A Phase II Study to Evaluate the Safety, Pharmacokinetics, and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumours
Phase: PHASE2
Conditions: Locally Advanced or Metastatic Solid Tumours
Sponsor: AstraZeneca

Cover page
Protocol number: D8151C00001
Document title: A Phase II Study to Evaluate the Safety, Pharmacokinetics, and Clinical 
Activity of AZD0171 in Combination with Durvalumab and Chemotherapy in Participants 
with Locally Advanced or Metastatic Solid Tumours
NCT number: NCT04999969
Version number: 5.0
Date of the document: 03 May 2024

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Clinical Study Protocol  
Study Intervention 
AZD0171 
Study Code 
D8151C00001 
Version 
5.0 
Date 
03 May 2024 
A Phase II Study to Evaluate the Safety, Pharmacokinetics, and 
Clinical Activity of AZD0171 in Combination with Durvalumab 
and Chemotherapy in Participants with Locally Advanced or 
Metastatic Solid Tumours  
Sponsor Name: AstraZeneca AB 
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden. 
Regulatory Agency Identifier Number(s) 
IND number: 135273 
EudraCT number: 2021-002040-78 
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: D8151C00001 
Amendment Number: 4 
Study Intervention: Investigational AZD0171, durvalumab and standard of care gemcitabine, 
nab-paclitaxel 
Study Phase: II 
Short Title: Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination with 

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Durvalumab and Chemotherapy in Locally Advanced or Metastatic Solid Tumours 
Study Physician Name and Contact Information will be provided separately 
International co-ordinating investigator 
 
 
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VERSION HISTORY  
Version 5.0, [03 May 2024] 
The protocol was amended to include more recent clinical results from prior studies. The 
following sections were updated: 
• 
Section 2.2.3: This section was amended to include more recent safety data on 
AZD0171.  
• Section 2.2.4: This section was amended to include more recent study data on 
durvalumab. 
• 
Section 2.3.1: The risk assessment was updated to include new identified risks of 
durvalumab (uveitis, immune-mediated arthritis, Guillain-Barre syndrome). 
• 
Section 4.3: This section was added to the protocol to include details of the 
continued treatment period.  
• 
Section 8.2.6 (Table 13): Clinical chemistry was updated to include carbon dioxide 
as an alternative to bicarbonate.  
• Section 9.2: The number of participants planned to be screened for this study was 
increased from 240 to 370.  
• Section 10, Appendix A1: The regulatory reporting requirements for SAEs were 
updated to cover the European Union safety reporting requirements.  
• 
Global: Minor editorial corrections (typos, formatting, abbreviations etc.) were 
made for document quality. 
 
Version 4.0, [3 Mar 2023] 
This amendment includes clarifications identified from previous feedback on the clinical 
study protocol have been included, as follows: 
• Sections 1.3 (Table 2) and 8.2.3 Table 11: Section amended to add pre-dose ECG 
measurement at Cycle 1 Day 1, Cycle 2 Day 15, and Cycle 4 Day 1 to enable 
collection of high quality ECG data. 
• Section 2.2.3: Addition of safety information from the first 41 patients enrolled in 
this study. 
• Section 2.3.2: Section amended to fix spelling of periodic to periodontal. 
• Sections 4.1 and 6.2.6: Section amended to clarify that the patient monitoring for at 
least 30 minutes after the end of last infusion Day 1 of each cycle is required, but 
this is not necessary on Day 8 and Day 15. 
• Section 5.2: Introduced clarifications in wording for Exclusion 4 on thromboembolic 
events. 

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• Section 5.4: Added context to better explain instances where rescreening of patients 
would be allowed. 
• Section 6.2.5: Removed the wording about patients being greater than or equal to 35 
kg weight. 
• Section 6.6.1: Added information regarding a chemotherapy holiday. 
 
Updates to align with latest sponsor protocol template wording have been added: Sections 
4.4, 8.3.11, A6, A7, A9, A11, and E4. 
Version 3.0, [10 May 2022] 
This amendment includes changes in response to durvalumab Investigator’s Brochure 
update in the following sections: 
• Section 2.3.1 and 8.3.6.2: Updated safety information per Investigator’s Brochure 
update for durvalumab. 
Language on staggered enrolment approach for safety run-in participants has been included. 
In addition, clarifications identified from previous feedback on the clinical study protocol 
have been included, as follows: 
• Sections 1.1, 1.3 (Table 2), 3, 4.1, 4.2.2, 8.5.1, 8.5.1.1, 8.5.3.2, 9.4.5.1, 9.4.6.1, and 
9.4.6.2: Sections amended to remove total leukaemia inhibitory factor from 
pharmacokinetic (PK) endpoint and to add it as a pharmacodynamic endpoint. 
• Sections 1.1 and 2.1: Deletion of “rates” after treatment response/survival. 
• Sections 1.1, 3, and 4.2.2: Language on secondary efficacy endpoint updated for 
clarity. 
• Sections 1.1 and 4.1: Updated approximate number of sites participating in this 
study. 
• Sections 1.1 and 9.4.2: Deletion of “rates of” before objective response rate and 
disease control rate. 
• Sections 1.1 and 9.6: Clarification that additional safety reviews may be conducted 
at the discretion of the Safety Review Committee (SRC). 
• Section 1.3 (Table 2): Additional plasma sample for circulating tumour DNA will be 
taken on Cycle 1 Day 1 for accurate assessment of baseline level. Updated Table 
footnote for correction and clarification that anti-drug antibodies (ADA) samples are 
collected on pre-dose PK timepoints on specified days. 
• Section 4.1: Clarification that staggered approach to dosing of study intervention 
may be required for safety run-in participants and when ambiguous findings or 
unexplained safety issues occur or if deemed necessary by SRC. 

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• Sections 4.1 and 6.2.6: Clarification that all participants will be monitored for at 
least 60 minutes after the end of last study intervention infusion on Cycle 1 Day 1, 
and 30 minutes after the end of last infusion on subsequent visits. 
• Sections 4.1.2, 5.4, 7.1.4, and Appendix B 2: Section amended to state that 
participants can be rescreened only once. 
• Section 4.2.2: Updated to correct that overall survival is not the primary endpoint. 
• Section 4.3.1.1: Section amended to align wording with interpretation and 
conclusions of modelling. 
• Section 4.3.1.2: Section amended to include information from Phase I study. 
• Section 4.3.2.1: Language on data from completed studies on durvalumab was 
updated for better clarity. 
• Section 4.4: Definition of end of study was amended for simplification. 
• Section 5.1: Clarification added to state that: 
o the window of all eligibility criteria applies within 28 days prior to Cycle 1 
Day 1. 
o the participants with metastatic pancreatic adenocarcinoma are eligible. 
• Section 5.2.:  
o Updated exclusion criterion 4 of patients with thromboembolism to align 
with the clinical practice based on patient population. 
o Updated exclusion criterion 8 as the benefit/risk of enrolling participants 
with positive Coronavirus disease 2019 (COVID-19) testing has changed due 
to changes in the COVID-19 pandemic situation. This change in eligibility 
criteria aims to increase trial access for patients with life-threatening 
pancreatic cancer once investigators have considered the overall well-being 
and best interests of trial participants. 
o Updated exclusion criterion 14 to clarify the exceptions to this criterion. 
• Sections 6.1.1, 6.1.1.4, and 6.1.2: Updated Section number 6.1.1.4 to 6.1.2 and 
moved Table 6 under the new section for clarification that chemotherapy is not 
investigational medicinal product. 
• Section 6.2.2: Clarification added to state that the window for AZD0171 standard 
infusion time is 60 min (+ 10 minutes). 
• Section 6.2.4: Updated wording to state that “Durvalumab IV infusion will start 
15 minutes after the end of AZD0171 infusion” for consistency with Section 6.2.5. 
• Section 6.2.5: Figure 2 footnote for the waiting time between Day 15 AZD0171 
infusion and nab-paclitaxel IV infusion was updated to “15-30 minutes”. 
• Section 6.6.1: Clarification added for chemotherapy dosing and interruptions due to 
adverse event (AE)/toxicity in a cycle. 

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This amendment includes changes in response to FDA queries, which are: 
• Section 6.2.4: Section amended to state that a dose of 1500 mg durvalumab will be 
prepared for participants > 30 kg in weight. 
• Section 6.2.5: Clarification added to state that for participants > 30 kg or 
weight-based dosing at 20 mg/kg for participants ≤ 30 kg, as applicable, durvalumab 
1500 mg will be administered over 60 minutes by IV infusion, 15 minutes after the 
end of AZD0171 infusion. 
• Section 6.5.2: Information added to state that Investigator clinical judgement should 
be exercised to ensure participants are eligible to receive gemcitabine and 
nab-paclitaxel in accordance with the guidelines in the local package insert, prior to 
first dose of study intervention and during the study. In addition, caution should be 
exercised (or alternative medication should be considered) when nab-paclitaxel is 
administered concomitantly with medicines known to inhibit or induce either 
CYP2C8 or CYP3A4. 
In addition, minor clarifications identified from previous feedback on the clinical study 
protocol have been included, as follows: 
• Section 1.3: Serum LIF samples have been added on Day -3 of Cycle 1.  
• Section 5.2: Exclusion criterion 11 amended to state that mean QTcF ≥470 ms will 
be calculated from 3 ECGs (within 5 minutes at 1 minute apart). 
• Section 6.1.1.2: Addition of 25mM histidine to the AZD0171 solution.  
• Section 6.2.2: Section amended to state that a dose of 
 mg AZD0171 will be 
prepared for participants ≥ 35 kg in weight.  
• Section 6.2.4: Section amended to state that a dose of 1500 mg durvalumab will be 
prepared for participants > 30 kg in weight. 
• Section 6.2.5: Clarification added to state participants will be ≥ 35 kg for AZD0171 
 mg.  
• Section 6.2.5: Clarification added to state that for participants > 30 kg or 
weight-based dosing at 20 mg/kg for participants ≤ 30 kg, as applicable, durvalumab 
1500 mg will be administered over 60 minutes by IV infusion, 15 minutes after the 
end of AZD0171 infusion. 
• Section 6.5.2: Information added to state that Investigator clinical judgement should 
be exercised to ensure participants are eligible to receive gemcitabine and 
nab-paclitaxel in accordance with the guidelines in the local package insert, prior to 
first dose of study intervention and during the study. In addition, caution should be 
exercised (or alternative medication should be considered) when nab-paclitaxel is 
administered concomitantly with medicines known to inhibit or induce either 
CYP2C8 or CYP3A4. 
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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
VERSION HISTORY ................................................................................................................ 3 
TABLE OF CONTENTS ........................................................................................................... 9 
1 
PROTOCOL SUMMARY .................................................................................... 15 
1.1 
Synopsis ................................................................................................................ 15 
1.2 
Schema .................................................................................................................. 18 
1.3 
Schedule of Activities ........................................................................................... 18 
2 
INTRODUCTION ................................................................................................ 30 
2.1 
Study Rationale ..................................................................................................... 30 
2.2 
Background ........................................................................................................... 31 
2.2.1 
Disease Background ............................................................................................. 31 
2.2.2 
Chemotherapy Treatment in Pancreatic Ductal Adenocarcinoma ........................ 31 
2.2.3 
AZD0171 .............................................................................................................. 32 
2.2.4 
Durvalumab .......................................................................................................... 33 
2.3 
Benefit/Risk Assessment ...................................................................................... 34 
2.3.1 
Risk Assessment ................................................................................................... 34 
2.3.2 
Benefit Assessment ............................................................................................... 35 
2.3.3 
Overall Benefit: Risk Conclusion ......................................................................... 36 
2.3.4 
Benefit/Risk Pertaining to Study Conduct During the COVID-19 Pandemic ...... 37 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 39 
4 
STUDY DESIGN ................................................................................................. 42 
4.1 
Overall Design ...................................................................................................... 42 
4.1.1 
Safety Review Committee .................................................................................... 42 
4.1.2 
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................. 43 
4.2 
Scientific Rationale for Study Design .................................................................. 44 
4.2.1 
Rationale for Study Design and Population ......................................................... 44 
4.2.2 
Rationale for Study Endpoints .............................................................................. 44 
4.3 
Continued Treatment Period ................................................................................. 46 
4.4 
Justification for Dose ............................................................................................ 46 
4.4.1 
AZD0171 .............................................................................................................. 46 
4.4.1.1 
Dose Justification (AZD0171) .............................................................................. 46 
4.4.1.2 
Rationale for Fixed Dosing (AZD0171) ............................................................... 47 
4.4.2 
Durvalumab .......................................................................................................... 47 
4.4.2.1 
Dose Justification (Durvalumab) .......................................................................... 47 
4.4.2.2 
Rationale for Fixed Dosing (Durvalumab) ........................................................... 48 
4.4.3 
Chemotherapy ....................................................................................................... 48 
4.5 
End of Study Definition ........................................................................................ 48 
5 
STUDY POPULATION ....................................................................................... 49 

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5.1 
Inclusion Criteria .................................................................................................. 49 
5.2 
Exclusion Criteria ................................................................................................. 51 
5.3 
Lifestyle Considerations ....................................................................................... 54 
5.3.1 
Contraception ........................................................................................................ 54 
5.4 
Screen Failures...................................................................................................... 55 
6 
STUDY INTERVENTION ................................................................................... 56 
6.1 
Study Intervention(s) Administered ...................................................................... 56 
6.1.1 
Investigational Products........................................................................................ 56 
6.1.1.1 
Identity of Investigational Product(s) ................................................................... 57 
6.1.1.2 
AZD0171 .............................................................................................................. 57 
6.1.1.3 
Durvalumab .......................................................................................................... 57 
6.1.2 
Gemcitabine + Nab-paclitaxel .............................................................................. 58 
6.1.3 
Reporting Product Complaints ............................................................................. 58 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 59 
6.2.1 
Storage of AZD0171 ............................................................................................. 59 
6.2.2 
AZD0171 Infusion Preparation ............................................................................ 59 
6.2.3 
Storage of Durvalumab ......................................................................................... 60 
6.2.4 
Durvalumab Infusion Preparation ........................................................................ 61 
6.2.5 
Treatment Administration ..................................................................................... 61 
6.2.6 
Monitoring of Dose Administration ..................................................................... 63 
6.3 
Measures to Minimise Bias: Randomisation and Blinding .................................. 63 
6.4 
Study Intervention Compliance ............................................................................ 63 
6.5 
Concomitant Therapy ........................................................................................... 63 
6.5.1 
Permitted Concomitant Medications .................................................................... 64 
6.5.2 
Prohibited Concomitant Medications ................................................................... 65 
6.6 
Dose Modification ................................................................................................ 66 
6.6.1 
Management of Study Intervention Related Toxicities ........................................ 66 
6.6.1.1 
Management of AZD0171-Related Toxicities ...................................................... 68 
6.6.1.2 
Management of Durvalumab-Related Toxicities .................................................. 68 
6.6.1.3 
Management of Chemotherapy-Related Toxicities .............................................. 68 
6.7 
Intervention After the End of the Study ................................................................ 68 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................. 69 
7.1 
Discontinuation of Study Intervention ................................................................. 69 
7.1.1 
Temporary Discontinuation .................................................................................. 70 
7.1.2 
Treatment Beyond Progression ............................................................................. 70 
7.1.3 
Withdrawal of Informed Consent for Data and Biological Samples .................... 71 
7.1.4 
Procedures for Handling Incorrectly Enrolled Participants .................................. 71 
7.2 
Participant Withdrawal from the Study ................................................................ 71 
7.3 
Lost to Follow-up ................................................................................................. 72 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................ 72 
8.1 
Efficacy Assessments ............................................................................................ 73 

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8.1.1 
Tumour Assessments ............................................................................................ 73 
8.1.2 
Survival Assessments ........................................................................................... 74 
8.2 
Safety Assessments ............................................................................................... 75 
8.2.1 
Physical Examinations .......................................................................................... 75 
8.2.2 
Vital Signs ............................................................................................................. 75 
8.2.3 
Electrocardiograms ............................................................................................... 76 
8.2.4 
ECHO/MUGA ...................................................................................................... 77 
8.2.5 
Performance Status ............................................................................................... 77 
8.2.6 
Clinical Safety Laboratory Assessments .............................................................. 77 
8.3 
Adverse Events and Serious Adverse Events ....................................................... 80 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ................. 80 
8.3.2 
Follow-up of AEs and SAEs ................................................................................. 81 
8.3.3 
Causality Collection.............................................................................................. 82 
8.3.4 
Adverse Events Based on Signs and Symptoms .................................................. 82 
8.3.5 
Adverse Events Based on Examinations and Tests .............................................. 82 
8.3.6 
Adverse Events of Special Interest ....................................................................... 83 
8.3.6.1 
Adverse Events of Special Interest for AZD0171 ................................................ 83 
8.3.6.2 
Adverse Events of Special Interest for Durvalumab ............................................ 84 
8.3.7 
Hy’s Law ............................................................................................................... 85 
8.3.8 
Disease Progression .............................................................................................. 86 
8.3.8.1 
New Cancers ......................................................................................................... 86 
8.3.8.2 
Deaths ................................................................................................................... 86 
8.3.9 
Reporting of Serious Adverse Events ................................................................... 86 
8.3.10 
Pregnancy ............................................................................................................. 87 
8.3.10.1 
Maternal Exposure ................................................................................................ 87 
8.3.10.2 
Paternal Exposure ................................................................................................. 88 
8.3.11 
Medication Error ................................................................................................... 88 
8.3.11.1 
Medication Error ................................................................................................... 88 
8.3.11.2 
Drug Abuse ........................................................................................................... 89 
8.3.11.3 
Drug Misuse.......................................................................................................... 89 
8.4 
Overdose ............................................................................................................... 89 
8.5 
Human Biological Samples .................................................................................. 89 
8.5.1 
Pharmacokinetics .................................................................................................. 90 
8.5.1.1 
Determination of Drug Concentration .................................................................. 91 
8.5.2 
Immunogenicity Assessments ............................................................................... 98 
8.5.3 
Pharmacodynamics ............................................................................................... 98 
8.5.3.1 
Collection of Samples ........................................................................................... 98 
8.5.3.2 
Collection of Serum and Plasma Samples for Circulating Soluble Factors ......... 98 
8.5.3.3 
 .............................. 98 
8.5.3.4 
Collection of Tumour Biopsies ............................................................................. 99 
8.6 
 .............................................................. 100 
8.6.1 
 .................................. 100 
8.6.2 
 .......................................................... 100 
8.7 
 ................................................................. 100 
8.8 
Health Economics OR Medical Resource Utilisation and Health Economics ... 101 
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9 
STATISTICAL CONSIDERATIONS ................................................................. 101 
9.1 
Statistical Hypotheses ......................................................................................... 101 
9.2 
Sample Size Determination ................................................................................ 101 
9.3 
Populations for Analyses .................................................................................... 101 
9.4 
Statistical Analyses ............................................................................................. 102 
9.4.1 
General Considerations ....................................................................................... 102 
9.4.2 
Efficacy Analyses ............................................................................................... 102 
9.4.2.1 
Primary Endpoint ................................................................................................ 103 
9.4.2.2 
Secondary Endpoints .......................................................................................... 103 
9.4.3 
Safety Analyses ................................................................................................... 105 
9.4.3.1 
Primary Endpoint ................................................................................................ 105 
9.4.4 
Immunogenicity .................................................................................................. 106 
9.4.4.1 
Secondary Endpoint ............................................................................................ 106 
9.4.5 
Pharmacokinetic ................................................................................................. 106 
9.4.5.1 
Secondary Endpoint ............................................................................................ 106 
9.4.5.2 
Exploratory Endpoint.......................................................................................... 106 
9.4.6 
Pharmacodynamic............................................................................................... 107 
9.4.6.1 
Secondary Endpoint ............................................................................................ 107 
9.4.6.2 
Exploratory Endpoints ........................................................................................ 107 
9.4.7 
 ........................................................................................................... 107 
9.4.7.1 
Exploratory Endpoints ........................................................................................ 107 
9.5 
Interim Analyses ................................................................................................. 107 
9.6 
Data Monitoring Committee ............................................................................... 108 
10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS .......................................................................................... 108 
11 
REFERENCES ................................................................................................... 144 
 
LIST OF FIGURES 
Figure 1 
Study Design ............................................................................................... 18 
Figure 2 
Study Intervention Administration Schedule .............................................. 62 
 
LIST OF TABLES 
Table 1 
Schedule of Activities (Screening) .............................................................. 19 
Table 2 
Schedule of Activities (Treatment Period) .................................................. 22 
Table 3 
Schedule of Activities (End of Treatment and Follow-up) ......................... 27 
Table 4 
Objectives and Endpoints ............................................................................ 39 
Table 5 
Investigational Products .............................................................................. 56 
Table 6 
Chemotherapy (Standard-of-Care) .............................................................. 58 
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Table 7 
Permitted Concomitant Medication ............................................................ 65 
Table 8 
Prohibited Concomitant Medication ........................................................... 66 
Table 9 
Collection Times for Vital Signs During the Study Intervention Period .... 76 
Table 10 
ECG Recording Timepoints (Safety Run-in Participants Only) ................. 76 
Table 11 
ECG Recording Timepoints (All Other Participants) ................................. 77 
Table 12 
Eastern Cooperative Oncology Group Performance Status ........................ 77 
Table 13 
Clinical Chemistry (Serum or Plasma) ....................................................... 79 
Table 14 
Haematology/Coagulation ........................................................................... 79 
Table 15 
Urinalysis (Dipstick) ................................................................................... 80 
Table 16 
Lipid Panel .................................................................................................. 80 
Table 17 
Pregnancy Test (Women of Childbearing Potential Only) ......................... 80 
Table 18 
PK Sampling Timepoint Schedule for AZD0171 and Total LIF (PD) a 
(Safety Run-in: 10 to 12 Participants Only) ................................................ 92 
Table 19 
PK Sampling Timepoint Schedule for AZD0171 and Total LIF (PD) a 
(First 40 Participants Only: Including Safety Run-in) ................................ 93 
Table 20 
PK Sampling Timepoint Schedule for AZD0171 and Total LIF (PD) a 
(All Participants) ......................................................................................... 94 
Table 21 
PK Sampling Timepoint Schedule for Durvalumab a (First 40 
Participants Only: Including Safety Run-in) ............................................... 95 
Table 22 
PK Sampling Timepoint Schedule for Durvalumab a (All Participants) ..... 95 
Table 23 
PK Sampling Timepoint Schedule for Chemotherapy a (Safety Run-in: 
10 to 12 Participants Only) ......................................................................... 96 
Table 24 
PK Sampling Timepoint Schedule for Chemotherapy a (First 40 
Participants Only: Including Safety Run-in) ............................................... 97 
Table 25 
Populations for Analysis ........................................................................... 101 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations ........................ 108 
Appendix B 
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis .............................. 116 
Appendix C 
Contraception Requirements ..................................................................... 117 
Appendix D 
Response Evaluation Criteria in Solid Tumours Version 1.1 ................... 119 
Appendix E 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ......................................................................... 122 
Appendix F 
Handling of Human Biological Samples ................................................... 128 

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Appendix G 
 ....................................................... 130 
Appendix H 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ............................................................................ 133 
Appendix I 
National Institute of Allergy and Infectious Disease and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis ............. 139 
Appendix J 
Abbreviations ............................................................................................ 140 
 
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1 
PROTOCOL SUMMARY  
1.1 
Synopsis  
Protocol Title: A Phase II Study to Evaluate the Safety, Pharmacokinetics, and Clinical 
Activity of AZD0171 in Combination with Durvalumab and Chemotherapy in Participants 
with Locally Advanced or Metastatic Solid Tumours 
Short Title: Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination with 
Durvalumab and Chemotherapy in Locally Advanced or Metastatic Solid Tumours 
Rationale: Leukaemia inhibitory factor (LIF) is an immunosuppressive cytokine linked to 
tumourigenesis/metastasis. Elevated levels of LIF expression correlate with poor clinical 
outcomes and chemoresistance. In tumour biopsy samples and blood from pancreatic ductal 
adenocarcinoma (PDAC) patients, LIF levels are elevated and significantly correlate with 
disease pathology worsening (tumour cell differentiation), high levels of the PDAC 
 
carbohydrate antigen 19–9 (CA19–9), and poor treatment response/survival. In pre-clinical 
tumour models of pancreatic cancer, LIF promotes tumour-initiating cell biology and 
epithelial-mesenchymal transition, and the combination of anti-LIF with gemcitabine 
improves survival. Furthermore, LIF also promotes an immunosuppressive tumour 
microenvironment, reducing recruitment of cytotoxic cluster of differentiation 8 (CD8+) 
effector T cells to tumours. In pre-clinical tumour models anti-LIF sensitises tumours to 
blockade of PD1 / PD-L1 immune checkpoint to induce tumour regression and antitumour 
immunity. 
The effect on CD8+ T cells is significant because the presence and cross-linking of 
programmed cell death proteins between T cells and tumour cells is a mechanism that limits 
tumour infiltrating CD8+ T cell effector function through immune checkpoint signalling. 
Interestingly, combined effects of anti-LIF and immune checkpoint inhibition further induce 
tumour regression and improve survival in pre-clinical tumour models. Taken together, anti-
LIF has the potential to aid standard-of-care chemotherapy to overcome chemoresistance and 
work additively or synergistically alongside anti-PD-L1 durvalumab to achieve a robust 
antitumour response in PDAC. 
The proposed study is designed for PDAC patients to receive standard-of-care chemotherapy 
in combination with AZD0171 (anti-LIF) and durvalumab (anti-PD-L1). 
Additional cohorts for different tumour types may be explored and added in a future 
amendment to the clinical study protocol (CSP). 
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Overall Design 
This is a Phase II, open-label, single arm, multicentre study to assess the safety, preliminary 
antitumour activity, immunogenicity, PD, and PK of AZD0171 in combination with 
durvalumab and chemotherapy (gemcitabine and nab-paclitaxel) in participants with 1L 
mPDAC. 
Number of Participants: Approximately 115 participants with 1L mPDAC will be enrolled 
at up to approximately 40 to 50 sites globally 
Intervention Groups and Duration: Participants will receive in each 28-day cycle, 
AZD0171 (
 mg intravenous [IV]every 2 weeks [Q2W]) along with durvalumab (1500 mg 
IV every 4 weeks [Q4W]) and chemotherapy IV (gemcitabine 1000 mg/m2 + nab-paclitaxel 
125 mg/m2 on Days 1, 8 and 15 in each cycle). All participants will be treated until 
progressive disease or unacceptable toxicity or withdrawal of consent or another 
discontinuation criterion is met. All participants will be followed for survival until the end of 
study. 
No dose reductions of AZD0171 and durvalumab will be allowed. Dose modification and 
toxicity management for AZD0171 and durvalumab -related toxicity, including management 
of immune-mediated reactions, infusion-related reactions, and non-immune-mediated 
reactions will be provided in the Toxicity Management Guidelines (provided as an Annex to 
the CSP). 
Data Monitoring Committee: No 
A safety review committee (SRC) will conduct a safety review of the initial approximately 10 
to 12 participants after they have completed their first cycle. The SRC may make 
recommendations regarding continuation, modification, or termination of any study 
intervention for safety concerns. Additional safety reviews may be conducted at the discretion 
of the SRC. 
Statistical Methods 
Tabular summaries will be presented as defined in the SAP. Categorical data will be 
summarised by the number and percentage of participants in each category. Continuous 
variables will be summarised by descriptive statistics. 
Efficacy: For the primary efficacy endpoint the Kaplan-Meier method will be used to estimate 
the OS probability and the proportion of participants surviving at 12 months, OS-12, with 
80% CI. The secondary endpoints, ORR and DCR based on RECIST v1.1 will be summarised 
with 80% CI estimated using the exact binomial distribution. Time-to-event endpoints (DoR, 
PFS, PFS-4, and OS) will be analysed using the Kaplan-Meier method. 
Safety: Safety data including AEs, SAEs, laboratory evaluations and vital signs results will be 
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acquisition; MRI=magnetic resonance imaging; PID=participant identification; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; 
T3=triiodothyronine; T4=thyroxine; THS=thyroid stimulating hormone; WOCBP=woman of childbearing potential. 
 

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including the safety run-in participants will be collected according to schedules in Table 18 to Table 24. 
l 
Biopsies will be obtained at acceptable risk as judged by the investigator using low-risk procedures. 
Abbreviations: ADA=anti-drug antibody; AE=adverse event; aPTT=activated partial thromboplastin time; β-hCG=beta-human chorionic gonadotropin; C=cycle; CA19-
9=carbohydrate antigen 19-9; CSP=clinical study protocol; CT=computed tomography; 
; D=Day; ECG=electrocardiogram; 
ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOI=End of Infusion; EOT=end of treatment; Ig=immunoglobulin; imAE=immune mediated adverse 
event; INR=international normalised ratio; LIF=leukaemia inhibitory factor; MUGA=multigated acquisition; MRI=magnetic resonance imaging; n=visit number; 
PK=pharmacokinetics; Q2W=every 2 weeks; Q3=every 3; Q3W=every 3 weeks; Q4W=every 4 weeks; Q8W=every 8 weeks; Q12W=every 12 weeks; SAE=serious adverse event; 
T3=triiodothyronine; T4=thyroxine; TSH=thyroid stimulating hormone; WOCBP=woman of childbearing potential. 
 
 
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for tests performed at home. If urine test is positive or equivocal then serum β-hCG testing should be performed for confirmation. 
c 
Only for participants who discontinued for reasons other than progressive disease. If post-baseline radiological imaging indicates progressive disease, a separate consent must 
be signed before the participant may continue treatment. 
d 
Biopsies will be obtained at acceptable risk as judged by the investigator using low-risk procedures. 
Abbreviations: ADA=anti-drug antibody; aPTT=activated partial thromboplastin time; AE=adverse event; β-hCG=beta-human chorionic gonadotropin; CA19-9=carbohydrate 
antigen 19-9; CT=computed tomography; 
; CSP=clinical study protocol; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; 
FUP=follow-up; INR=international normalised ratio; MRI=magnetic resonance imaging; PK=pharmacokinetics; Q4W=every 4 weeks; Q8W=every 8 weeks; Q12W=every 
12 weeks; SAE=serious adverse event; T3=triiodothyronine; T4=thyroxine; TSH=thyroid stimulating hormone; WOCBP=woman of childbearing potential. 
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2 
INTRODUCTION  
This is a Phase II, open-label, single arm, multicentre study of AZD0171 in combination with 
durvalumab (IMFINZI®) as an addition to standard of care chemotherapy (gemcitabine and 
nab-paclitaxel) in participants with 1L mPDAC. The term “study intervention” throughout the 
CSP, refers to study treatment/drug (AZD0171, durvalumab, or standard of care 
chemotherapy). The term “Investigational product” where used refers to AZD0171 and/or 
durvalumab. 
2.1 
Study Rationale  
Leukaemia inhibitory factor is an immunosuppressive cytokine linked to 
tumourigenesis/metastasis. Elevated levels of LIF expression correlate with poor clinical 
outcomes and chemoresistance. In tumour biopsy samples and blood from PDAC patients, 
LIF levels are elevated and significantly correlate with disease pathology worsening (tumour 
cell differentiation), high levels of the PDAC 
 CA19–9, and poor treatment 
response/survival (Shi et al, 2019). In pre-clinical tumour models of pancreatic cancer, LIF 
promotes tumour-initiating cell biology and epithelial-mesenchymal transition, and the 
combination of anti-LIF with gemcitabine improves survival (Shi et al, 2019, Wang et al, 
2019). Furthermore, LIF also promotes an immunosuppressive tumour microenvironment, 
reducing recruitment of cytotoxic CD8+ effector T cells to tumours. In pre-clinical tumour 
models anti-LIF sensitises tumours to blockade of PD1 / PD-L1 immune checkpoint to induce 
tumour regression and antitumour immunity (Pascual-García et al, 2019). 
The effect on CD8+ T cells is significant because the presence and cross-linking of 
programmed cell death proteins between T cells and tumour cells is a mechanism that limits 
tumour infiltrating CD8+ T cell effector function through immune checkpoint signalling. 
Interestingly, combined effects of anti-LIF and immune checkpoint inhibition further induce 
tumour regression and improve survival in pre-clinical tumour models. Taken together, anti-
LIF has the potential to aid standard-of-care chemotherapy to overcome chemoresistance and 
work additively or synergistically alongside anti-PD-L1 durvalumab to achieve a robust 
antitumour response in PDAC. 
The proposed study is designed for PDAC patients to receive standard-of-care chemotherapy 
in combination with AZD0171 (anti-LIF) and durvalumab (anti-PD-L1). 
Additional cohorts for different tumour types may be explored and added in a future 
amendment to the CSP. 
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2.2 
Background  
2.2.1 
Disease Background  
Pancreatic Ductal Adenocarcinoma accounts for 2.6% of global cancer cases and is the third 
and fourth most common cause of cancer death in the US and Europe, respectively 
(GLOBOCAN, 2020). In 2012, approximately 337,972 new cases of pancreatic cancer were 
recorded globally with 330,391 reported deaths (GLOBOCAN, 2012). By 2020, this had 
increased (47%) to 495,773 with an estimated increase (41%) in reported deaths to 466,003 
(GLOBOCAN, 2020). Projections estimate that PDAC will become the second leading cause 
of cancer-related death in the US by 2030 (Rahib et al, 2014). Currently, PDAC accounts for 
90% of pancreatic cancers and has an extremely poor prognosis (Kleeff et al, 2016). The 
aggressiveness of the disease is reflective in the 1-year survival rate of less than 25% for 
PDAC (Latenstein et al, 2020 and National Cancer Institute, 2018) and an estimated 5-year 
survival rate of less than 8% (Siegel et al, 2020). 
The abundance of cytotoxic T cell infiltrates has important implications for patient outcome 
and therapeutic design for PDAC. A high number of CD8+ lymphocytes were significantly 
and independently associated with longer overall survival (Fukunaga et al, 2004, Zhang et al, 
2017, Orhan et al, 2020, Liu et al, 2021). Higher levels of baseline CD8+ T cells were also 
associated with improvements in PFS with PDAC patients treated with nab-paclitaxel, 
gemcitabine and anti-PD-1 (Wainberg et al, 2020). The levels of CD8+ T cells in these 
patients are considered low in both primary and basal metastatic tumour tissues. The rationale 
for selection of participants with baseline CD8+ T cells is that they will maximally benefit 
from immune checkpoint inhibition. 
Based on a pre-determined benchmarked PDAC external sample set, a 25% quartile cut-off 
will likely include 75% of pancreatic cancer patients which may predict response to 
immunotherapy-based treatment along with standard of care chemotherapy. In the proposed 
study, CD8+ T cells in pancreatic tumour tissue will be assessed by a central laboratory using 
an histological method to determine study eligibility for the proposed single arm trial 
assessing the role of AZD0171 and durvalumab as addition to standard of care nab-paclitaxel 
and gemcitabine-based chemotherapy. This approach may be able to find a subset of PDAC 
patients who will benefit from these additional immunotherapy agents to standard of care 
chemotherapy. 
2.2.2 
Chemotherapy Treatment in Pancreatic Ductal Adenocarcinoma  
Current treatment guidelines in PDAC are based on diseases stage presentation at diagnosis 
(American Joint Committee on Cancer 2017). The majority of patients (80-90%) present with 
late stage clinical disease with locally advanced, distant metastases or borderline-
resectable/non-resectable tumours. Systemic disease is treated with chemotherapy 
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NCCN guidelines (NCCN v2.2021), recommend the use of gemcitabine and nab-paclitaxel as 
category 1 for patients with ECOG performance status 0 to 2, whereas FOLFIRINOX is 
reserved for those patients with good performance status (0-1) due to a better tolerability 
profile of the former regimen. Importantly, NCCN recommends the use of olaparib as 
maintenance therapy for patients who harbor breast cancer type 1/type 2 (BRCA1/2) germline 
mutations and respond or have stable disease with platinum containing chemotherapy. 
Similarly, ESMO guidelines (Ducreux et al, 2015) recommend gemcitabine and nab-paclitaxel 
as first line therapy for patients with ECOG performance status 0 to 1. Overall, these 
chemotherapy combinations provide a median OS of less than 12 months. Therefore, PDAC 
still remains a fast growing disease of poor prognosis with a high unmet clinical need.  
The recent approvals of immunotherapy for many types of tumours has raised interest on 
whether these agents would be effective in the treatment of PDAC alone or in combination 
with chemotherapy. Interestingly, PD-1 blockade using pembrolizumab in combination with 
gemcitabine and nab-paclitaxel showed improved OS of 15 months (Singh and O’Reilly, 
2020). Furthermore, the combination of durvalumab + tremelimumab + gemcitabine and nab-
paclitaxel showed an OS of 9.8 months and an encouraging ORR of 30% (Renouf et al, 2020). 
Additionally, targeting the CD40 pathway in PDAC has yielded some interesting results in a 
recent Phase I study. The combination of gemcitabine and nab-paclitaxel with nivolumab + 
anti-CD40 was shown to be tolerable with an ORR of 67% and OS of 10.3 months, although 
the number of patients were limited and requires further confirmation (O'Hara et al, 2021).  
Despite the numerous preclinical studies that showed initial efficacy of immunotherapy 
combinations, no large Phase II/III studies to date have confirmed the initial findings. In this 
regard, one of the main challenges of immunotherapy in PDAC is the unique tumour immune 
microenvironment where the presence of CD8+ T cells has been associated with favourable 
prognosis (Knudsen et al, 2017). Therefore, selection of participants with higher frequencies 
of CD8+ T cells could possibly increase responses and survival rate. To this end, the 
opportunity to combine immunotherapy approaches that will synergise the demonstrated 
efficacy of chemotherapy (gemcitabine and nab-paclitaxel) might lead to increased efficacy. 
2.2.3 
AZD0171  
AZD0171 is a first-in class-humanised mAb of the IgG1κ subclass that binds potently and 
specifically to LIF - an immunosuppressive human cytokine. Leukaemia inhibitory factor is a 
member of the IL6 family of cytokines (Nicola and Babon, 2015) and AZD0171 inhibits LIF 
signalling by blocking recruitment of the gp130 receptor subunit to the LIF receptor subunit. 
As a result, this prevents downstream receptor signalling and phosphorylation of STAT3. In a 
Phase I study (MSC-1-101), AZD0171 monotherapy in advanced solid tumours showed a 
favourable safety profile at all doses with no dose-limiting toxicities. Thirteen patients 
(34.2%) had a best overall response of SD and the remaining patients had progressive disease. 
A prolonged SD > 16 weeks was observed in 23.7% of patients on the study. Overall median 

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PFS was approximately 6 weeks (min, max of 2 to 28 weeks). 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
Further details of the non-clinical and clinical experience with AZD0171 are provided in the 
current AZD0171 IB. 
2.2.4 
Durvalumab  
Durvalumab is a human mAb of the IgG1κ subclass that blocks the interaction of PD-L1 (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 
mechanism of action for durvalumab is interference in the interaction of PD-L1 with PD-1 and 
CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition 
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of immune responses, including those that may result in tumour elimination. In vitro studies 
demonstrate that durvalumab antagonises the inhibitory effect of PD-L1 on primary human T 
cells resulting in the restored proliferation 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-L1 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 30 April 2023, an estimated 16852 patients have received durvalumab 
in AstraZeneca or MedImmune-sponsored interventional studies in multiple tumour types, 
stages of disease and lines of therapy. The safety profile of durvalumab as monotherapy and 
combined with other anticancer agents is consistent with the pharmacology of the target and 
other agents in the immune checkpoint inhibitor class. Most ADRs seen with the immune 
checkpoint inhibitor class of agents are thought to be due to the effects of inflammatory cells 
on specific tissues and could occur in any organ system. 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. 
Further details of the non-clinical and clinical experience with durvalumab is provided in the 
current durvalumab IB. 
2.3 
Benefit/Risk Assessment  
2.3.1 
Risk Assessment  
Potential Risks 
 
 
 
 
 
 
 
 
. 
Identified risks with durvalumab include diarrhoea/colitis, pneumonitis and ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hypothyroidism, hyperthyroidism, type 1 diabetes mellitus, and diabetes insipidus), 
hepatitis/increases in transaminases, nephritis/increases in creatinine, rash/dermatitis including 
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pemphigoid, myocarditis, myositis/polymyositis, pancreatitis, encephalitis, IRRs, myasthenia 
gravis, uveitis, immune-mediated arthritis, Guillain-Barre syndrome, and immune 
thrombocytopenia. Potential risks with durvalumab include hypersensitivity reactions, 
including anaphylaxis, infections, immunogenicity, cytokine release syndrome, and other rare 
or less frequent inflammatory events including neuromuscular toxicities (eg, Guillain-Barre 
syndrome). For information on all identified and potential risks with durvalumab, refer to the 
current durvalumab IB. 
CD8+ assessment for eligibility will be performed using tissue obtained as part of standard of 
care diagnostic biopsy. If diagnostic biopsy sample is not available, investigator may perform 
 based on risk assessment and only if considered safe to perform. 
Potential Combination Toxicity 
 
 
 
 
 
 
The design of the current study aims to minimise potential risks to participants based on the 
CSP inclusion and exclusion criteria, restrictions on concomitant medication during the study, 
safety monitoring (including review of all safety, PK, and other relevant data by the safety 
review committee), and TMGs. The potential risks associated with the toxicity of the 
combination regimen are designated AESIs and hence are subject to intensive safety 
monitoring. 
2.3.2 Benefit Assessment  
Metastatic PDAC is a disease with an extremely poor prognosis, for which standard-of-care 
chemotherapy has limited impact on survival. As such, there is a significant unmet medical 
need for this patient population which require novel therapies.  
AZD0171 is considered to have a favourable safety profile for participants with mPDAC. 
Pre-clinical data suggest that a robust antitumour response in patients with PDAC may be 
achieved with anti-LIF activity in combination with anti-PD-L1 therapy.  
In a mouse PDAC model, LIF-neutralising antibodies plus gemcitabine induced a robust 
antitumour response by reversing suppression of effector T cells (Wang et al, 2019). Similarly, 
anti-LIF in combination with anti-PD-1 demonstrated antitumour activity and improved 
survival (Pascual-García et al, 2019). This indicates the therapeutic potential of AZD0171 to 
enhance the antitumour response when used in combination with standard-of-care 
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chemotherapy and immune checkpoint inhibition in mPDAC. 
Importantly, CD8+ cytotoxic T cells play a significant role in the observed antitumour activity 
in murine tumour cancer models and they are important for antitumour responses in a number 
of human solid tumour malignancies including PDAC (Balachandran et al, 2017). 
Early proof of concept data from a Phase I dose finding study (MSC-1-101) in 41 patients 
showed 34.2% of patients as having SD. A total of 23.7% of patients had SD ≥ 16 weeks; 
1 patient had SD for 28 weeks. AZD0171-related AEs, as assessed by the investigator, were 
reported in 46.3% of patients, the majority being Grade 1, and the most common being fatigue 
(19.5%) and nausea (9.8%). Grade 1 AZD0171-related AEs (increased AST, increased ALT), 
Grade 2 AZD0171-related AE (GGT increase) and Grade 3 AZD0171-related AE (increased 
AST) were reported. There were no reports of Grade 4 or 5 AZD0171-related events were 
reported. There was 1 case of AZD0171-related SAE reported, Grade 2 osteonecrosis of the 
mandible, in a head and neck cancer patient who had previously received high dose radiation 
to the area and had a history of receptor activator of nuclear factor kappa-B ligand 
(RANKL) -inhibitor therapy (denosumab) and active periodontal disease. There were no DLTs 
or discontinuations due to AZD0171-related AEs. 
Notably, AZD0171 monotherapy increased the frequency of CD8+ T cells in matched on-
treatment vs pre-treatment biopsies in a subset of participants. The potential for AZD0171 to 
reinvigorate T cell response or tumour infiltrating lymphocytes may be of clinical benefit in 
participants with basal detectable tumoral CD8+ T cells especially when combined with an 
immune checkpoint inhibitor. 
Additionally, the emerging safety data described in section 2.2.3 from this Phase 2 study are 
consistent with recent findings from other 1L mPDAC studies (Padrón et al, 2022, Tempero et 
al, 2021). 
Therefore, targeting LIF with AZD0171 in combination with durvalumab and standard-of-care 
chemotherapy may lead to more synergistic durable responses in 1L mPDAC participants with 
pre-determined tumoural CD8+ T cells. 
Participants in this study will benefit from the monitoring of all AEs arising during the clinical 
study, related or not related to the study intervention. In addition, they will be contributing to 
the development of new therapies for advanced cancer. 
2.3.3 
Overall Benefit: Risk Conclusion  
All study participants will receive nab-paclitaxel plus gemcitabine which is a current globally 
accepted standard of care for PDAC which will give benefits similar to other PDAC patients 
for their disease. Taking into account the measures taken to minimise risk to participants 
enrolling in this study, the potential risks identified in association with AZD0171 and 

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durvalumab when added to standard-of-care chemotherapy, are justified by the anticipated 
benefits that may be afforded to participants with mPDAC. 
Further details can be found in the current AZD0171 and durvalumab IBs. 
2.3.4 
Benefit/Risk Pertaining to Study Conduct During the COVID-19 
Pandemic  
Cancer patients have an increased risk of exposure to SARS-CoV-2 due to frequent hospital or 
clinic visits for treatment and monitoring. A retrospective cohort study of 28 COVID-19-
infected cancer patients from 3 hospitals in Wuhan, China, reported that a third of patients 
(28.6%; N = 8) were suspected to have acquired the infection by hospital-associated 
transmission (Yu et al, 2020, Zhang et al, 2020). Patients with cancer may have a higher risk 
from COVID-19 than individuals without cancer but current evidence appears insufficient to 
support a conclusive association between cancer in general and COVID-19 (Kumar et al, 
2019, Xia et al, 2020). 
This study will enrol participants with PDAC. Participants in this study will receive antibody 
interventions that lead to inhibition of LIF and PD-L1 as part of the treatment strategy. 
Overall, the interventions received and procedures during the course of this study are 
considered to have low risk for increasing susceptibility to COVID-19 infection. 
Furthermore, at this stage of disease, participants would typically have frequent healthcare-
related visits, irrespective of the participation in a clinical study. Therefore, it is anticipated 
that overall their participation in this clinical study should not significantly increase their risk 
of exposure to COVID-19 infection. 
Novel treatment options are needed to improve the long-term prognosis for patients with 
PDAC which is associated with chemoresistance, extremely poor prognosis, and a high risk of 
developing cancer-related death. AZD0171 could be a potential treatment option in the PDAC 
patient population with high unmet medical need. The scheduled safety monitoring visits that 
are considered in excess of standard-of-care monitoring are intended to protect participants 
involved in the study. Thus, although there may be increased risk to patients by exposure to 
SARS-CoV-2 during study visits, this is offset by the benefit that patients may receive in the 
form of an extended period of PFS. 
In accordance with EMA and FDA guidelines (EMA-CTFG-EC 2020, FDA 2020), a risk 
assessment will be conducted in collaboration with investigators for each site and participant 
prior to site initiation/participant enrolment and on an ongoing basis throughout the study to 
assess whether additional measures may be necessary to ensure participant safety and data 
validity. Measures may include postponement of study start on a global, country, or site level 
or suspension of recruitment of participants in locations with an increased risk of 
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If there is a need to reconsent study participants for the implementation of new urgent changes 
in study conduct, additional guidance on alternative means of obtaining reconsent to avoid 
unnecessary study visits is provided as Appendix A (as a supplement to the standard consent 
procedures in Appendix A 3 of the CSP). Any deviations to the CSP necessary to safeguard 
participant safety or data validity as a result of COVID-19-related disruption will be recorded 
and any permanent changes requiring an amendment to the CSP will be communicated to 
Regulatory Authorities and IRBs/IECs in line with relevant local guidance and procedures. 

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Type 
Objectives 
Endpoints 
 
 
 
 
 
 
− 
 
 
 
 
− 
 
 
 
  
− 
 
 
 
 
 
− 
 
 
 
 
 
 
 
 
 
 
− 
 
 
 
 
 
 
− 
 
Abbreviation: 1L=first line; ADA=anti-drug antibody; AE=adverse event; AUC=area under the concentration-
time curve; CA19-9=carbohydrate antigen 19-9; CD=cluster of differentiation; CD8+=cluster of differentiation 
8; CL=clearance; Cmax=maximum observed concentration; 
 
 DCR=disease 
control rate; DNA=deoxyribonucleic acid; DoR=duration of response; ECG=electrocardiogram; 
 
 imAE=immune mediated adverse 
events; LIF=leukaemia inhibitory factor; mRNA=messenger ribonucleic acid; ORR=objective response rate; 
OS=median overall survival; OS-12=overall survival at 12 months; mPDAC=metastatic pancreatic ductal 
adenocarcinoma; PD=pharmacodynamic(s); PD-1=programmed cell death protein 1; 
 PFS=median progression free 
survival; PFS-4=progression free survival at 4 months; PK=pharmacokinetic(s); RECIST=Response Evaluation 
Criteria in Solid Tumours; RNA=ribonucleic acid; SAE=serious adverse event; t1/2=half-life; 
 
 
 
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4 
STUDY DESIGN  
4.1 
Overall Design  
This is a Phase II, open-label, single arm, multicentre study to assess the safety, preliminary 
antitumour activity, immunogenicity, PD, and PK of AZD0171 in combination with 
durvalumab and standard of care chemotherapy (gemcitabine and nab-paclitaxel) in 
participants with 1L mPDAC. 
Approximately 115 participants with 1L mPDAC will be enrolled at up to approximately 40 to 
50 sites globally. Participants will receive in each 28-day cycle, AZD0171 (
 mg IV Q2W) 
along with durvalumab (1500 mg IV Q4W) and chemotherapy IV (gemcitabine 1000 mg/m2 + 
nab-paclitaxel 125 mg/m2 on Days 1, 8 and 15 in each cycle). All participants will be treated 
until progressive disease or unacceptable toxicity or withdrawal of consent or another 
discontinuation criterion is met. The study schema is presented in Figure 1.  
There will be a safety run-in setup for initial participants. The first 5 participants on the study 
will have at least 24 hours between each participant’s dosing to ensure adequate monitoring 
for IRRs. All participants enrolled on the study will be monitored for at least 60 minutes after 
the end of last study intervention infusion on C1D1. At subsequent visits, participants will 
continue to be monitored for at least 30 minutes after the end of last infusion on study 
intervention on Day 1 of each cycle, but this is not necessary on Day 8 and Day 15. An SRC 
will review the safety profile after up to approximately 10 to 12 initial participants have 
completed the first cycle of treatment. Intensive PK of AZD0171, chemotherapy, and QT 
prolongation risk will also be assessed in the 10 to12 safety run-in participants. 
For the safety run-in participants, a delay of approximately 7 days may be mandated between 
each subsequent participant prior to administration of first dose of study intervention. 
Providing there are no safety concerns after review by the SRC, this staggered approach to 
dosing of study intervention may not be required. However, should ambiguous findings or 
unexplained safety issues occur, the SRC may choose to stagger dosing between participants 
until adequate safety information is available to support exposure of a large number of study 
participants. 
An interim analysis of ORR will be performed when approximately 40 evaluable participants 
have been dosed and have had opportunity to complete 2 post-baseline scans (see Section 9.5). 
4.1.1 
Safety Review Committee  
An SRC will conduct a safety review of the initial approximately 10 to 12 participants after 
they have completed their first cycle. The SRC may make recommendations regarding 
continuation, modification, or termination of any study intervention for safety concerns. The 
safety monitoring of ongoing AEs, concomitant medications or therapies, clinical laboratory 
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tests, vital signs, physical examinations, ECGs, and echocardiography or MUGA scans (as 
clinically indicated), including the incidence of dose interruptions, dose modifications, and 
discontinuations will be reviewed. The SRC may request additional data as needed. Additional 
safety reviews may be conducted at the discretion of the SRC. The SRC will reach agreement 
on its recommendations. 
The SRC will include, but is not limited to, the following: 
• 
SRC Chairperson (AstraZeneca Clinical Lead) 
• 
Study Physician 
• 
Global Safety Physician 
• 
The PI or their delegate from each site at which participants under review were enrolled. 
• 
Study Statistician 
• 
SRC coordinator 
• 
Appropriate CRO staff (for example: CRO project manager, CRO physician) 
 
The Clinical Development Scientist, Patient Safety Scientist, and other delegates may also be 
invited as appropriate. Other internal and external experts may be consulted by the SRC as 
necessary. The membership, roles, responsibilities, and details on the process 
flow/communication plan will be provided in the SRC Charter. 
4.1.2 
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis  
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with SARS-CoV-2 or similar pandemic 
infection) which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study-site staff or the participant’s ability to conduct the study. The 
investigator or designee should contact the study sponsor to discuss whether the mitigation 
plans below should be implemented. 
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimise risks to study integrity. 

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Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies), or local government, these changes may include the following options: 
• 
Rescreening: Rescreening for screen failure and to confirm eligibility to participate in the 
clinical study can be performed in previously screened participants; as defined in 
Section 5.4. Prior to rescreening, the investigator should confirm with the designated 
study physician. 
• 
Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the ICF should be signed at the participant’s next contact with the 
study site). 
• 
Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video. For further details on study conduct 
during civil crisis, natural disaster, or public health crisis, refer to Appendix B. 
 
4.2 
Scientific Rationale for Study Design  
4.2.1 
Rationale for Study Design and Population  
This study is designed to evaluate the safety and OS-12 of AZD0171 in combination with 
durvalumab and chemotherapy using fixed dosing in 1L mPDAC patients. 
This study will complement and add to data from the completed Phase I study (MSC-1-101). 
The study will assess short and long-term safety including evaluation of the nature of 
toxicities (AEs, SAEs, imAEs), and outcomes of treatment of events. The study will also yield 
in depth understanding of rare events, or new imAEs that may occur through long-term 
administration of study intervention. 
As part of the clinical drug development programme for AZD0171, investigations into 
variations in PD and exploratory 
 and their relationship to drug effect are 
planned. These 
 may be derived from 
 
There are many potential benefits of this exploratory research, including
 
 
 This research may result in an 
understanding of the 
 
 The collection of samples is also included to allow 
characterisation of the PK of AZD0171 for safety. 
4.2.2 
Rationale for Study Endpoints  
Primary Endpoints 
The primary objective for the study is to determine the safety profile and tolerability including 
preliminary overall survival of AZD0701 and durvalumab in combination with standard-of-
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care chemotherapy in 1L mPDAC. The incidence of AEs, imAEs, SAEs, and clinically 
significant ECGs will be used to assess the safety profile of the study intervention. The 
preliminary improvement in the OS-12 will be used to assess the overall survival of the study 
intervention. These data may allow continued development in disease-expansion cohorts and 
later-stage clinical trials, which will further define safety and efficacy. 
Secondary Endpoints 
The secondary objectives include determination of the preliminary antitumour activity of and 
survival activity after treatment with AZD0701 and durvalumab in combination with standard-
of-care chemotherapy in 1L mPDAC according to RECIST 1.1. Specifically, ORR, DCR and 
DoR endpoints will be used to characterise the preliminary antitumour activity; PFS-4, median 
PFS and median OS will be used to assess the impact on survival. Further, preliminary 
antitumour efficacy will also be assessed by circulating 
 Specifically, serum levels 
of CA19-9 will be used to evaluate preliminary antitumour activity of the study intervention. 
Additional secondary objectives include determination of PK, immunogenicity and evaluation 
of the PD activity of AZD0701 and durvalumab in combination with standard-of-care 
chemotherapy in 1L mPDAC. The PK parameters for AZD0171, durvalumab and 
chemotherapy and or their metabolites will be determined. Specifically, measurements of 
Cmax, time to reach Cmax, AUC, CL and t1/2 will be used to further determine and understand 
PK profile of the study intervention combination. Incidence of anti-drug antibodies in serum 
will be used to assess the immunogenicity profile of the IMP. For PD activity, changes of total 
LIF concentration from baseline will be assessed. Changes in tumour infiltrated CD8+ T cells 
from baseline in paired tumour biopsies will be used to assess and confirm the proposed 
mechanism of action of the study intervention in mPDAC. Participants will only undergo new 
biopsies if it is considered a medically acceptable risk by the treating physician.  
Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
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4.3 
Continued Treatment Period  
The DCO for the primary endpoint will be in Q4 2024. Data analysis will be performed, and a 
CSR will be written based on this DCO. 
Any patients still receiving IP at the time of this DCO will be able to continue to receive 
AZD0171 or durvalumab or both within the current study through a Continued Treatment 
Period. Patients are eligible for the Continued Treatment Period if the Investigator determines 
the patient is deriving clinical benefit from treatment and the patient has not fulfilled 
discontinuation criteria. If Investigators decide to keep patients on treatment, these patients 
may continue for 2 years. 
During the Continued Treatment Period, assessments will revert to the standard of care for 
each individual site. Data will not be entered into the clinical study database after the DCO 
date. Patients will continue to be monitored for all AEs, SAEs, overdoses, and pregnancies up 
to 90 days after the last dose of IP. Paper-based reporting will be used for any SAE, overdose, 
or pregnancy identified after the DCO, and must be reported within times outlined in the 
protocol. All reported events will be entered into the AstraZeneca global safety database. 
The Interactive Voice and Web Response System will be closed following the DCO, and sites 
will manually order IP. The IP dispensation and reconciliation will be handled by the study 
site at each participant’s visit. Drug accountability information must still be collected until all 
participants have completed treatment.  
After the DCO for the CSR, individual study sites will be closed once their final participant 
completes the study. The Continued Treatment Period will remain available to participants 
until the last participant discontinues treatment. The Last Subject Last Visit in the Continued 
Treatment Period is defined as the date of the last participant’s final visit. 
4.4 
Justification for Dose  
4.4.1 
AZD0171  
4.4.1.1 
Dose Justification (AZD0171)  
The selected dose and schedule of 
 mg IV Q2W of AZD0171 in this study are based on a 
good laboratory practice toxicology study in monkeys and the completed Phase I MSC-1-101 
study. 
Based on the good laboratory practice toxicology study in monkeys (10, 30 and 100 mg/kg 
Q1W for 4 weeks), there will be a sufficient safety margin in exposure between the 
cynomolgus monkey NOAEL and the selected dose and schedule of AZD0171 in this study 
(
 mg IV Q2W); the estimated margins are 6.28-fold for Cmaxss and 2.9-fold for AUCt at 
steady state. 
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In the completed Phase I data from the MSC-1-101 study in patients with advanced solid 
tumours, AZD0171 was administered by one-hour IV infusion Q3W at 5 dose levels: 75 mg 
(2 patients), 225 mg (1 patient), 750 mg (10 patients), 1125 mg (10 patients), and 1500 mg 
(18 patients). AZD0171 was well tolerated in 41 treated patients including the 18 patients with 
the dose 
mg Q3W. There were no DLTs or discontinuations due to AZD0171 related 
AEs. 
A safety run-in is also incorporated in this Phase II study for the first 10 to 12 participants 
with 
 mg Q2W. In addition, this dose and schedule is aligned with dosing schedules for 
chemotherapy (gemcitabine 1000 mg/m2 + nab-paclitaxel 125 mg/m2 on Days 1, 8 and 15, 
Q4W cycle) and durvalumab (1500 mg Q4W) for clinical feasibility for mPDAC participants 
in this study.  
Pharmacokinetic/PD/tumour receptor occupancy modelling and simulations show that 
 mg Q2W will yield a higher PK trough concentration compared to 
 mg Q3W, which 
potentially would result in greater target engagement. The semi-mechanistic PK/PD model 
predicts 80% of tumour LIF occupancy for 90% of the population for 
 mg Q2W 
compared to 83% of the population for 
 mg Q3W. 
Overall, based on the safety margin, the completed Phase I MSC-1-101 study, clinical 
feasibility for mPDAC participants, PK/PD modelling, as well as the potential to drive greater 
downstream PD; coupled with safety lead in the current Phase II study, the selected dose and 
schedule of AZD0171 in this study is 
mg IV Q2W. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD0171 is 
provided in the current AZD0171 IB. 
4.4.1.2 
Rationale for Fixed Dosing (AZD0171)  
A fixed dosing approach was chosen based on preliminary population PK analysis on the 
Phase I clinical trial data showing no clear relationship between dose-normalised AUC or 
dose-normalised Cmax with body weight in conjunction with the absence of test-article related 
adverse findings in animal models suggesting the potential for a wide therapeutic window in 
humans, and the general observation that for humanised mAbs, a fixed dosing approach 
appears to present an appropriate dosing scheme (Ducreux et al, 2015, Keytruda® 2020, 
Opdivo® 2020, Tecentriq® 2020). 
4.4.2 
Durvalumab  
4.4.2.1 
Dose Justification (Durvalumab)  
The dose and schedule of durvalumab 1500 mg Q4W was selected based on PK/PD, safety 
and efficacy data from numerous studies containing durvalumab. As detailed in the current 
durvalumab IB, a fixed dose of 1500 mg Q4W (equivalent to 20 mg/kg) has been investigated 
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in numerous studies and found to be safe and tolerable. In completed studies conducted with 
durvalumab, this durvalumab dose was found to be well tolerated both in durvalumab 
monotherapy and in durvalumab combination therapy(ies) with other drugs. Durvalumab PK 
exposures observed in combination therapy were consistent with the observed monotherapy 
exposures. 
Previous studies and PK simulations of durvalumab have indicated that a similar AUC at 
steady state (4 weeks) is expected following both 10 mg/kg Q2W and 20 mg/kg Q4W. As 
such, durvalumab 1500 mg Q4W is considered to be equivalent to durvalumab 10 mg/kg 
Q2W. 
Considering all available PK, safety and tolerability data, a 1500 mg Q4W dose of 
durvalumab is proposed in combination with AZD0171 and chemotherapy to potentially 
derive the maximum benefit. 
4.4.2.2 
Rationale for Fixed Dosing (Durvalumab)  
Many published articles have previously reported a similarity of exposures following either 
fixed or body size-based dosing of mAbs (Ng et al, 2006, Wang et al, 2009, Zhang et al, 2012, 
Narwal et al, 2013). 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 mAbs 
(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/PD parameters (Zhang et al, 2012).  
A fixed dosing approach is also preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given the expectation of similar PK exposure and variability, it is 
considered feasible to use fixed dosing regimens based on average body weight of 75 kg. 
4.4.3 
Chemotherapy  
The standard-of-care agents gemcitabine and nab-paclitaxel being administered in 
combination with AZD0171 and durvalumab will be dosed according to standard practice for 
the regimens. 
4.5 
End of Study Definition  
For the purpose of Clinical Trial Transparency (CTT) the definition of the end of the study 
differs under FDA and EU regulatory requirements: 
European Union requirements define study completion as the last visit of the last subject for 
any protocol related activity. 
Food and Drug Administration requirements defines two completion dates: 

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Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure with 
different completion dates, this term refers to the date on which data collection is completed 
for all of the primary outcomes. 
Study Completion Date – the date the final participant is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures and 
AEs (for example, last participant’s last visit), whether the clinical study concludes according 
to the pre-specified protocol or is terminated. 
A participant is considered to have completed the study if he/she has completed all periods of 
the study including the last visit (FUP-2 visit) or the last scheduled procedure (survival 
follow-up) shown in the SoA, whichever is later. 
The end of the study is defined as the date of the last visit or the last scheduled procedure for 
the last participant in the study, whichever comes later. 
5 
STUDY POPULATION  
Prospective approval of CSP deviations to recruitment and enrolment criteria, also known as 
CSP waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria  
Study participants will provide 
 or recently performed standard of care 
diagnostic biopsy for CD8+ assessment as an eligibility requirement. If diagnostic biopsy 
sample is not available, investigator may perform 
 based on risk assessment and 
only if considered safe to perform. 
Participants are eligible to be included in the study only if all of the following criteria apply 
within 28 days prior to Cycle 1 Day 1: 
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 CSP. 
2) Written informed consent and any locally required authorisation (eg, data privacy) 
obtained from the participant prior to performing any CSP-related procedures, including 
screening evaluations. 
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Age 
3) Participant must be aged ≥ 18 years at the time of screening or age of consent according 
to law. 
Type of Participant and Disease Characteristics 
4) ECOG performance status of 0 or 1 at screening/enrolment. 
5) Life expectancy ≥ 12 weeks. 
6) Must have a Gustave Roussy Immune Score (GRIm-Score) of 0 or 1 
− 
Neutrophil-to-lymphocyte ratio > 6 = 1 point. 
− 
Lactate dehydrogenase > ULN = 1 point.  
− 
Albumin < 3.5 g/dL = 1 point. 
7) Participants diagnosed with histologically confirmed metastatic pancreatic 
adenocarcinoma. 
8) Participants must have at least 1 measurable lesion to be called a target lesion according 
to RECIST v1.1.  
− 
A previously irradiated lesion can be considered a target lesion if the lesion is 
progressing and well defined.  
− 
For participants who undergo biopsies at screening and/or on-treatment, it is 
preferred though not required, that the biopsied lesion, is a target lesion. 
9) All participants must consent to providing sufficient 
 taken 
during metastatic stage or 
 for tumoural CD8+ T cell testing 
for enrolment. 
− 
 sample is strongly recommended to be shipped for 
central testing within 2 weeks of ICF signing. 
10) Presence of tumoural CD8+ T cells above a 25% quartile cut-off based on a pre-
determined benchmarked PDAC external sample set by central laboratory testing. 
11) Normal organ and bone marrow function measured within 28 days prior to first dose of 
study intervention as described below: 
 
Parameter 
Value 
Haematological 
Haemoglobin 
≥ 9.0 g/dL (5.59 mmol/L) with no blood 
transfusions (packed red blood cells) within 14 days 
prior to first dose. 
Absolute neutrophil count 
≥ 1.5 × 109/L (1,500 per mm3). 
Platelet count 
≥ 100 x 109/L (100,000 per mm3) with no platelet 
transfusions within 14 days prior to first dose. 
Hepatic 
Total bilirubin 
≤ 1.5 × ULN in the absence of Gilbert’s syndrome. 
≤ 3 × ULN if participant has Gilbert’s syndrome. 
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Parameter 
Value 
Alanine transaminase and 
Aspartate transaminase 
≤ 3 x ULN in the absence of liver metastasis. 
≤ 5 x ULN in the case of liver metastasis. 
Albumin 
≥ 3 g/dL. 
Renal 
Calculated creatinine 
clearance 
≥ 40 mL/minute (per Cockcroft-Gault using actual 
body weight or 24-hour urine creatinine clearance). 
Abbreviations: ULN=upper limit normal. 
 
Weight 
12) Body weight ≥ 35 kg. 
Sex 
13) Participants (and their sexual partners if applicable) must agree to use contraceptive(s) 
and should be consistent with local regulations regarding the methods of contraception for 
those participating in clinical studies (see Section 5.3.1). 
 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1) Symptomatic CNS metastasis or any history of leptomeningeal disease or cord 
compression. 
2) A participant with an already known BRCA mutation for pancreatic cancer. 
3) A participant with an already known sensitising mutation or tumour characteristic for 
pancreatic cancer for which there is a preferred local standard of care treatment (eg, ALK, 
MSI etc). 
4) History of thromboembolic events within the past 3 months prior to the scheduled first 
dose of study intervention. NOTE: Participants with venous thromboembolism without 
history of pulmonary embolism, who either do not require treatment or who have already 
been on stable treatment with anticoagulants for 14 days or longer prior to start of study 
intervention may be enrolled and should be closely monitored. 
5) Any unresolved toxicities ≥ Grade 2 per CTCAE v5.0 from prior therapy (excluding 
vitiligo, alopecia, controlled diabetes).  
− 
Participants with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis 
after consultation with the study physician. 
− 
Participants with irreversible toxicity not reasonably expected to be exacerbated by 
treatment may be included only after consultation with the study physician. 
6) History of solid organ transplantation.  
7) History of active primary immunodeficiency.  

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8) Ongoing or an active infection, including tuberculosis (clinical evaluation that includes 
clinical history, physical examination and radiographic findings, and tuberculosis testing 
in line with local practice), hepatitis B (known positive HBsAg result), hepatitis C, or 
human immunodeficiency virus (positive HIV 1/2 antibodies). Participants with a past or 
resolved HBV infection are eligible. Participants positive for HCV antibody are eligible 
only if PCR is negative for HCV RNA. 
− 
A negative COVID-19 PCR test taken within 28 days of the start of the study 
treatment is required. However, fully vaccinated participants who test positive for 
COVID-19 can be enrolled at the investigator’s discretion, provided they satisfy one 
of the following conditions, but should be closely monitored: 
o 
Remained asymptomatic for at least 5 days after the test or, 
o 
Had developed COVID-19 symptoms after the test but recovered, and have been 
asymptomatic for at least 5 days before treatment on Day 1. 
9) Uncontrolled intercurrent illness, including but not limited to symptomatic congestive 
heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac 
arrhythmia, active ILD, serious chronic gastrointestinal conditions associated with 
diarrhoea, or psychiatric illness/social situations that would limit compliance with study 
requirement, substantially increase risk of incurring AEs or compromise the ability of the 
participant to give written informed consent.  
10) Participants with prior history of myocardial infarction, transient ischemic attack, 
coronary bypass, or stroke within the past 3 months prior to the first dose of study 
intervention. 
11) Mean QTcF ≥470 ms calculated from 3 ECGs (within 5 minutes at 1 minute apart). 
12) Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:  
− 
Participants with vitiligo or alopecia.  
− 
Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement.  
− 
Any chronic skin condition that does not require systemic therapy.  
− 
Participants without active disease in the last 5 years may be included but only after 
consultation with the study physician. 
− 
Participants with celiac disease controlled by diet alone.  
13) History of another primary malignancy except for:  

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− 
Malignancy treated with curative intent and with no known active disease ≥ 3 years 
before the first dose of study intervention and of low potential risk for recurrence. 
− 
Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of 
disease. 
− 
Adequately treated carcinoma in situ without evidence of disease. 
Prior/Concomitant Therapy 
14) Receipt of any conventional or investigational anticancer therapy prior to the scheduled 
first dose of study intervention. 
− 
Participants must not have received systemic therapy for metastatic pancreatic 
adenocarcinoma. The exception to this criterion is if participant received prior 
neoadjuvant or adjuvant chemotherapy and progressed ≥ 12 months of the last dose, 
this participant is eligible. 
15) Prior receipt of any immune-mediated therapy including, but not limited to, anti-CTLA-4, 
anti-PD-1, anti-PD-L1 antibodies, and agents targeting LIF, excluding therapeutic 
anticancer vaccines. 
16) Use of immunosuppressive medication within 14 days prior to the first dose of study 
intervention is excluded. The following are exceptions to this criterion: 
− 
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intraarticular 
injection).  
− 
Systemic corticosteroids at physiological doses not to exceed 10 mg/day of 
prednisone or its equivalent. 
− 
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication). 
17) Receipt of live, attenuated vaccine within 28 days prior to the first dose of study 
intervention (Note: Participants, if enrolled, should not receive live vaccine during the 
study and 180 days after the last dose of study intervention).  
− 
Participants can receive non-live COVID-19 vaccines, at the discretion of the 
investigator, following a benefit/risk evaluation for the individual participant and in 
accordance with local rules and regulations and vaccination guidelines. Please avoid 
if possible vaccine administration on same day as study intervention to clearly 
differentiate allergic reaction of vaccine to treatment related infusion reaction. 
Prior/Concurrent Clinical Study Experience 
18) Participants with known allergy or hypersensitivity reactions to any study intervention or 
components. 
19) Concurrent enrolment in another clinical study unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an interventional 
study.  

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Other Exclusions 
20) Documented history of alcohol or drug abuse within 6 months of signing informed 
consent. 
21) Major surgery including highly invasive dental procedures (as defined by the investigator) 
within 28 days prior to scheduled first dose of study intervention or still recovering from 
prior surgery. 
22) Females who are pregnant, lactating, or intend to become pregnant during their 
participation in the study or for 6 months after the last dose of study intervention. 
23) Any condition that, in the opinion of the investigator, would prevent participation.  
24) Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
25) Judgement by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements. 
26) Genetics research - future use and genomics initiative (optional):  
Exclusion criteria for participation in the optional (DNA) genetics research component of 
the study include: 
− 
Previous allogeneic bone marrow transplant. 
− 
Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample 
collection. 
 
5.3 
Lifestyle Considerations  
Due to the potential risk of osteonecrosis of the jaw it is important that participants maintain 
good oral hygiene throughout the study and continue to see their dentist for regular check-ups 
during the study intervention period in addition to the oral examination by the investigator per 
SoA (Section 1.3) 
There is no requirement for meals and dietary restrictions, caffeine, alcohol, and tobacco 
restrictions, or physical activity restrictions. 
Restrictions for concomitant medications are described in Section 6.5. 
5.3.1 
Contraception  
Female participants 
Female participants of childbearing potential:  
• 
Must have negative pregnancy test at screening and at Day 1 of each cycle. 

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• 
If sexually active with a non-sterilised male partner, must use at least 1 highly effective 
method of birth control from screening to 6 months after the last dose of study 
intervention. 
• 
It is strongly recommended that sexually active non-sterilised male partners of female 
participants of childbearing potential use a male condom plus spermicide, from screening 
to 6 months after the last dose of study intervention. (Note: Male condoms are not reliable 
as a sole contraception method). 
• 
Cessation of contraception after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. 
 
Female participants must not breastfeed and must not donate, or retrieve for their own use, ova 
from screening to 6 months after the last dose of study intervention. 
Male participants 
Non-sterilised male participants who are sexually active with a female partner of childbearing 
potential must use a condom with spermicide from screening to 6 months after the last dose of 
study intervention.  
It is strongly recommended for the female partners of a male participant to also use at least 
1 highly effective method of contraception throughout this period. 
In addition, male participants must refrain from fathering a child or donating sperm while on 
the study and for 6 months after the last dose of study intervention. 
The requirements and restrictions pertaining to reproduction and contraception use for both 
female and male participants are further detailed in Appendix C. 
5.4 
Screen Failures  
Screen failures are defined as participants 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 participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE. 
Individuals may be rescreened once. For example, those who require an urgent procedure with 
palliative intent (per local standard of care) to alleviate clinical symptoms leading to a delay in 
the initiation of treatment may be rescreened to redetermine eligibility. These rescreened 
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1 Day 1 – if CD8 levels are known to be positive then CD8 testing does not need to be 
repeated. If CD8 results are not available due to sample quality issues or logistical reasons 
within the initial screening time frame, participants can also be rescreened. Rescreening 
should occur within 28 days of initial screen failure date and participants can be rescreened a 
single time if benefit/risk assessment is deemed satisfactory by the investigator and confirmed 
by the study sponsor. 
Rescreened participants should be assigned the same participant number as for the initial 
screening. However, rescreening should be documented so that its effect on study results, if 
any, can be assessed. 
These participants should have the reason for screen failure recorded in the electronic case 
report form (eCRF). 
6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), or marketed product(s), 
intended to be administered to a study participant according to the CSP. 
6.1 
Study Intervention(s) Administered  
6.1.1 
Investigational Products  
Eligible participants will receive study intervention as described in Table 5. 
Table 5 
Investigational Products  
Intervention 
name 
AZD0171 
Durvalumab (MEDI4736) a 
Type  
Biologic 
Biologic 
Dosage form 
Concentrate for solution for infusion 
Concentrate for solution for infusion 
Unit dose 
strength(s) 
20 mg/mL 
50 mg/mL 
Dosage level(s) 
 mg Q2W 
1500 mg Q4W 
Route of 
administration 
IV infusion 
IV infusion 
Use 
Experimental 
Experimental 
IMP and NIMP 
IMP 
IMP 
Sourcing 
AstraZeneca R&D 
AstraZeneca R&D 
Packaging and 
labelling 
Study Intervention will be provided in 
glass vials. Each vial will be labelled 
as required per country requirement 
Study Intervention will be provided in 
vials. Each vial will be labelled as 
required per country requirement 
a 
Label text prepared for durvalumab (MEDI4736) will show the product name as “MEDI4736” or 
“durvalumab (MEDI4736)” depending upon the agreed product name used in the approved study master 
CCI

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label document. All naming conventions are correct during this transitional period. 
Abbreviations: IMP=investigational medicinal product; IV=intravenous; Q2W=every 2 weeks; Q4W=every 4 weeks. 
 
6.1.1.1 
Identity of Investigational Product(s)  
The investigational product kit has a unique number that is printed on all labels within the kit 
(ie, the outer carton label and the label of each container within the carton). Each carton and 
vial is labelled with the same unique sequence number range. 
6.1.1.2 
AZD0171  
AZD0171 will be supplied by AstraZeneca as a 200 mg vial concentrate for solution for 
infusion. The solution contains 20 mg/mL AZD0171, 25mM histidine, 6% (w/v) sucrose, and 
0.01% (w/v) polysorbate 80; it has a pH of 6.0. The label-claim volume is 10 mL. 
AZD0171 is a sterile, clear, colourless to pink solution, essentially free from visible particles. 
AZD0171 Product Inspection 
Each vial selected for dose preparation should be inspected. If any defects are noted with the 
study intervention, the investigator and site monitor should be notified immediately. Refer to 
the product complaint section (Section 6.1.3) for further instructions. 
During the inspection if the solution is turbid or if any discoloration, or particulates are 
observed, the site monitor should be notified immediately and the vial(s) should be stored in 
QUARANTINE at refrigerated (2°C to 8°C [36°F to 46°F]) temperature for drug 
accountability and potential future inspection. 
6.1.1.3 
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 
(w/v) polysorbate 80; the solution has a pH of 6.0 and density of 1.054 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. 
Durvalumab Product Inspection 
Each vial selected for dose preparation should be inspected. If any defects are noted with the 
study intervention, the investigator and site monitor should be notified immediately. Refer to 
the product complaint section (Section 6.1.3) for further instructions. 
During the inspection if the solution is turbid or if any discoloration, or particulates are 

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observed, the site monitor should be notified immediately and the vial(s) should be stored in 
QUARANTINE at refrigerated (2 °C to 8 °C [36 to 46 °F]) temperature for drug 
accountability and potential future inspection. 
6.1.2 
Gemcitabine + Nab-paclitaxel  
Each standard-of-care chemotherapy agent (gemcitabine and nab-paclitaxel) will be sourced 
as commercially available material/locally sourced, prescribed according to local regulations, 
and will be administered according to prescribing information or treatment guidance in 
general use by the investigating site. Please refer to Tempero et al, 2017 treatment guidelines 
for the management of participants with mPDAC. This will be labelled with text translated 
into local languages in accordance with regulatory guidelines. 
Eligible participants will receive chemotherapy as described in Table 6. 
Table 6 
Chemotherapy (Standard-of-Care) 
Intervention 
name 
Gemcitabine 
Nab-paclitaxel 
Type  
Drug 
Drug 
Dose form 
Solution  
Solution  
Dosage level(s) 
1000 mg/m2 on Days 1, 8 & 15 in 
each cycle 
125 mg/m2 on Days 1, 8 & 15 in each 
cycle 
Route of 
administration 
IV infusion 
IV infusion 
Use 
Standard of care 
Standard of care 
IMP and NIMP 
NIMP 
NIMP 
Sourcing 
Provided locally by the study site, 
subsidiary, or designee. 
Provided locally by the study site, 
subsidiary, or designee. 
Packaging and 
labelling 
Standard packaging and labelling 
Standard packaging and labelling 
Abbreviations: IMP=investigational medicinal product; IV=intravenous; NIMP=non-investigational medicinal product. 
 
6.1.3 
Reporting Product Complaints  
Any defects with AZD0171 or durvalumab study intervention must be reported immediately 
to AstraZeneca by the site with further notification to the site monitor. All defects will be 
communicated to AstraZeneca and investigated further. During the investigation of the 
product complaint, all AZD0171 or durvalumab study intervention must be stored at labelled 
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6.2 
Preparation/Handling/Storage/Accountability  
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines by AstraZeneca R&D supply chain. The labels will fulfil Good Manufacturing 
Practice Annex 13 requirements for labelling. Label text will be translated into local language. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorised site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labelled storage conditions with access limited to the investigator and authorised site 
staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the investigator instructions document. 
 
6.2.1 
Storage of AZD0171  
Investigational product vials are stored at 2 °C to 8 °C (36 °F to 46 °F) and must not be 
frozen. Investigational product must be kept in original packaging until use to prevent 
prolonged light exposure. 
The investigator’s or site’s designated study intervention product manager is required to 
maintain accurate study intervention accountability records. Upon completion of the study, 
copies of study intervention accountability records will be returned to sponsor. All unused 
study interventions will be returned to a sponsor-authorised depot or disposed of upon 
authorisation by sponsor according to the investigational site policy. 
6.2.2 
AZD0171 Infusion Preparation  
The dose of AZD0171 for administration must be prepared by the investigator’s or site’s 
designated IP manager using aseptic technique. Total time from needle puncture of the 
AZD0171 vial to the start of administration must not exceed: 
• 
24 hours at 2 °C to 8 °C (36 °F to 46 °F) 
• 
4 hours at room temperature 

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If the final product is stored at both refrigerated and ambient temperatures, the total time must 
not exceed 24 hours. 
No incompatibilities between AZD0171 and polyvinyl chloride and between AZD0171 and 
polyolefin have been observed for IV administration. A dose of 
 mg (for participants 
≥ 35 kg in weight) will be administered using an IV bag containing 0.9% (w/v) saline, with a 
final AZD0171 concentration of 8 mg/mL and delivered through an IV administration set with 
a 0.2- or 0.22- μm filter. 
. The IV bag size 
should be selected such that the final concentration is 8 mg/mL. Mix the bag by gently 
inverting to ensure homogeneity of the dose in the bag. 
Standard infusion time is 60 minutes (+ 10 minutes), however if there are interruptions, the 
total allowed time must not exceed 8 hours at room temperature. 
Do not co-administer other drugs through the same infusion line at the same time. 
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. 
If either preparation time or infusion time exceeds the time limits a new dose must be 
prepared from new vials. AZD0171 does not contain preservatives, and any unused portion 
must be discarded. 
If an IRR occurs, participants will be monitored until complete resolution of symptoms and 
treated as clinically indicated, including interruption and/or slowing of infusion rate as 
necessary (refer to TMGs Annex). 
6.2.3 
Storage of Durvalumab  
Investigational product 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 intervention 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. 
Durvalumab must be kept in original packaging until use to prevent prolonged light exposure. 
The dose of durvalumab for administration must be prepared by the investigator’s or site’s 
CCI
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designated study intervention manager using aseptic technique. Total time from needle 
puncture of the durvalumab vial to the start of administration must not exceed: 
• 
24 hours at 2 °C to 8 °C (36 °F to 46 °F) 
• 
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. 
6.2.4 
Durvalumab Infusion Preparation  
A dose of 1500 mg (for participants > 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 participant weight falls to ≤ 30 kg, weight-based dosing at 20 mg/kg will be prepared using 
an IV bag size selected such that the final concentration is within 1 to 15 mg/mL 
Durvalumab infusions are to be delivered 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.  
Durvalumab IV infusion will start 15 minutes after the end of AZD0171 infusion (see 
Section 6.2.5 and Figure 2). Standard infusion time for durvalumab is 60 minutes 
(+ 10 minutes); however, if there are interruptions, the total allowed time must not exceed 
8 hours at room temperature. 
Do not co-administer other drugs through the same infusion line at the same time. 
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. 
If either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials. Durvalumab does not contain preservatives, and any unused portion 
must be discarded. 
6.2.5 
Treatment Administration  
The first day of dosing is considered Day 1. Dose preparation and administration instructions 

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On Day 15, wait 15-30 minutes after AZD0171 infusion before starting nab-paclitaxel IV infusion. 
Abbreviations: IV=intravenous. 
 
6.2.6 
Monitoring of Dose Administration  
Participants will be monitored during infusions of each study intervention, during intervals 
between each study intervention, and after the last infusion of study intervention. All 
participants enrolled in the study will be monitored for at least 60 minutes after the end of last 
study intervention infusion on C1D1. At subsequent visits, participants will continue to be 
monitored for at least 30 minutes after the end of last infusion on study intervention on Day 1 
of each cycle, but this is not necessary on Day 8 and Day 15. Vital signs will be measured 
according to the schedules described in the SoA (Section 1.3). 
Management of AZD0171 or durvalumab-related toxicities are described in Section 6.6.1. 
Acetaminophen and/or an antihistamine (eg, diphenhydramine) may be administered at the 
discretion of the investigator. If the IRR is severe or prolonged, methylprednisolone 100 mg 
(or the equivalent) should be administered as well. Investigators may administer steroids at 
their discretion as clinically indicated and per their institution’s guidelines. The study 
physician should be informed if steroids are utilised for management of an IRR. 
As with any biologic product, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognise and treat anaphylaxis. 
6.3 
Measures to Minimise Bias: Randomisation and Blinding  
This study does not include randomisation or blinding. 
6.4 
Study Intervention Compliance  
When participants are dosed at the site, they will receive study intervention directly from 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 intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. 
6.5 
Concomitant Therapy  
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) that the participant is receiving at the time of enrolment or receives during the 
study (including those administered for the treatment of AEs) must be recorded along with: 
• 
Reason for use 

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• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
 
The study physician should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Authorised/approved COVID-19 vaccines can be given to participants enrolled in this study as 
long as these do not represent a prohibited concomitant medication (see exclusion 
criterion 16). Investigators should follow the CSP, their local prescribing information, and 
policies when considering if vaccination against COVID-19 is appropriate for their 
participants enrolled in an AstraZeneca clinical study. 
For any authorised/approved COVID-19 vaccine, specific considerations should be given to 
the relevant labelling information (ie, “Indications,” “Contraindications,” “Warnings and 
Precautions,” “Adverse Reactions”) on its use in this study including flexibility of vaccination 
72 hours prior to the first dose of study intervention. In any case, COVID-19 vaccination 
details must be captured in the eCRF as concomitant medication, and adverse reactions 
reported. 
6.5.1 
Permitted Concomitant Medications  
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care as described in Table 7, except for those medications 
identified as “prohibited” as listed in Section 6.5.2. 

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Table 7 
Permitted Concomitant Medication  
Supportive Medication/Class of Drug 
Usage 
Premedication for management of diarrhoea, nausea, 
and vomiting 
Permitted after but not before the first dose of study 
intervention 
Blood transfusions 
Permitted at any time after Cycle 1 Day 1 
Erythropoietin 
Prophylactic erythropoietin should not be started 
during Cycle 1 of the study but may be started during 
Cycle 2 and after 
G-CSF 
G-CSF should not be used prophylactically during 
Cycle 1, but may be considered after Cycle 1 
following discussion with the Study Physician 
Megestrol acetate 
Permitted for appetite stimulation 
Bisphosphonates 
Permitted for treatment of bone metastases 
Concomitant medications or treatments (eg, 
paracetamol/acetaminophen or diphenhydramine) 
deemed necessary to provide adequate prophylactic 
or supportive care, except for those medications 
identified as “prohibited,” as listed in Table 8. 
To be administered as prescribed by the investigator 
Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management [including 
palliative radiotherapy to non-target lesions, etc]) 
Should be used, when necessary, for all participants 
Inactivated viruses, such as those in the influenza 
vaccine and COVID-19 vaccine. 
Permitted 
Abbreviations: G-CSF=granulocyte colony stimulating factor. 
 
6.5.2 
Prohibited Concomitant Medications  
Other than the medications described above, use of concomitant medications is discouraged. 
Participants must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator.  
Investigator clinical judgement should be exercised to ensure participants are eligible to 
receive gemcitabine and nab-paclitaxel in accordance with the guidelines in the local package 
insert, prior to first dose of study intervention and during the study. Caution should be 
exercised (or alternative medication should be considered) when nab-paclitaxel is 
administered concomitantly with medicines known to inhibit or induce either CYP2C8 or 
CYP3A4. 
Concomitant medications as described in Table 8 are prohibited (see Section 5.2). 

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Table 8 
Prohibited Concomitant Medication  
Prohibited Medication/Class of Drug 
Usage 
Any investigational therapy including anticancer 
therapy other than those under investigation in this 
study 
Should not be given concomitantly while the 
participant is on study intervention 
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal therapy for 
cancer treatment other than those under investigation 
in this study 
Should not be given concomitantly while the 
participant is on study intervention. (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 
Should not be given within 28 days prior to the first 
dose through 180 days after the last dose of study 
intervention 
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 
Should not be given concomitantly or used for 
premedication prior to the immunotherapy infusions. 
The following are allowed exceptions: 
Use of immunosuppressive medications for the 
management of study intervention-related AEs 
Premedication for management of ≥ Grade 2 IRRs 
after Cycle 1 Day 1 per institutional standards and at 
the investigator’s discretion; however, steroids should 
not be used as routine premedication for Grade 1 or 2 
IRRs (refer to TMGs Annex) 
Use in participants with contrast allergies 
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 participant (eg, chronic 
obstructive pulmonary disease, radiation, nausea, etc) 
Herbal and natural remedies which may have 
immune-modulating effects 
Should not be given concomitantly 
Abbreviations: AE=adverse event; IRR=infusion-related reaction; TMGs=Toxicity Management Guidelines. 
 
6.6 
Dose Modification  
6.6.1 
Management of Study Intervention Related Toxicities  
Toxicity Management Guidelines have been developed to assist investigators with the 
recognition and management of toxicities associated with use of AZD0171 in combination 

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with immune-checkpoint inhibitors, such as durvalumab (PD-L1 inhibitor). Additionally, these 
guidelines are applicable when AZD0171 and durvalumab are used in combination with other 
anti-cancer drugs (ie, antineoplastic chemotherapy, targeted agents) which are administered 
concurrently or sequentially as part of a CSP-specific treatment regimen. 
The TMGs provide information for the management of immune-mediated reactions, IRRs, and 
non-immune-mediated reactions that may be observed with 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 (Section 6.6.1.3). The 
most current version of the TMGs, entitled “Dosing Modification and Toxicity Management 
Guidelines (TMGs) for AZD0171 in Combination with Durvalumab and other Products”, is 
provided to the investigative site as an Annex document and is maintained within the Site 
Master File. The TMGs detail a more conservative framework on the toxicity guidelines for 
immune checkpoint inhibitors and is applicable to AZD0171 in combination with durvalumab. 
The following general guidance should be followed for management of toxicities. If toxicity is 
clearly attributed to a component of study intervention (chemotherapy or investigational 
product), that particular component may be discontinued or delayed (or dose reduced 
chemotherapy only) without any impact on other components of study intervention. For 
AZD0171 and durvalumab related toxicity, please follow the TMGs. 
• 
If participants experience a toxicity clearly related to any chemotherapeutic agent 
necessitating the permanent discontinuation of that agent only, then the non-offending 
chemotherapeutic agent, durvalumab and AZD0171 may still be continued until the 
participant meets the guidelines for treatment discontinuation. 
• 
In the event that durvalumab and AZD0171 is discontinued or delayed as part of the 
TMGs, chemotherapy may still be administered as scheduled. If AZD0171 is delayed, it 
will be synchronised with the durvalumab cycle. 
• 
If chemotherapy and/or the investigational products (durvalumab and AZD0171) are 
withheld because of toxicity for more than 8 weeks (approximately 56 days), it is 
recommended the investigator contacts the study monitor if treatment planning is to be 
resumed. 
• 
Study intervention cycles are scheduled as 4 weeks cycles, with chemotherapy 
components scheduled on Day 1, Day 8, and Day 15. If Day 1 of a new cycle cannot be 
dosed due to AE/toxicity, it can be dosed with delay of the cycle upon AE recovery. 
• 
After Day 1 dosing, if a subsequent therapy visit (eg, for chemotherapy Day 8 and 
Day 15) cannot be dosed due to AE/toxicity, this will be considered as a dose interruption 
and participants should be dosed as scheduled for the next dosing visit. 

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• 
If a patient exhibits disease control after approximately 6 months of study treatment, a 
chemotherapy holiday (dispensing with day 8 chemotherapy) can be considered after 
discussion with the study physician. 
 
If unsure how to manage a participant, the study physician should be contacted to discuss 
individual cases. All toxicities will be graded according to NCI CTCAE v5.0. 
6.6.1.1 
Management of AZD0171-Related Toxicities  
The management of toxicities related to AZD0171 are also provided in the TMGs. 
6.6.1.2 
Management of Durvalumab-Related Toxicities  
The management of toxicities related to durvalumab are also detailed in the TMGs (refer to 
TMGs Annex). 
Participants should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other aetiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
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 
should be permanently discontinued. Following the first dose of study intervention, 
subsequent administration of durvalumab can be modified based on toxicities observed as 
described in the TMGs.  
6.6.1.3 
Management of Chemotherapy-Related Toxicities  
Toxicities related to chemotherapy should be managed by following local standard-of-care 
guidelines and prescribing information label including dose omission, dose modification, and 
discontinuation of therapy. 
6.7 
Intervention After the End of the Study  
Participants are often removed from immunotherapy treatment after 2 years because the 
necessity for further treatment is not clear and disease control with immunotherapy can last 
for a year or more after the end of treatment. Therefore, participants may continue on 
durvalumab and AZD0171 for a total of 2 years; thereafter further discussion with the sponsor 
may be required for those whom the investigator considers to be benefitting from the 
immunotherapy treatment. 
Provisions will be in place for participants still enrolled at the end of the study to continue to 
receive study intervention if, in the opinion of the investigator, they are continuing to receive 
benefit from treatment.  
After the end of the study, intervention is as determined by the treating physician. Therapeutic 

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interventions administered during the survival follow-up period will be recorded in the eCRF.  
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
Discontinuation of Study Intervention  
An individual participant will not receive any further study intervention if any of the 
following occur in the participant in question: 
1) Withdrawal of consent from the study or from further study intervention by participant. 
2) Unacceptable toxicity/AE that in the opinion of the investigator or sponsor, warrants 
discontinuation of further dosing or meets criteria for discontinuation from study 
intervention as described here. 
3) Lack of clinical activity or clinical benefit to the participant, in the opinion of the 
investigator. 
4) Unequivocal or equivocal progressive disease. Treatment in the setting of progressive 
disease may continue if treatment criteria are not met (ie, absence of clinical symptoms or 
signs indicating clinically significant progressive disease; no decline in ECOG 
performance status indicating rapid decline; AND absence of rapid progressive disease or 
threat to vital organs/critical anatomical sites requiring urgent alternative medical 
intervention). 
5) Initiation of alternative anticancer therapy including another investigational agent. 
6) Intercurrent illness which, in the judgement of the investigator, would significantly affect 
assessments of clinical status. 
7) Lost to follow-up. 
8) Pregnancy (Section 8.3.10) or intent to become pregnant. 
9) Participant is determined to have met 1 or more of the exclusion criteria for study 
participation at study entry and continuing treatment with study intervention might 
constitute a safety risk. 
10) Participant non-compliance (eg, refusal to adhere to visit schedule) that, in the opinion of 
the investigator or sponsor, warrants withdrawal. 
11) Sponsor termination of study for reasons including but not limited to unfavourable 
risk/benefit or change in drug development plan. 
 
Participants who are permanently discontinued from receiving study intervention will be 
followed for CSP-specified assessments including follow-up of any AEs unless consent is 
withdrawn from further study participation (Section 7.1) or the participant is lost to follow-up 
(Section 7.3). 

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Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study. 
See the SoA for data to be collected at the time of intervention discontinuation (EOT) and 
follow-up and for any further evaluations that need to be completed. 
7.1.1 
Temporary Discontinuation  
Temporary discontinuations are described in Section 6.6.1.  
7.1.2 
Treatment Beyond Progression  
Participants may continue receiving investigational products (AZD0171 and durvalumab), at 
the investigator’s discretion, after the first overall time point assessment of progressive disease 
by RECIST version 1.1 until one of the following criteria is met: 
• 
Progressive disease is confirmed on a repeat follow-up scan (unequivocal radiological 
progressive disease) following the initial assessment of progressive disease by RECIST 
version 1.1, preferably at the next tumour assessment visit and no earlier than 4 weeks 
after initial assessment of progressive disease. 
• 
Participants have any significant, unacceptable, or irreversible toxicities that indicate 
continuing investigational products will not be of further benefit.  
• 
Presence of clinical symptoms or signs indicating clinically significant disease 
progression such as the benefit-risk ratio of continuing investigational products is no 
longer justified. 
• 
Decline in ECOG performance status indicating rapid decline. 
• 
Rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumour compression, or spinal cord compression) 
requiring urgent alternative medical intervention (concurrent radiation treatment is not 
permitted), and/or continuation of investigational products that would prevent initiation of 
such intervention. 
 
Participants with unequivocal or equivocal radiologic progressive disease who are eligible to 
continue receiving investigational products will be made aware of the potential benefits and 
risks of continuing investigational products in the setting of progressive disease and must 
provide a written informed consent prior to continuation on study intervention. 
Participants who AstraZeneca and the investigator determine may not continue investigational 
products after progressive disease will be followed up for survival. Participants who have 
discontinued treatment due to toxicity or symptomatic deterioration will be followed up until 
radiological progressive disease and for survival. Participants who have commenced 
subsequent anticancer therapy will be followed up only for survival and details of subsequent 

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anticancer therapy/therapies collected. 
7.1.3 
Withdrawal of Informed Consent for Data and Biological Samples  
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. Procedures for withdrawal 
from the exploratory research on collected samples are outlined in Appendix F 2. 
7.1.4 
Procedures for Handling Incorrectly Enrolled Participants  
Participants who fail to meet the eligibility criteria (screening failures) may be rescreened as 
defined in Section 5.4. Participants who are enrolled (by error), but subsequently found not to 
meet all the eligibility criteria must not be initiated on-treatment, and must be withdrawn from 
the study. 
Where a participant does not meet all the eligibility criteria but is incorrectly started 
on-treatment, the investigator should inform the AstraZeneca study physician or designee 
immediately, and a discussion should occur between the AstraZeneca study physician (or 
designee) and the investigator regarding whether to continue or discontinue the participant 
from treatment. The AstraZeneca study physician or designee must ensure all decisions are 
appropriately documented. 
7.2 
Participant Withdrawal from the Study  
• 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon. 
• 
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records). 
• 
At the time of withdrawal from the study, if possible, an EOT visit should be conducted, 
as shown in the SoA. See SoA for data to be collected at the time of study withdrawal and 
follow-up and for any further evaluations that need to be completed. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• 
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried 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. 
 

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7.3 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
• 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomised, including 
those who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix A 9. 
8 
STUDY ASSESSMENTS AND PROCEDURES  
• 
Study procedures and their timing are summarised in the SoA. Protocol waivers or 
exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 

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record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
− 
Retesting of safety laboratory values during the screening period is allowed if 
clinically indicated. 
• 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the CSP-specified criteria and were performed 
within the time frame defined in the SoA. 
• 
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 300 mL 
(over a 1-month period). Repeat or unscheduled samples may be taken for safety reasons 
or for technical issues with the samples. 
 
Demographics 
Participant characteristics including age, gender, ethnicity (if available or allowed by local 
regulations), race (if available or allowed by local regulations), and geographic residence will 
be collected as per SoA (Section 1.3). Tobacco use, prior therapies and prior imaging (if 
available or allowed by local regulations) will also be collected. 
Medical History 
Findings from medical history collected as per SoA (Section 1.3) will be given a baseline 
grade according to the procedure for AEs. Increases in severity of pre-existing conditions 
during the study will be considered AEs, with resolution occurring when the grade returns to 
at or below the pre-study baseline. 
Prior and Concomitant Medication and Cancer Treatment History 
Prior anticancer therapy, therapy type (targeted or nontargeted) and agents received, start and 
end-dates, radiation therapy, and surgery received prior to study enrolment must be 
documented as per SoA (Section 1.3). Additionally, any medication that the participant has 
ingested 30 days prior to study entry, including dose, frequency and the medical condition for 
which it was prescribed, must be documented. 
8.1 
Efficacy Assessments  
8.1.1 
Tumour Assessments  
The assessment of tumour response will be based on RECIST version 1.1 (Eisenhauer et al, 
2009; see Appendix D) and will be performed according to the SoAs in Section 1.3. 
All images will be collected and stored for possible future central re-analysis. It is important 

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to follow the tumour assessment schedule per SoA as closely as possible. If an unscheduled 
assessment is performed (eg, to investigate clinical signs/symptoms of progression) and the 
participant has not progressed, every attempt should be made to perform the subsequent 
assessments at the next scheduled visit. Treatment continues until clinical progression/ 
deterioration or confirmed radiological progression. Imaging/tumour assessments continue 
throughout treatment until defined radiological progression plus an additional follow-up scan 
(if clinically feasible) (see Section 7.1). 
After discontinuation of study intervention(s), all participants will complete the EOT visit and 
enter follow-up; disease evaluation will be performed according to the SoA in Table 3. 
Additional disease assessments may be performed as clinically indicated. 
Tumour assessments may include the following evaluations: cross-sectional imaging using CT 
or MRI scan of the chest, abdomen, pelvis; and brain. CT or MRI scan of the chest, abdomen, 
and pelvis will be performed with each disease assessment for all participants. Additionally, 
CT or MRI (preferred) scan of the brain will be performed at screening for all participants 
with clinical concern for brain metastasis. Any participants with brain metastases at screening 
or any participants who develop neurologic or other clinical symptoms that warrant imaging 
must also have brain imaging with each disease assessment. The preferred method of disease 
assessment is CT with contrast; if CT with contrast is contraindicated, CT without contrast is 
preferred over MRI. The preferred method for CNS imaging is MRI; if CT scan is performed, 
CT with contrast is required. The same method is required for all subsequent tumour 
assessments. 
Computed tomography scan 
• 
CT (contrast preferred) scans of the chest, abdomen, and pelvis should be performed with 
contiguous cuts in slice thickness of 5 mm or less. Spiral CT should be performed using a 
5 mm contiguous reconstruction algorithm. The same imaging device should be used for 
serial evaluations. 
Magnetic resonance imaging scan 
• 
MRI scan of the chest, abdomen, and pelvis is acceptable for measurement of lesions 
provided that the same anatomical plane is used for serial assessments. 
• 
In case of MRI, measurements will be preferably performed in the axial (transverse) plane 
on contrast-enhanced T1-weighted images. However, there are no specific sequence 
recommendations. 
 
8.1.2 
Survival Assessments  
The survival status of the participant will be collected as per SoA (Section 1.3) post EOT and 
during follow-up. After follow-up Visit 1 (28 days after last dose), participants will continue 

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to be followed for survival and subsequent anticancer treatment (via telephone contact with 
the participant or the participant’s family, or by contact with the participant’s current physician 
or email if visits are discontinued) at follow-up Visit 2 (90 days after last dose) and then Q8W 
from 20 weeks post last dose. The survival status (including cause of death) and the date of 
death or last follow-up date will be collected. 
8.2 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 
Physical Examinations  
• 
At screening, a complete physical examination (including body weight, height, and oral 
cavity) will be performed and include an assessment of the following: general appearance, 
respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and 
throat), lymph nodes, thyroid, musculoskeletal (including spine and extremities) and 
neurological systems (Section 1.3).  
− 
Study participants will have oral examination by the investigator as part of the 
physical examination to assess oral health status prior to first dose of study 
intervention. As applicable, any relevant oral health disease or symptoms considered 
as medical history, should be documented in the medical notes and captured in the 
eCRF. 
• 
During the treatment period and follow-up period, only symptom directed physical 
examination (including body weight and oral cavity) is necessary. 
• 
Physical examination information will only be reported in the eCRF if abnormalities are 
reported as AEs. For information on how AEs based on physical examination should be 
recorded and reported, see Section 8.3.5. 
 
8.2.2 
Vital Signs  
• 
Vital signs including pulse, BP (systolic and diastolic), and temperature will be monitored 
at screening and at every visit during the study as per SoA (Section 1.3). Specific timing 
of measurement during the treatment period is described in Table 9. 
• 
During AZD0171, durvalumab, and gemcitabine + nab-paclitaxel infusions, vital signs 
should be monitored as per the SoA in terms of pre-dose and post infusion measurements. 
Vital signs will be measured and recorded at all visits from screening to the EOT visit and 
follow-up visits. 
• 
For all vital sign measurements, participants should rest for at least 10 minutes in a supine 
or semi-recumbent position, and all vital sign measurements should be taken prior to any 
blood draws or other procedures whenever possible. 
 

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Table 9 
Collection Times for Vital Signs During the Study Intervention Period  
AZD0171 
Durvalumab 
Chemotherapy a 
Pre-dose 
EOI 
Pre-dose 
EOI 
Pre-dose 
EOI 
Within 
30 minutes 
Within 
15 minutes 
Same as 
AZD0171 EOI 
Within 
15 minutes 
Same as 
AZD0171 EOI or 
durvalumab EOI 
or within 30 
minutes on 
chemotherapy 
only infusion days 
Within 
15 minutes 
a 
Vital signs should be collected pre-dose and at EOI for each individual chemotherapy. 
Abbreviations: EOI=end of infusion. 
 
8.2.3 
Electrocardiograms  
• 
Resting 12-lead digital ECGs with central laboratory recording will be measured as 
specified in the SoA (Section 1.3). Digital recordings will be obtained after the participant 
has been resting semi-supine for at least 10 minutes prior to times indicated. All ECGs 
should be recorded with the participant in the same physical position. Triplicate ECG 
recordings should be taken within a 5 minute interval (3 reads at least 1 minute apart).  
• 
A standardised digital ECG machine should be used, and the participant should be 
examined using the same machine throughout the study, where feasible. During 
AZD0171, durvalumab, and gemcitabine + nab-paclitaxel infusions, digital ECGs should 
be recorded as per the SoA and collection times. 
• 
In the safety run-in participants of approximately the first 10 to 12 participants, intensive 
digital ECG recordings will be obtained per Table 10. For all other participants digital 
ECG recordings will follow Table 11. 
• 
In case of clinically significant ECG abnormalities including an ECG that demonstrates a 
QTcF value > 500 ms, 2 additional digital 12-lead ECGs should be obtained over a brief 
period (eg, 30 minutes) to confirm prolongation based on the average QTcF value 
manually over-read by a medically qualified person. The first additional 12-lead digital 
ECGs should be obtained within 15 minutes. 
 
Table 10 
ECG Recording Timepoints (Safety Run-in Participants Only)  
 
Cycle 1 Day 1 
Cycle 1 Day 15 
Cycle 4 Day 1 
Safety run-in 
participants 
only 
AZD0171 Pre-dose (within 30 minutes) 
AZD0171 EOI ± 15 minutes 
6 hours post AZD0171 infusion ± 30 minutes 
Abbreviations: EOI=end of infusion. 
 

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Table 11 
ECG Recording Timepoints (All Other Participants)  
 
Cycle 1 Day 1, Cycle 2 Day 15 and Cycle 4 Day 1 
All other 
participants 
AZD0171 Pre-dose (within 30 minutes)- on C1D1, C2D15, C4D1 
End of last study intervention infusion (within 30 minutes)- on C1D1, C4D1 
 
8.2.4 
ECHO/MUGA  
• 
Left ventricular ejection fraction will be measured by ECHO or MUGA scan at screening 
and as clinically indicated thereafter, eg, if the participant exhibits any symptoms 
indicative of myocarditis (eg, chest pain, dyspnoea, palpitations, etc) or other cardiac AEs 
(Section 1.3). 
8.2.5 
Performance Status  
• 
Performance status will be assessed as per SoA (Section 1.3) and according to US ECOG 
criteria (Table 12). 
• 
These scales and criteria are used by doctors and researchers to assess how a participant's 
disease is progressing, assess how the disease affects the daily living abilities of the 
participant, and determine appropriate treatment and prognosis (Oken et al, 1982). 
 
Table 12 
Eastern Cooperative Oncology Group Performance Status  
Grade 
ECOG 
0 
Fully active, able to carry out all pre-disease activities without restrictions 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature eg, light housework, office work 
2 
Ambulatory and capable of self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled, cannot carry on self-care, totally confined to bed or chair 
5 
Dead 
Abbreviations: ECOG=Eastern Cooperative Oncology Group. 
 
8.2.6 
Clinical Safety Laboratory Assessments  
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
and urinalysis will be taken at the visits indicated in the SoA (Section 1.3). 
Clinical laboratory safety tests, including serum pregnancy tests, will be performed at a 
licensed clinical laboratory at or near to the investigator site according to local standard 
procedures. Pregnancy tests may be performed at the site using a licensed test (urine or serum 
pregnancy test).  

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Sample tubes and sample sizes may vary depending on laboratory method used and routine 
practice at the site. Abnormal clinically significant laboratory results should be repeated as 
soon as possible (preferably within 24 to 48 hours). Clinically significant (as assessed by the 
investigator) laboratory abnormalities will be recorded in the eCRF as AEs. 
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 following laboratory variables listed in Table 13 (clinical chemistry), Table 14 
(haematology), Table 15 (urinalysis), Table 16 (lipid panel), and Table 17 (pregnancy test) will 
be measured. Other safety tests to be performed at Screening include assessment for Hepatitis 
B surface antigen (HBsAg), hepatitis C antibodies, hepatitis A antibodies, severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (eg, 
HIV-1 and HIV-2) antibodies. 
 
 

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Table 13 
Clinical Chemistry (Serum or Plasma)  
Albumin 
Glucose 
ALP 
Lactate dehydrogenase 
ALT 
Lipase 
Amylase  
Magnesium 
AST 
Phosphorus 
Bicarbonate or carbon dioxide 
Potassium 
B type natriuretic peptide (BNP)a 
Sodium 
BUN or Urea depending on local practice 
Total Bilirubin (A direct bilirubin should be 
obtained if total bilirubin is > ULN) 
Calcium (total) 
Total Protein 
CA19-9 
Troponina 
Chloride 
TSH 
Creatinine 
T3 (reflex) 
C-reactive protein 
T4 (reflex) 
Creatinine clearance (Cockcroft-Gault) 
Uric acid 
Gamma glutamyl transpeptidase 
 
a 
Safety run-in participants only at baseline. 
Note for serum/plasma chemistry: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently 
and assessed concurrently. 
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. 
Abbreviations: AE=adverse event; ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate 
transaminase; BUN=blood urea nitrogen; CA19-9=carbohydrate antigen 19-9; T3=Free tri-iodothyronine; 
T4=free thyroxine; TSH=thyroid stimulating hormone; ULN=upper limit of normal; WBC=white blood cell. 
 
NB. In case a participant shows an AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN 
please refer to Appendix H ‘Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law’, for further instructions.  
 
Table 14 
Haematology/Coagulation  
Absolute (or differential, %) basophil count 
Haematocrit 
Absolute (or differential, %) eosinophil count 
Hb 
Absolute (or differential, %) lymphocyte count 
INR 
Absolute (or differential, %) monocyte count 
Platelet count 
Absolute (or differential, %) neutrophil count 
Prothrombin 
aPTT 
WBC 

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Coagulation tests: If international normalised ratio is not available the sites may substitute a prothrombin time.  
Note: For coagulation parameters, aPTT (either as a ratio or as an absolute value, in seconds) and international 
normalised ratio are to be assessed at baseline on Day 1 (unless all screening laboratory haematology 
assessments are performed within 3 days prior to Day 1), and as clinically indicated. 
Abbreviations: aPTT= activated partial thromboplastin time; Hb=haemoglobin; INR=international normalised 
ratio; WBC=white blood cell. 
 
Table 15 
Urinalysis (Dipstick)  
Appearance and colour 
Ketones 
Bilirubin 
pH 
Blood (microscopic examination will be 
performed only if the results of the urinalysis 
dipstick evaluation are positive) 
Protein 
Glucose 
Specific gravity 
Note: Urinalysis should be done at baseline (screening) and then as clinically indicated. 
 
Table 16 
Lipid Panel  
Total Cholesterol 
Triglyceride 
 
Table 17 
Pregnancy Test (Women of Childbearing Potential Only)  
Urine hCG 
Serum β-hCG 
Serum β-hCG at screening only and if a urine hCG is equivocal or positive during the remainder of the study. 
Abbreviations: β-hCG=beta-human chorionic gonadotropin; hCG=human chorionic gonadotropin. 
 
8.3 
Adverse Events and Serious Adverse Events  
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section. 
The definitions of an AE or SAE can be found in Appendix E. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorised representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information  
Adverse Events will be collected from time of signature of ICF throughout the treatment 
period and including the follow-up period (FUP-2). 

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SAEs will be recorded from the time of signing of the ICF. 
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the sponsor. 
8.3.2 
Follow-up of AEs and SAEs  
Any AEs that are unresolved at the participant’s last AE assessment or other assessment/visit 
as appropriate in the study are followed up by the investigator for as long as medically 
indicated, but without further recording in the eCRF. AstraZeneca retains the right to request 
additional information for any participant with ongoing AE(s)/SAE(s) at the end of the study, 
if judged necessary. 
Adverse event variables 
'The following variables will be collected for each AE; 
• 
AE (verbatim) 
• 
The date and time when the AE started and stopped 
• 
CTCAE grade/changes in CTCAE grade 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the study intervention (yes or no) 
• 
Action taken with regard to study intervention 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date investigator became aware of SAE 
• 
AE is serious due to 
• 
Date of hospitalisation 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
 

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8.3.3 Causality Collection  
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the study intervention?’ 
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix E 3 to the CSP.  
8.3.4 Adverse Events Based on Signs and Symptoms  
All AEs spontaneously reported by the participant or care provider or reported in response to 
the open question from the study site staff: ‘Have you had any health problems since the 
previous visit or since you were last asked?’, or revealed by observation will be collected and 
recorded in the eCRF. When collecting AEs, the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms. However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis 
and each sign or symptom will be recorded separately. 
8.3.5 Adverse Events Based on Examinations and Tests  
The results from the CSP-mandated laboratory tests and vital signs will be summarised in the 
CSR. 
Deterioration as compared to baseline in CSP-mandated laboratory values, vital signs and 
other safety assessments should therefore only be reported as AEs if they fulfil any of the SAE 
criteria, are the reason for discontinuation of treatment with the study intervention or are 
considered to be clinically relevant as judged by the investigator (which may include but not 
limited to consideration as to whether treatment or non-planned visits were required or other 
action was taken with the study intervention, eg, dose adjustment or drug interruption). 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 

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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 
Adverse Events of Special Interest  
An AESI is one of scientific and medical interest specific to understanding of the study 
intervention and may require close monitoring and rapid communication by the investigator to 
sponsor. An AESI may be serious or non-serious. The rapid reporting of AESIs allows 
ongoing surveillance of these events in order to characterise and understand them in 
association with the use of study intervention. 
8.3.6.1 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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. 
8.3.6.2 
Adverse Events of Special Interest for Durvalumab  
AESIs 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 and other immunosuppressants, and/or hormone replacement 
therapy. These AESIs are being closely monitored in clinical studies with durvalumab 
monotherapy and combination therapy. An imAE is defined as an AE that is associated with 
drug exposure and is consistent with an immune-mediated mechanism of action and where 
there is no clear alternate aetiology. Serologic, immunologic, and histologic (biopsy) data, as 
appropriate, should be used to support an imAE diagnosis. Appropriate efforts should be made 
to rule out neoplastic, infectious, metabolic, toxin, or other aetiologic causes of the imAE. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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If the investigator has any questions regarding whether an AE is an imAE, the investigator 
should promptly contact the study physician. 
AESIs/imAEs observed with anti-PD-L1/PD-1 agents such as durvalumab include: 
• 
Pneumonitis 
• 
Hepatitis 
• 
Diarrhoea/colitis 
• 
Intestinal perforation 
• 
Endocrinopathies (ie, events of hypophysitis/hypopituitarism, type 1 diabetes mellitus, 
adrenal insufficiency, hyperthyroidism, and hypothyroidism) 
• 
Nephritis 
• 
Rash/dermatitis 
• 
Myocarditis 
• 
Myositis/polymyositis 
• 
Pancreatitis 
• 
Rare/less frequent imAEs including neuromuscular toxicities (eg, Guillain-Barre 
syndrome and myasthenia gravis) and encephalitis 
• 
Other inflammatory responses that are rare/less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and 
other events involving the eye, skin, haematological events, rheumatological events, 
vasculitis and non-infectious meningitis. It is possible that events with an inflammatory or 
immune-mediated mechanism could occur in nearly all organs. 
 
In addition, IRRs and hypersensitivity/anaphylactic reactions with a different underlying 
pharmacological aetiology are also considered AESIs. 
Further information on these risks (eg, presenting symptoms) can be found in the current 
durvalumab IB. More specific guidelines for their evaluation and treatment are described in 
detail in in the TMGs (refer to TMGs Annex). 
8.3.7 Hy’s Law  
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN may 
need to be reported as SAEs. Please refer to Appendix H for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law. 
Refer to TMGs for management of Hy’s Law cases. 

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8.3.8 Disease Progression  
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the investigational product is being studied. It may be an increase in 
the severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE. Events, which are unequivocally 
due to disease progression, should not be reported as an AE during the study. 
8.3.8.1 
New Cancers  
The development of a new cancer should be regarded as an SAE. New cancers are those that 
are not the primary reason for the administration of the study intervention and have been 
identified after the participant’s inclusion in the study. New metastatic lesion(s) of the 
participant’s known cancer should not be reported as a new cancer. 
8.3.8.2 
Deaths  
All deaths that occur during the study, including the CSP-defined follow-up period (FUP-2) 
must be reported as follows: 
• 
Death clearly the result of disease progression should be reported and documented on the 
statement of death eCRF but should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to disease progression, the AE causing the 
death must be reported as an SAE within 24 hours. The report should contain a comment 
regarding the co-involvement of disease progression, if appropriate, and should assign 
main and contributory causes of death. 
• 
Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
(autopsy) 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 the sponsor within the usual 
timeframes (see Section 8.3.9). 
 
8.3.9 
Reporting of Serious Adverse Events  
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, investigators or other site personnel will 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 will work 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 

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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 
to the appropriate AstraZeneca representative by telephone. 
For further guidance on the definition of an SAE, see Appendix E 2. 
The AstraZeneca representative will advise the investigator/study site staff how to proceed. 
The reference documents for definition of expectedness/listedness are the current AZD0171 
and durvalumab IB’s. 
8.3.10 
Pregnancy  
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
• 
If the pregnancy is discovered before the study participant has received any study 
intervention 
 
8.3.10.1 
Maternal Exposure  
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital anomaly/birth defect) should be followed up and documented even 
if the participant was discontinued from the study. 
If any pregnancy occurs during exposure to study intervention, 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. 

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The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.9) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy. 
8.3.10.2 
Paternal Exposure  
Male participants should refrain from fathering a child or donating sperm during the study and 
for 6 months following the last dose of study intervention. 
Pregnancy of the participant’s partners is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly), occurring from the date of the first dose until 6 months after the 
last dose and as indicated by previous studies (pre-clinical and clinical) should, if possible, be 
followed up and documented in the Pregnancy Report Form. Consent from the partner must be 
obtained before the Pregnancy Report Form is completed.  
8.3.11 
Medication Error  
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 
1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes 
aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error, drug abuse, or misuse (see Section 8.3.9) and 
within 30 days for all other medication errors. 
The definition of a Medication Error can be found in Appendix E 4.  
8.3.11.1 
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 or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant. 
The full definition and examples of medication error can be found in Appendix E 4. 

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8.3.11.2 
Drug Abuse  
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix E 4. 
8.3.11.3 
Drug Misuse  
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, or 
for unauthorized IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
The full definition and examples of drug misuse can be found in Appendix E 4. 
8.4 
Overdose  
For this study, any dose of study intervention greater than those specified in the CSP will be 
considered an overdose. This may include a higher dose of study intervention or study 
intervention taken at the correct dose but for longer duration. 
• An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
• An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on an AstraZeneca study drug 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 8.3.9) and within 30 days 
for all other overdoses. 
8.5 
Human Biological Samples  
Instructions for the collection and handling of biological samples will be provided in the study 
specific Laboratory Manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples see Appendix F. 
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated.  

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• 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalisation or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses.  
− 
Pharmacokinetic samples may be disposed of or anonymised by pooling. Additional 
analyses may be conducted on the anonymised, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR. 
• 
Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years following issue of the CSR. 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. 
 
8.5.1 
Pharmacokinetics  
• 
Serum samples (AZD0171 and durvalumab) and plasma samples (gemcitabine and nab-
paclitaxel) will be collected for measurement of study intervention concentrations as 
specified in the SoA (Section 1.3). 
• 
Individual sampling timepoints are provided in Table 18, Table 19, and Table 20 for 
AZD0171 and total LIF, Table 21 and Table 22 for durvalumab, and Table 23 and 
Table 24 for chemotherapy (gemcitabine and nab-paclitaxel). 
• 
All sampling PK timepoints including end of infusion are relative to their respective study 
intervention infusion on the day of administration. 
• 
Day 8 AZD0171 pre-dose PK sampling will be collected prior to study intervention 
administration. 
• 
A single sample will be taken at the AZD0171 sampling timepoints which will be split 
into 2 samples for the individual analysis of AZD0171 PK and an aliquot for analysis of 
total LIF (PD). 
• 
Intensive PK sampling will be collected from the 10 to 12 safety run-in participants. Non-
intensive PK sampling will be collected in the first 40 participants only (including the 
run-in participants, ie, 10 to 12 safety run-in participants plus 28 to 30 non-intensive 
participants). Pre-dose PK samples matched to AZD0171 and durvalumab ADA samples 
will be collected for all participants. 
• 
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. 

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• 
Serum samples will be used to analyse the PK of AZD0171, and durvalumab, and plasma 
samples will be used analyse the PK of gemcitabine, gemcitabine metabolite 
2′,2′-difluoro-deoxyuridine (dFdU), and nab-paclitaxel. Samples collected for analyses of 
study intervention concentrations may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study. 
• 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual. 
 
8.5.1.1 
Determination of Drug Concentration  
Samples for determination of study intervention concentration in serum or plasma will be 
assayed by bioanalytical test sites operated by or on behalf of AstraZeneca, using an 
appropriately validated bioanalytical method. Full details of the analytical method used will be 
described in a separate Bioanalytical Report. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report. 

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8.5.2 
Immunogenicity Assessments  
Blood samples collected as per the SoA (Section 1.3) for determination of ADA in serum for 
AZD0171 and durvalumab will be assayed by bioanalytical test sites operated by or on behalf 
of AstraZeneca, 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, labelled, stored, and shipped as detailed in the Laboratory Manual. 
8.5.3 
Pharmacodynamics  
Pharmacodynamic
 will be used to inform the extent and duration of LIF and 
PD-L1 target inhibition following treatment with AZD0171 in combination with durvalumab 
and chemotherapy. PD 
 analyses will also be used to obtain assessment of the 
AZD0171 PK-PD relationship in participants and determine any retrospective correlations for 
response to study intervention. 
8.5.3.1 
Collection of Samples  
The collection of blood based PD 
 samples and tumour samples will provide 
assessment of downstream effects of AZD0171 administration in combination with 
durvalumab and chemotherapy in participants. 
 
 
 
 
 
For storage, re-use and destruction of PD samples see Section 8.5 and Appendix F. 
8.5.3.2 
Collection of Serum and Plasma Samples for Circulating Soluble Factors  
A peripheral blood sample will be collected to provide serum and plasma prior to 
administration of any study intervention for analysis of, but not limited to, baseline circulating 
LIF protein, total LIF, circulating levels of soluble factors and immune mediators of 
antitumour immune response to explore their association with treatment and clinical outcome. 
Blood samples are to be collected as detailed in the SoA (Section 1.3). Serum samples for total 
LIF will be collected at the same timepoints as AZD0171 PK samples (Section 8.5.1.1). 
8.5.3.3 
  
 
 
 
 
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8.5.3.4 
Collection of Tumour Biopsies  
All study participants must consent to provide an 
 or the collection of a 
 tumour biopsy specimen at screening. The screening tumour biopsy specimen 
must meet eligibility criteria for presence of tumour CD8+ T cell population based on central 
laboratory testing above a pre-specified cut-off (Section 5.1). 
Paired screening and on-study tumour biopsy specimens with sufficient and evaluable tissue 
material are required from up to 
participants on the study. Tumour biopsy specimens from 
the same lesion is preferable and may be from the primary (preferred) or metastatic tumour. In 
the event that a participant is eligible at study entry but paired on-study tumour biopsies are 
not medically feasible, and the required number of on-study biopsies has not been achieved, 
such a participant may continue to be evaluated for study entry with the sponsor’s permission. 
 samples at screening from either primary or metastatic tumour will be accepted if 
performed during metastatic stage and tissue from the primary tumour is preferred. In case of 
multiple 
, most recent biopsy to be sent. 
If 
 is not available or if the 
 was taken over 3 months prior to 
consent, then participants must consent to the collection of a 
 as part of screening 
prior to first dose of study intervention (Section 5.1). It is strongly recommended that 
shipment of tumour biopsy specimens to the central laboratory test facility should occur 
within 2 weeks of signed ICF. 
Approximately 
 sections from the archival tumour block are 
accepted if tumour blocks cannot be submitted, however tumour tissue blocks are preferred. 
Fine needle aspirates or bone decalcified samples are inadequate to establish participant 
eligibility. Where available, provision of a copy of the pathology report associated with the 
tumour sample is also required. 
All study participants will have the opportunity to provide on-study tumour biopsy specimens 
per SoA (Section 1.3). 
Once at least 20 paired screening and on-study tumour biopsy specimens with sufficient and 
evaluable tissue material have been collected, the sponsor will inform all investigative sites 
that further paired biopsies are no longer required to be collected. 
Biopsies will be obtained at acceptable risk as judged by the investigator using low-risk 
procedures at screening and during study intervention. Collection timepoints can be found in 
the SoA (Section 1.3).  
Consent for optional tumour biopsy specimen at disease progression may also be provided by 
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participants. 
Tumour lesions planned for biopsy are to be target lesions (preferred though not required). 
Core biopsies and archival tissues may be used for correlative studies such as but not limited 
to IHC, tumour mutation analysis, proteomic analysis, and immunodiversity. 
Full details of collecting 
, sample collection (
), 
processing, shipping and storage will be described in the Laboratory Manual. 
8.6 
  
8.6.1 
  
 
 
 
 
8.6.2 
  
 
 
 
 
  
8.7 
  
 
 
 
 
 
 
 
 
 
  
  
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8.8 
Health Economics OR Medical Resource Utilisation and Health 
Economics  
Health Economics/Medical Resource Utilisation and Health Economics parameters are not 
evaluated in this study. 
9 
STATISTICAL CONSIDERATIONS  
9.1 
Statistical Hypotheses  
No formal statistical hypotheses will be tested. A statistical estimation approach will be used 
with appropriate CIs determined to address the objectives described in Section 3. 
9.2 
Sample Size Determination  
Approximately 370 participants will be screened/enrolled to achieve approximately 115 
assigned to study intervention and up to approximately 115 evaluable participants. 
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants 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. 
 
 
 
 
 
 
 
9.3 
Populations for Analyses  
The following populations are defined: 
Table 25 
Populations for Analysis  
Population/Analysis set 
Description 
Enrolled 
All participants who signed the ICF. 
Safety 
All participants who receive any amount of investigational product. 
ITT 
All participants who receive any dose of study intervention. 
Response Evaluable 
All dosed participants who had measurable disease at baseline. 
Interim Response Evaluable 
All dosed participants who had measurable disease at baseline and who had 
first dose at least 17 weeks prior to data extract (where 17 is 2 × the 
protocol lead time between scans + 1 week to allow for a late assessment). 
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Population/Analysis set 
Description 
PK 
All participants who received any amount of study intervention with at least 
1 reportable PK measurement. 
PD 
All participants who received any amount of study intervention with at least 
1 reportable PD measurement. 
Immunogenicity 
All participants who receive at least 1 dose of investigational product with 
at least 1 reportable immunogenicity assessment. 
Abbreviations: AE=adverse event; ICF=informed consent form; ITT=intent-to-treat; PD=Pharmacodynamic; 
PK=pharmacokinetic. 
 
9.4 
Statistical Analyses  
The SAP will be finalised prior to database lock and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints. Any deviations from the planned analysis will be described in 
an SAP addendum and justified in the final integrated CSR. 
9.4.1 
General Considerations  
All statistical analyses will be performed by Parexel International Biostatistics or other 
designated third party providers, under the direction of the Biostatistics Group, AstraZeneca. 
Further details will be provided in the SAP. All statistical analyses presented in the CSP will 
be performed using the latest available version of SAS® (SAS Institute Inc., Cary, North 
Carolina, US), version 9.4 or higher. Exploratory endpoint analyses may be reported outside 
of the CSR. 
Data will be presented as defined in the SAP. Descriptive statistics will be used for all 
variables. Continuous variables will be summarised by the number of observations, mean, 
standard deviation, median, minimum, and maximum. 
Categorical variables will be summarised by frequency counts and percentages for each 
category. Unless otherwise stated, percentages will be calculated based on the population total 
and by timepoint as appropriate. 
Depending on the extent of any impact, summaries of data relating to participants diagnosed 
with COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, 
delayed or discontinued study intervention, and other CSP deviations) may be generated. 
More detail will be provided in the SAP. 
9.4.2 
Efficacy Analyses  
The efficacy analyses of antitumour activity will be based on the response evaluable set 
(defined in Section 9.3). The ORR and DCR based on RECIST v1.1 will be summarised based 

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on the exact binomial distribution. 
Time-to-event endpoints (DoR, PFS, and OS) will be analysed using the Kaplan-Meier 
method. Additional analyses of antitumour activity may be conducted in the safety analysis 
population. Additional details will be provided in the SAP. The following efficacy endpoints 
will be analysed. 
9.4.2.1 
Primary Endpoint  
• 
The primary analysis will be performed after all dosed participants have had opportunity 
for 12 months survival follow-up or died, whichever is sooner. 
• 
The primary efficacy endpoint is OS-12, defined as the proportion of participants 
alive/surviving at 12 months after initiation of study intervention. The Kaplan-Meier 
method to estimate the OS curve on the ITT analysis set, then the OS-12 estimate is 
estimated from curve that with 80% CI. The OS curve will be censored on the last date 
when participants are known to be alive. 
 
9.4.2.2 
Secondary Endpoints  
Secondary efficacy endpoints based on RECIST v1.1 include ORR, DCR, DoR, PFS, PFS-4, 
and OS. Analysis sets to be used for each endpoint will be described in the SAP. 
Objective Response Rate 
Objective response rate will be assessed per RECIST v1.1 criteria. ORR is defined as the 
proportion of participants with a best overall response of confirmed CR or PR that occurs 
prior to the initiation of subsequent anti-cancer treatment and prior to progression, with the 
denominator defined as the number of participants in the response evaluable set.  
The best overall response of CR or PR must be confirmed, which means a response of CR/PR 
is recorded at a visit and confirmed by repeat imaging not less than 28 days (4 weeks) after the 
visit when the response was first observed with no evidence of progression between the initial 
and CR/PR confirmation visit. 
The ORR and its 80% CI will be estimated using the exact binomial distribution and will be 
summarised. 
Disease Control Rate 
The DCR is defined as the percentage of participants with a best overall response of 
confirmed CR or PR, or who have SD maintained for 16 weeks from first dose, where 
16 weeks is the DCR time point. DCR and its 80% CI will be calculated using the exact 
binomial distribution. 

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Duration of response 
The DoR is defined as the time from the date of first documented response until the date of 
documented progression or death (in the absence of disease progression). 
Duration of response will be measured for responding participants (participants with 
confirmed CR or confirmed PR) only. Detailed analysis and censoring rules for DoR will be 
specified in the SAP. 
Overall Survival 
OS is defined as the time from the start of treatment to the date of death due to any cause. If 
there is no death reported for a participant before the DCO for the OS analysis, OS will be 
censored at the last contact date at which the participant is known to be alive. 
OS will be analysed using the Kaplan-Meier method. Median OS will be estimated with 
80% CI. 
Progression Free Survival 
PFS is defined as the time from the start of treatment until the date of objective disease 
progression or death (by any cause in the absence of progression), whichever is earlier, 
regardless of whether the participant withdraws from therapy or receives another anti‑cancer 
therapy prior to progression. Participants who have not progressed or died at the time of 
analysis will be censored at the time of the latest date of assessment from their last evaluable 
RECIST assessment. 
The PFS time will always be derived based on scan/assessment dates, not visit dates. 
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied: 
• 
Date of progression will be determined, based on the earliest of the dates of the 
component that triggered the progression.  
• 
When censoring a participant for PFS, the participant will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
 
PFS will be analysed using the Kaplan-Meier method. Median PFS will be estimated with 
80% CI. 
Additionally, the proportion of participants alive and PFS-4 and its associated 80% CI will be 
estimated using the Kaplan-Meier method. Other landmark time points may similarly be 
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9.4.3 
Safety Analyses  
9.4.3.1 
Primary Endpoint  
Adverse Events 
Adverse events will be coded using the most recent version of MedDRA that will have been 
released for execution at AZ/designee. 
AEs will be presented for each treatment group by SOC, HLT and/or PT covering number and 
percentage of participants reporting at least one event and number of events where 
appropriate. 
AE summary tables will include only treatment-emergent AEs. AEs will be defined as 
treatment-emergent if they have an onset or worsen (by investigator report of a change in 
intensity/severity), during treatment until the last dose of any study intervention or the safety 
follow-up period, but prior to subsequent cancer therapy. AEs occurring 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 CSR. A similar review of laboratory/vital signs (pulse and BP)/ECG data will be 
performed for identification of OAEs. Examples of these could be marked haematological and 
other laboratory abnormalities, and certain events that lead to intervention (other than those 
already classified as serious), dose reduction, or significant additional treatment. 
Treatment-emergent: 
The following events are considered treatment emergent: 
• 
Adverse events with an onset date on or after first dose of study intervention and within 
90 days after last dose of study intervention or up to the day prior to start of subsequent 
therapy, whichever comes first.  
• 
Worsening of pre-existing events on or after first dose of study intervention and within 
90 days after last dose of study intervention or up to the day prior to start of subsequent 
therapy, whichever comes first. 
 
Immune Mediated Adverse Events: 
Duration of exposure will be summarised. 
Safety data including AEs, SAEs, laboratory evaluations and vital signs results will be 
summarised for all participants based on the safety analysis set. Summary statistics will be 

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provided for AEs, imAEs, including AESIs, SAEs, and AE grade (severity) and relationship to 
study interventions (AZD0171, durvalumab, and chemotherapy), clinical laboratory 
parameters, ECGs, and vital signs. AEs will be graded according to NCI CTCAE v5.0 and 
described by system organ class and preferred term using MedDRA. Laboratory abnormalities 
with toxicity grades according to the NCI CTCAE v5.0 will be derived and summarised. 
Details of any deaths will be listed for all participants. Graphical presentations of safety data 
will be presented as appropriate. Further details will be provided in the SAP. 
Descriptive statistics will be provided for the clinical laboratory results and changes from 
baseline by scheduled time of evaluation and by treatment including EOT visit as well as for 
the maximum and minimum post-baseline values. 
In general, the baseline value for statistical analysis is the last non-missing value prior to 
administration of the first dose of study intervention. Details are described in the SAP. 
9.4.4 
Immunogenicity  
9.4.4.1 
Secondary Endpoint  
All participants who receive at least 1 dose of IMP with at least 1 reportable immunogenicity 
assessment will be evaluated. 
The immunogenic potential of AZD0171 and durvalumab will be assessed by summarising the 
number and percentage of participants who develop detectable ADAs. The impact of ADAs on 
PK, PD and safety will be assessed if data allow. Samples will be collected for potentially 
evaluating the neutralising capacity of ADAs in the future. 
9.4.5 
Pharmacokinetic  
9.4.5.1 
Secondary Endpoint  
All participants who receive any amount of study intervention with at least 1 reportable PK 
measurement will be evaluated. 
Pharmacokinetic analyses will be performed using the PK analysis set. Plasma concentrations 
for individual AZD0171, durvalumab and chemotherapies and/or their metabolites will be 
tabulated along with descriptive statistics. Non-compartmental PK data analysis will be 
performed from each study intervention with scheduled PK sample collection where data 
allow. Relevant descriptive statistics of non-compartmental PK parameters will be provided 
and will include: Cmax, AUC, CL, and terminal elimination t1/2. 
9.4.5.2 
Exploratory Endpoint  
. 
 
 
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presented separately from the main CSR. 
9.4.6 
Pharmacodynamic  
Analyses will be performed using the PD analysis population. 
9.4.6.1 
Secondary Endpoint  
Tissue obtained as part of the screening procedure and mandatory/optional biopsies obtained 
during treatment will be assessed for CD8+ T cell tumour infiltration. Descriptive statistics 
will be used to describe participant and treatment specific changes from baseline. Serum 
CA19-9 and total LIF may be similarly analysed.  
9.4.6.2 
Exploratory Endpoints  
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4.7 
  
9.4.7.1 
  
 
 
9.5 
Interim Analyses  
An analysis of ORR will be performed, without pausing enrolment, after approximately 40 
dosed participants have had the opportunity to complete 2 post-baseline scans. It is 
recommended that further recruitment to the study would be stopped if there is ≤ 10% chance 
that the ORR is at the TV or above.  
Data for other endpoints may also be reviewed at time of this interim analysis. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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The SAP will describe the planned interim analyses in greater detail. 
9.6 
Data Monitoring Committee  
Not applicable. 
An SRC will conduct a safety review of the initial approximately 10 to 12 participants after 
they have completed their first cycle. The SRC may make recommendations regarding 
continuation, modification, or termination of any study intervention for safety concerns. 
Additional safety reviews may be conducted at the discretion of the SRC. 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
Appendix A Regulatory, Ethical, and Study Oversight Considerations  
A 1 
Regulatory and Ethical Considerations  
• 
This study will be conducted in accordance with the CSP 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 
• 
The CSP, CSP amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the 
IRB/IEC before the study is initiated. 
• 
Any amendments to the CSP will require IRB/IEC and applicable Regulatory Authority 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
• 
AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca. 
• 
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. 
 

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Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators. 
• 
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. 
All SUSARs to IMP will be reported to the Eudra Vigilance database within the required 
regulatory timelines. 
• 
For all studies except those utilising medical devices, investigator safety reports must be 
prepared for SUSAR according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
 
A 2 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
A 3 
Informed Consent Process  
• 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study. 
• 
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study centre. 

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• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative. 
 
Participants who are rescreened as defined in Section 5.4 are required to sign a new ICF. 
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
Potential Changes to Informed Consent During the COVID-19 Outbreak 
General Principles 
The rights, safety, and wellbeing of the study participants are the most important 
considerations and should prevail over interests of science and society. All informed consent 
activities must follow ICH GCP; the CSP; and local laws, regulations, and guidance. 
Prospective CSP waivers with respect to enrolment remain unacceptable. Participants should 
not be included in studies without written informed consent according to national laws and 
regulations and proper eligibility assessment. 
The reconsent process described in this appendix must be adopted only at sites/countries 
affected by the COVID-19 outbreak where reaching the site means placing the study 
participant under unnecessary risk. The described process does not overrule local laws, 
regulations and guidance; where differences arise, the latter must be followed. 
If the need for re-consenting study participants arises, visiting the investigator sites for the 
sole purpose of obtaining reconsent should be avoided. 
Any validated and secure electronic system already used in the study for obtaining informed 
consent can be used as per usual practice and if in compliance with local regulations. 
Process for Reconsent of Study Participants at Sites Affected by the COVID-19 Outbreak 
Before reconsent is obtained, the approved updated participant information sheet and consent 

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form should be provided to study participants by email. If the study participant is not able to 
receive emails, courier or mail should be used. 
Verbal consent via phone or teleconference is allowed. 
If possible, verbal consent should be supplemented with email confirmation. The investigator 
should emphasise that study participants should only use email to confirm their ICF consent 
and that the participant should not include any sensitive personal identifier (eg, date of birth, 
social security number) or medical information including AEs. 
Please note: Study participants should not sign the document at home after giving verbal 
consent. The phone call or teleconference should be informative. The document will be signed 
and filed with the participant’s source data once the study participant is able to attend the site. 
Under no circumstances should the study participant scan and send the document back via 
email. 
Verbal consent and print-out of the email confirmation (if available and once possible) must 
be documented by the investigator or delegate (if applicable) in the study participant’s medical 
records. 
Documentation should include details on when the contact took place, the reason why the 
study participant could not reach the site, any important details of the consenting call/concerns 
raised, and any questions raised (especially on safety measures) by the study participant and 
that these were answered satisfactorily by the site consenting party. 
At the earliest possible occasion, consent must be documented via standard consent process. 
This would not apply if the study participant is lost to follow-up, dies, or the study ends before 
the COVID-19 outbreak is over. In this case the reason why the study participant did not sign 
the document in person has to be documented in the study participant’s medical records. 
A 4 
Data Protection  
• 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• 
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent  
• 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 

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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  
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons, as otherwise statistical analysis is not relevant. 
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical study and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the main study is 
conducted. 
A 7 
Data Quality Assurance  
• 
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy, 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, 
responsibilities and requirements, including handling of non-compliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
Monitoring Plan. 
• 
AstraZeneca or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Monitoring Plan. 

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• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (eg, CROs). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved CSP and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 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  
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• 
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. Source data 
are contained in source documents (original records or certified copies). 
• 
A digital copy of all imaging scans should be stored as source documents. 
 
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 
participants. 
The first act of recruitment is when the first participant consents to participate in the study and 
will be the study start date. 
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. 

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AstraZeneca reserves the right to temporarily suspend or permanently terminate this study or 
components of the study at any time. The reasons for temporarily suspending or permanently 
terminating the study may include, but are not limited to the following: 
Fatal event deemed related to study therapy (probable or certain causality after full etiological 
work-up). This will also result in a comprehensive review of safety. 
Unexpected and life-threatening events deemed related to study therapy. 
Sponsor decision that the study participants are placed at undue safety risk. 
Participant enrolment is unsatisfactory. 
Noncompliance that might significantly jeopardize the validity or integrity of the study. 
Sponsor decision to terminate development of the study intervention. 
If AstraZeneca determines that temporary suspension or permanent termination of the study or 
components of the study is required, AstraZeneca will discuss the reasons for taking such 
action with all participating Investigators. When feasible, AstraZeneca will provide advance 
notice to all participating Investigators of the impending action. 
If the study or components of the study are suspended or terminated for safety reasons, 
AstraZeneca will promptly inform all Investigators and/or institutions conducting the study. 
AstraZeneca will also promptly inform the relevant regulatory authorities of the 
suspension/termination along with the reasons for such action. Where required by applicable 
regulations, the Investigator must inform the IRB/IEC promptly and provide the reason(s) for 
the suspension/termination. If the study or components of the study is suspended for safety 
reasons and it is deemed appropriate by AstraZeneca to resume the study or components of the 
study, approval from the relevant regulatory authorities (and IRBs/IECs when applicable) will 
be obtained prior to resuming the study. 
A 10 
Publication Policy  
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
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. 

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• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
A 11 
Regulatory Reporting Requirements for Serious Breaches  
Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of the 
protocol or regulations is essential so that legal and ethical obligations are met. 
• 
A ‘serious breach’ means a breach likely to affect to a significant degree the safety and 
rights of a participant or the reliability and robustness of the data generated in the clinical 
study. 
 
If any (potential) serious breach occurs in the course of the study, investigators or other site 
personnel will inform the appropriate AstraZeneca representatives immediately after he or she 
becomes aware of it. 
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches. 
• 
AstraZeneca will comply with country-specific regulatory requirements relating to serious 
breach reporting to the regulatory authority, IRB/IEC, and investigators. If EU Clinical 
Trials Regulation 536/2014 applies, AstraZeneca is required to enter details of serious 
breaches into the European Medicines Agency (EMA) Clinical Trial Information System 
(CTIS). It is important to note that redacted versions of serious breach reports will be 
available to the public via CTIS. 
 
The investigator should have a process in place to ensure that: 
• 
O The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach 
• 
A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca. 

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Appendix B Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis  
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from the Sponsor. 
B 1 
Reconsent of Study Participants During Study Interruptions  
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on-site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Consent for the alternative 
means of carrying our visits and assessments will be obtained at study entry. 
B 2 
Rescreening of Participants to Reconfirm Study Eligibility  
Rescreening for screen failure due to study disruption can be performed in previously 
screened participants; as defined in Section 5.4. Prior to rescreening, the investigator should 
confirm with the designated study physician. 
B 3 
Telemedicine Visit to Replace On-site Visit (Where Applicable)  
In this appendix, the term telemedicine visit refers to remote contact with the participants 
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices. 
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow adverse events and concomitant medications to be reported 
and documented. 
B 4 
Data Capture During Telemedicine or Home/Remote Visits  
Data collected during telemedicine or home/remote visits will be captured by the qualified 
healthcare professional from the study site or third party vendor service in the source 
documents, or by the participant themselves. 

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Appendix C Contraception Requirements  
Contraception requirements for this study are as follows. 
C 1 
Women of Childbearing Potential  
Please note, women of childbearing potential are defined as those who are not either 
permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or 
who are post-menopausal. 
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months 
prior to the planned date of first dose of study intervention without an alternative medical 
cause. The following age-specific requirements apply: 
• 
Women < 50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
replacement therapy and with luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution. 
• 
Women ≥ 50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal 
replacement therapy. 
 
A highly effective method of contraception is defined as one that can achieve a failure rate of 
< 1% per year when used consistently and correctly. 
C 2 
Contraceptive Methods  
The highly effective methods of contraception are described in the table below. 
Highly Effective Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system (IUS)a 
• 
Bilateral tubal occlusion 
• 
Vasectomised partnerb 
• 
Sexual abstinencec 
Combined (oestrogen and progestogen containing 
hormonal contraception) 
• 
Oral (combined pill) 
• 
Injectable 
• 
Transdermal (patch) 
Progestogen-only hormonal contraception associated 
with inhibition of ovulationd 
• 
Injectable 
• 
Implantable 
• 
Intravaginal 

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a 
This is also considered a hormonal method. 
b 
With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate). 
c 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the 
participant. However, periodic or occasional abstinence, the rhythm method, and the withdrawal method are 
not acceptable methods of contraception. 
d 
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action 
(eg, minipill), is not accepted as a highly effective method. 

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Appendix D Response Evaluation Criteria in Solid Tumours Version 1.1  
Measurability of Tumour Lesions 
Tumour lesions will be categorised as follows: 
• 
Measurable Lesions - Must be accurately measured in at least 1 dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
− 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm). 
− 
10 mm calliper measurement by clinical examination (when superficial). 
− 
Malignant lymph nodes are considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). 
• 
Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or 
sites of disease), including small lesions (longest diameter <10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis). Lesions considered truly nonmeasurable include 
the following: leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques. 
• 
Target Lesions - At baseline, all lesions up to a maximum of 5 lesions total (and a 
maximum of 2 lesions per organ) representative of all involved organs should be 
identified as target lesions. It may be the case that, on occasion, the largest lesion does not 
lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. 
• 
Non-target Lesions - It is possible to record multiple non-target lesions involving the 
same organ as a single item (eg, “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”). 
• 
New Lesions - Though only certain new lesion measurements will be included in the 
tumour burden, all new lesions that can be accurately measured should be recorded. Other 
new lesions will be included into the non-tumour burden. 

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RECIST Version 1.1 Response Criteria 
Evaluation of Target Lesions 
• 
Complete Response (CR) - Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm (the 
sum may not be “0” if there are target nodes). 
• 
Partial Response (PR) - At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
• 
Progressive Disease - At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 1 or more 
new lesions is also considered progressive disease.) 
• 
Stable Disease (SD) - Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease, taking as reference the smallest sum of 
diameters while on study. 
 
Evaluation of Non-target Lesions 
• 
Complete Response (CR) - Disappearance of all non-target lesions and normalisation of 
tumour marker level. All lymph nodes must be non-pathological in size (< 10 mm short 
axis). 
• 
Non-complete response/Non-progressive disease (Non-CR/Non-progressive disease) - 
Persistence of 1 or more non-target lesion(s) and/or maintenance of tumour marker level 
above the normal limits. 
• 
Progressive Disease - Unequivocal progression of existing non-target lesions will be 
defined as the overall level of substantial worsening in non-target disease such that, even 
in presence of SD or PR in target disease, the overall tumour burden has increased 
sufficiently to merit discontinuation of therapy (see Section 7.1). In the absence of 
measurable disease, change in nonmeasurable disease comparable in magnitude to the 
increase that would be required to declare progressive disease for measurable disease. 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large,’ an increase in 
lymphangitic disease from localised to widespread. 
 
Appearance of New Lesions 
The appearance of new lesions is considered progressive disease according to RECIST 
version 1.1. Considering the unique response kinetics that have been observed with 
immunotherapy, new lesions can nonetheless derive clinical benefit (Borghaei et al, 2015). 

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Evaluation of Overall Response 
For the overall response based on RECIST version 1.1, confirmation of CR and PR is required 
by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. 
A confirmatory scan will also be required after an initial assessment of progressive disease for 
the purpose of managing treatment. If a participant discontinues the study due to progressive 
disease and begins another treatment, a confirmatory scan is not required. Treatment of 
participants may continue between the initial assessment of progressive disease and 
confirmation of progressive disease (which is not required by RECIST version 1.1). In the 
absence of clinical deterioration, such modifications to the RECIST may discourage the early 
discontinuation of treatment and provide a more complete evaluation of study therapy 
antitumour activity than would be seen with conventional response criteria. 
Overall responses for all possible combinations of tumour responses in target and non-target 
lesions with or without the appearance of new lesions are provided below. 
Evaluation of Overall Response using RECIST v1.1 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response (or no non-target lesion) 
No 
Complete response 
No target lesiona 
Complete response 
No 
Complete response 
Complete response 
Not evaluableb 
No 
Partial response 
Complete response 
Non-complete response / non-progressive 
disease 
No 
Partial response 
Partial response 
Non-progressive disease and not evaluable 
(or no non-target lesion)b 
No 
Partial response 
Stable disease 
Non-progressive disease and not evaluable 
(or no non-target lesion)b 
No 
Stable disease 
Not all evaluated 
Non-progressive disease 
No 
Not evaluable 
No target lesiona 
Not all evaluated 
No 
Not evaluable 
No target lesiona 
Non-complete response / non-progressive 
disease 
No 
Non-complete response / 
non-progressive disease 
Progressive disease 
Any 
Yes/No 
Progressive disease 
Any 
Progressive disease 
Yes/No 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
No target lesiona 
Unequivocal progressive disease 
Yes/No 
Progressive disease 
No target lesiona 
Any 
Yes 
Progressive disease 
a 
Defined as no target lesion at baseline. 
b 
Not evaluable is defined as either when no or only a subset of lesion measurements are made at an assessment. 
Abbreviations: RECIST=Response Evaluation Criteria in Solid Tumours; v=version. 
Reference: Eisenhauer et al, 2009. 
 

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Appendix E Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
E 1 
Definition of Adverse Events  
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered. 
E 2 
Definitions of Serious Adverse Events  
An SAE is an AE occurring during any study period (ie, run-in, treatment, washout, follow-
up), that fulfils 1 or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-participant hospitalisation or prolongation of existing hospitalisation  
• 
Results in persistent or significant disability or incapacity.  
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent 1 of the outcomes listed above. 
 
Adverse Events for malignant tumours reported during a study should generally be assessed 
as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion 
should be used. In certain situations, however, medical judgement on an individual event basis 
should be applied to clarify that the malignant tumour event should be assessed and reported 
as a non-serious AE. For example, if the tumour is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalisation, may be assessed as non-serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
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The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 
is being treated by the study intervention under study and is not the development of new or 
progression of existing metastasis to the tumour under study). Malignant tumours that – as 
part of normal, if rare, progression – undergo transformation (eg, Richter’s transformation of 
B-cell chronic lymphocytic leukaemia into diffuse large B-cell lymphoma) should not be 
considered a new malignant tumour. 
Life-threatening 
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the study intervention would result in 
the participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself 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 participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study. 
Important Medical Event or Medical Treatment 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent 1 or more outcomes listed in the definition of serious. 
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
• 
Development of drug dependency or drug abuse 
 

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Intensity Rating Scale: 
• 
Mild (awareness of sign or symptom, but easily tolerated) 
• 
Moderate (discomfort sufficient to cause interference with normal activities) 
• 
Severe (incapacitating, with inability to perform normal activities) 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix E 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix E 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix E 2. 
The grading scales found in the revised NCI CTCAE latest version will be utilised for all 
events with an assigned CTCAE grading. For those events without assigned CTCAE grades, 
the recommendation in the CTCAE criteria that converts mild, moderate and severe events 
into CTCAE grades should be used. A copy of the CTCAE can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable version 
of CTCAE should be described clearly. 
E 3 
A Guide to Interpreting the Causality Question  
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• 
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge. 

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• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognised feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With 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. 
E 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 IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error:  
• 
Occurred 
• 
Was identified and participant received the drug 
• 
Did not occur, but circumstances were recognised that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 

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• 
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the participant 
• 
Drug not administered as indicated, eg, wrong route or wrong site of administration 
• 
Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet  
• 
Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature  
• 
Wrong participant received the medication (excluding IRT/RTSM errors) 
• 
Wrong drug administered to participant (excluding IRT/RTSM errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IRT/RTSM - including those which led to one of the 
above listed events that would otherwise have been a medication error  
• 
Participant accidentally missed drug dose(s), eg, forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Participant failed to return unused medication or empty packaging  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 
Drug Abuse 
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP 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 Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used both 
if the drug abuse happened in a study participant or if the drug abuse involves a person not 
enrolled in the study (such as a relative of the study participant). 
Examples of drug abuse include but are not limited to: 
• 
The drug is used with the intent of getting a perceived reward (by the study participant or 
a person not enrolled in the study) 
• 
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high  
 

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

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Appendix F Handling of Human Biological Samples  
F 1 
Chain of Custody  
A full chain of custody is maintained for all samples throughout their lifecycle. 
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal. 
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers 
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle. 
F 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 participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research. 
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 
The investigator: 
• 
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate. 
• 
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented. 
• 
Ensures that the participant and AstraZeneca are informed about the sample disposal. 
 
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 

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withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site is notified. 
F 3 
International Airline Transportation Association 6.2 Guidance 
Document  
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN 3373 and IATA 650 
 
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class. 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf). 
• 
Biological samples transported in dry-ice require additional dangerous goods 
specification for the dry-ice content 

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Appendix G 
  
G 1 
  
• 
 
 
 
 
 
 
 
• 
 
  
• 
 
• 
 
 
 
G 2 
  
 
• 
 
 
 
 
 
 
 
 
 
• 
 
 
− 
 
− 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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• 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
• 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
• 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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• 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
 
 
 
 
 
 
 
• 
 
. 
• 
 
 
 
 
 
 
 
  
• 
 
 
• 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Appendix H Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law  
H 1 
Introduction  
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.  
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study. 
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.  
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events. 
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the study intervention. 
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. 
H 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 medication 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 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 

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same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
H 3 
Identification of Potential Hy’s Law Cases  
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥ 3 × ULN 
• 
AST ≥ 3 × ULN 
• 
TBL ≥ 2 × ULN 
 
Local Laboratories Being Used: 
The investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Notify the AstraZeneca representative 
• 
Determine whether the participant meets PHL criteria (see Section H 2 for 
definition) by reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory eCRF 
 
H 4 
Follow-up  
H 4.1 
Potential Hy’s Law Criteria not met  
If the participant does not meet PHL criteria the investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the CSP. 
 
H 4.2 
Potential Hy’s Law Criteria met  
If the participant does meet PHL criteria the investigator will: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study 
intervention (see Section H 6) 
• 
Notify the AstraZeneca representative who will then inform the central Study Team  
• 
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting. 

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• 
For participants that met PHL criteria prior to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the participant’s 
condition 
• 
The study physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data 
• 
Subsequent to this contact the investigator will: 
− 
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required. 
− 
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the study physician.  
− 
Complete the 3 Liver eCRF Modules as information becomes available  
 
#A ‘significant’ change in the participant’s condition refers to a clinically relevant change 
in any of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study physician if there is any uncertainty. 
H 5 
Review and Assessment of Potential Hy’s Law Cases  
The instructions in this Section should be followed for all cases where PHL criteria are met. 
As soon as possible after the biochemistry abnormality was initially detected, the study 
physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days from 
date PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global 
Safety Physician will also be involved in this review together with other subject matter experts 
as appropriate.  
According to the outcome of the review and assessment, the investigator will follow the 
instructions below. 
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF 

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

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− 
If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Section H 4.2  
 
H 7 
Actions Required for Repeat Episodes of Potential Hy’s Law  
This section is applicable when a participant meets PHL criteria on study intervention and has 
already met PHL criteria at a previous on study intervention visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
Was the alternative cause for the previous occurrence of PHL criteria being met found 
to be the disease under study eg, chronic or progressing malignant disease, severe 
infection or liver disease or did the participant meet PHL criteria prior to starting study 
intervention and at their first on study intervention visit as described in Section 6 of 
this Appendix?  
If No: follow the process described in Section H 4.2 for reporting PHL as an SAE. 
If Yes: Determine if there has been a significant change in the participant’s condition# 
compared with when PHL criteria were previously met. 
• 
If there is no significant change no action is required 
• 
If there is a significant change# follow the process described in Section H 4.2 for 
reporting PHL as an SAE 
 
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study physician if there is any uncertainty. 
H 8 
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 

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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 I 
National Institute of Allergy and Infectious Disease and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis  
National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis 
Network define anaphylaxis as a serious allergic reaction that is rapid in onset and may cause 
death. They recognise 3 categories of anaphylaxis, with criteria designated to capture from 
80% of cases (category 1) to > 95% of all cases of anaphylaxis (for all 3 categories). 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalised hives, pruritus or flushing, swollen lips-tongue-
uvula) AND AT LEAST ONE OF THE FOLLOWING 
2. Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia). 
3. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence). 
4. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
5. Involvement of the skin-mucosal tissue (eg, generalised hives, itch-flush, swollen lips-
tongue-uvula). 
6. Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia). 
7. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence). 
8. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)  
9. Reduced BP after exposure to known allergen for that participant (minutes to several 
hours): 
10. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
participant’s baseline. 
 
Reference: Sampson et al, 2006. 

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Appendix J 
Abbreviations  
Abbreviation or special 
term 
Explanation 
1L 
first line 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase/transaminase 
AST 
aspartate aminotransferase/transaminase 
AUC 
area under the concentration-time curve 
BP 
blood pressure 
BRCA 
breast cancer gene 
CA19–9 
carbohydrate antigen 19–9 
CD 
cluster of differentiation 
CD8+ 
cluster of differentiation 8 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
Clearance 
Cmax 
maximum observed concentration; 
CNS 
central nervous system 
COVID-19 
Coronavirus disease 2019 
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 
 
 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DCO 
Data cut-off 
DCR 
disease control rate 
DILI 
Drug Induced Liver Injury 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid  
DoR 
duration of response 
CCI
CCI

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Abbreviation or special 
term 
Explanation 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EOI 
end of infusion 
EOT 
end of treatment 
ESMO 
European Society for Medical Oncology 
FDA 
United States Food and Drug Administration 
 
 
FOLFIRINOX 
folinic acid, fluorouracil, irinotecan, oxaliplatin 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
gp130 
glycoprotein 130 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency viruses 
HL 
Hy’s Law 
HLT 
higher level term 
IATA 
International Airline Transportation Association 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFNγ 
interferon-gamma 
IgG1κ 
immunoglobulin G1 kappa 
IHC 
Immunohistochemistry 
IL6 
interleukin 6 
ILD 
interstitial lung disease 
imAE 
immune mediated adverse events 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IRR 
infusion-related reactions 
CCI
CCI

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Abbreviation or special 
term 
Explanation 
IV 
Intravenous 
IWRS 
Interactive Web Response Systems 
LIF 
leukaemia inhibitory factor 
LRV 
lower reference value 
mAbs 
monoclonal antibodies 
MedDRA 
Medical Dictionary for Regulatory Activities 
mPDAC 
metastatic pancreatic ductal adenocarcinoma 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MUGA 
multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NOAEL 
no-observed-adverse-effect level 
OAE 
other adverse event 
ONJ 
osteonecrosis of the jaw 
ORR 
objective response rate 
OS 
median overall survival 
OS-12 
overall survival at 12 months 
PCR 
polymerase chain reaction 
PD-1 
programmed cell death protein 1 
PDAC 
pancreatic ductal adenocarcinoma 
PD 
pharmacodynamic(s) 
PD-L1 
programmed death-ligand 1 
PEF 
peak expiratory flow 
PHL 
Potential Hy’s Law 
PI 
Principal investigator  
PID 
participant identification number 
PK 
pharmacokinetic(s) 
PFS 
median progression free survival 
PR 
partial response 
PT 
preferred term 
Q1W 
every week 
Q2W 
every 2 weeks 
Q3 
every 3 
Q3W 
every 3 weeks 

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Abbreviation or special 
term 
Explanation 
Q4W 
every 4 weeks 
Q8W 
every 8 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia's formula 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RNA 
ribonucleic acid; 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
stable disease 
SoA 
Schedule of Activities 
SOC 
system organ class 
SRC 
Safety Review Committee 
STAT3 
signal transducer and activator of transcription 3 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2 
half-life 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse events 
TMG 
toxicity management guidance 
TV 
target value 
ULN 
upper limit of normal 
US(A) 
United States (of America) 
WOCBP 
woman of childbearing potential 
YAP1 
yes1 associated transcriptional regulator 

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11 
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