(Section 1.3). 
The investigator should assess the available results with regard to clinically relevant 
abnormalities in documentation. Any clinically significant abnormal laboratory values should 
be repeated as clinically indicated and recorded on the eCRF. Situations in which laboratory 
safety results should be reported as AEs are described in Section 8.3.5. 
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from study treatment must be followed and have further tests performed until the laboratory 
values have returned to Grade 1 or 2, unless these values are not likely to improve because of 
the underlying disease. 

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8.2.6 
Other Safety Assessments  
8.2.6.1 
Echocardiogram/Multigated Acquisition Scan  
An echocardiogram or MUGA scan to assess LVEF will be performed at the visits as shown 
in SoA (Table 1, Table 2, and Table 3). The modality of the cardiac function assessments must 
be consistent for a given patient (ie, if echocardiogram is used for the screening assessment 
for a given patient, then echocardiogram should also be used for subsequent scans for that 
patient). The patient should also be examined using the same machine and operator whenever 
possible, and quantitative measurements should be taken (ie, accurate to 1% and not estimated 
to 5%). 
If a patient has had an echocardiogram or MUGA performed within 4 weeks prior to treatment 
discontinuation, the discontinuation visit echocardiogram/MUGA scan is not required unless 
clinically indicated. If a patient has any clinically significant decrease in LVEF (greater than 
10 percentage points to below 50%), there should be follow-up within 4 weeks until 
resolution. 
Situations in which echocardiogram or MUGA results should be reported as AEs are 
described in Section 8.3.5. 
8.2.6.2 
Pneumonitis (Interstitial Lung Disease) Investigation  
If new or worsening pulmonary symptoms (eg, dyspnoea) or radiological abnormality 
suggestive of pneumonitis/ILD is observed, toxicity management as described in detail in the 
Dosing Modification and Toxicity Management Guidelines (see the Annex document to this 
CSP) will be applied. The results of the full diagnostic workup (including high-resolution CT, 
blood and sputum culture, haematological parameters, etc) will be captured in the eCRF. It is 
strongly recommended to perform a full diagnostic workup, to exclude alternative causes such 
as lymphangitic carcinomatosis, infection, allergy, cardiogenic oedema, or pulmonary 
haemorrhage. In the presence of confirmatory high-resolution CT scans where other causes of 
respiratory symptoms have been excluded, a diagnosis of pneumonitis (ILD) should be 
considered and the Dosing Modification and Toxicity Management Guidelines (see the 
Annex document to this CSP) should be followed. 
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis. The results of the 
assessment will be collected. 
x 
Physical examination 
 
Signs and symptoms (cough, shortness of breath, and pyrexia, etc) including 
auscultation for lung field will be assessed. 
x 
Saturation of peripheral oxygen (SpO2) 

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x 
Other items 
 
When pneumonitis (ILD) is suspected during study treatment, the following markers 
should be measured where possible: 
o 
ILD markers (KL-6, SP-D) and β-D-glucan. 
o 
Tumour markers: Particular tumour markers that are related to disease 
progression. 
o 
Additional clinical chemistry: C-reactive protein and LDH. 
 
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 B. 
Adverse events will be reported by the patient (or, when appropriate, by a caregiver, 
surrogate, or the patient’s legally authorised representative). For country-specific requirements 
for Germany see Appendix K 1.3. 
The investigator and any designees are responsible for detecting, documenting, recording and 
reporting events that meet the definition of an AE. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information  
Adverse events and SAEs will be collected from time of signature of ICF, throughout the 
treatment period and including the safety follow-up period (30 days after last dose of study 
treatment for ceralasertib monotherapy or 90 days after last dose of study treatment for 
ceralasertib and durvalumab combination).  
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
treatment that occurs after the end of the clinical study in a patient treated by him or her, the 
investigator shall, without undue delay, report the SAE to the sponsor as described in 
Section 8.3.12. 
For patients continuing in the PTAP, AEs and SAEs will be recorded by the treating physician 
from the time the participant signs informed consent and will continue throughout the program 
until the end of the PTAP or until consent has been withdrawn. Collection and reporting of 
AEs and SAEs after the final DCO is described in Section 8.3.11. 
8.3.2 
Follow-up of AEs and SAEs  
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
investigator for as long as medically indicated (this may be beyond the 90 days after the last 

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dose of durvalumab), but without further recording in the eCRF. AstraZeneca retains the right 
to request additional information for any patient with ongoing AE(s)/SAE(s) at the end of the 
study, if judged necessary. 
Adverse event variables 
The following variables will be collected for each AE: 
x 
AE (verbatim) 
x 
The date and time when the AE started and stopped 
x 
Maximum intensity or changes in intensity 
x 
CTCAE grade (version 5.0) 
x 
Whether the AE is serious or not (Appendix B) 
x 
Whether the AE is an AESI or not (Section 8.3.10) 
x 
Investigator causality rating against the study treatment(s) (yes or no) 
x 
Action taken with regard to study treatment(s) 
x 
AE caused patient’s withdrawal from study (yes or no) 
x 
Administration of treatment for the AE 
x 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
x 
Date AE met criteria for SAE 
x 
Date investigator became aware of SAE 
x 
AE is serious due to 
x 
Date of hospitalisation 
x 
Date of discharge 
x 
Probable cause of death 
x 
Date of death 
x 
Autopsy performed 
x 
Causality assessment in relation to study procedure(s) 
x 
Causality assessment to other medication 
 
The grading scales found in the National Cancer Institute CTCAE Version 5.0 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 

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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). 
8.3.3 Causality Collection  
The investigator should assess causal relationship between study treatment 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 treatment?’ 
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B to the protocol. 
8.3.4 Adverse Events Based on Signs and Symptoms  
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study site staff: ‘Have you/the patient had any health problems since 
the previous visit/you were last asked?’, or revealed by observation will be collected and 
recorded in the 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 protocol mandated laboratory tests, vital signs, physical examinations, 
ECGs, and echocardiograms/MUGA scans will be summarised in the CSR. 
Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
should therefore only be reported as AEs if they fulfil any of the SAE criteria, are the reason 
for discontinuation of treatment with the study treatment 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 study treatment interruption). 
If deterioration in a laboratory value/vital sign/physical 
examination/ECG/echocardiogram/MUGA is associated with clinical signs and symptoms, the 
sign or symptom will be reported as an AE and the associated laboratory result/vital 
sign/physical examination/ECG/echocardiogram/MUGA 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 

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or symptoms, clinically relevant deteriorations in non-mandated parameters should be 
reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression per 
RECIST 1.1, should not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.3.6 Hy’s Law  
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may need 
to be reported as SAEs. Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law. 
8.3.7 Disease Progression  
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the study treatment is being evaluated. 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. If the disease 
progression worsens in terms of time-course or severity compared to what would normally be 
expected for that patient, or if the investigator considers that there was a causal relationship 
between treatment with the study medication(s) or protocol procedures and the disease 
progression, the event must be reported as an SAE/SUSAR. 
8.3.8 
New Cancers  
The development of a new cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria. New primary cancers are those that are not the primary reason 
for the administration of study treatment and are identified after the patient’s inclusion in this 
study. They do not include metastases of the original cancer. 
8.3.9 
Deaths  
All deaths that occur during the study treatment period, or within the protocol-defined 
follow-up period after the administration of the last dose of study treatment, must be reported 
as follows: 
x 
Death clearly resulting from disease progression should be documented in the eCRF in 
the Statement of Death page. It should not be reported as an SAE. 

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x 
Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported as an SAE within 24 hours. It should also be 
documented in the Statement of Death page in the eCRF. The report should contain a 
comment regarding the co-involvement of PD, if appropriate, and should assign the main 
and contributory causes of death. 
x 
Deaths with an unknown cause should always be reported as an SAE and documented in 
the Statement of Death page in the eCRF, but every effort should be made to determine a 
cause of death. A post-mortem may be helpful in the assessment of the cause of death, 
and if performed, a copy of the post-mortem results should be forwarded to AstraZeneca 
Patient Safety or its representative within the usual time frames. 
 
Deaths occurring after the protocol-defined follow-up period after the administration of the 
last dose of study treatment should be documented in the Statement of Death page. If the death 
occurred as a result of an event that started after the defined follow-up period and the event is 
considered to be due to a late-onset toxicity to study treatment, then it should also be reported 
as an SAE. 
8.3.10 
Adverse Events of Special Interest  
Adverse events of special interests are events of scientific and medical interest specific to the 
further understanding of durvalumab and ceralasertib safety profile and require close 
monitoring and rapid communication by the investigators to AstraZeneca. An AESI can be 
serious or non-serious. All AESIs will be recorded in the eCRF. Serious AESIs will be 
recorded and reported as per Section 8.3.12. 
AESIs for durvalumab  
Adverse events of special interest for durvalumab include but are not limited to events with a 
potential inflammatory or immune-mediated mechanism and which may require more 
frequent monitoring and/or interventions such as steroids, immunosuppressants and/or 
hormone replacement therapy. An immune-mediated AE is defined as an AESI that is 
associated with drug exposure and is consistent with an immune-mediated MoA and where 
there is no clear alternate aetiology. 
If the investigator has any questions in regard to an event being an immune-mediated AE, the 
investigator should promptly contact the AstraZeneca clinical lead. 
Adverse events of special interest/immune-mediated AE observed with anti-PD-(L)1/PD-1 
agents such as durvalumab include pneumonitis, hepatitis, diarrhoea/colitis, intestinal 
perforation, endocrinopathies (hypo- and hyperthyroidism, adrenal insufficiency, 
hypophysitis/hypopituitarism and Type 1 diabetes mellitus), nephritis, rash/dermatitis, 
myocarditis, myositis/polymyositis, pancreatitis and rare/less frequent events (including, but 

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not limited to haematological events, neuromuscular toxicities [such as myasthenia gravis and 
Guillain-Barré syndrome], non-infectious encephalitis, non-infectious meningitis, pericarditis, 
rheumatological events, sarcoidosis, skin events, uveitis [and other events involving the eye] 
and vasculitis). 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs. 
More detailed guidelines for their evaluation and treatment are described in detail in the Dose 
Modification and Toxicity Management Guidelines (see the Annex document to this CSP). 
These guidelines have been prepared by the sponsor to assist the investigator in the exercise of 
his/her clinical judgement in treating these types of toxicities. These guidelines apply to AEs 
considered causally related to the study treatment/study regimen by the reporting investigator. 
AESIs for ceralasertib  
At present there are no AESIs defined for ceralasertib. 
8.3.11 
Safety Data to be Collected Following the Final Data Cut Off of the 
Study  
See Section 6.7 for treatment after the final DCO and patient management. 
For patients continuing to receive ceralasertib or ceralasertib plus durvalumab after the final 
DCO in the PTAP, no data collection is required except for reporting of non-serious AEs, 
SAEs, and special situations (ie, pregnancy, overdoses, medication error, and drug abuse and 
misuse) until the end of post-trial access or until consent has been withdrawn. All data after 
the final DCO and database closure will be recorded in the patient notes but will not be 
reported for the purposes of this study except for the safety data mentioned above. 
All SAEs that occur in patients still receiving ceralasertib or ceralasertib plus durvalumab in 
the PTAP must be reported as detailed in Section 8.3.12.  
After study completion, when EDC is closed and if an AE/SAE needs to be reported, paper 
AE/SAE form should be used. 
8.3.12 
Reporting of Serious Adverse Events  
All SAEs have to be reported, whether or not considered causally related to the study 
treatment, or to the study procedure(s). All SAEs will be recorded in the eCRF during the 
study conduct.  
After study completion, when EDC is closed and SAE needs to be reported, paper SAE form 
should be used. 

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If any SAE occurs in the course of the study, then investigators or other site personnel must 
inform the appropriate AstraZeneca representatives within 1 day ie, immediately but no later 
than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
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 will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day ie, immediately but no later than 24 hours of when he or she becomes 
aware of it. 
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative. 
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
via secure method to the appropriate AstraZeneca representative. Investigators or other site 
personnel send relevant paper CRF modules by fax to the designated AstraZeneca 
representative. 
The AstraZeneca representative will advise the investigator/study site staff how to proceed. 
When the EDC is temporarily not accessible, the AstraZeneca Study Representative should 
confirm that the investigator/site personnel enter the SAE in the AstraZeneca EDC when 
access resumes. 
For further guidance on the definition of a SAE, see Appendix B of the CSP. 
For regulatory reporting requirements for SAEs, see Appendix A 1. 
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
IMPs. 
8.3.13 
Pregnancy  
All pregnancies, including pregnancy in the partner of male patients, and outcomes of 
pregnancy, with conception dates following the first date of study treatment, should be 
reported to AstraZeneca. 

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8.3.13.1 
Maternal Exposure  
Women of childbearing potential are allowed to be included in this study. Should a pregnancy 
occur, the study treatment should be discontinued immediately, and the pregnancy reported to 
AstraZeneca. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment 
under study may have interfered with the effectiveness of a contraceptive medication. All 
pregnancies should be collected and provided to the AstraZeneca Data Entry Site (DES) via 
PREGREP module in the eCRF. If an AE/SAE is associated with the pregnancy, AE/SAE 
eCRF modules should also be completed and sent to AstraZeneca DES. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly/birth defect) should be followed up and documented even if the 
patient was discontinued from the study. The paper based PREGOUT form should be used to 
report the outcome of the pregnancy. 
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.8) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
8.3.13.2 
Paternal Exposure  
Non-sterilised male patients who intend to be sexually active with a female partner of 
childbearing potential should refrain from fathering a child or donating or banking sperm for 
6 months after the last dose of study treatment. 
Pregnancy in a patient’s partner(s) is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital anomaly), occurring from the date of the first dose until 90 days after the last 
dose and as indicated by previous studies (preclinical and clinical) should, if possible, be 
followed up and documented in the medical record and provided to the AstraZeneca Patients 
Safety data entry site. Consent from the partner must be obtained before the information is 
collected and reported to AstraZeneca via the Pregnancy Report Form. For country-specific 
requirements for Belgium and France see Appendices K 1.1 and K 1.2, respectively. 

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Where the report of pregnancy in a patient’s partner is received, prior to obtaining information 
about the pregnancy, the investigator must obtain the consent of the patient’s partner. The 
local study team should adopt the Master Pregnant Partner Form in line with local procedures 
and submit it to the relevant Regulatory Authority/IRBs/IECs prior to use. 
8.3.14 
Medication Error, Drug Abuse, and Drug Misuse  
8.3.14.1 
Timelines  
Medication error, Drug Abuse and Drug Misuse alone are not AE/SAE. All Medication 
Errors/Drug Abuse/Drug Misuse are to be collected for IMPs and provided to AstraZeneca 
DES via the respective Medication Error eCRF module or Drug Abuse/Drug Misuse paper 
CRF forms. If an AE/SAE is associated with the Medication Error/Drug Abuse/Drug Misuse, 
the AE/SAE eCRF modules should also be completed and sent to AstraZeneca DES. 
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one calendar day, ie, immediately but no later than 24 hours of when they become aware of 
it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within one (initial fatal/life-threatening or follow-up 
fatal/life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the event of medication error, drug abuse, or misuse (see Section 8.3.12) 
and within 30 days for all other events. 
8.3.14.2 
Medication Error  
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP that either causes harm to the patient or has the potential 
to cause harm to the patient. 
The definition of a medication error can be found in Appendix B 4.  
8.3.14.3 
Drug Abuse  
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP for 
a perceived reward or desired non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix B 4. 
8.3.14.4 
Drug Misuse  
Drug misuse is the intentional and inappropriate use (by a study patient) of IMP for medicinal 
purposes outside of the authorised product information, or for unauthorised IMPs, outside the 

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intended use as specified in the protocol and includes deliberate administration of the product 
by the wrong route. 
The full definition and examples of drug misuse can be found in Appendix B 4. 
8.4 
Overdose  
For this study, any dose of study treatment greater than those specified in the protocol is 
considered to be an overdose. There is currently no specific treatment in the event of overdose 
of durvalumab or ceralasertib, and possible symptoms of overdose are not established. This 
may include a higher dose of study treatment or study treatment taken at the correct dose but 
for longer duration. 
Overdose alone is not an AE/SAE. All overdoses are collected for IMPs and provided to 
AstraZeneca DES: 
x 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. 
x An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on an AstraZeneca study treatment occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it. 
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 8.3.12) and within 
30 days for all other overdoses. 
8.5 
Human Biological Samples  
Instructions for the collection, storage, and shipping 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. 
Samples will be stored for a maximum of 15 years from the end of the study (last patient last 
visit) in line with consent and local requirements, after which they will be 
destroyed/repatriated. 
x 
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. 

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 
Pharmacokinetic samples may be disposed of or anonymised by pooling. Additional 
analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses 
may be reported separately from the CSR. 
x 
Remaining sample aliquots will be retained at AstraZeneca or its designee for a maximum 
of 15 years from the end of the study (last patient last visit). Additional use includes but is 
not limited to further characterisation of any ADAs, confirmation and/or requalification 
of the assay as well as additional assay development work. The results from future 
analysis will not be reported in the CSR. 
 
No personal details identifying the individual will be available to the sponsor or designated 
organisations working with the DNA. 
The patient’s consent to the use of donated biological samples is mandatory. 
Biological samples (eg, archival tumour samples, on-study tumour samples, and blood) will be 
collected as detailed in the Laboratory Manual in order to carry out biomarker analysis to 
assess correlations with disease activity, effects of study drug, clinical outcomes and toxicity. 
The tumour specimens should be of sufficient quality and quantity to allow for next 
generation sequencing and other analyses to be carried out (see the Laboratory Manual). 
The biomarker data may also be pooled with biomarker data from other studies to test existing 
hypotheses or to generate hypotheses to be tested in future studies with the agents studied. 
For further details on Handling of Human Biological Samples see Appendix C. 
8.5.1 
Pharmacokinetics  
x 
Venous blood samples for determination of concentrations of study treatment in plasma 
or serum will be taken at the times specified in the SoA (Section 1.3). The date and time 
of collection of each sample will be recorded. 
x 
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 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring. The total volume of blood taken from each patient will not 
exceed that presented in Section 8. 
x 
Plasma or serum blood samples will be used to analyse the PK of the study treatment. 
Samples collected for analyses of study treatment concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study. 
 

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Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
8.5.1.1 
Determination of Drug Concentration  
Samples for determination of study treatment concentration in plasma or serum will be 
assayed by bioanalytical test sites operated by or on behalf of AstraZeneca, using an 
appropriately validated bioanalytical method. Full details of the analytical method used will be 
described in a separate bioanalytical report. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report. 
8.5.2 
Immunogenicity Assessments  
Blood samples for determination of ADA in serum/plasma will be assayed by bioanalytical 
test sites operated by or on behalf of the sponsor, using an appropriately validated 
bioanalytical method. Full details of the methods used will be described in a separate report. 
ADA samples may also be further tested for characterisation of the ADA response. 
Samples will be collected to evaluate immunogenicity to durvalumab as specified in the SoA. 
Evaluations will be performed using validated immunoassays. Tiered analyses will be 
performed to include screening, confirmatory, and titer assay components. Blood samples 
(~3.5 mL) will be collected at screening, then pre-dose on Day 1 of Cycles 1, 2, 3, and 4, then 
every 4 cycles, end of treatment, and 30 days after last dose for ceralasertib monotherapy and 
30 days, 90 days and 6 months after last dose for ceralasertib and durvalumab combination. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
8.5.3 
Pharmacodynamics  
8.5.3.1 
Collection of Samples  
Blood and urine samples are mandatory and will be collected as per the timepoints detailed in 
the SoA (Section 1.3). 
For storage, re-use and destruction of pharmacodynamic samples see Section 8.5 and 
Appendix C. 
8.6 
Human Biological Sample Biomarkers  
8.6.1 
Collection of Mandatory Samples for Biomarker Analysis  
By consenting to participate in the main or biopsy sub-study the patient consents to participate 
in the mandatory research components of the study. 

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Tumour and blood samples for biomarker research are required and will be collected from all 
patients in this study as specified in the SoA (Section 1.3). Samples will be tested for primary, 
secondary and exploratory objectives, to understand potential candidate predictive biomarkers, 
pharmacodynamics and MoA of ceralasertib and ceralasertib plus durvalumab, early/late 
biomarkers of response, and potential resistance mechanisms. The samples may also be used 
for future diagnostic development
All patients (main study and biopsy sub-study) will be required to provide archival tumour 
samples (Section 8.6.1.1). The main study will require collection of tumour biopsies at 
screening, if medically feasible (Section 8.6.1.2). Biopsy sub-study will require collection of 
serial mandatory tumour biopsies.
Any sample material remaining after completion of analyses to fulfil the study objectives may 
be used to develop methods, assays, prognostics, and/or diagnostic tests related to cancer, 
disease process, pathways associated with disease state.
For further details on Handling of Human Biological Samples, including storage, re-use and 
destruction, refer to Section 8.5 and Appendix C.
8.6.1.1
Mandatory Archival Tumour Samples
Archival tumour tissue (FFPE blocks) obtained within 5 years prior to enrolment and 
associated pathology report(s) should be obtained at screening for all patients enrolled into the
study. Archival tumour tissue must have been formalin fixed for 24 to 48 hours immediately 
after collection and then embedded in paraffin blocks. If FFPE blocks of archival tumour 
tissue obtained within 5 years prior to enrolment are not available, then unstained slides (a 
minimum of 20 freshly cut unstained sections, prepared less than 6 months prior to enrolment) 
from the relevant archival tumour tissue must be available. 
8.6.1.2
Tumour Biopsies for Main and Biopsy Sub-Study
All patients must consent to the mandatory use of donated biological samples.
Details of the tumour biopsy collection for the main study and biopsy sub-study are mentioned 
below. The associated pathology report(s) for fresh tumour samples will be required at 
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screening and requested on-treatment for all patients enrolled into the study (details in the 
Laboratory Manual). Where clinically feasible, serial biopsies should be taken from the same 
lesion and when not feasible, serial biopsies should be taken from the same tissue. Biopsies 
should be completed with a minimum 18-gauge needle. Fine needle aspirates are not 
acceptable. Biopsies should not be obtained from bone metastasis. If clinically practical, 
subjects should undergo 4 core biopsies, but a minimum of at least 3 core biopsies are 
required. The first and third core biopsies will be placed in formalin and processed for FFPE, 
while the second and fourth core biopsies (4th biopsy, if available) will be immediately frozen 
in liquid nitrogen and then stored at -80°C. 
Details for fresh tumour sample collection, processing, storage, and shipment are provided in 
the Laboratory Manual. Per institutional practice, image-guided fresh core needle tumour 
biopsies should be preferentially obtained from tumour tissues that are safely accessible, as 
determined by the investigator, and are not obtained from sites that require significant risk 
procedures. For fresh tumour biopsies, the tumour lesion should not be used as a RECIST 
target lesion, unless this is the only soft tissue lesion. If a RECIST 1.1 target lesion is used for 
biopsy, the lesion must be ≥ 2 cm in the longest diameter. 
Tumour samples will be analysed for a number of biomarkers with potential association to 
response or resistance to treatment and/or with the MoA of ceralasertib as monotherapy or in 
combination with durvalumab. Biomarker may include, but not be limited to: mutations or 
polymorphisms in specific genes; tumour mutational burden; expression of genes or gene 
signatures; the number, phenotype, and expression profile of immune cells such as T-cells; the 
expression of one or more proteins; epigenetic or mutational profiles or signatures. 
For main study, A fresh tumour biopsy sample will be collected at screening (Days -21 to -1) 
unless medically (or technically) not feasible. If a biopsy is not feasible, a tumour tissue 
sample collected within 5 years prior to enrolment must be provided. If a further tissue 
sample, independent of age, is available in addition to the mandatory pre-treatment sample, 
then this should also be provided. 
For biopsy sub-study, all study patients are required to provide 3 mandatory fresh tumour 
biopsy samples for testing at: 
x 
Screening (Days -21 to -1) 
x 
On-ceralasertib treatment, Cycle 0 (on Day 7) of ceralasertib monotherapy, and 
x 
Off-ceralasertib treatment, Cycle 0 (between Days 15 to 28). 
 
Any additional tumour tissue (optional) available should also be submitted. 

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8.6.1.3
Blood Samples for Exploratory Biomarker Assessments
8.6.1.3.1
8.6.1.3.2
8.6.1.3.3
8.6.1.3.4
8.6.1.3.5
8.6.1.3.6
 
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8.6.1.3.7
8.6.2
Collection of Optional Biomarker Samples
8.6.2.1
Optional Biopsies
 
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8.6.3
Other Study Related Biomarker Research
8.6.4
Optional Future Scientific Research
8.7
x
x
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See Appendix D for information regarding the Genomics Initiative genetic sample.
8.8
Health Economics OR Medical Resource Utilization and Health 
Economics
Medical Resource Utilisation and Health Economics parameters are not evaluated in this 
study. Health Economics/Medical Resource Utilisation and Health Economics parameters are 
not evaluated in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
No formal statistical hypotheses are being conducted for this study.
9.2
Sample Size Determination
9.2.1
Main Study
Objective response rate is the primary endpoint in this study. The primary analysis will be 
conducted once all randomised patients have had a minimum of months of follow-up after 
start of study treatment or have discontinued from the study, whichever occurs first. It is 
anticipated that the median duration of follow up for DoR will be at least 
 months at this 
point, however if not, then the primary analysis may be postponed to ensure a minimum of 
months median duration of follow up. At this primary analysis the CSR will be written.
It is anticipated at least approximately 
% of all randomised patients will have progressed or 
died at the time of the primary analysis. However, if this is not the case, a later analysis for 
PFS may be conducted once approximately 
% of all randomised patients have progressed or 
died.
A 
 analysis will be conducted once approximately 
% of all randomised patients have 
died, or years from when the last patient starts treatment, whichever is earliest.
Each treatment arm is experimental and thus will be analysed separately for ORR. The study 
will recruit approximately 100 patients in the ceralasertib and durvalumab combination 
therapy arm. With 100 patients the expected 
 width of the 
% CI for ORR will be up to 
approximately 
% when the proportion of patients with an objective response is in the range 
% to 
%. For example, ORR 
%, 
% CI 
%, 
%. The study will recruit 
approximately 50 patients in the ceralasertib monotherapy arm. With 50 patients, the expected 
 width of the 
% CI for ORR will be up to approximately 
% when the proportion of 
patients with an objective response is in the range % to
%. For example, ORR 
%, 
% 
CI 
%, 
%. The sample size of the ceralasertib monotherapy arm may be expanded up 
to a total of approximately 100 patients. This would occur in the event an efficacy signal is 
observed, and subject to a protocol amendment.
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There is no standard of care after anti-PD-(L)1 immunotherapy for the intended patient 
population. Objective response rate for chemotherapy treatment options for patient second line 
and beyond, post-ipilimumab, are previously reported to be 4% (95% CI 2%, 9%) and 10% 
(95% CI 5%, 16%). There is no prospective clinical trial data on response rates for 
chemotherapy specifically in the post CPI-resistant setting. An ORR of 
% is considered an 
upper limit of expected response rate for alternative available treatment options for the 
intended patient population in this study. Per the proposed Phase 2 study design, with 
100 evaluable patients in the ceralasertib and durvalumab combination therapy arm, success 
will be achieved if a minimum ORR of
% is observed, for which the 
% exact CI would 
be (
%, 
%).
A secondary objective is to compare the ORR between the two treatment arms. With
150 patients (100 patients randomised to ceralasertib and durvalumab combination therapy 
arm and 50 patients randomised to ceralasertib monotherapy), there will be at least 
% power 
at a 
 of 
 to detect a difference in ORR, assuming an ORR for ceralasertib 
plus durvalumab of 
% and an ORR for ceralasertib monotherapy of 
%.
Enrolled
Estimated 
patients
Randomly assigned
Estimated 150 patients
Evaluable patients
Estimated 150 patients
Note: “Enrolled” means a patient’s, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process. Potential 
patients who are screened for the purpose of determining eligibility for the study, but are not 
randomly assigned/assigned in the study, are considered “screen failures”, unless otherwise 
specified by the protocol. For country-specific requirements for Germany see Appendix K 1.3.
9.2.2
Biopsy Sub-Study
Approximately 
 patients are planned to be enrolled such that approximately 30 patients have 
at least 2 evaluable paired biopsies (at the baseline and off ceralasertib treatment) including at 
least 15 patients with at least 3 evaluable biopsies (at baseline, on ceralasertib treatment and 
off ceralasertib treatment).
Sample sizing is based on expected 
fold increase in CD8+ T-cells infiltration. The 
fold
assumption represents the observed increase in proliferating CD8+ T-cells infiltration in 
association with Pembrolizumab and Nivolumab or Nivolumab/Ipilimumab efficacy in 
melanoma (Tumeh et al, 2014; Grasso et al, 2020).
The sample size of 30 evaluable patients is expected to give adequate sample size to assess 
changes of CD8+ T-cells from baseline. With 30 evaluable patients and a standard deviation 
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of
-scale), the expected 
% CI for CD8+ T-cells fold change from baseline is 
presented in the table below for a range of example observed values.
Table 15
Expected 
% CI for CD8 T-cells Fold Change from Baseline with a 
Standard Deviation of 
-scale) and 30 Evaluable Patients
CD8+ T-cells Change from Baseline
% Confidence Interval
The primary analysis for the biopsy sub-study will be conducted once all enrolled patients 
have had a minimum of months of follow-up after start of study treatment or have 
discontinued from the study, whichever occurs first. At this primary analysis the CSR for the 
biopsy sub-study will be written, which may be finalised after the CSR is finalised for the 
main study. A 
 analysis will be performed either 
 months after the last patient is 
enrolled, or 
% of patients have died, whichever is the earlier event.
9.3
Populations for Analyses
The populations for analysis are listed in Table 16.
Table 16
Populations for Analysis
Population/Analysis 
set
Description
Endpoint/Output
Enrolled analysis set
All patients who sign the ICF.
Disposition
Safety analysis set
All patients receiving at least 1 dose of study 
treatment. Patients will be summarised according to 
the treatment received.
Baseline and demography
Exposure
Safety
ORR
BOR
TTR
DoR
Tumour size
PFS (biopsy sub-study 
only)
OS (biopsy sub-study)
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Population/Analysis 
set
Description
Endpoint/Output
Full analysis set (main 
study only)
All patients who are randomised in the study. The 
FAS will be used for all the efficacy analyses 
including PROs. Treatment groups will be compared 
on the basis of randomised study treatment, 
regardless of the treatment actually received. 
Patients who were randomised but did not 
subsequently receive study treatment are included in 
the analysis in the treatment group to which they 
were randomised.
Baseline and demography 
(supportive)
ORR (for comparative 
analysis)
PFS
OS
PK analysis set
All dosed patients with reportable ceralasertib or 
durvalumab plasma concentrations. Patients will be 
summarised according to the treatment received.
PK concentrations
PD analysis set
All patients who receive at least 1 dose of study 
treatment with at least 1 reportable 
pharmacodynamic measurement.
PD endpoints
Interim response 
evaluable (main study 
only)
All dosed patients who have measurable disease at 
baseline by BICR and who have first dose at least 
 
 prior to data cut off.
ORR (interim)
BOR (interim)
TTR (interim)
DoR (interim)
Tumour size (interim) 
9.4
Statistical Analyses
The statistical analysis plan will be finalised within 90 days of first subject in 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.
9.4.1
General Considerations
Statistical analyses will be performed by AstraZeneca or its representatives including CROs. 
No adjustments for multiplicity are planned.
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9.4.2 
Efficacy  
9.4.2.1 
Primary Endpoint(s)  
9.4.2.1.1 
Calculation or Derivation of Tumour Response Variables  
9.4.2.1.1.1 Investigator RECIST 1.1-based assessments:  
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues study treatment or 
receives another anti-cancer therapy. 
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, 
PR, stable disease, disease progression, or not evaluable depending on the status of their 
disease compared with baseline and previous assessments. Baseline will be assessed within 
the 21 days prior to randomisation (or first dose of study drug for the biopsy sub-study). The 
tumour response endpoints (ORR, DoR, BOR, TTR, PFS, and change in tumour size) will 
then be derived from the scan dates and overall visit responses. 
9.4.2.1.1.2 BICR (Main study only):  
A BICR of radiological scans will be performed on all patients in the main study to confirm 
the robustness of the investigator-assessed ORR, DoR, BOR, TTR, PFS, and change in 
tumour size endpoints. 
All images will be collected centrally. The imaging scans will be reviewed by 2 independent 
radiologists using RECIST 1.1 and will be adjudicated, if required. For each patient, the BICR 
will define the overall visit response data (CR, PR, stable disease, disease progression, or not 
evaluable) and the relevant scan dates for each time point (ie, for visits where response or 
progression is/is not identified). Patients who have RECIST 1.1-defined disease progression 
on study treatment based on progression of non-target disease, may also require submission of 
additional scans/images/photographs eg, brain scan or photographs of cutaneous lesions. If a 
patient has had a tumour assessment that cannot be evaluated, then the patient will be assigned 
a visit response of not evaluable (unless there is evidence of progression, in which case the 
response will be assigned as disease progression). Endpoints ORR, DoR, BOR, TTR, and PFS 
will then be derived from the scan dates and overall visit responses. 
The discordance between investigator assessment and BICR evaluation of measurable disease 
at baseline will be monitored. If the discordance is high (eg, > 5%), eligibility criteria may be 
amended to require measurable disease by BICR at baseline. 
Further details of the BICR will be documented in an Independent Review Charter. 
9.4.2.1.2 
Objective Response Rate  
Determination of ORR by BICR is the primary objective, and as a sensitivity analysis, ORR 
by investigator recorded assessments will also be evaluated. Objective response rate is defined 

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as the proportion of patients who have a 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 safety analysis set. A sensitivity analysis will 
also be provided in the subset of patients in the safety analysis set who also have measurable 
disease at baseline by BICR. Data obtained from randomisation up until progression, or the 
last evaluable assessment in the absence of progression, will be included in the assessment of 
ORR, regardless of whether the patient withdraws from therapy. Patients who discontinue 
treatment without a response or progression, receive a subsequent therapy, and then respond 
will not be included as responders in the ORR. 
As primary analysis, ORR will be summarised for each treatment arm non-comparatively with 
95% CI (Clopper-Pearson). 
As a secondary objective, ORR will be compared between the treatment arms using logistic 
regression adjusting for PD-(L)1 resistance type and LDH per randomisation stratification as 
covariates. The results of the analysis will be presented in terms of an odds ratio for study 
treatments together with associated 95% profile likelihood CI and p-value (based on twice the 
change in in log-likelihood resulting from the addition of a treatment factor to the model). 
This comparative analysis will be provided using the full analysis set. 
9.4.2.2 
Secondary Endpoints  
9.4.2.2.1 
Duration of Response  
Duration of response will be defined as the time from the date of first documented confirmed 
response until date of documented progression per RECIST 1.1 as assessed by BICR or death 
due to any cause. Sensitivity analyses will report DoR using investigator-based assessments 
with programmatic derivation of the visit response. 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 patient 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 patients, by 
Kaplan-Meier method including the medians, and landmark estimates at 6, 9, 12, 15, and 
18 months with corresponding 95% CI. 
9.4.2.2.2 
Time to Response  
Time to response is defined as the time from the date of randomisation (or date of first dose of 
study treatment, for the biopsy sub-study) until the date of first documented response. The 
date of first documented response should coincide with that used for the DoR endpoint. Time 
to response will not be defined for those patients who do not have a documented response. 

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The TTR will be summarised (ie, number of patients [%] based upon the number of 
responders for each treatment arm) by the scheduled assessment timepoint that the response 
was first observed. Additionally, descriptive summary statistics (ie, minimum, maximum, 
median, Q1 and Q3) will also be presented. 
9.4.2.2.3 
Progression Free Survival  
Progression free survival is defined as the time from the date of randomisation (or date of first 
dose for the biopsy sub-study) until the date of objective disease progression per RECIST 1.1 
as assessed by BICR or death (by any cause in the absence of progression), (ie, date of event 
or censoring – date of randomisation/the first dose of study treatment + 1). PFS will be 
analysed using the full analysis set (main study) and the safety analysis set (biopsy sub-study), 
and will include all patients in the analysis set regardless of whether the patient withdraws 
from therapy or receives another anti-cancer therapy or clinically progresses prior to 
RECIST 1.1 progression. Patients who have not progressed or died at the time of analysis will 
be censored at the time of the latest date of assessment from their last evaluable RECIST 
assessment. However, if the patient progresses or dies immediately after 2 or more 
consecutive missed visits, the patient will be censored at the time of the latest evaluable 
RECIST assessment prior to the 2 missed visits (Note: Not evaluable visit is not considered as 
missed visit). If the patient has no evaluable visits or does not have baseline data, they will be 
censored at Day 1 unless they die within 2 visits of baseline (16 weeks plus 1 week allowing 
for a late assessment within the visit window). 
The PFS time will always be derived based on scan/assessment dates and not visit dates. 
RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates. The following rules will be applied: 
x 
For investigator assessments, the date of progression will be determined based on the 
earliest RECIST assessment/scan dates of the component that indicates progression. 
x 
For BICR assessments, the date of progression will be determined based on the earliest 
dates of the component that triggered the progression on the first set of scans that 
indicates progression for the adjudicated reviewer selecting disease progression per 
RECIST 1.1, or of either reviewer where both reviewers select disease progression per 
RECIST 1.1 as a time point response, and there is no adjudication for central review 
(BICR) data. 
x 
When censoring a patient for PFS, the patient will be censored at the latest scan dates 
contributing to a particular overall visit assessment. 
 
Analysis methods: 
PFS will be analysed for both BICR and investigator recorded assessment. 

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Kaplan-Meier plots of PFS will be presented by treatment group. Summaries of the number 
and percentage of patients experiencing a PFS event and the type of event (RECIST 1.1 or 
death) will be provided along with median PFS for each treatment. The proportion of patients 
alive and progression free at 3, 6, 9, and 12 months from randomisation will be summarised 
by treatment group. 
PFS will be analysed using a log rank test stratified by the randomisation stratification factors 
(baseline LDH and IO resistance). The HR together with its 95% CI and p-value will be 
presented. The HR and CI will be estimated from a stratified Cox proportional hazards model 
(with ties = Efron), and the CI will be calculated using a profile likelihood approach. The 
stratification variables will be defined according to data from the IXRS. 
Further sensitivity analyses to explore the robustness of the primary PFS endpoint will be 
documented in the SAP. 
9.4.2.2.4 
Overall Survival  
The OS is defined as the time from the date of randomisation (or date of first dose for the 
biopsy sub-study) until death due to any cause regardless of whether the patient withdraws 
from study treatment or receives another anti-cancer therapy. Any patient not known to have 
died at the time of analysis will be censored based on the last recorded date on which the 
patient was known to be alive. 
Note: Survival calls will be made following the date of DCO for the analysis (these contacts 
should generally occur within 7 days of the DCO). If patients are confirmed to be alive or if 
the death date is after the DCO date, then these patients will be censored at the date of DCO. 
OS will be analysed using the same methodology specified for PFS, but with landmark 
estimates summarised at 6, 9, 12, and 18 months from randomisation. 
9.4.2.2.5 
Change in Tumour Size  
Percentage change from baseline in TL tumour size is based on the RECIST 1.1 TL 
measurements as assessed by BICR. Tumour size is the sum of the longest diameters of the 
TLs. The percentage change from baseline in TL tumour size at post-baseline assessment 
(Week 16) is obtained for each patients taking the difference between the sum of the TLs at 
post-baseline assessment and the sum of the TLs at baseline divided by the sum of the TLs at 
baseline times 100. 
Patients who progress before week 16 should have had a tumour assessment performed at the 
time of progression prior to treatment discontinuation. The tumour size from their latest 
progression assessment will be used instead of the week 16 assessment for these patients. Best 
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Best percentage change
The absolute change and percentage change from baseline in the sum of tumour size at each 
visit will be calculated. The best change in tumour size (ie, depth of response) is the largest 
decrease from baseline or the smallest increase from baseline in the absence of a reduction and 
will include all assessments prior to the earliest of death in the absence of progression, any 
evidence of progression, the start of subsequent anti-cancer therapy or the last evaluable 
RECIST assessment if the patient has not died, progressed or started subsequent anti-cancer 
therapy.
The percentage change in target lesion tumour size from baseline at 16 weeks, and best 
percentage change in tumour size will be presented visually for each patient by waterfall and 
spider plots.
9.4.2.3
Subgroup Analysis
Subgroup analyses will be conducted, estimating primary and secondary endpoints (ORR, 
PFS, OS) in the following subgroups (but not limited to):
x
Resistance to prior IO treatment (primary / early relapse on adjuvant versus acquired)
x
Baseline LDH (<= ULN versus > ULN)
x
Resistance to prior IO treatment (primary versus early relapse on adjuvant versus 
acquired)
x
Baseline LDH 
x
Sex (male versus female)
x
Age at randomisation (< 65 years versus >= 65 years of age)
x
Melanoma subtype (cutaneous versus acral versus mucosal)
x
Presence of liver metastases (yes vs no)
x
Presence of brain metastases (yes vs no)
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment groups. The purpose of the subgroup analyses is to assess 
the consistency of treatment effect across expected prognostic and/or predictive factors.
The subgroup analyses for the stratification factors will be based on the values entered into the 
IWRS; all other factors will be based on the values recorded on the eCRF, or from the 
third-party vendor data.
Additional subgroups of interest and analysis methods will be outlined in the SAP.
9.4.2.4
Exploratory Endpoint(s)
Planned analysis of exploratory endpoints will be detailed in the SAP.
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9.4.3 
Safety  
All safety analyses will be performed on the safety analysis set. Safety and tolerability will be 
assessed in terms of AEs (including SAEs), deaths, laboratory data, vital signs, and ECOG. 
These will be collected for all patients. Appropriate summaries of these data will be presented. 
In general, the baseline values for statistical analysis is the last non-missing value prior to 
administration of the first dose of study treatment. Details are described in the SAP. 
9.4.3.1 
Adverse Events  
AEs will be listed individually by patient and treatment group. For patients who undergo a 
dose modification, all AEs (due to drug or otherwise) will be assigned to the initial dose 
group. 
Medical Dictionary for Regulatory Activities will be used to code AEs. Adverse events will be 
graded according to the National Cancer Institute CTCAE (Version 5.0). The number of 
patients in each treatment arm experiencing each AE will be summarised by MedDRA system 
organ class and preferred term. The number and percentage of patients with AEs in different 
categories (eg, causally related, CTCAE Grade ≥ 3, etc) will be summarised by treatment arm; 
events in each category will be further summarised by MedDRA system organ class and 
preferred term. Serious adverse events will be summarised separately, if a sufficient number 
occurs. 
Adverse event summary tables will include only treatment-emergent AEs. Adverse Events 
will be defined as treatment-emergent if they onset or worsen (by investigator report of a 
change in intensity), during the study treatment or safety follow-up period (defined as 30 days 
after last dose of study treatment) but prior to subsequent cancer therapy. AEs outside this 
period will only be listed. 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to discontinuation. Based on 
the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered OAEs and reported as 
such in the clinical study report. A similar review of laboratory/vital signs (pulse and blood 
pressure) will be performed for identification of OAEs. Examples of these could be marked 
haematological and other laboratory abnormalities, and certain events that lead to treatment 
(other than those already classified as serious), dose reduction, or significant additional 
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9.4.3.2
Other Safety Endpoint(s)
Clinical chemistry, haematology, urinalysis, and vital signs will be listed individually by 
patient and appropriately summarised. For all laboratory variables that are included in the 
CTCAE (version 5.0), the CTCAE grade will be calculated.
Details of any death will be listed for all patients.
9.4.4
Other Analyses
Biopsy sub-study: CD8+ T-cells tumour infiltration and other biomarkers measured in 
tumour and periphery will be summarised descriptively in baseline, ceralasertib on-treatment 
and ceralasertib off-treatment samples, and longitudinal blood samples. Data will be 
transformed as appropriate eg, log2-transformation, and analysed by MMRM with fixed effect 
for timepoint. An unstructured variance-covariance matrix will be used to accommodate 
repeated measures within a patient, assuming model convergence otherwise alternatives will 
be used as detailed in the SAP. The least square means for each timepoint will be presented, 
together with the difference to baseline visit and 95% confidence interval.
Association of biomarkers to clinical outcomes will be presented visually, eg, boxplots by 
BOR.
9.5
Interim Analyses
 analyses of efficacy data will be conducted during the study.
The 
 analysis will be once approximately 
patients have been enrolled 
(approximately 
 patients in the ceralasertib and durvalumab combination therapy arm and 
approximately 
 patients in the ceralasertib monotherapy arm) and had the opportunity for 
approximately 
weeks follow up. The 
weeks follow up enables RECIST scans for 
confirmation of response. The rationale for this approach is to ensure the ORR is not 
artificially underestimated at an interim analysis eg, if there are patients ongoing treatment 
with unconfirmed response who are yet to have their confirmatory scan.
The IDMC may recommend to stop recruitment to the ceralasertib plus durvalumab treatment 
arm if there are or 
 responses out of 
patients, ie, ORR ≤ 
%. This stop rule 
corresponds to < 
% predictive probability of success should recruitment continue to the end 
of the study. There is % risk to incorrectly stop if the true ORR = 
%.
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The IDMC may recommend to stop recruitment to the ceralasertib monotherapy arm if there 
are responses out of 
patients ie, ORR= %. The stop rule for the monotherapy arm is 
more conservative, intended to mitigate risk of harm relative to other treatment options for 
patients eg, chemotherapy, but otherwise continuing recruitment in order to have adequate 
precision in the comparison to the ceralasertib plus durvalumab arm to characterise the 
contribution of components at study end. Should the combination treatment arm be terminated 
at the interim analysis, the monotherapy arm may also be terminated if there are or 
 
responses out of
patients, ie, ORR ≤ 
% since in this situation it is unlikely to achieve the 
target ORR to warrant future development should it continue to the end of the study.
The 
 analysis will be once approximately 
patients have been enrolled
(approximately 
 patients in the ceralasertib and durvalumab combination therapy arm and 
approximately 
 patients in the ceralasertib monotherapy arm) and had the opportunity for 
approximately 
 weeks follow up. The 
weeks follow up enables RECIST scans for 
confirmation of response and also preliminary characterisation of the durability of response, 
which is a key secondary endpoint. The IDMC may recommend to stop recruitment to 
combination treatment arm if there are or fewer responses out of 
 patients, ie, ORR 
≤
%. The IDMC may recommend to stop recruitment to monotherapy treatment arm if there 
are
or
responses out of 
 patients ie, ORR ≤% and the exact 
 
% CI for the 
proportion of patients with non-progressive disease at week  is <
%.
Should the combination treatment arm be terminated at the interim analysis, the monotherapy 
arm may also be terminated if there are
or fewer responses out of 
patients, ie, ORR 
≤
% since in this situation it is unlikely to achieve the target ORR to warrant future 
development should it continue to the end of the study. In addition, 
ORR will be evaluated by BICR at interim analyses. The IDMC will review all available 
safety and efficacy data at each interim analysis and any recommendation to stop recruitment 
to a treatment arm will be based on review of the totality of data across the study. Recruitment 
will not be paused during the conduct of the interim analyses. Full details on the content of 
safety and efficacy data reviews will be documented in the IDMC charter.
The SAP will describe the planned interim analyses in greater detail.
In addition, the number of patients with primary IO resistance, early relapse on adjuvant 
therapy or acquired IO resistance will be monitored throughout the study, and enrolment may 
be capped to any group at any time to ensure a minimum of approximately 
% of patients 
with primary and approximately 
% of patients with secondary resistance.
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9.6
Independent Data Monitoring Committee
An IDMC comprised of independent experts will be convened and will meet for a safety 
review approximately when 
patients in the ceralasertib and durvalumab combination 
therapy arm and patients in the ceralasertib monotherapy arm achieve 1 cycle (4 weeks) 
worth of data. The IDMC will convene to review the unblinded safety and tolerability data 
and the unblinded efficacy data from the interim analyses, in order to recommend to the 
sponsor to continue, amend, or stop the study based on the safety and efficacy findings. The 
committee will meet approximately every 3 months thereafter. The IDMC would also perform 
the interim analysis at the timepoints detailed in Section 9.5.
This committee will be composed of a minimum of 3 therapeutic area experts and 
biostatisticians, who are not employed by the sponsor and are free from conflict of interest. 
The precise timings of the initial IDMC meeting and subsequent meetings will be specified in 
the IDMC Charter. The IDMC Charter will be approved prior to the first IDMC Data Review 
meeting.
Following the reviews, the IDMC will recommend whether the study should continue 
unchanged, be stopped, or be modified in any way. Once the IDMC has reached a 
recommendation, a report will be provided to an unblinded review committee at the sponsor. 
The report will include the recommendation and any potential CSP amendments. The final 
decision to modify or stop the study will sit with the sponsor. The sponsor or IDMC may call 
additional meetings if at any time there is a concern about the safety of the study.
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
IDMC charter.
For details on IDMC, refer to Appendix A 5.
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
Appendix A Regulatory, Ethical, and Study Oversight Considerations  
A 1 
Regulatory and Ethical Considerations  
x 
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 GCP Guidelines 
 
Applicable laws and regulations 
x 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
x 
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study patients. 
x 
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. 
x 
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations. 
 
Regulatory Reporting Requirements for SAEs 
x 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a 
study treatment under clinical investigation are met. 
x 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators. 
x 
In the European Union, the Sponsor will comply with safety reporting requirements and 
procedures as described in the European Clinical Trials Regulation (EU) No 536/2014. 

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All SUSARs to investigational medicinal product will be reported to the EudraVigilance 
database within the required regulatory timelines. 
x 
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for SUSARs according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
 
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 
x 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
 
Regulatory Reporting Requirements for Serious Breaches of Protocol or GCP 
A ‘Serious Breach’ means any deviation of the approved version of the protocol or Good 
Clinical Practice (GCP) that is likely to affect the safety, rights of study patients and/or data 
reliability and robustness to a significant degree in a clinical trial. 
All parties (Sponsor, service provider, investigator site staff) involved in the conduct of the 
clinical trial:  
x 
Are responsible for promptly identifying and documenting any actual or potential 
serious breach. 
x 
Should have a process in place to ensure that they are able to identify the occurrence of a 
(actual/potential) serious breach. 
x 
Should report to AstraZeneca (or delegated party) without delay, through the contacts 
(email address or telephone number) provided by AstraZeneca. 
 
A 2 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
A 3 
Informed Consent Process  
x 
The investigator or his/her representative will explain the nature of the study to the patient 
or his/her legally authorised representative and answer all questions regarding the study. 

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x 
Patients must be informed that their participation is voluntary and they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the 
study. Patients or their legally authorised representative will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study centre. 
x 
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. 
The authorised person obtaining the informed consent must also sign the ICF. 
x 
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
x 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorised 
representative. 
 
For country-specific requirements for Germany see Appendix K 1.3. 
Patients 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 patient the objectives of the analysis to be done on the samples 
and any potential future use of the samples and the data obtained from these samples. Patients 
will be told that they are free to refuse to participate in any optional samples or the future use 
and may withdraw their consent at any time and for any reason during the retention period. 
If a patient’s partner becomes pregnant within 90 days after the last dose of durvalumab, the 
partner is asked to sign the “Adult Study Informed Consent Form for Pregnant Partners of 
Study Patients” and provide information about the pregnancy accordingly. 
A 4 
Data Protection  
x 
Patients will be assigned a unique identifier by Trusted Third Party contracted by the 
Sponsor or by a Principal Investigator. Any patient records or datasets that are transferred 
to AstraZeneca will contain the identifier only; patient names or any information which 
would make the patient identifiable will not be transferred. 
x 
The patient must be informed that their personal study-related and coded 
(pseudonymised) data will be used by AstraZeneca in accordance with local data 
protection law. The purposes of use and the level of disclosure and use of their data 
(including the legal basis AstraZeneca relies upon processing their data, where required) 
must also be explained to the patient in the informed consent. 

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x 
The patients must be informed that their medical records may be examined by Quality 
Assurance auditors or other authorised personnel appointed by AstraZeneca, who are 
independent of the staff involved in the study in accordance with current Quality 
Assurance Standard Operating Procedures and Quality Assurance Audit Schedule; by 
appropriate IRB/IEC members; and by inspectors from regulatory authorities. 
x 
The patient must be informed that data will be collected and used to develop the 
drug/investigational product, get permission to introduce and keep it on the market, 
monitor its safety and get it reimbursed eg, by governments eg, throughout the drug 
development programme, which includes related research activities necessary for this 
drug development programme, including to: understand how the study drug(s) and similar 
drugs work in the body (eg, evaluate the study drug mode of action, alone or in 
combination with other study drugs); better understand the studied disease and associated 
health problems; develop diagnostic tests for the disease; learn from past studies to plan 
new studies or improve scientific analysis methods; publish research results in scientific 
journals or use them for educational purposes. AstraZeneca will only collect and use the 
minimum amount of personal data to support the research and safety monitoring activities 
within the drug development programme and will not make personal data available to 
anyone (including internal staff) who is not authorised or does not have a business need to 
know the information. 
x 
The patient must be informed that in some cases their data may be further pseudonymised 
and/or anonymised.  
x 
Appropriate safeguards will be implemented to protect coded data during and after the 
study that include: 
 
Access to the coded data will be restricted and monitored, and limited to specific 
individuals subject to confidentiality obligations (including the obligation to not 
attempt to re-identify individuals/decode the clinical data). 
 
The coded data will be protected with security measures to avoid data alteration, loss, 
and unauthorised accesses and further de-identification techniques may be applied; as 
well as other high-standard technical security means such as encryption. 
 
A data protection impact assessment, where required, will apply to identify and 
mitigate privacy risks, if any, associated with each scientific research. 
 
The coded data will not be shared for direct marketing purposes or other purposes 
that are not legal duties or are not related to scientific research purposes of the study. 
In particular, it will not be used to make decisions about future services available to 
the patient, such as insurance. 
x 
Patients are also protected legally by the following means, if the coded data will be shared 
with third parties - other companies within the Sponsor group; Service providers; 

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Research partners, who may be located in countries which do not offer the same level of 
protection as the patients’ country for which the patient will be informed in the ICF: 
 
Within the Sponsor group, the patients' coded data are protected by BCR. More 
information about the Sponsor's BCR is provided here: 
www.astrazenecabindingcorporaterules.com, or by other contractual arrangements as 
may be required under local law. 
 
In all other cases, the patients' coded data is protected by contractual arrangements, 
Codes of Conduct, or certifications that set the rules for personal data protection to 
those available in the patient's country or other alternatives set forth in the law, as 
well as any supplementary technical and organisational measures that may results out 
of conducted transfer impact assessments, where required. 
 
Personal Data Breaches 
 A ‘personal data breach’ means a breach of security leading to the accidental or unlawful 
destruction, loss, alteration, unauthorised disclosure of, or access to, personal data transmitted, 
stored or otherwise processed. 
x 
In compliance with applicable laws, the Data Controller1 for the processing activity where 
the personal data breach occurred (AstraZeneca or respectively the site), will notify the 
data protection authorities without undue delay within the legal terms provided for such 
notification and within the prescribed form and content. 
x 
Whilst AstraZeneca has processes in place to deal with personal data breaches it is 
important that investigators that work with AstraZeneca have controls in place to protect 
patient data privacy. 
 
The Investigator should have a process in place to ensure that: 
x 
Allow site staff or service providers delegated by the investigator/institution to identify 
the occurrence of a (potential) personal data breaches. 
x 
Any (potential) personal data breach is promptly reported to AstraZeneca or delegated 
party, through the contacts (e-mail address or telephone number) provided by 
AstraZeneca. 
 
 
 
1 The data controller determines the purposes for which and the means by which personal 
data is processed, as defined by the European Commission 

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AstraZeneca and the site must demonstrate that they: 
x 
have taken all necessary steps to avoid personal data breaches and 
x 
have undertaken measures to prevent such breaches from occurring in the first place and 
to mitigate the impact of occurred data breaches (eg, applying encryption, maintaining 
and keeping systems and IT security measures up-to-date, regular reviews and testing, 
regular training of employees, and developed security policies and standards). 
x 
where possible, have developed an internal data breach reporting and investigation 
process and internal protocols with guidance on how to respond swiftly and diligently to 
the occurrence of a personal data breach. 
x 
where it has not been possible to develop an internal data breach reporting and 
investigation process, the site follows AstraZeneca’s instructions. 
 
Notification of personal Data Breach to patient: 
x 
Notification to patient is done by the site for the data breaches that occurred within the 
processing activities for which the site is the Data Controller and for data breaches 
occurred within the processing activities of AstraZeneca as the Data Controller, the 
notification is done in collaboration with the site and is performed by the site and/or 
Principal Investigator, acting on behalf of AstraZeneca, so that AstraZeneca has no access 
to the identifying personal information of the patient. The site and/or Principal 
Investigator shall conduct the notification by contacting the patient using the information 
that they gave for communication purposes in clinical research. 
x 
If a personal data breach occurs in a processor’s systems, engaged by AstraZeneca, the 
processor under contractual obligations with AstraZeneca promptly and in due course 
after discovering the breach notifies AstraZeneca and provides full cooperation with the 
investigation. In these cases, to the extent AstraZeneca is the Data Controller for the 
processing activity where the breach occurred, it will be responsible for the notification to 
data protection authorities and, if applicable, to patient. If the personal data breach needs 
to be notified to the patient, the notification to patient is done in collaboration with the 
site and is performed by the site and/or Principal Investigator, acting on behalf of the 
Sponsor, so that AstraZeneca has no access to the identifying personal information of the 
patient. 
x 
If a personal data breach involving an AstraZeneca’s representative device (ie, Study 
Monitor laptop), AstraZeneca representative will provide AstraZeneca with all of the 
information needed for notification of the breach, without disclosing data that allows 
AstraZeneca directly or indirectly to identify the patient. The notification will be done by 
AstraZeneca solely with the information provided by the Study Monitor and in no event 
with access to information that could entail a risk of re-identification of the patient. If the 
data breach must be notified to the data subjects, the notification will be done directly by 

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the Study Monitor in collaboration with the site and/or Principal Investigator, acting on 
behalf of the Sponsor, so that AstraZeneca has no access to the identifying personal 
information of the patient. The contract between AstraZeneca and the Study Monitor shall 
expressly specify these conditions. 
x 
The contract between the site and AstraZeneca for performing the clinical research 
includes the provisions and rules regarding who is responsible for coordinating and 
directing the actions in relation to the breaches and performing the mandatory 
notifications to authorities and patients, where applicable. 
 
A 5 
Committees Structure  
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators. 
A 6 
Dissemination of Clinical Study Data  
Study overall results, both technical and written in lay language (Trial Results Summary, also 
known as Lay Language Summary of overall study results), will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, to ensure scientific 
integrity, completeness, robustness and reliability of data published results. 
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov and https://euclinicaltrials.eu/ as will the summary of the study 
results when they are available. The clinical study and/or summary of study results may also 
be available on other websites according to the regulations of the countries in which the study 
is conducted. 
A 7 
Data Quality Assurance  
x 
All patient data relating to the study will be recorded on eCRF unless transmitted to the 
sponsor or designee electronically (eg, laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
x 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
x 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory authority inspections and provide direct access to source data documents. 
x 
Monitoring details describing strategy including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality such as Risk Management 
and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 

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responsibilities and requirements, including handling of non-compliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
Monitoring Plan/contracts. 
x 
The sponsor or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Monitoring Plan/contracts. 
x 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
x 
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organisations). 
x 
Study monitors will perform ongoing source data verification as per the Monitoring 
Plan(s) to confirm that data entered into the eCRF by authorised site personnel are 
accurate, complete, and verifiable from source documents; that the safety and rights of 
patients are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
x 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for a minimum of 25 years after study archiving or as 
required by local regulations, according to the AstraZeneca Global retention and Disposal 
(GRAD) Schedule. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
 
A 8 
Source Documents  
x 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
x 
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. 
x 
Definition of what constitutes source data can be found in Source Data Agreement. All 
information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study are defined as source documents.  
 

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A 9 
Study and Site Start and Closure  
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The first act of recruitment is the first site open and will be the study start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. Reasons for the early 
closure of a study site by the sponsor or investigator may include but are not limited to: 
x 
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 
x 
Inadequate recruitment of patients by the investigator 
x 
Discontinuation of further study treatment development 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the patient and 
should assure appropriate patient therapy and/or follow-up. 
A 10 
Publication Policy  
x 
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. 
x 
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. 
x 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Detailed authorship 
guidelines will be outlined in a separate authorship policy. 
 

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Appendix B Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
B 1 
Definition of Adverse Events  
An adverse event is the development of any untoward medical occurrence (other than 
progression of the malignancy under evaluation) in a patient or clinical study patient 
administered a study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavourable and unintended sign (eg, an 
abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
B 2 
Definitions of Serious Adverse Event  
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria: 
x 
Results in death 
x 
Is immediately life-threatening 
x 
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
x 
Results in persistent or significant disability or incapacity 
x 
Is a congenital abnormality or birth defect 
x 
Is an important medical event that may jeopardise the patient or may require medical 
treatment to prevent one of the outcomes listed above 
 
Adverse Events (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; 

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examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy. 
The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 
is being treated by the Investigational Product under study and is not the development of new 
or progression of existing metastasis to the tumour under study). Malignant tumours that – as 
part of normal, if rare, progression – undergo transformation (eg, Richter’s transformation of 
B-cell chronic lymphocytic leukaemia into diffuse large B-cell lymphoma) should not be 
considered a new malignant tumour. 
Life-threatening 
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the patient was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. 
Important Medical Event or Medical Treatment 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
x 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
x 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
x 
Intensive treatment in an emergency room or at home for allergic bronchospasm 

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x 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
x 
Development of drug dependency or drug abuse 
 
Intensity Rating Scale: 
x 
Mild (awareness of sign or symptom, but easily tolerated) 
x 
Moderate (discomfort sufficient to cause interference with normal activities) 
x 
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 B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2. 
The grading scales found in the revised National Cancer Institute CTCAE, version 5.0, will be 
utilised for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly. 
B 3 
A Guide to Interpreting the Causality Question  
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
x 
Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
x 
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? 
x 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 

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x 
No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors. 
x 
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. 
x 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
x 
Is this a recognised feature of overdose of the drug? 
x 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With no available facts or arguments to suggest 
a causal relationship, the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
B 4 
Medication Error, Drug Abuse, and Drug Misuse  
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study treatment that either causes harm to the patient 
or has the potential to cause harm to the patient. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient. 
Medication error includes situations where an error: 
x 
Occurred 
x 
Was identified and intercepted before the patient received the drug 
x 
Did not occur, but circumstances were recognised that could have led to an error 
 

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Examples of events to be reported in clinical studies as medication errors: 
x 
Drug name confusion 
x 
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the patient 
x 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
x 
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 
x 
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 
x 
Wrong patient received the medication (excluding IVRS/IWRS errors) 
x 
Wrong drug administered to patient (excluding IVRS/IWRS errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
x 
Errors related to or resulting from IVRS/IWRS – including those which lead to one of the 
above listed events that would otherwise have been a medication error 
x 
Patient accidentally missed drug dose(s) eg, forgot to take medication 
x 
Accidental overdose (will be captured as an overdose) 
x 
Patient failed to return unused medication or empty packaging 
x 
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. 
Drug Abuse 
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect. 
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded 
to the DES using the Drug Abuse Report Form. This form should be used both if the drug 
abuse happened in a study patient or if the drug abuse involves a person not enrolled in the 
study (such as a relative of the study patient). 

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Examples of drug abuse include but are not limited to: 
x 
The drug is used with the intent of getting a perceived reward (by the study patient or a 
person not enrolled in the study) 
x 
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high 
 
Drug Misuse 
Drug misuse is the intentional and inappropriate use (by a study patient) of IMP for medicinal 
purposes outside of the authorised product information, or for unauthorised IMPs, outside the 
intended use as specified in the protocol and includes deliberate administration of the product 
by the wrong route. 
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study patient or if the drug misuse regards a person not enrolled in the 
study (such as a relative of the study patient). 
Examples of drug misuse include but are not limited to: 
x 
The drug is used with the intention to cause an effect in another person 
x 
The drug is sold to other people for recreational purposes 
x 
The drug is used to facilitate assault in another person 
x 
The drug is deliberately administered by the wrong route 
x 
The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole 
x 
Only half the dose is taken because the study patient feels that he/she is feeling better 
when not taking the whole dose 
x 
Someone who is not enrolled in the study intentionally takes the drug 

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Appendix C Handling of Human Biological Samples  
C 1 
Chain of Custody  
A full chain of custody is maintained for all samples throughout their lifecycle. 
The investigator at each centre keeps full traceability of collected biological samples from the 
patients while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal. 
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers 
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle. 
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner. 
C 2 
Withdrawal of Informed Consent for Donated Biological Samples  
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent. 
If a patient withdraws consent specifically to the subsequent use of donated biological 
samples, the samples will be disposed of/destroyed/repatriated, and the action documented. If 
samples are already analysed, AstraZeneca is not obliged to destroy the results of this 
research. The patient will be presented with the option to opt out of the subsequent use of the 
donated samples during the withdrawal process. If the patient decides to opt out, then the 
donated samples will be disposed of. If the patient withdraws consent without opting out for 
the subsequent use of the donated samples, then the samples will be used as per protocol. 
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 

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The investigator: 
x 
Ensures patient’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate. 
x 
Ensures that relevant human biological samples from that patient, if stored at the study 
site, are immediately identified, disposed of as appropriate, and the action documented. 
x 
Ensures that the patient and AstraZeneca are informed about the sample disposal. 
 
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site notified. 
C 3 
International Airline Transportation Association 6.2 Guidance 
Document  
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name: 
x 
UN 3373 – Biological Substance, Category B 
x 
are to be packed in accordance with UN 3373 and IATA 650 
 

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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. 
x 
Clinical study samples will fall into Category B or exempt under IATA regulations 
x 
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) 
x 
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry ice content 

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Appendix D
D 1
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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 patient 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 AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events. 
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than drug-induced liver injury (DILI) caused by the study treatment.  
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
E 2 
Definitions  
Potential Hy’s Law  
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3 × ULN together 
with Total Bilirubin (TBL) ≥ 2× ULN at any point during the study following the start of 
study treatment irrespective of an increase in ALP.  
Hy’s Law  
AST or ALT ≥ 3× ULN together with TBL ≥ 2× ULN, where no other reason, other than the 
study treatment, can be found to explain the combination of increases, eg, elevated ALP 
indicating cholestasis, viral hepatitis, another drug.  

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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified 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 patient who meets any of the following identification criteria in 
isolation or in combination: 
x 
ALT ≥ 3 × ULN 
x 
AST ≥ 3 × ULN 
x 
TBL ≥ 2 × ULN 
 
Local Laboratories Being Used: 
The investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
x 
Notify AstraZeneca representative 
x 
Determine whether the patient meets PHL criteria (see Appendix E 2 for definition) by 
reviewing laboratory reports from all previous visits 
x 
Promptly enter the laboratory data into the laboratory eCRF 
 
E 4 
Follow-up  
E 4.1 
Potential Hy’s Law Criteria Not Met  
If the patient does not meet PHL criteria the investigator will: 
x 
Inform the AstraZeneca representative that the patient has not met PHL criteria.  
x 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP. 
 

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E 4.2 
Potential Hy’s Law Criteria met  
If the patient does meet PHL criteria the investigator will: 
x 
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (see Appendix E 6) 
x 
Notify the AstraZeneca representative who will then inform the central Study Team  
x 
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criterion “Important medical event” and causality assessment “yes/related” 
according to CSP process for SAE reporting 
x 
For patients that met PHL criteria prior to starting study treatment, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the patient’s 
condition 
x 
The study clinical lead contacts the investigator, to provide guidance, discuss and agree 
an approach for the study patients’ follow-up (including any further laboratory testing) 
and the continuous review of data 
x 
Subsequent to this contact the investigator will: 
 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required. 
 
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the study clinical lead. This includes deciding whether the tests 
available in the Hy’s law lab kit should be used. 
 
Complete the three Liver eCRF Modules as information becomes available  
 
#A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study clinical lead 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 
clinical lead contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
study treatment, to ensure timely analysis and reporting to health authorities within 15 
calendar days from date PHL criteria was met. The AstraZeneca Global Clinical Lead or 

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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: 
x 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF 
x 
If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study treatment: 
x 
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: 
x 
Provides any further update to the previously submitted SAE of PHL, (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to study treatment and 
seriousness criteria is medically important, according to CSP process for SAE reporting. 
x 
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. 
 

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E 6 
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Treatment  
This section is applicable to patients 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 patient’s condition# compared with the 
last visit where PHL criteria were met#  
 
If there is no significant change no action is required. 
 
If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Appendix E 4.2 
 
E 7 
Actions Required for Repeat Episodes of Potential Hy’s Law  
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.  
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following questions: 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study eg, chronic or progressing malignant disease, severe infection or liver 
disease.  
If No: follow the process described in Appendix E 4.2 for reporting PHL as an SAE 
If Yes: Determine if there has been a significant change in the patient’s condition# compared 
with when PHL criteria were previously met 
x 
If there is no significant change no action is required 
x 
If there is a significant change# follow the process described in Appendix E 4.2 for 
reporting PHL as an SAE 
 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 

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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 
Laboratory Tests  
The list below represents the standard, comprehensive list of follow-up tests, which are 
recommended but not mandatory. The list may be modified based on clinical judgement. Any 
test results need to be recorded. 
Hy’s Law Lab Kit  
Additional standard chemistry and coagulation 
tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
HbsAg 
IgM and IgG anti-HBc 
HCV DNA a 
IgM and IgG anti-HCV 
HCV RNA a 
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM & IgG anti-CMV 
IgM & IgG anti-HSV 
IgM & IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate deficient transferrin (CD-transferrin) b 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab (Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin b 
Transferrin saturation 
CMV = cytomegalovirus; DNA = deoxyribonucleic acid; EBV = Epstein-Barr virus; GGT = gamma glutamyl transferase; 
HAV = hepatitis A virus; HBc = hepatitis B core antigen; HbsAg = hepatitis B surface antigen; HCV = hepatitis C virus; 
HEV = hepatitis E virus; HSV = herpes simplex virus; IgG = immuno-globulin G; IgM = immuno -globulin M; 
INR = international normalised ratio; LDH = lactate dehydrogenase; RNA = ribonucleic acid. 
a 
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive. 
b 
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly 
 

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E 9 
References  
Aithal et al, 2011  
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815. 
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 Regarding Potential Interactions of Ceralasertib 
with Concomitant Medications
Restrictions regarding drugs affecting 
 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 
 
metabolism, therefore 
 may increase or decrease exposure to 
ceralasertib, respectively. 
 of 
 should not be combined 
with ceralasertib. In vitro data also suggest that ceralasertib may be metabolised by 
 
but a lesser extent, therefore caution should be applied with co-administration of potent 
inhibitors or inducers of 
.
These lists are not intended to be exhaustive, and similar restrictions will apply to other agents 
that are known to modulate 
 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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Drugs Known to be Inhibitors or Inducers of
Potent 
 inhibitors
Potent 
 inducers
a
b
Drugs Known to be Inhibitors and Inducers of 
Potent 
 inhibitors
Potent 
 inducers
List created using the University of Washington Drug-Drug Interaction Database Jan 2020.
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Drugs known to be inhibitors or inducers of 
 and/or 
, undertake appropriate 
monitoring if co-administration is necessary
Ceralasertib is a substrate of 
 and 
. Co-administration of 
 inhibitors/inducers or 
 inhibitors/inducers may affect exposure to ceralasertib 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 
 activity or 
 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.
Drugs Known to be Inhibitors or Inducers of 
Drugs Known to be Inhibitors of 
Drugs Known to be Inducers of 
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Drugs Known to be Inhibitors of 
Drugs Known to be Inducers of 
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Drugs Known to be Inhibitors of 
Drugs Known to be Inducers of 
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Drugs Known to be Inhibitors of 
Drugs Known to Be Inducers of 
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Drugs Known to be Inhibitors of 
Drugs Known to Be Inducers of 
Drugs known to be substrates of 
 and/or 
 or 
 or 
, or 
undertake appropriate monitoring if co-administration is necessary
Ceralasertib is a potential inducer of 
 and a potential 
inhibitor of 
. Therefore, caution should be applied with co-
administration of drugs that are either completely metabolised by 
, or that are substrates of 
and also have a narrow therapeutic index. Investigators should be aware 
that the exposure of other drugs co-administered with ceralasertib that are metabolised by 
 may be increased due to inhibition, and exposure of other 
drugs co-administered with ceralasertib that are metabolised by 
 may be reduced due to induction.
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Drugs known to be metabolised by 
Metabolised by 
Metabolised 
by 
Metabolised 
by 
Metabolised by 
Metabolised by 
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Metabolised by 
Metabolised 
by 
Metabolised 
by 
Metabolised by 
Metabolised by 
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Metabolised by 
Metabolised 
by 
Metabolised 
by 
Metabolised by 
Metabolised by 
(NTR) drug listed in the Narrow Therapeutic Index list by 
 in DrugBank
Drugs known to be substrates of 
, undertake appropriate 
monitoring if co-administration is necessary 
Ceralasertib is also an inhibitor of 
. Caution should be applied with 
co-administration of substrates of 
 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.
Drugs Known to be Substrates of 
 
* 
 
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Drugs known to be substrates of 
 
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Appendix G 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 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 
Patients with at least one lesion (measurable and/or non-measurable) that can be accurately 
assessed at baseline by computerised tomography, MRI or plain X-ray should be included in 
this study. 
Measurability of tumour lesions at baseline 
RECIST 1.1 measurable lesions at baseline 
A tumour lesion that can be accurately measured at baseline as ≥ 10 mm in the longest 
diameter for non-nodal lesions or ≥ 15 mm in short axis2 diameter for lymph node lesions with 
IV contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. 
Please see additional RECIST 1.1 guidance below on measurability of intrahepatic 
hepatocellular carcinoma lesions and porta hepatis lymph nodes. 
Non-measurable lesions at baseline 
x 
Truly non-measurable lesions include the following: 
 
Bone lesions (see exception below for soft tissue component). 
 
Leptomeningeal disease. 
 
Ascites, pleural effusion, or pericardial effusion. 
 
Inflammatory breast disease. 
 
Lymphangitic involvement of skin or lung. 
x 
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 mm to < 15 mm short axis diameter at baseline).3 
 
 
2 
The short axis is defined as the longest in-plane axis perpendicular to the long axis. 
3 
Lymph nodes with < 10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs. 

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x 
Previously irradiated lesions. 
x 
Brain metastasis. 
Special considerations regarding lesion measurability at baseline 
x 
Bone lesions: 
 
Bone scan, PET scan, or plain X-ray are not considered adequate imaging techniques 
to measure bone lesions; however, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. 
 
Blastic lesions are considered non-measurable. 
x 
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the criteria for measurability from a radiological point of view, but if 
non-cystic lesions are present in the same patient, these should be selected over cystic 
lesions as TLs. 
 
RECIST 1.1 TL selection at baseline 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TLs at baseline. TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis diameter for nodal lesions), but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement, in which circumstance the next largest lesion that can be measured reproducibly 
should be selected. 
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal 
glands), a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a 
single organ. 
The site and location of each TL should be documented, as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimetres. At baseline, the sum of the diameters for all 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. 

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Special cases for TL assessment at baseline 
x 
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 
diameter. 
x 
When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non-nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter. 
x 
Tumour lesions selected for newly acquired screening biopsy should not be selected as 
TLs, unless imaging occurred at least approximately 2 weeks after biopsy, allowing time 
for healing. 
x 
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. 
x 
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a NL. 
 
RECIST 1.1 NTL selection at baseline 
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up. 
Evaluation of tumour response and progression 
RECIST 1.1 TL assessment at follow-up 
This section defines the criteria used to determine objective tumour visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter 
for non-nodal lesions or short axis diameter for lymph node lesions. All measurements should 
be recorded in millimetres. The sum of the diameters for all TLs at each follow-up visit will 
be compared with the baseline sum of diameters (for response or SD) or to the smallest prior 
(nadir) sum of diameters (for progression). 
Special cases for TL assessment at follow-up: 
x 
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL. 
x 
If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded. 
x 
If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 

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lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the vector of the longest diameter of the coalesced mass should be used to 
determine the perpendicular vector for the maximal short axis diameter. 
x 
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. 
x 
If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. The choice of “Too large to measure” in the CRF will trigger an overall 
visit response of PD. 
x 
When a TL has had any intervention (eg, definitive radiotherapy, embolisation, surgery, 
transarterial chemoembolisation, etc) during the study, the size of the TL should still be 
provided where possible and the intervention recorded in the RECIST 1.1 CRF for the 
current imaging visit and all subsequent visits. If a TL has been completely removed 
(surgery) or disappears, the longest diameter should be recorded as 0 mm. 
 
Table 17 
RECIST 1.1 Evaluation of Target Lesions  
CR 
Disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs 
must have a reduction in short axis diameter to < 10 mm. 
PR 
At least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline 
sum of diameters. 
SD 
Neither sufficient decrease in the sum of diameters to qualify for PR nor sufficient increase 
to qualify for PD. 
PD 
At least a 20% increase in the sum of diameters of TLs, taking as reference the smallest 
previous sum of diameters (nadir). This includes the baseline sum if that is the smallest on 
study. In addition to the relative increase of 20%, the sum must demonstrate an absolute 
increase of at least 5 mm from nadir. 
NE 
Only relevant if any of the TLs at follow-up were not assessed or NE (eg, missing 
anatomy) or had a lesion intervention at this visit. Note: If the sum of diameters meets the 
PD criteria, PD overrides NE as a TL response. 
Not applicable 
Only relevant if no TLs present at baseline. 
CR, complete response; NE, not evaluable; PD, progression of disease; PR, partial response; SD, stable disease; TL, target 
lesion. 
 
RECIST 1.1 NTL assessment at follow-up 
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. 
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, 

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the overall tumour burden has increased sufficiently to merit unequivocal progression by 
NTLs. A modest “increase” in the size of 1 or more NTLs is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the basis 
of change in non-target disease in the face of SD or PD of target disease will therefore be 
extremely rare. 
Table 18 
RECIST 1.1 Evaluation of Non-Target Lesions  
CR 
Disappearance of all NTLs since baseline. All lymph nodes must be 
non-pathological in size (< 10 mm short axis). 
Non CR/non PD 
Persistence of 1 or more NTLs. 
PD 
Unequivocal progression of existing NTLs. Unequivocal progression may be due 
to an important progression in 1 lesion only or in several lesions. In all cases, the 
progression MUST be clinically significant for the physician to consider changing 
(or stopping) therapy. 
NE 
Only relevant when 1 or some of the NTLs were not assessed and, in the 
investigator’s opinion, they are not able to provide an evaluable overall NTL 
assessment at this visit. 
Note: For patients without TLs at baseline, this is relevant if any of the NTLs 
were not assessed at this visit and the progression criteria have not been met. 
Not applicable 
Only relevant if no NTLs present at baseline. 
CR, complete response; NE, not evaluable; NTL, non-target lesion; PD, progression of disease; TL, target lesion. 
 
RECIST 1.1 NL identification at follow-up 
Details, including the imaging modality, the date of scan, and the location of any NLs will 
also be recorded in the CRF. The presence of 1 or more NLs is assessed as progression. The 
finding of a NL should be unequivocal, ie, not attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumour. If a NL is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the previously (pre-existing) NL has been assessed as 
unequivocal at a follow-up visit, and then the progression date should be declared using the 
date of the initial scan when the NL first appeared. 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate PD. 
RECIST 1.1 evaluation of overall visit response at follow-up 
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 19. 
Most studies should require at least 1 TL at baseline (please see Inclusion Criteria). For these 
studies, please delete the rows and footer text in green font below. For studies where there is 
no mandatory requirement to have measurable disease at baseline and therefore it is possible 

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to have not applicable in TLs at baseline, please retain rows and footer text in green font. For 
country-specific requirements for Germany see Appendix K 1.3. 
Table 19 
RECIST 1.1 Overall Visit Response  
Target lesions 
Non-target lesions 
New lesions 
Overall visit 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 or NA 
No 
PR 
SD  
Non PD or NE or NA 
No 
SD 
NA 
Non-CR/Non-PD 
No 
SD (non-CR/non-PD) 
NE 
Non PD or NE 
No 
NE 
NA 
NE 
No 
NE 
NA 
NA 
No 
NED 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Non-CR/Non-PD for overall response if only NTL (no TLs) are present at baseline. 
Note: An overall assessment of CR (all other disease disappears/reverts to normal) would be changed to PR if ascites remains 
present radiologically. 
CR, complete response; NA, not applicable (only relevant if there were no TLs at baseline or NTLs at baseline), NE, not 
evaluable; NED, no evidence of diseases (only relevant if there were neither TLs nor NTLs at baseline); NTL, non-target 
lesion; PD, progression of disease; PR, partial response; SD, stable disease; TL, target lesion. 
 
The following overall visit responses are possible depending on the extent of tumour disease 
at baseline: 
x 
For patients with TLs (at baseline): CR, PR, SD, PD, or NE. 
x 
For patients with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE. 
x 
For patients with no disease at baseline: no evidence of disease (available as an option in 
the eCRF), PD, or NE. 
 
Evaluation of scans subsequent to RECIST 1.1-defined progression 
A follow-up scan is requested at least 4 weeks after a RECIST 1.1-defined radiological 
progression and no longer than the next regularly scheduled imaging visit. The follow-up 
scans provide additional information to the investigator for patient management and further 
treatment decisions, and since the published RECIST 1.1 criteria (Eisenhauer et al, 2009) do 
not provide guidance on how to assess scans acquired after RECIST 1.1-defined PD, 

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supplemental instructions for investigators on how to evaluate these follow-up scans are 
provided below. An immediate prior RECIST 1.1-defined radiologic PD would be considered 
confirmed if any of the following criteria are met in the subsequent follow-up scan: 
x 
≥ 20% increase and at least a 5 mm increase in the sum of diameters of TLs compared 
with the nadir sum of diameters at 2 consecutive visits, and a further increase of ≥ 5 mm 
in the sum of diameters at the follow-up scan time point compared with the immediate 
prior time point. 
x 
Significant progression (worsening) of NTLs at the follow-up scan time point compared 
with the immediate prior time point. 
x 
Significant progression (worsening) of previously NLs (pre-existing NLs) at the follow-
up scan time point compared with the immediate prior time point. 
x 
Additional brand-new unequivocal lesions at the follow-up scan time point. 
 
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 the below table and those 
excluded for tumour assessments in this study are discussed below, with the rationale 
provided. 
Table 20 
Summary of Methods of Assessment  
Target Lesions 
Non-target Lesions 
New Lesions 
CT (preferred) 
CT (preferred) 
CT (preferred) 
MRI 
MRI 
MRI 
 
Plain X-ray 
Plain X-ray 
 
Chest X-ray 
Chest X-ray 
 
 
Bone scan (Scintigraphy) 
 
 
18F-fluoro-deoxyglucose-PET/CT 
CT = computed tomography; PET/CT = positron emission tomography; MRI = magnetic resonance imaging. 
 
For skin lesions, documentation by colour photography including a ruler to estimate the size 
of the lesion, is required (2 dimensions is acceptable). When lesions can be evaluated by both 
clinical examination and imaging, imaging evaluation should be undertaken since it is more 
objective and may also be reviewed at the end of the study. 
Photographs include a close-up view of the index lesion area(s), anatomical location view of 
the index lesion area(s). Two exposures for each location and lesion will be taken. 

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CT and MRI 
CT with IV contrast is the preferred imaging modality (although MRI with IV contrast is 
acceptable if CT is contraindicated) to generate reproducible anatomical images for tumour 
assessments (ie, for measurement of TLs, assessment of NTLs, and identification of NLs). It is 
essential that the same correct imaging modality, image acquisition parameters (eg, anatomic 
coverage, imaging sequences, etc), imaging facility, tumour assessor (eg, radiologist), and 
method of tumour assessment (eg, RECIST 1.1) are used consistently for each patient 
throughout the study. The use of the same scanner for serial scans is recommended, if 
possible. It is important to follow the image collection/tumour assessment schedule as closely 
as possible (refer to the SoA), and this on-study imaging schedule MUST be followed 
regardless of any delays in dosing or missed imaging visits. If an unscheduled assessment is 
performed (eg, to investigate clinical signs/symptoms of progression) and the patient has not 
progressed, every attempt should be made to perform the subsequent scan acquisitions at the 
next scheduled imaging visit. 
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 
scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artefacts (eg, heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence. In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. 
The most critical CT and MRI image acquisition parameters for optimal tumour evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval. 
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the 
chest-abdomen (-pelvis). Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual patients. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a NL representing 
PD, 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. 

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Required anatomical regions to be imaged for assessment of tumour burden (TLs and/or 
NTLs) at baseline and follow-up visits vary according to the study, and these time points are 
specified in the SoA. Examples include the following: 
x 
IV contrast-enhanced CT of chest-abdomen (including the entire liver and both adrenal 
glands) (-pelvis). 
x 
Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire liver 
and both adrenal glands) (-pelvis). 
x 
IV contrast-enhanced CT or MRI of the head and neck. 
x 
IV contrast-enhanced MRI (preferred) or CT of the brain. 
 
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order 
of preference, with additional options (2 to 4) for consideration when patients have sensitivity 
to IV contrast or have compromised renal function: 
1 
Chest-abdomen (-pelvis) CT with IV CT contrast (most preferred). 
2 
Chest CT without IV-contrast + abdomen (-pelvis) MRI with IV MRI contrast, if CT IV 
contrast (iodine based) is medically contraindicated at any time during the study. 
3 
Chest-abdomen (-pelvis) CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the patient has compromised renal function. 
4 
Chest-abdomen (-pelvis) MRI with IV MRI contrast, if CT cannot be performed at any 
time during the study. 
 
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumours require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumour 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given patient. Oral contrast is recommended to help visualise and 
differentiate structures in the abdomen and pelvis. 
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤ 5 mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses > 5 mm. If this 
occurs, the minimum size of measurable lesions at baseline should be twice the slice thickness 
of the baseline scans. 
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 

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TL should be measured on the same window setting for repeated examinations throughout the 
study. 
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 patients 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. 
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. However, there is preference that a higher resolution modality, such as CT, be 
used to confirm the presence of NLs. 
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 per baseline 
assessment (CT, MRI, or X-ray). 
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 
equivocal hot-spot on a bone scan that cannot be verified with correlative imaging (CT, MRI, 
or X-ray) of the same anatomical region shall not be the only trigger for a PD assessment at 
that time point. 
18F-Fluoro-deoxyglucose-PET/CT 
18F-fluoro-deoxyglucose positron emission tomography (PET)/CT scans may be used as a 
method for identifying new extrahepatic lesions (but not intrahepatic lesions) for RECIST 1.1 
assessments according to the following algorithm: NLs will be recorded where there is 

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positive 18F-Fluoro-deoxyglucose uptake4 not present on baseline or prior 
18F-fluoro-deoxyglucose-PET scan or in a location corresponding to a NL on a companion 
CT/MRI collected close in time to the 18F-fluoro-deoxyglucose-PET scan. The PET portion of 
the PET/CT introduces additional data that may bias an investigator if it is not routinely or 
serially performed. Therefore, if there is no baseline or prior 18F-fluoro-deoxyglucose-PET 
scan available for comparison, and no evidence of NLs on companion CT/MRI scans, then 
follow-up CT/MRI assessments should continue as per the regular imaging schedule to verify 
the unequivocal presence of NLs. 
At present, low-dose or attenuation correction CT portions of a combined 
18F-fluoro-deoxyglucose-PET/CT scan are of limited use in anatomically based efficacy 
assessments, and it is therefore suggested that they should not substitute for dedicated 
diagnostic contrast-enhanced CT scans for tumour measurements by RECIST 1.1. In 
exceptional situations, if a site can document that the CT performed, as part of a PET/CT 
examination, is of identical diagnostic quality (with IV contrast) to a dedicated diagnostic CT 
scan, then the CT portion of the PET/CT can be used for RECIST 1.1 tumour assessments. 
Caution that this is not recommended because the PET portion of the CT introduces additional 
(PET) data that may bias an investigator if it is not routinely or serially performed. 
Ultrasound 
Ultrasound examination will not be used for RECIST 1.1 assessment of tumours as it is not a 
reproducible acquisition method, is subjective in interpretation, and may not provide an 
accurate assessment of tumour size. Tumours identified by ultrasound will need to be assessed 
by correlative CT or MRI anatomical scan. 
Other tumour assessments 
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST 1.1 assessments. Tumours identified by clinical examination will 
need to be assessed by correlative CT or MRI anatomical scans. 
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour measurements. 
 
 
4 
A positive 18F-fluoro-deoxyglucose-PET scan lesion should be reported only when an uptake (eg, standard uptake value) greater than twice that of the surrounding 
tissue or liver is observed. 

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Tumour markers 
Tumour markers on tumour biopsy samples 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 (eg, ascites, pericardial 
effusion, and pleural effusion) that appears or worsens during the study will not be used as 
part of the tumour response assessment as per RECIST 1.1. 
Furthermore, an overall assessment of CR (all other disease disappears/reverts to normal) 
would be changed to PR if an effusion remains present radiologically. 
G 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 H Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis, including COVID 19 Outbreak  
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with SARS-CoV- or similar pandemic infection) during which 
patients may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from the sponsor. 
H 1 
Reconsent of Study Patients During Study Interruptions  
During study interruptions, it may not be possible for the patients to complete study visits and 
assessments on site and alternative means for carrying out the visits and assessments may be 
necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Appendices H 2 to H 5. Local and regional regulations and/or guidelines 
regarding reconsent of study patients should be checked and followed. Reconsent may be 
verbal if allowed by local and regional guidelines (note, in the case of verbal reconsent the 
ICF should be signed at the patient’s next contact with the study site). Visiting the study sites 
for the sole purpose of obtaining reconsent should be avoided. 
H 2 
Rescreening of Patients To Reconfirm Study Eligibility  
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened patients. The investigator should confirm this with the designated 
AstraZeneca clinical lead. 
In addition, during study disruption there may be a delay between confirming eligibility of a 
patients and either enrolment into the study or commencing of dosing with study treatment. If 
this delay is outside the screening window specified in in the appropriate Schedule of 
Assessment Table, the patient will need to be rescreened to reconfirm eligibility before 
commencing study procedures. This will provide another opportunity to re-screen a patient in 
addition to that detailed in Section 5.4. The procedures detailed in Section 5.4 must be 
undertaken to confirm eligibility using the same randomisation number as for the patient 
H 3 
Home or Remote Visit to Replace On-site Visit (where applicable)  
A qualified HCP from the study site or third party vendor service will visit the patients home / 
or other remote location as per local standard operating procedures (SOPs), as applicable. 

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Supplies will be provided for a safe and efficient visit. The qualified HCP will be expected to 
collect information per the CSP. 
H 4 
Telemedicine Visit to Replace On-site Visit (where applicable)  
In this appendix, the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices. 
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the patients will allow adverse events, concomitant medication, Eastern Cooperative 
Oncology Group performance status (ECOG PS) to be reported and documented. 
H 5 
Data Capture During Telemedicine or Home/Remote Visits  
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site or TPV service, or by the patient themselves. 
H 6 
COVID-19 Risk Assessment  
The safety of patients is of primary importance. Any potential risks of participating in the 
study, particularly with the added challenges due to COVID-19 outbreak, should be weighed 
against the anticipated benefit (see also principle 2.2 of ICH GCP). Investigators are advised 
to use clinical judgement in determining infection prevention precautions for study patients. 
The emergence of SARS-CoV-2 presents a potential safety risk for cancer patients. Patients 
enrolling in this study may require more frequent visits to the site for study treatment 
administration and for study assessments compared to patients receiving standard of care. 
Therefore, several risk mitigation factors have been implemented related to study conduct 
during the COVID-19 outbreak, for patient management in an event of COVID 19, and 
actions to be taken on study treatment (see Appendix H 9). With these measures in place, it is 
considered that the anticipated potential benefits for the patients enrolled in this study 
outweigh the potential risks. All implemented measures prioritise trial patient safety and data 
validity; in case these 2 conflict with each other, trial patient safety should always prevail (see 
also European Medicines Agency Guidance on the management of clinical trials during the 
COVID-19 [coronavirus] pandemic [EMA 2020]). 
Notably, patients with active COVID-19 infection confirmed by local laboratory testing will 
not be eligible for study enrolment (see CSP Section 5.2). 

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

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

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H 10.4 
Vaccination Against COVID-19  
Protocol restrictions applying to live attenuated vaccines are relevant for live attenuated 
COVID-19 vaccines as well. Investigators should apply their discretion assessing the risk 
benefit of other types of COVID-19 vaccines for patients in clinical trials. Ideally, 
administration of the vaccine should be done on a different day other than the day of study 
drug administration to differentiate any potential AEs seen from the vaccine and study drug. 
The administration of the vaccine and any potential AEs associated with the vaccine are to be 
documented on the concomitant medication and AE eCRFs, respectively. 
H 11 
References  
Curigliano et al 2020  
Curigliano G, Banerjee S, Cervantes A, Garassino M, Garrido P, Girard N. Managing cancer 
patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus. Ann 
Oncol 2020;31(10):1320-35. 
EMA 2020  
EMA, Clinical Trials Facilitation and Coordination Group, European Commission. Guidance 
on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, 
Version 2, 27 March 2020. Available from: URL: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. Accessed: 17 December 2020. 

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Appendix I
Patient Reported Outcomes
I 1
CCI
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CCI

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I 2
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I 3
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I 4
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I 5
 
 
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I 6
 
 
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I 7
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Appendix J
Abbreviations
Abbreviation or special 
term
Explanation
ADA
anti-drug antibody
ADE
adverse device effect
ADR
adverse drug reaction
AE
adverse event
AESI
adverse events of special interest
AIDS
acquired immunodeficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase/transaminase
AML
Acute myeloid leukaemia
ANC
absolute neutrophil count
AST
aspartate aminotransferase/transaminase
ATM
ataxia telangiectasia mutated
ATR
ataxia and telangiectasia related
BCR
Binding Corporate Rules
BD
twice daily
BICR
blinded independent central review
BOR
Best Overall Response
BP
blood pressure
BRAF
B-Rapidly Accelerated Fibrosarcoma gene
BRCA
Breast Cancer gene
BRCP
Breast Cancer Resistance Protein
CAPA
corrective action preventive action
CI
confidence interval
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CPI
checkpoint inhibitors
CR
complete response
CRO
Contract Research Organisation
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
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Abbreviation or special 
term
Explanation
CTIS
Clinical Trials Information System
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
CTR
clinical trials regulation
DCO
data cut off
DES
data entry site
DILI
Drug Induced Liver Injury
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
DoR
duration of response
EAP
early access program
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
ePRO
electronic PRO
EU
European Union
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GzmB
Granzyme B
HbsAg
HBV surface antigen
HBV
hepatitis B virus
HCP
healthcare professional
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HL
Hy’s Law
HR
hazard ratio
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
informed consent form
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Abbreviation or special 
term
Explanation
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFN
interferon
IgG
immunoglobulin G
ILD
interstitial lung disease
imAE
immune-mediated AE
INR
international normalised ratio
IO
immune-oncology
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISG
IFN stimulated genes
IV
intravenous
IVRS/IWRS
Interactive Voice/Web Response System
KL-6
Krebs von den Lungen-6
LDH
lactate dehydrogenase
LVEF
left ventricular ejection fraction
MDS
Myelodysplastic syndrome
MEK
mitogen-activated protein kinase gene
MMRM
mixed effect model repeated measures
MoA
mechanism of action
MRI
magnetic resonance imaging
MSI
microsatellite instability
MUGA
multigated acquisition
NF1
neurofibromatosis type 1
NSCLC
non-small-cell lung carcinoma
ORR
Objective response rate
OS
overall survival
PARP
poly-adenosine 5’-diphosphate-ribose polymerase
PD-(L)1
programmed death ligand 1
PD1
programmed cell death protein 1
PFS
progression free survival
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Abbreviation or special 
term
Explanation
PHL
Potential Hy’s Law
PI
Principal investigator 
PK
pharmacokinetic
PR
partial response
PRO
patient reported outcome
PTAP
Post-Trial Access Program
Q28D
every 28 days
QoL
quality of life
QTcF
QTc interval using the Fridericia formula
RECIST
Response Evaluation Criteria in Solid Tumours
RNA
ribonucleic acid
RTSM
Randomisation and Trial Supply Management
SADE
serious adverse device effect
SAE
serious adverse event 
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SoA
Schedule of Activities
SP-D
surfactant protein D
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin
TIL
tumour infiltrating lymphocyte
TL
target lesion
TMG
Toxicity Management Guidelines
TPV
third party vendor
TSH
thyroid stimulating hormone
TTR
time to objective response
ULN
upper limit of normal
US
United States
USADE
unanticipated serious adverse device effect
WBC
white blood cell
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Abbreviation or special 
term 
Explanation 
WOCBP 
women of childbearing potential 
 

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Appendix K Country-specific Requirements  
K 1 
European Union Requirements  
K 1.1 
Country-specific Requirements for Belgium  
Section 1.1 (Synopsis) 
Revised text 
After study treatment discontinuation, all patients will be followed up for safety assessments 
30 days after their last dose of study treatment for ceralasertib monotherapy or 90 days after 
last dose of study treatment for ceralasertib and durvalumab combination. A urine pregnancy 
test must be also performed for WOCBP at 6 months after last dose of study treatment 
(ceralasertib monotherapy or ceralasertib in combination with durvalumab). All randomised 
patients in the main study and all patients in the biopsy sub study will be followed for survival 
status and post discontinuation anti-cancer therapies. 

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Section 1.3 (Schedule of Activities) Table 1 
Revised table 
Procedure 
Screening a  
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in 
CSP section 
 or appendix 
Cycles 1-2 
Cycle 3 
C4-onwards 
Study Treatment Discontinued 
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-21 
to 
 -1 
Day 1 
Day 7 
Day 8 
Day 15 
Day 1 
Day 7 
Day 8 
Day 1 
Day 8 
30 days 
60 days 
90 days 
6 months 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
± 3 
± 1 
± 3 
± 7 
± 7 
+ 7 
 
Pregnancy test 
(WOCBP only) o 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Section 
8.2.5 
 
Revised text 
o Women of childbearing potential only. Serum pregnancy test at screening, urine test at other time points up to 6 months after the last 
dose of study treatment. 

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Section 1.3 (Schedule of Activities) Table 2 
Revised table 
Procedure 
Screening a 
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in CSP 
section 
or appendix 
Cycles 1-2 
Cycle 3 
C4-onwards 
Study Treatment 
Discontinued 
(Last dose of study treatment) 
Safety follow-up 
Progression/Sur
vival 
Follow-up 
 
(Q8W until 
18 months, then 
Q12W) 
 
Cycle Day  
-21 
to 
 -1 
Day 1 
Day 7 
Day 15 
Day 1 
Day 7 
Day 15 
Day 1 
Day 15 
30 days 
after last 
dose 
6 months 
after last 
dose 
 
 
 
Visit window 
(± days)  
- 
- 
- 
± 1 
± 3 
- 
± 1 
± 3 
± 1 
± 3 
+ 7 
± 7 
 
Coagulation 
parameters n 
X 
 
X 
Section 8.2.5 
Pregnancy test 
(WOCBP only) o 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Section 8.2.5 
 
Revised text 
o Women of childbearing potential only. Serum pregnancy test at screening, urine test at other time points up to 6 months after the last 
dose of study treatment. A urine pregnancy test must be locally performed for WOCBP 6 months after last dose of study treatment. If 
the pregnancy test is positive, the investigator must report it per procedures outlined in Section 8.3.13. 

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Section 1.3 (Schedule of Activities) Table 3 
Revised table 
Procedure 
Screening a  
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in CSP 
section 
 or appendix 
Cycle 0 
Cycle 1 
C2-
onwards 
Study Treatment Discontinued 
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-21 
to 
 -1 
Day 1 
Day 7 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
30 days 
60 days 
90 days 
6 months 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
 
± 3 
± 1 
± 3 
± 7 
± 7 
+ 7 
 
Pregnancy test 
(WOCBP only) o 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Section 8.2.5 
 
Revised text 
o Women of childbearing potential only. Serum pregnancy test at screening, urine test at other time points up to 6 months after the last 
dose of study treatment. 
 

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Section 1.3 (Schedule of Activities) Table 3 
Revised text 
x Cycle 1 may start after the off-treatment biopsy is collected ie, between Cycle 0, Days 22 to 
28, and if blood parameters are within limits. 
Section 5.1 (Inclusion Criteria) 
Inclusion criterion 16 
Revised text 
16 Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies (Section 5.3.1) 
(a) Male patients: Male patients who intend to be sexually active with a female partner of 
childbearing potential must be surgically sterile or using an acceptable method of 
contraception (see Section 5.3.1) from the time of screening throughout the total 
duration of the study and 6 months after the last dose of the study treatment, 
(ceralasertib monotherapy and ceralasertib in combination with durvalumab), in 
order to prevent pregnancy in a partner. Male patients must not donate or bank sperm 
during this same time period. 
(b) Female patients: 
(i) Negative pregnancy test (serum) for women of childbearing potential. 
(ii) Women of childbearing potential must agree to use one highly effective method 
of birth control (Table 7) from enrolment throughout the study until 6 months 
after last dose of study treatment (ceralasertib monotherapy and ceralasertib in 
combination with durvalumab). Non sterilised male partners of a woman of 
childbearing potential must use a male condom plus spermicide (condom alone 
in countries where spermicides are not approved) throughout this period. 
 
Section 5.2 (Exclusion Criteria) 
Exclusion criterion 29 
Revised text 
29 Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 6 months after the last dose of study treatment (ceralasertib monotherapy and 
ceralasertib in combination with durvalumab). 
 
Section 5.3.1 (Contraception) 
Revised text 
Male patients: 

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Non-sterilised male patients (including males sterilised by a method other than bilateral 
orchidectomy, eg, vasectomy) who intend to be sexually active with male partners and women 
of non-child bearing potential must be using an acceptable method of contraception such as 
male condom plus spermicide (condom alone in countries where spermicides are not 
approved) from the time of screening throughout the total duration of the study and for 1 week 
after the last dose of study treatment to prevent exposure to ceralasertib via the semen. Where 
a sexual partner of a male patient is a ‘woman of childbearing potential’ who is not using 
effective contraception, or who is already pregnant, then the male patient must use a condom 
plus spermicide (where approved), during the study and for a further 6 months after the last 
dose of study treatment (ceralasertib monotherapy and ceralasertib in combination with 
durvalumab) to prevent pregnancy in a partner. 
Female patients: 
x 
Women of childbearing potential must use highly effective form of birth control, as 
defined in Table 7, from the time of signing the informed consent until 6 months after last 
dose of study treatment (ceralasertib monotherapy and ceralasertib in combination with 
durvalumab). For all women of childbearing potential, cessation of contraception after the 
above defined time point should be discussed with a responsible physician. 
 
Section 7.1.2 (Follow-up of Patients Post Discontinuation of Study Treatment) 
Revised text 
After study treatment discontinuation, all patients will be followed up for safety assessments 
30 days after their last dose of study treatment for ceralasertib monotherapy or 90 days after 
last dose of study treatment for ceralasertib and durvalumab combination. Patients will also be 
followed for survival status and post discontinuation anti-cancer therapies. A urine pregnancy 
test must also be performed for WOCBP 6 months after last dose of study treatment 
(ceralasertib monotherapy or ceralasertib in combination with durvalumab). Additional 
assessments to be performed at the time of the safety follow up are detailed in the SoA 
(Section 1.3). 
Section 8.3.13.2 (Paternal Exposure) 
Revised text 
Pregnancy in a patient’s partner(s) is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital anomaly), occurring from the date of the first dose until 180 days after the last 
dose and as indicated by previous studies (preclinical and clinical) should, if possible, be 
followed up and documented in the medical record and provided to the AstraZeneca Patients 
Safety data entry site. Consent from the partner must be obtained before the information is 
collected and reported to AstraZeneca via the Pregnancy Report Form. 

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K 1.2 
Country-specific Requirements for France  
Section 1.1 (Synopsis) 
Revised text 
After study treatment discontinuation, all patients will be followed up for safety assessments 
30 days after their last dose of study treatment for ceralasertib monotherapy or 90 days after 
last dose of study treatment for ceralasertib and durvalumab combination. A urine pregnancy 
test must be performed for WOCBP at 6 months after their last dose of study treatment 
(ceralasertib monotherapy and ceralasertib in combination with durvalumab). All randomised 
patients in the main study and all patients in the biopsy sub study will be followed for survival 
status and post discontinuation anti-cancer therapies. 

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Section 1.3 (Schedule of Activities) Table 1 
Revised table 
Procedure 
Screening a  
 
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in 
CSP section 
 or appendix 
Cycles 1-2 
Cycle 3 
C4-onwards 
Study Treatment Discontinued 
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-21 
to 
 -1 
Day 1 
Day 7 
Day 8 
Day 15 
Day 1 
Day 7 
Day 8 
Day 1 
Day 8 
30 days 
60 days 
90 days 
6 months 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
± 3 
± 1 
± 3 
± 7 
± 7 
+ 7 
 
Pregnancy test 
(WOCBP only) o 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Section 
8.2.5 
 
Revised text 
o Women of childbearing potential only. Serum pregnancy test at screening, urine test at other time points up to 6 months after the last 
dose of study treatment. 

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Section 1.3 (Schedule of Activities) Table 2 
Revised table 
Procedure 
Screening a 
 
Intervention period (28-day cycles) 
 
Post-intervention follow-up period 
Details in CSP 
section 
 or appendix 
Cycles 1-2 
Cycle 3 
C4-onwards 
Study Treatment  
Discontinued  
(Last dose of study treatment) 
Safety follow-up  
 
Progression/Survival 
Follow-up  
(Q8W until  
18 months, then 
Q12W) 
 
Cycle Day  
-21 
to 
 -1 
Day 1 
Day 7 
Day 15 
Day 1 
Day 7 
Day 15 
Day 1 
Day 15 
30 days 
after 
last dose 
6 months 
 
 
Visit window 
(± days)  
- 
- 
- 
± 1 
± 3 
- 
± 1 
± 3 
± 1 
± 3 
+ 7 
± 7 
 
Pregnancy test 
(WOCBP only) o 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Section 8.2.5 
 
Revised text 
o Women of childbearing potential only. Serum pregnancy test at screening, urine test at other time points up to 6 months after the last 
dose of study treatment. A urine pregnancy test must be locally performed for WOCBP 6 months after last dose of study treatment. If 
pregnancy test is positive, the investigator must report it per procedure outlines in Section 8.3.13 
 

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Section 1.3 (Schedule of Activities) Table 3 
Revised table 
Procedure 
Screening a  
Intervention period (28-day cycles) 
Post-intervention follow-up period 
Details in CSP 
section 
 or appendix 
Cycle 0 
Cycle 1 
C2-
onwards 
Study Treatment Discontinued 
(last dose of study treatment) 
Safety follow-up  
(# of days after last dose) 
Progression/Survival  
Follow-up (Q8W until  
18 months, then Q12W) 
 
Cycle Day  
-
21 
to 
 -1 
Day 1 
Day 7 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
30 days 
60 days 
90 days 
6 months 
 
 
Visit window 
(± days)  
- 
- 
- 
- 
± 1 
± 3 
- 
± 1 
 
± 3 
± 1 
± 3 
± 7 
± 7 
+ 7 
 
Pregnancy test 
(WOCBP only) o 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Section 8.2.5 
 
Revised text 
o Women of childbearing potential only. Serum pregnancy test at screening, urine test at other time points up to 6 months after the last 
dose of study treatment. 
 

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Section 4.1 (Overall Design) 
Revised text 
Patients with BRAF mutations must have received a BRAF or BRAF plus MEK inhibitor if 
eligible to do so. 
Section 5.1 (Inclusion Criteria) 
Inclusion criterion 7 
Revised text 
7 
No intervening treatment eg, investigational therapy is permitted between the 
anti-PD-(L)1 therapy and study treatment. However, patients with BRAF or c-Kit 
mutations that are eligible for targeted treatment, must receive the targeted treatment 
before or after licensed anti-PD-(L)1 therapy and prior to study entry. 
Inclusion criterion 9 
Revised text 
9 
BRAF V600E or V600K mutation status must be known at screening. Patients with 
BRAF mutant melanoma must have had a prior treatment regimen that included 
vemurafenib, dabrafenib, or an approved BRAF and approved MEK inhibitor. 
Inclusion criterion 16 
Revised text 
10 Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies (Section 5.3.1) 
(a) Male patients: Male patients who intend to be sexually active with a female partner of 
childbearing potential must be surgically sterile or using an acceptable method of 
contraception (see Section 5.3.1) from the time of screening throughout the total 
duration of the study and until 5 times the half-life (2.5 days) plus 6 months after the 
last dose of the study treatment, (ceralasertib monotherapy and ceralasertib in 
combination with durvalumab), in order to prevent pregnancy in a partner. Male 
patients must not donate or bank sperm during this same time period. 
(b) Female patients: 
(i) Negative pregnancy test (serum) for women of childbearing potential. 
(ii) Women of childbearing potential must agree to use one highly effective method 
of birth control (Table 7) from enrolment throughout the study until 5 times the 
half-life (2.5 days) plus 6 months after the last dose of study treatment 
(ceralasertib monotherapy and ceralasertib in combination with durvalumab). 
Non sterilised male partners of a woman of childbearing potential must use a 
male condom plus spermicide (condom alone in countries where spermicides are 
not approved) throughout this period. 

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Section 5.2 (Exclusion Criteria) 
Exclusion criterion 29 
Revised text 
11 Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening until 5 times the half-life (2.5 days) plus 6 months after the last dose of study 
treatment (ceralasertib monotherapy and ceralasertib in combination with durvalumab). 
 
Section 5.3.1 (Contraception) 
Revised text 
Male patients: 
Non-sterilised male patients (including males sterilised by a method other than bilateral 
orchidectomy, eg, vasectomy) who intend to be sexually active with male partners and women 
of non-child bearing potential must be using an acceptable method of contraception such as 
male condom plus spermicide (condom alone in countries where spermicides are not 
approved) from the time of screening throughout the total duration of the study and for 1 week 
after the last dose of study treatment to prevent exposure to ceralasertib via the semen. Where 
a sexual partner of a male patient is a ‘woman of childbearing potential’ who is not using 
effective contraception, or who is already pregnant, then the male patient must use a condom 
plus spermicide (where approved), during the study until 5 times the half-life (2.5 days) plus 6 
months after the last dose of study treatment (ceralasertib monotherapy and ceralasertib in 
combination with durvalumab) to prevent pregnancy in a partner. Male patients should refrain 
from fathering a child or donating sperm from the start of dosing until 5 times the half-life 
(2.5 days) plus 6 months after the last dose of study treatment, if there is a concern about 
damaging the developing foetus from drug in ejaculate. 
Female patients: 
x 
Women of childbearing potential must use highly effective form of birth control, as 
defined in Table 7, from the time of signing the informed consent until 5 times the 
half-life (2.5 days) plus 6 months after last dose of study treatment (ceralasertib 
monotherapy and ceralasertib in combination with durvalumab). For all women of 
childbearing potential, cessation of contraception after the above defined time point 
should be discussed with a responsible physician. 
 

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Section 6.6 (Dose Modification) Table 11
Revised table
Table 11
Guidance for Dose Modifications, Interruptions, and Discontinuations for 
Ceralasertib (all treatment arm) and Ceralasertib plus Durvalumab
Event
Action
CCI

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Event
Action
Section 7.1 (Discontinuation of Study Treatment)
Added text
Note that discontinuation from study treatment is NOT the same thing as a withdrawal from 
the study.
If patients in the combination therapy arm discontinue treatment with either one of the
combination agents due to toxicity, they may continue on monotherapy with the other drug as
long as they are continuing to show clinical benefit, as judged by the investigator and in the
absence of discontinuation criteria.
Section 7.1.2 (Follow-up of Patients Post Discontinuation of Study Treatment)
Revised text
After study treatment discontinuation, all patients will be followed up for safety assessments 
30 days after their last dose of study treatment for ceralasertib monotherapy or 90 days after 
CCI

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last dose of study treatment for ceralasertib and durvalumab combination. Patients will also be 
followed for survival status and post discontinuation anti-cancer therapies. A urine pregnancy 
test must also be performed for WOCBP at 6 months after their last dose of study treatment 
(ceralasertib monotherapy and ceralasertib in combination with durvalumab). Additional 
assessments to be performed at the time of the safety follow up are detailed in the SoA 
(Section 1.3). 
Section 8.3.13.2 (Paternal Exposure) 
Revised text 
Non-sterilised male patients who intend to be sexually active with a female partner of 
childbearing potential should refrain from fathering a child or donating or banking sperm for 
5 times the half-life (2.5 days) plus 6 months after the last dose of study treatment. 
Pregnancy in a patient’s partner(s) is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital anomaly), occurring from the date of the first dose until 5 times the half-life 
(2.5 days) plus 6 months after the last dose and as indicated by previous studies (preclinical 
and clinical) should, if possible, be followed up and documented in the medical record and 
provided to the AstraZeneca Patients Safety data entry site. Consent from the partner must be 
obtained before the information is collected and reported to AstraZeneca via the Pregnancy 
Report Form. 
K 1.3 
Country-specific Requirements for Germany  
Section 1.1 (Synopsis), Section 4.1 (Overall Design), Section 9.2 (Sample Size 
Determination) 
Revised text 
Note: “Enrolled” means a patient’s, or their legally acceptable representative’s agreement to 
participate in a clinical study following completion of the informed consent process. Potential 
patients who are screened for the purpose of determining eligibility for the study, but are not 
randomised/assigned in the study, are considered “screen failures”, unless otherwise specified 
by the protocol. 
Section 8.3 (Adverse Events and Serious Adverse Events) 
Revised text 
Adverse events will be reported by the patient (or, when appropriate, by a caregiver or 
surrogate, or the patient’s legally authorised representative). 

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Appendix A 3 (Informed Consent Process) 
Revised text 
x 
The investigator or his/her representative will explain the nature of the study to the patient 
or his/her legally authorised representative and answer all questions regarding the study. 
x 
Patients must be informed that their participation is voluntary, and they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the 
study. Patients or their legally authorised representative will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study centre. 
x 
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. 
The authorised person obtaining the informed consent must also sign the ICF. 
x 
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
x 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorised 
representative. 
 
Appendix G (Guidelines for Evaluation of Objective Tumour Response Using RECIST 
1.1 (Response Evaluation Criteria in Solid Tumours)) 
RECIST 1.1 evaluation of overall visit response at follow-up 
Revised text 
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 19. 
Most studies should require at least 1 TL at baseline (please see Inclusion Criteria). For these 
studies, please delete the rows and footer text in green font below. For studies where there is 
no mandatory requirement to have measurable disease at baseline and therefore it is possible 
to have not applicable in TLs at baseline, please retain rows and footer text in green font. 
 

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Appendix L Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the TOC. 
Amendment 2 – 14 March 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: 
Clinical Study Protocol Amendment 2 was prepared to update the CSP to reflect the change in 
ceralasertib dosing schedule, to update the randomisation ratio and the sample size, to update 
the language and align it with the Durvalumab and Late Phase Oncology CSP Template, to 
update data based on the ceralasertib and durvalumab IB and PSSR updates, and in response 
to queries from regulatory authorities. 
Formatting improvements, such as updates to abbreviations and punctuation corrections, are 
not presented in this summary. 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
Summary of Changes in Protocol Amendment 2 
Section 1.1 Synopsis, 
Section 1.3 Schedule of 
Activities, Section 2.2 
Background, Section 2.3 
Benefits/Risks Assessment, 
Section 4 Study Design, 
Section 5 Study Population, 
Section 6 Study Treatment 
Section 7 Discontinuation of 
Study Treatment and Patient 
Discontinuation/Withdrawal, 
Section 8 Study 
Assessments and 
Procedures, Section 9 
Statistical Considerations, 
and Section 10 Supporting 
Documentation and 
Operational Considerations 
The language has been 
updated 
To align with the 
Durvalumab and Late 
Phase Oncology CSP 
Template. 
Non-substantial 
Section 1.1 Synopsis, 
Section 1.2 Schema, 
Section 1.3 Schedule of 
Activities, Section 2.3 
Benefit/Risk Assessment, 
Change in dosing 
schedule of ceralasertib, 
from a 14-day dosing 
schedule to a 7-day 
dosing schedule, both in 
Emerging pre-clinical and 
clinical data from the 
HUDSON study and 
preliminary PKPD 
modelling of peripheral 
Substantial 

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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Section 4 Study Design, 
Section 6 Study Treatment 
combination with 
durvalumab and as 
monotherapy, in the 
main study and biopsy 
sub-study.
blood markers from other 
ongoing studies, are 
supportive of the 
therapeutic benefit of the 
7-day duration treatment
Section 1.1 Synopsis, 
Section 1.2 Schema, 
Section 4 Study Design, 
Section 9 Statistical 
Considerations
Changes made to the 
sample size of the 
ceralasertib monotherapy 
arm
The sample size of 
ceralasertib monotherapy 
is revised as the clinical 
activity of ceralasertib 
240 mg BD using a 7-day 
schedule has not been 
assessed yet in this patient 
population
Substantial
Section 1.1 Synopsis, 
Section 1.2 Schema, 
Section 4 Study Design, 
Section 6.3.1 Measures to 
Minimise Bias: 
Randomisation and 
Blinding, Main Study
Change in randomisation 
ratio
To align it with the change 
in sample size of the 
ceralasertib monotherapy 
arm
Substantial
Synopsis and Section 3
Objectives and Endpoints
Secondary objective 
added for the biopsy 
sub-study
To evaluate additional 
pharmacodynamic 
biomarkers of ceralasertib
Substantial
Section 1.1 Synopsis and 
Section 9.5 Interim Analyses
Adjustments to the 
triggers for 
 
 analyses
The trigger for the 
 
interim analysis was 
revised to ensure this 
delivers contribution of 
components with no 
overlap in confidence 
intervals taking into 
consideration the revised 
sample size for ceralasertib 
monotherapy arm.
The trigger for the 
 
interim analysis was 
revised to ensure that 
adequate study data from 
approximately 
% of the 
enrolled patients are 
available for analysis. 
Substantial
Section 1.3 Schedule of 
activities
Update to the collection 
of fresh tumour biopsy at 
screening and at 
subsequent timepoints 
To clarify optional 
on-treatment biopsies will 
be collected only if fresh 
Substantial
CCI
CC
CCI
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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
(optional on-treatment 
biopsies) 
tumour biopsy is available 
at screening.  
Section 1.3 Schedule of 
Activities, Section 8.2.2 
Vital Signs 
Respiratory rate added to 
vital signs assessments 
Update based on a finding 
by an EC at one of the 
clinical sites in EU. 
Non-substantial 
Section 1.3 Schedule of 
Activities, Section 8.2.1 
Physical Examination 
Updates made to the 
timepoints of the 
physical examination and 
also to the language on 
physical examination 
These changes were made 
as response to the 
questions raised by 
BfARM.  
Non-Substantial 
Section 2.2.3 Durvalumab 
Exposure numbers 
updated 
To align with the updates 
to the durvalumab IB 
Non-substantial 
Section 2.3 Benefit/Risk 
Assessment 
Benefit-risk information 
updated 
Based on updates to the 
durvalumab and 
ceralasertib IBs and PSSRs 
Non-substantial 
Section 4.3.2 Ceralasertib 
and Durvalumab 
Combination Therapy Dose 
Rationale 
Median PFS and median 
OS corrected 
Erroneous data were 
presented for median PFS 
and median OS from the 
Kwon M et al, 2021 
publication, which were 
corrected. 
Non-substantial 
Section 5.1 Inclusion 
Criteria 
Update to the inclusion 
criterion 5 to clarify that 
an archival tumour 
sample must be available 
at screening and a fresh 
tumour biopsy will be 
taken at screening if 
medically feasible.  
To clarify that it is 
mandatory that an archival 
tumour sample of the 
patient is available at 
screening.  
Substantial 
Section 5.1 Inclusion 
Criteria 
Update to the inclusion 
criterion 6 to state that 
patients must not have 
received any more than 2 
prior regimens of 
approved therapy in the 
metastatic setting 
To align with intended 
patient population. 
Substantial 
Section 5.1 Inclusion 
Criteria 
Update to the inclusion 
criterion 8 
To clarify that a minimum 
timeperiod of 14 days must 
be maintained between the 
first dose of study regimen 
and the last dose of 
BRAF/MEK inhibitors.  
Substantial 

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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Section 5.3.1 Contraception
The duration for which 
the male and female 
patients in the study are 
expected to use 
contraception was 
updated. 
In response to feedback 
from regulatory authorities 
to align the contraceptive 
requirements with the 
ceralasertib and 
durvalumab IBs. 
Substantial
Section 5.3.2 Meal and 
Dietary Restrictions
Energy drinks added to 
the list of restricted foods
Based on the ceralasertib 
IB. 
Non-substantial
Section 5.3.3 Lifestyle 
Considerations - Skin
Sunglasses added to the 
measures to be adopted 
by the patients to prevent 
prolonged exposure to 
the sun. 
Patients in the study are 
expected to use sunglasses 
to avoid prolonged 
exposure to sun during the 
study treatment and 4 
weeks after the last dose of 
study treatment
Non-substantial
Section 6.6 Dose 
Modification
Updates to the 
assessment timepoints 
for patients with 
≥Grade 3 of anaemia, 
neutropenia, or 
thrombocytopaenia later 
than Cycle 2
Changes are made in 
response to the questions 
raised by ANSM
Substantial
Section 6.6 Dose 
Modification
Updates to the table 
‘Guidance for Dose 
Modifications, 
Interruptions, and 
Discontinuations for 
Ceralasertib (all 
treatment arm) and 
Ceralasertib plus 
Durvalumab’
To align with ceralasertib 
PSSR update
Substantial
Section 6.5.1 Drug-Drug 
Interaction Between 
Ceralasertib and Other 
Drugs
Updates made to 
 
metabolism impacted by 
ceralasertib
To align with the updates 
to the ceralasertib IB
Non-substantial
Section 8.3.5
MUGA scans added AEs 
based on examinations 
and tests
To align with the addition 
of echocardiogram/MUGA 
scans as other safety 
assessments
Non-substantial
Section 8.5.2 
Immunogenicity assessment
Language updated to 
clarify that blood 
samples will be collected 
to evaluate 
immunogenicity to 
To keep the language 
relevant to the study design
Non-substantial
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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
durvalumab alone and 
not to other antigens.  
Section 9.5 Interim Analyses 
Revision to the criteria 
for the IDMC to stop 
recruitment into the 
treatment arms 
To align it with the change 
in sample size of the 
ceralasertib monotherapy 
arm 
Substantial 
 
Amendment 1 – 01 July 2021  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
Inclusion of updates for Amendment 1 was prepared in response to queries from the Food and 
Drug Administration (FDA) and Central Institutional Review Board (CIRB).  
Formatting improvements, such as updates to abbreviations and punctuation corrections, are 
not presented in this summary. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
And 
3.0 Objectives and 
Endpoints 
Deletion of listed biomarkers in a 
Biopsy sub-study secondary objective 
and endpoint 
Amended text due to previous 
feedback from competent 
authority  
1.1 Synopsis 
And 
9.4 Statistical Analysis 
Clarified the analysis set for 
comparative analyses 
In response to feedback from 
competent authority 
1.1 Synopsis 
And 
7.1.2 Follow-up of Patients 
Post Discontinuation of 
Study Treatment 
Updated follow-up safety assessments 
to ‘30 days after last dose of study 
treatment for ceralasertib monotherapy 
or 90 days after last dose of study 
treatment for ceralasertib and 
durvalumab combination’ 
To align with durvalumab safety 
requirements and feedback from 
competent authority. 
1.2 Schema 
Edited wording on the Biopsy sub-
study  
To clarify treatment design. 
1.3 Schedule of Activities 
Additional visits (60 and 90 day) in 
safety follow-up in Table 1 and 3 
To align with durvalumab safety 
requirements.  

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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities  
Added the following wording to 
footnotes ‘o’ and ‘p’ in Table 1 and 
footnotes ‘l’ and ‘m’ in Table 3: 
 ‘in all patients (at pre-dose for 
durvalumab dosing day)’ and changed 
term “until” to “up to” 
To clarify biomarker collection 
1.3 Schedule of Activities 
Added Day 8 and 15 to footnote ‘r’ in 
Table 2 
To clarify PK sample collection 
days 
1.3 Schedule of Activities 
Table 3 
Updated activity names to ‘Plasma for 
circulating soluble factors’ and ‘Serum 
for circulating factors’ 
To better align with same 
activities in the Main Study 
(Table 1) 
1.3 Schedule of Activities 
Updated ECOG in Table 1 and 3 
To align with durvalumab safety 
requirements. 
1.3 Schedule of Activities – 
Table 1 and 2- ePRO 
Updated some measures in the 
schedule of activities to be required 
every 3 weeks rather than every 4 
weeks 
To better align with timing of 
treatment cycles 
1.3 Schedule of Activities – 
Table 2- ePRO 
Changed D14 to D15 
To be aligned with measurement 
in Table 1 
1.3 Schedule of Activities 
Removed specification of timing for 
PRO administration for Table 1 and 
Table 2 
It is not necessary to specify 
timing of PRO administration 
relative to dosing for either 
ceralasertib (due to 2 doses a day) 
or durvalumab (due to pre-
specified dosing and visit 
schedule 
3 Objectives and Endpoints 
Updated the Biopsy sub-study 
Objectives and Endpoints 
Amendment of the listed 
Secondary objectives and 
Endpoints 
4.3.1 Ceralasertib 
Monotherapy Dose Rational 
Updated ceralasertib monotherapy 
dose rational 
Rationale updated to include 
findings from preliminary 
population PK and clarification 
on the sigmoid model. 
5.1 Inclusion criteria 
Text ‘> 30 kg’ was added.  
Clarified that weight should be 
above 30kg. 
5.2 Exclusion criteria  
Harmonization of the QTcF resting 
interval between male and female 
In response to feedback from 
competent authority  
5.2 Exclusion criteria  
Updated total bilirubin exclusion 
threshold 
In response to feedback from 
competent authority 
6.1.1 Study Treatments 
Added timing in Table 6 for 
ceralasertib treatment 
To aid clarity 

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Section # and Name
Description of Change
Brief Rationale
6.1.1 Study Treatments
Moved a paragraph from 
Section 6.2.1.2 Durvalumab Infusion 
preparation
To aid clarity and flow
6.3 Measures to Minimise 
Bias: Randomisation and 
Blinding
Provided additional detail on 
stratification factors in the Main Study 
(Section 6.3.1)
In response to feedback from 
competent authority
6.5.2 Rescue Medication
Replaced original paragraph with 
durvalumab requirements
To align with durvalumab safety 
requirements.
6.6 Dose Modification
Text ‘> 30 kg’ and ≤30 kg was added.
To clarify the durvalumab dose 
management based on patient 
weight. 
8.2.4.2.2
Changed from 4 to 5 items by adding 
“cough”. 
Updated according to the 
guidelines. 
8.3 Adverse Events and 
Serious Adverse Events
Extended AE/SAEs collection to 90 
days after last dose of study treatment 
for ceralasertib and durvalumab 
combination 
To align with durvalumab safety 
requirements.
8.3.11 Safety Data to be 
Collected Following the 
Final Data Cut Off of the 
Study
Extended safety data collection to 90 
days after last dose of study treatment 
for ceralasertib and durvalumab 
combination
To align with durvalumab safety 
requirements.
8.3.13 Pregnancy
Removed word ‘not’ and repetitive 
sentence
Clarifying that women of 
childbearing potential are eligible 
for study inclusion. 
8.3.13 Pregnancy
Clarification:
Pregnancy of the partner of male 
patient should be reported to 
AstraZeneca
To align with Section 8.3.13.2
8.5.2 Immunogenicity 
Assessments
Added extra immunogenicity 
assessment at 90 days and 6 months 
after last dose for ceralasertib and 
durvalumab combination
To align with durvalumab safety 
requirements.
8.8 Tumour Biopsies for 
Main and Biopsy sub-study
Added mandatory archival tumour 
tissue collection in the Main Study. 
Clarified in the biopsy sub-study 
section that additional tumour tissue 
collection is ‘optional’
To better align with the schedule 
of assessments. 
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Section # and Name
Description of Change
Brief Rationale
8.10.1.6 
Edit title for clarification
8.10.1.7 
 
Edit title for clarification
9.2.1 Main Study
Provide sample size justification for 
secondary objective to compare 
treatment arms for ORR.
In response to feedback from 
competent authority
Table 13 Populations for 
Analysis
Clarified the analysis set for 
comparative analyses 
In response to feedback from 
competent authority
Appendix I2 
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11 
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