Clinical trial NCT05140382
Conditions: Relapsed/Refractory Peripheral T-cell Lymphoma Relapsed/Refractory Classical Hodgkins Lymphoma
Keywords: AZD4573 Modular study Dose confirmation Dose expansion
Sponsor: AstraZeneca
Start date: 2021-12-15; Completion date: 2024-02-16
Enrollment: 52 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a modular dose confirmation and expansion study. The core study design is to assess the efficacy of AZD4573, administered as monotherapy or combination therapy, to participants with either r/r PTCL or r/r cHL and to confirm the safety profiles and PK in these populations. Module 1 of this study will evaluate the efficacy, safety, and tolerability of AZD4573 monotherapy in participants with r/r PTCL or r/r cHL. If AZD4573 monotherapy is found to have promising anti-tumour efficacy in Module 1, an AZD4573 monotherapy Phase II expansion may be added via a substantial protocol amendment.

Detailed description:
Module 1 will consist of two r/r PTCL cohorts and one cHL cohort; and each cohort includes 21 participants. A comprehensive initial review of all safety and PK/PD data will be conducted in approximately the first 6 participants of each cohort (safety run-in), with separate Safety Review Committees (SRCs) for each cohort executed independently. The safety assessment will be undertaken by the SRC. Each cohort will have a separate dose confirmation, assessed independently by the SRC, to assess safety and PK/PD data compared to the known profiles in the first time in human study (Study D8230C00001) lymphoma population. These SRC reviews will confirm whether the recommended phase II dose for lymphoma (IV infusion 12 mg once weekly, including intra-participant ramp-up) is safe and tolerable or if additional dose optimisation is indicated at a revised dose and/or schedule. All cohorts can be opened and delivered independently of each other.

Arms: arm 1: Eligible participants with either r/r PTCL, r/r NKTCL or r/r cHL will receive AZD4573 as monotherapy.
Interventions: intervention 1: AZD4573
Intervention descriptions: intervention 1: AZD4573 will be given intravenously

Protocol documents:
Prot_000.pdf: 
A Modular Phase II, Open-label, Multicentre 
Study to Assess AZD4573 Efficacy and 
Safety as Monotherapy or in Combination 
with Anti-cancer Agents in Patients with 
Relapsed/Refractory Peripheral T-cell 
Lymphoma or classical Hodgkin Lymphoma
ClinicalTrials.gov Identifier: NCT05140382 
Clinical Study Protocol: version 2.0, dated 09 Sep 2021 
Clinical Study Protocol - 2.0
AZD4573 - D8231C00001
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AZDoc0189620


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Clinical Study Protocol 
Study Intervention
AZD4573
Study Code
D8231C00001
Version
2.0
Date
09 Sep 2021
A Modular Phase II, Open-label, Multicentre Study to Assess 
AZD4573 Efficacy and Safety as Monotherapy or in Combination
with Anti-cancer Agents in Patients with Relapsed/Refractory 
Peripheral T-cell Lymphoma or classical Hodgkin Lymphoma
Sponsor Name: AstraZeneca
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifier Numbers
EudraCT number: 2021-002570-54
IND number: 156169
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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Protocol Number: D8231C00001
Amendment Number: 1
Study Intervention: AZD4573
Study Phase: Phase II
Short Title: AZD4573 as Monotherapy or in Combination with Anti-cancer Agents in 
Patients with r/r PTCL or r/r cHL 
Study Physician Name and Contact Information will be provided separately
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Version 2.0, Amendment 1
09-Sep-2021
Version 1.0
25-Jun-2021
The Protocol Amendment Summary of Changes table is provided below for the current 
amendment.
Version 2.0, Amendment 1 (09 September 2021)
Overall Rationale for the Amendment:
This protocol amendment incorporates changes requested by the FDA arising from review of 
version 1.0 of the protocol.
The Clinical Study Protocol (CSP), Version 1.0, dated 25 June 2021, was updated with the 
following changes:
Section # and Name
Description of Change
Brief Rationale
Title page
Regulatory Agency Identifier 
Numbers updated.
Correction of typographical error 
in EudraCT number.
IND number added.
Section 1.1 Synopsis
Text related to objective response 
rate removed from primary and 
secondary efficacy objectives in 
the Core Objectives table to align 
with Table 3, Section 3 
(Objectives and Endpoints), and 
Section 10.9.4.2.2 (Secondary 
Efficacy Endpoints) and due to a 
typographical error in secondary 
Typographical error in secondary 
objectives (“by evaluation of 
objective response rate”).


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Section # and Name
Description of Change
Brief Rationale
objectives (objective response 
rate not evaluated). 
Section 5.1 Inclusion Criteria
Inclusion criteria in Module 1 
(Section 10.5.1) have been 
moved to the Core protocol 
(Section 5.1).
Updated in line with response to 
FDA request.
Section 5.2 Exclusion Criteria
Exclusion criteria from Module 1 
(Section 10.5.2) have been 
moved to the Core protocol 
(Section 5.2).
Updated in line with response to 
FDA request.
Section 7.1 Discontinuation of Study 
Intervention
Text moved to new section 7.1.1. 
dedicated to study-wide stopping 
rules for safety.
Amended in line with response to 
FDA request.
Section 7.1.1 Criteria for stopping or 
pausing the study recruitment
New section added to specify in 
greater detail study-wide stopping 
rules for safety that would trigger 
SRC evaluation and potential 
study pause.
New text added in line with 
response to FDA request.
Section 10.1.2 Schedule of 
Activities, footnote c; Section 
10.8.2.5 Clinical Safety Laboratory 
Assessments
Footnote was updated and 
Section 10.8.2.5 amended for 
clarification of the haematologic 
and chemistry criteria required to 
initiate each cycle of therapy.
Clarification as per FDA request.
Section 10.4.1 Module 1 Design: 
AZD4573 monotherapy
Inclusion of a requirement for 
pooled safety monitoring 
assessments to be conducted at 
3-monthly intervals.
Amended in line with response to 
FDA request.
Section 10.5.1 Additional Module 1 
Inclusion Criteria
All additional module 1 inclusion 
criteria were moved to Section 
5.1 Inclusion Criteria.
Updated in line with response to 
FDA request.
Section 10.5.2 Additional Module 1 
Exclusion Criteria
All additional module 1 exclusion 
criteria were moved to Section 
5.2 Exclusion Criteria.
Updated in line with response to 
FDA request.


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Section # and Name
Description of Change
Brief Rationale
Section 10.6.1 Dose Modification
Update of Grade 3 or 4 
non-haematological toxicities 
Table 11 to add the guidance of 
one dose level reduction in order 
to resume AZD4573 dosing after 
resolution of a Grade 4 
non-haematological (excluding 
liver and TLS) AE to Grade 1,
and guidance on discontinuation 
following a third occurrence.
Amended in line with response to 
FDA request.
In addition, minor formatting and editorial changes were made throughout the CSP.


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 2
TABLE OF CONTENTS ...................................................................................................... 5
LIST OF FIGURES .............................................................................................................. 9
LIST OF TABLES ................................................................................................................ 9
LIST OF APPENDICES ..................................................................................................... 10
1
PROTOCOL SUMMARY ................................................................................ 11
1.1
Synopsis ........................................................................................................... 11
1.2
Schema............................................................................................................. 13
1.3
Schedule of Activities ....................................................................................... 14
2
INTRODUCTION............................................................................................ 15
2.1
Study Rationale ................................................................................................ 15
2.2
Background ...................................................................................................... 17
2.3
Benefit/Risk Assessment................................................................................... 19
2.3.1
Risk Assessment ............................................................................................... 19
2.3.2
Benefit Assessment........................................................................................... 22
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 22
2.3.4
Benefit/Risk Pertaining to AZD4573 Study Conduct During the COVID-19 
Pandemic.......................................................................................................... 23
3
OBJECTIVES AND ENDPOINTS................................................................... 25
4
STUDY DESIGN ............................................................................................. 26
4.1
Overall Design.................................................................................................. 26
4.1.1
Modular Protocol Structure............................................................................... 27
4.1.2
Module Naming Conventions ........................................................................... 28
4.1.3
Regulatory Amendment for Additional Modules ............................................... 28
4.1.3.1
Europe and Rest of World ................................................................................. 29
4.1.3.2
United States of America .................................................................................. 29
4.1.4
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 29
4.2
Scientific Rationale for Study Design ............................................................... 30
4.3
Justification for Dose........................................................................................ 31
4.4
End of Study Definition.................................................................................... 31
5
STUDY POPULATION.................................................................................... 31
5.1
Inclusion Criteria .............................................................................................. 31
5.2
Exclusion Criteria ............................................................................................. 36
5.3
Lifestyle Considerations ................................................................................... 39
5.4
Screen Failures ................................................................................................. 39


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STUDY INTERVENTION ............................................................................... 40
6.1
Study Intervention(s) Administered................................................................... 40
6.2
Preparation/Handling/Storage/Accountability ................................................... 40
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 40
6.4
Study Intervention Compliance......................................................................... 41
6.5
Concomitant Therapy........................................................................................ 41
6.6
Dose Modification ............................................................................................ 43
6.7
Intervention after the End of the Study.............................................................. 43
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 44
7.1
Discontinuation of Study Intervention............................................................... 44
7.1.1
Criteria for stopping or pausing the study recruitment....................................... 45
7.2
Participant Withdrawal from the Study.............................................................. 46
7.3
Lost to Follow up.............................................................................................. 46
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 47
8.1
Efficacy Assessments........................................................................................ 47
8.2
Safety Assessments........................................................................................... 47
8.2.1
30-Day Follow-up Visit .................................................................................... 48
8.2.2
Long-term Follow-up Visit................................................................................ 48
8.2.3
Survival Follow-up ........................................................................................... 48
8.3
Adverse Events and Serious Adverse Events..................................................... 48
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 49
8.3.2
Follow-up of AEs and SAEs ............................................................................. 49
8.3.3
Causality Collection.......................................................................................... 50
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 50
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 51
8.3.6
Adverse Events of Special Interest.................................................................... 51
8.3.7
Potential Hy’s Law Cases ................................................................................. 52
8.3.8
Disease Progression and Disease Under Study.................................................. 52
8.3.9
Reporting of Serious Adverse Events ................................................................ 52
8.3.10
Pregnancy......................................................................................................... 53
8.3.10.1
Maternal Exposure............................................................................................ 53
8.3.10.2
Paternal Exposure............................................................................................. 54
8.3.11
New Cancers..................................................................................................... 54
8.3.12
Deaths .............................................................................................................. 55
8.3.13
Medication Error............................................................................................... 55
8.4
Overdose .......................................................................................................... 56
8.5
Human Biological Samples............................................................................... 56
8.5.1
Pharmacokinetics.............................................................................................. 57
8.5.2
Pharmacodynamics........................................................................................... 57
8.5.3
Immunogenicity Assessments ........................................................................... 57
8.6
............................................................. 57
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8.7
Optional Genomics Initiative Sample................................................................ 57
8.8
Health Economics............................................................................................. 58
9
STATISTICAL CONSIDERATIONS................................................................ 58
9.1
Statistical Hypotheses....................................................................................... 58
9.2
Sample Size Determination............................................................................... 58
9.3
Populations for Analyses................................................................................... 58
9.4
Statistical Analyses ........................................................................................... 58
9.4.1
General Considerations..................................................................................... 58
9.4.2
Efficacy Analyses ............................................................................................. 59
9.4.3
Safety Analyses ................................................................................................ 59
9.4.4
Pharmacokinetic Analyses ................................................................................ 60
9.4.5
Pharmacodynamics 
 Analyses........................................... 60
9.5
Interim Analyses............................................................................................... 60
9.6
Data Monitoring Committee ............................................................................. 60
10
MODULE 1...................................................................................................... 61
10.1
Summary – Module 1........................................................................................ 61
10.1.1
Schema............................................................................................................. 61
10.1.2
Schedule of Activities ....................................................................................... 62
10.2
Introduction – Module 1 ................................................................................... 67
10.3
Objectives and Endpoints – Module 1............................................................... 67
10.4
Study Design – Module 1.................................................................................. 68
10.4.1
Module 1 Design: AZD4573 monotherapy........................................................ 69
10.4.2
Justification for Dose........................................................................................ 71
10.4.3
End of Module Definition................................................................................. 72
10.4.4
Safety Review Committee................................................................................. 72
10.5
Study Population – Module 1............................................................................ 73
10.6
Study Intervention – Module 1.......................................................................... 73
10.6.1
Dose Modification ............................................................................................ 74
10.6.2
Prevention and Toxicity Management of Risks for AZD4573 Monotherapy...... 78
10.6.2.1
Tumour Lysis Syndrome (TLS)......................................................................... 79
10.6.2.2
Transaminases Increase With or Without Concomitant Bilirubin Increase and 
the Risk of Liver Injury..................................................................................... 82
10.6.2.3
Diarrhoea.......................................................................................................... 83
10.6.2.4
Nausea and Vomiting ........................................................................................ 84
10.6.2.5
Neutropenia and Febrile Neutropenia................................................................ 84
10.6.2.6
Infection/Bone Marrow Toxicity with Peripheral Effect/Lymphoid Tissue 
Hypocellularity................................................................................................. 85
10.6.2.7
Pancreatic and Cortical Adrenal Injury (as well as Surveillance for Renal, 
Thymus, and Spleen Toxicity)........................................................................... 85
10.6.2.8
Drug-Drug Interactions..................................................................................... 85
10.6.2.9
Myocardial Ischaemia and Heart Rate Increase ................................................. 86
10.6.3
Criteria for Restarting Treatment....................................................................... 86
10.7
Discontinuation 
of 
Study 
Intervention 
and 
Participant 
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CONSIDERATIONS ...................................................................................... 115
12
REFERENCES............................................................................................... 145
LIST OF FIGURES
Figure 1
AZD4573 Modular Phase II CSP in r/r PTCL and r/r cHL ....................... 13
Figure 2
.... 16
Figure 3
.... 16
Figure 4
Effect of AZD4573 on OS in Angioimmunoblastic T-cell Lymphoma 
Patient-derived Xenograft Model (DFTL-78024; n = 5)........................... 17
Figure 5
Module 1 Schema: AZD4573 Monotherapy in Participants with r/r 
PTCL and r/r HL ..................................................................................... 61
Figure 6
Module 1 AZD4573 Monotherapy Dosing Regimen in PTCL and cHL 
including Intra-Participant Dose Ramp-Up .............................................. 69
LIST OF TABLES
Table 1
Module 1: Planned Response-evaluable Participant Population................ 12
Table 2
Risk Assessment...................................................................................... 20
Table 3
Objectives and Endpoints......................................................................... 25
Table 4
Module Naming Conventions .................................................................. 28
Table 5
Criteria for Adequate Haematological Function ....................................... 33
Table 6
Criteria for Adequate Organ Function...................................................... 33
Table 7
Prohibited Concomitant Therapies ........................................................... 42
Table 8
Permitted Concomitant Therapies (Conditional) ...................................... 42
Table 9
Schedule of Activities: Module 1 (AZD4573 Monotherapy) .................... 62
Table 10
Module 1: Planned Response-Evaluable Participant Population ............... 70
Table 11
Recommended Dose Modifications for AZD4573.................................... 74
Table 12
Recommended Dose Modifications for AZD4573 for Abnormal Liver 
Chemistry Test Results ............................................................................ 76
Table 13
Mandatory TLS Prophylaxis Guidance (in Addition to Institutional 
Guidance)................................................................................................ 80
Table 14
The Lugano Response Criteria................................................................. 88
Table 15
Radiologic Scans and PET Scans for Tumour Assessments...................... 91
Table 16
Laboratory Safety Variables..................................................................... 98
Table 17
Exploratory Whole Blood Analyses Samples (All Participants).............. 102
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Table 18
 Sampling Schedule (All Participants) ............ 108
Table 19
Sample Size: Module 1 .......................................................................... 109
Table 20
............................................. 110
Table 21
............................................... 111
Table 22
Populations for Analyses ....................................................................... 112
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 116
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 121
Appendix C
Handling of Human Biological Samples ................................................ 126
Appendix D
Optional Genomics Initiative Sample..................................................... 128
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 131
Appendix F
Abbreviations ........................................................................................ 137
Appendix G
Cairo-Bishop Tumour Lysis Syndrome Definition and Grading Criteria 
(Howard Modification) .......................................................................... 141
Appendix H
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 143
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1.2
Schema
Please see the individual schema for each study module within the respective protocol section. 
Figure 1
AZD4573 Modular Phase II CSP in r/r PTCL and r/r cHL
a
Additional AZD4573 combination modules in r/r PTCL or r/r cHL may be added pending new pre-clinical/clinical data. Combination risk assessment for 
PTCL and cHL to be performed when their respective clinical monotherapy profiles are understood.
Abbreviations: AE, adverse events; cHL, classical Hodgkin Lymphoma; CSP, clinical study protocol; CTCAE, Common Terminology Criteria for Adverse 
Events; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; lab, clinical laboratory results; NK PTCL, natural killer/peripheral T-cell 
lymphoma; r/r, relapsed/refractory.


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1.3
Schedule of Activities
Please see the individual SoA for each study module within the respective protocol section.


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2
INTRODUCTION
AZD4573 is a potent, selective inhibitor of CDK9 that is being developed as a monotherapy 
and/or combination therapy for the treatment of several haematological malignancies, 
including r/r PTCL and r/r cHL.
2.1
Study Rationale
This is a modular, Phase II, multicentre, open label study of AZD4573 administered 
intravenously as monotherapy or in combination with other anti-cancer agents, to participants 
with r/r PTCL or r/r cHL.
As a CDK9 inhibitor, treatment with AZD4573 leads to rapid depletion of short lived gene 
transcripts, including MCL1 and BFL1 which are commonly overexpressed by cancers as a 
survival mechanism. AZD4573 induces apoptosis in cancer cells that are dependent on either
MCL1, BFL1 or both proteins for survival (Cidado et al 2020). 
Haematological malignancies exhibit a high frequency of MCL1 dependence, which is 
consistent with known lineage expression and dependency patterns of Bcl2 family 
anti-apoptotic proteins during haematopoiesis. Whereas CDK9 and MCL1 inhibitors exhibit 
similar preclinical activity profiles across leukaemias and myeloma, a number of lymphoma 
models which are insensitive to MCL1 inhibition are sensitive to acute CDK9 inhibition. This 
is due to additional dependence on, and AZD4573-mediated modulation of, BFL1 in 
lymphomas (Boiko et al 2020). BCL2A1, the gene encoding BFL1, is a target of NF-κB 
signalling, which is frequently dysregulated in many lymphomas, including PTCL and cHL. 
 
 
 
 
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Figure 4
Effect of AZD4573 on OS in Angioimmunoblastic T-cell Lymphoma 
Patient-derived Xenograft Model (DFTL-78024; n = 5)
Abbreviations: n, number; OS, overall survival.
Source: Cidado et al 2020
Module 1 of this study explores AZD4573 monotherapy in these patient populations; if 
monotherapy treatment shows anti-tumour efficacy in r/r PTCL or r/r cHL, AZD4573 may be 
investigated in combination with other anti-cancer agents for greater efficacy. In this case, 
combination therapy modules will be added to the study via a protocol amendment.
The overarching primary hypothesis for this study is: AZD4573 will demonstrate anti-tumour 
efficacy, as monotherapy or in combination with other anti-cancer agents, in participants with 
either r/r PTCL or r/r cHL. 
2.2
Background
Peripheral T-cell lymphomas represent a small heterogeneous subgroup of non-Hodgkin 
lymphomas (Swedlow et al 2017). Approximately 80000 new cases of non-Hodgkin 
lymphoma are diagnosed annually in the United States (Cancer Stat Facts: Non-Hodgkin 
Lymphoma) and 123000 cases annually in Europe (GLOBOCAN 2020). Less than 10% of 
these cases are PTCL (Armitage et al 2004). There are > 20 subtypes of PTCL and the main 
subtypes are: PTCL not otherwise specified (~30%), angioimmunoblastic T-cell lymphoma 
(AITL; 15% to 30%), anaplastic large cell lymphoma (ALCL; ~15%), and natural killer T-cell 
lymphoma (NKTCL; ~10%; Fiore et al 2020). Notably, the incidence of PTCL and proportion 
of subtypes differ across global regions. Of 240000 cases of non-Hodgkin lymphomas 
diagnosed annually in Asia (GLOBOCAN 2020), 15% to 30% are classified as PTCL. Hence, 
in contrast to the US and Europe, NKTCL is the major PTCL subtype in Asia (Park and Ko 
2014).
Most PTCL patients progress after receiving first line chemotherapy-based protocols, with or 
without auto-HSCT. Currently, 3 drugs are approved (as accelerated approvals) by the FDA 


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for use in all subtypes of r/r PTCL: pralatrexate (a novel antifolate agent); romidepsin; and
belinostat (histone deacetylase inhibitors). Of these, pralatrexate and romidepsin are also 
approved in Japan (along with several other therapies approved on the basis of single-arm trial 
data); and none are approved in the EU. None of these drugs provide a cure and the ORR is 
only 25% to 30% (Zain 2019). In addition, the anti-CD30 antibody-drug conjugate BV is 
approved for relapsed ALCL or CD30+ PTCL in the United States, EU, and Japan, based on 
an ORR of 86%. Patients with r/r PTCL, including patients with ALCL relapsing after BV, 
have limited treatment options and poor outcomes underscoring the high unmet medical need 
in these patient populations.
Classical Hodgkin Lymphoma (cHL) is a unique haematopoietic neoplasm characterised by 
cancerous Reed Sternberg cells. Approximately 9000 new cases of HL present each year in the 
US, ~20000 in Europe, and ~14000 in Asia (GLOBOCAN 2020). In HL the cure rate is high, 
which is reflected by a 5-year OS after initial diagnosis of 80% to 90% (Cancer Stat Facts: 
Hodgkin Lymphoma.). Historically, treatment has been based on chemotherapy and 
radiotherapy in first line and adding auto-HSCT in second line treatment. In recent years, BV 
and the anti-PD1 check point inhibitors nivolumab and pembrolizumab have been introduced 
as new approved treatments for cHL in the US (nivolumab under accelerated approval), EU, 
and Japan. Although these novel treatments have demonstrated high response rates, the 
majority of r/r cHL patients do not achieve durable remission and go on to develop 
progressive disease, highlighting the continuing need for additional treatments in this patient 
population (Connors et al 2020; Chen et al 2016; Chen et al 2019; Kuruvilla et al 2021). 
AZD4573 (formerly known as AZ13810325) is a potent and selective inhibitor of CDK9 with 
nanomolar potency against the enzyme (IC50 < 4nM) and excellent selectivity over other 
CDK family members. AZD4573 decreases pSer2RNAP2 levels (the phosphorylation levels 
of Ser2 found in the carboxyl-terminus domain of RNA polymerase II [RNAP2]). This 
decrease in pSer2RNAP2 is linked to preferential reduction of labile proteins like the Bcl2 
family anti-apoptotics MCL1 and BFL1 as well as other well-known oncoproteins like Myc, 
which leads to rapid induction of apoptosis in a broad range of human cancer cell lines 
derived from haematological malignancies (Cidado et al 2020, Boiko et al 2020). 
In a first time in human study (Study D8230C00001), the safety and tolerability of AZD4573 
monotherapy have been demonstrated in B cell non-Hodgkin lymphoma at the established 
RP2D of 12 mg 1QW starting with an intra-participant dose ramp-up. Furthermore, 
anti-lymphoma activity was reported in DLBCL patients. No patients with PTCL or cHL were 
enrolled in the study.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD4573 is 
provided in the IB.


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2.3
Benefit/Risk Assessment
More detailed information about the known and anticipated benefits and potential risks of
AZD4573 may be found in the IB and the relevant modules.
Refer to individual study modules for the benefit/risk assessment of other anti-cancer agents in 
combination with AZD4573.
2.3.1
Risk Assessment
The safety and tolerability of AZD4573 monotherapy at the established lymphoma RP2D 
(12 mg 1QW including intra-participant ramp-up) have already been demonstrated in the first 
time in human study (Study D8230C00001).
Based on nonclinical toxicology findings and clinical experience to date, including experience 
from other medicinal products in the same class, the following have been assessed as risks for 
AZD4573:


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Table 2
Risk Assessment
Potential risk of clinical 
significance
Summary of data/rationale for 
risk
Mitigation strategy
Important identified risks:
•
TLS
•
Transaminases increase
•
Bilirubin increase with 
transaminase (ALT or AST 
or both ALT and AST) 
increase
•
Diarrhoea
•
Nausea
•
Vomiting
•
Neutropenia (includes 
neutrophil count decreased)
•
Febrile neutropenia
Important potential risks:
•
Gastro-intestinal toxicity
•
Infection/bone marrow 
toxicity with peripheral 
effect/lymphoid tissue 
hypocellularity
•
Liver injury
•
Neutropenic sepsis
Potential risks for AZD4573 
include:
•
Pancreatic injury
•
Cortical adrenal injury
•
Drug-drug interactions
•
Myocardial ischaemia
•
Heart rate increase
Risks identified based on 
nonclinical and clinical data 
available to date.
These risks are monitored via 
routine pharmacovigilance 
activities and standard treatment 
practices. Further details of these 
risks can be found in the 
AZD4573 IB.
Risk minimisation activities are 
reflected in the study protocol 
specific inclusion and exclusion 
criteria, alongside the safety 
monitoring strategy (Section 8), 
dose modification guidance 
(Section 6.6), toxicity management 
guidelines (per module), and 
concomitant medication guidance 
(Section 6.5).
Additionally, enrolled participants 
will have been screened for 
adequate bone marrow function 
prior to commencing AZD4573 as 
per the exclusion criteria in the 
protocol.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; TLS, tumour lysis syndrome.
For a complete characterisation for each risk please refer to the IB for AZD4573. 
In general, the protocol includes measures such as frequent monitoring of blood counts and 
serum chemistry, along with other additional monitoring. A urine dip stick test will be also be 
performed, where a positive test will trigger urine microanalysis for the presence of casts (red 
cell and protein casts). For a summary of management for each risk, including dose 
modifications, see Section 6.6 and the Dose Modification section of the relevant module. 
In addition to these risks, embryo-foetal and reproductive toxicity is Missing information in 
relation to AZD4573.


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No reproductive toxicology or teratogenic studies have been conducted with AZD4573 to 
date, and it is unknown whether the drug is excreted in human milk. Therefore, WOCBP and 
men should agree to use highly effective contraception as specified in Section 5.1, and women 
who are breast feeding are excluded from the study. Women and men should be fully informed 
of the lack of reproductive toxicity testing, and women must have a negative pregnancy test 
before receiving IP.
AstraZeneca has procedures in place to ensure that new or emerging, important clinical safety 
findings are handled in accordance with a global best practises. This guarantees that 
AstraZeneca’s safety reporting obligations to Regulatory Authorities, investigators, and Ethics 
Committees are met and optimal risk management of participants is maintained. These 
procedures have been developed to be consistent with “ICH E2A Clinical Safety Data 
Management: Definitions and standards for reporting”, which provides guidance to support 
that serious unexpected adverse drug reactions information must be provided as early as early 
as possible, but no later than 7 days (fatal/life threating event) or otherwise 15 days. 
Safety issues may arise during or after a participant has completed the trial. Important clinical 
safety issues are those findings that might adversely influence the benefit-risk assessment of a 
medicinal product. Upon review of such findings, AstraZeneca may decide to communicate 
the finding in an expedited manner, so that investigators can manage participants accordingly 
and ensure that a positive risk benefit is maintained. AstraZeneca commits that any changes to 
the dosing, dose schedule, or any aspect of participant care, as a result of any new or emerging 
clinical safety finding, are handled in a way that is consistent with global best practises.
The majority of toxicities observed with AZD4573 to date have been gastrointestinal (nausea, 
vomiting, and diarrhoea), haematological (neutropenia, febrile neutropenia, and 
thrombocytopenia), hepatic (transaminase increase with or without concomitant bilirubin 
increase) and TLS. These toxicities are manageable with appropriate prophylaxis and 
treatment, and by dose modification.
Regarding the hepatic toxicity events, it has been observed that whilst the biochemical 
changes of increased transaminase with concomitant elevation in bilirubin seen in some 
participants could be classified as Hy’s law by its strict definition, they do not follow a pattern 
that is consistent with true Hy’s law predictive of severe hepatic injury (see the AZD4573 IB). 
The events are rapidly resolved and to date have not led to any clinical sequelae or lasting 
hepatic injury. Repeated dosing with AZD4573 following these events does not lead to 
adverse clinical sequelae or consistent increase in severity of events.
The safety and tolerability of AZD4573 monotherapy at the established lymphoma RP2D 
(12 mg 1QW including intra-participant dose ramp-up) have already been demonstrated in the 
first time in human study (Study D8230C00001). 


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2.3.2 Benefit Assessment
AZD4573 has the potential to provide clinical benefit in terms of anti-tumour efficacy, as 
monotherapy and in combination with other anti-cancer treatments, in participants with
relapsed/refractory PTCL or cHL.
Nonclinical studies support the hypothesis that inhibiting CDK9 may be a valid target for the 
treatment of haematological malignancies including lymphomas (Section 2.1). Furthermore, 
preliminary anti-tumour activity has been observed with AZD4573 as monotherapy in 
participants with relapsed or refractory haematological malignancies in the ongoing FIH, 
Phase I dose escalation study (Study D8230C00001). Best objective responses included 1 CR, 
1 PR, and 4 SD in 17 dosed participants with DLBCL. Signs of clinical activity were also
observed in participants with other haematological malignancies, such as CLL, AML, and 
MM.
In patients with r/r PTCL who have limited treatment options and patients with r/r cHL who 
have exhausted standard of care and not achieved remission, the potential clinical benefits 
with AZD4573 warrant investigation, as current preclinical data suggest that AZD4573 is an 
attractive investigational drug for these diseases.
Please refer to the individual study modules for the benefit/risk assessments for each 
combination treatment.
2.3.3 Overall Benefit: Risk Conclusion
The safety and tolerability of AZD4573 monotherapy (RP2D 12 mg 1QW including 
intra-participant dose ramp-up) have already been demonstrated in lymphoma patients in the 
first time in human study (Study D8230C00001).
Furthermore, taking into account the measures taken to minimise risk to participants in the 
current study, including specific monitoring and dose modification criteria specified in the 
protocol for cases of transaminase +/- bilirubin increase, the safety risks identified in 
association with AZD4573 are justified by the anticipated benefits that may be afforded to 
participants with r/r PTCL or r/r cHL.
The benefit-risk assessment for AZD4573 in combination with other anti-cancer therapies will 
be addressed in individual study modules following their addition by protocol amendment.
Please see Section 2.3.4 for the benefit/risk assessment pertaining to the conduct of this study 
during the COVID-19 pandemic.


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2.3.4
Benefit/Risk Pertaining to AZD4573 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 SARS-CoV-2 
(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 of developing 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 Phase II study will enrol participants with r/r PTCL and r/r cHL. Participants in this study 
will receive AZD4573, which leads to inhibition of CDK9. In Module 1, they will not be 
receiving chemotherapy, radical radiotherapy, immunotherapy, or other continuing antibody 
treatments for cancer as part of the treatment strategy. Overall, the study treatment and 
procedures received during the course of this study are considered to have low risk for 
increasing susceptibility to COVID-19 infection. 
Furthermore, this study population would typically have frequent healthcare-related clinic 
visits, irrespective of the participation in a study. Therefore, it is anticipated that overall, 
participation in this clinical study should not significantly increase this population’s risk of 
exposure to COVID-19 infection. 
The scheduled safety monitoring with increased clinic visits compared to standard of care 
monitoring are intended to protect participants in the study, but there may be increased risk to 
participants by exposure to SARS-CoV-2 due to study visits. However, this risk is offset by 
the benefit that participants may receive in the form of an extended period of PFS.
In accordance with EMA and FDA guidelines (EMA-CTFG-EC 2021, 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 COVID-19-
related disruption.
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 H 1 (as a supplement to the standard consent 
procedures in Appendix A 3). Any deviations to the protocol necessary to safeguard 
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and any permanent changes requiring an amendment to the protocol will be communicated to 
Regulatory Authorities and IRBs/IECs in line with relevant local guidance and procedures.






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Further modules may be added via protocol amendment. Study information applicable to all 
participants in this study is described in the core sections of this protocol; the rationale for 
each study treatment and cohort, and specific study information and assessments will be 
described in each separate module. This study is planned to take place in approximately 
30 centres across 10 countries. 
Module 1 will assess the efficacy, safety, tolerability, and PK of AZD4573 as a monotherapy 
in r/r PTCL and r/r cHL populations and explore pharmacodynamics in these disease subtypes. 
If AZD4573 monotherapy is found to have promising anti-tumour efficacy in Module 1, an 
AZD4573 monotherapy Phase II expansion may be added via a substantial protocol
amendment. Additional modules may also be added via substantial protocol amendments to 
assess AZD4573 in combination with other anti-cancer agents in r/r PTCL or r/r cHL based on 
emerging preclinical and clinical data and study rationale.
Future modules may include an initial combination dose confirmation phase, dependent on the 
AZD4573 combination partner being evaluated. The planned intra-participant dose escalation, 
the cohort escalation scheme, and the dosing schedule may be amended in light of emerging 
PK, safety, pharmacodynamic data and available efficacy data, which will be reviewed on an 
ongoing basis throughout the study.

A study-specific SRC will provide ongoing safety surveillance of the study, with 
regularly scheduled reviews of safety, PK, and other relevant data (see study design 
section of the relevant module).

The end of module is defined as the last scheduled visit or contact of the last 
participant enrolled in the module (Section 4.4).

The end of the study is defined as the last visit of the last participant undergoing the 
study, or as the last scheduled procedure shown in the relevant module’s SoA for the 
last participant in the study globally (Section 4.4).
4.1.1
Modular Protocol Structure
The structure of the protocol will also follow a modular design. Information relating to the 
overall study, including study objectives, rationale, core inclusion and exclusion criteria, 
safety assessments, and AE reporting can be found in this core protocol module (ie, Sections 1
to 9).
The starting dose/schedule of AZD4573 in further combination modules will not exceed the 
equivalent maximum dose of AZD4573 found to be tolerated in the monotherapy Module 1 or 
from other studies in the clinical programme at that point.
Study drug-specific information including doses and justifications, toxicity management, dose 


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modifications, and concomitant medications can be found in the relevant module.
4.1.2
Module Naming Conventions
The study will consist of 1 initial module (Module 1) evaluating the efficacy, safety, and 
tolerability of AZD4573 as monotherapy in participants who have either r/r PTCL or r/r cHL. 
Additional modules may be added by substantial amendment evaluating AZD4573 in 
combination with other anti-cancer agents in the r/r PTCL or r/r cHL population.
Table 4
Module Naming Conventions
Module
Tumour type
Intervention
Module 1 – Monotherapy
r/r PTCL
r/r cHL
AZD4573
Naming convention for potential combination therapy modulesa
Module X – AZD4573 + [combination treatment]
r/r PTCL
AZD4573 + 
[combination treatment]
Module Y – AZD4573 + [combination treatment]
r/r cHL
AZD4573 + 
[combination treatment]
a
Anticipated combination treatment modules will be numbered per the order added to the study protocol
(Module 1, Module 2, Module 3, ect). The order of addition of the combination treatment modules is to be 
determined based on clinical and nonclinical data.
Abbreviations: cHL, classical Hodgkin Lymphoma; PTCL, peripheral T-cell lymphoma; r/r, relapsed/refractory.
4.1.3
Regulatory Amendment for Additional Modules
New modules may be added in the future to assess treatment combinations in either r/r PTCL 
or r/r cHL. Up to 5 additional combination modules may be added. The combination partners
may include, but are not limited to, the following options: romidepsin, belinostat, pralatrexate, 
anti-PD1, and BV.
To support amendment of the protocol for additional modules/cohorts, AstraZeneca will 
provide a summary of all nonclinical and clinical data to support the cohort expansion or any 
new proposed combination treatment and dosing schedule; this will include updating the 
following:

Study objectives

Background information providing rationale for the proposed patient population(s) and 
the proposed treatment plan(s)

Study eligibility criteria

A detailed description of the proposed study treatment plans

A revised schedule of participant assessments


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
A summary of safety data from the completed or ongoing cohort(s)/modules(s) and the 
proposed toxicity management plans for any proposed new combination.

A description of any dose modifications and the data (clinical safety information, clinical 
PK data, and nonclinical data) that support the safety of the proposed dose modifications 
for the regimen in question.

A clearly stated sample size and justification for the proposed sample size based on the 
objectives for that specific cohort/module.

A detailed description of the method and performance characteristics of any test that will 
be used to identify the patient population to be enrolled in the cohort/module, if the 
population will be selected based on a diagnostic assay.
4.1.3.1
Europe and Rest of World
AstraZeneca will provide a substantial amendment for review and approval.
4.1.3.2
United States of America
AstraZeneca will provide an amendment to the FDA 60 days in advance of planned enrolment 
in a module for any combination involving a drug for which the recommended Phase II dose 
has not been determined for the proposed dosage regimen to be employed, or at least 30 days 
in advance of a planned enrolment in a module for drugs where the recommended Phase II 
dose has been determined for the proposed dosage regimen to be employed. AstraZeneca will 
begin enrolment of participants into that module in the United States after IRB approval.
4.1.4
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. 
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 


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
Obtaining reconsent for the mitigation procedures (note, in the case of verbal reconsent,
the ICF should be signed at the participant’s next contact with the study site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. The 
investigator should confirm this with the designated study physician. 

Home or Remote visit: Performed by a site qualified HCP or HCP provided by a TPV.

Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 

At-home IP administration: Performed by a site qualified HCP, HCP provided by a TPV, 
or by the participants or the participant’s caregiver, if possible and appropriate for the 
therapy. Additional information related to the visit can be obtained via telemedicine. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix H. 
4.2
Scientific Rationale for Study Design
This is a modular, Phase II, multicentre, open-label, dose confirmation and expansion study 
primarily designed to establish the efficacy of AZD4573, administered as monotherapy or 
combination therapy, to participants with either r/r PTCL or r/r cHL. The study will also 
confirm the safety profile and PK of the module-defined AZD4573 monotherapy or
combination therapy in these populations, and explore potential biological activity by 
assessing
 pharmacodynamics for anti-tumour efficacy. Module 1 
will assess the efficacy of AZD4573 as a monotherapy in r/r PTCL and r/r cHL populations.
If AZD4573 monotherapy is found to have promising anti-tumour efficacy in Module 1, an 
AZD4573 monotherapy Phase II expansion may be added via a substantial protocol
amendment. Additional modules may also be added via substantial protocol amendments to 
assess AZD4573 in combination with other anti-cancer agents in r/r PTCL or r/r cHL based on 
emerging preclinical and clinical data and study rationale. Future modules may include an 
initial combination dose confirmation phase, dependent on the AZD4573 combination partner
being evaluated. The planned intra-participant dose escalation, the cohort escalation scheme, 
and the dosing schedule may be amended in light of emerging PK, safety, and 
pharmacodynamic and available efficacy data, which will be reviewed on an ongoing basis 
throughout the study. 
The results from this study will form the basis for decisions for future studies. Biological 
samples will be collected in order to establish an archive and allow future meta-analysis of 
data derived from a number of studies with AZD4573.
CCI


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The statistical rationale for the study design and sample size criteria are provided in the 
respective modules. 
4.3
Justification for Dose
Information on dose justification is provided in the respective modules.
4.4
End of Study Definition
A participant is considered to have completed the study if they have completed all parts of the 
study including the last visit or the last scheduled procedure shown in the SoA.
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the study globally. The 
end of module is defined as the last scheduled visit or contact of the last participant enrolled in 
the module; see the relevant module for more information.
The results from each module will be reported to Regulatory Authorities within 1 year of the 
end of the module.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
All criteria and considerations listed in this section are for the core study design and apply to 
all modules of the study. Additional, module-specific criteria and considerations are listed in 
the study population section of the relevant module.
5.1
Inclusion Criteria
The below are the core inclusion criteria for all modules of the study; all participants must 
meet the criteria described in the relevant module in addition to those described below. Where 
module-specific criteria are more stringent than core study criteria, the module-specific 
criteria take precedent. 
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
1
Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
2
Provision of signed and dated, written informed consent prior to any mandatory 
study-specific procedures, sampling, and analyses. 


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3
Provision of signed and dated written Optional Genetic Research Information ICF is 
required prior to collection of samples for optional genetic research that supports the
Genomic Initiative.
Age
4
Participant must be at least 18 years of age inclusive at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
5
Participants who are diagnosed with one of the following, as defined by the World Health 
Organisation:
(a) Peripheral T-cell Lymphoma
(b) Classical Hodgkin Lymphoma
6
Eastern Cooperative Oncology Group performance status of ≤ 2.
7
Must have received at least 1 prior line of therapy for the treatment of current disease and 
have documented relapsed or refractory active disease requiring treatment, defined as:
(a) Recurrence of disease after response to prior line(s) of therapy, or
(b) Progressive disease after completion of or on the treatment regimen preceding entry 
into the study, or
(c) Disease which did not achieve an objective response (CR or PR).
8
Prior lines of therapy:
(a) PTCL: Participants must have failed at least 1 prior therapy for the treatment of 
PTCL.
(i)
Non NK-PTCL: Prior therapy must have included an alkylating agent and/or 
anthracycline. In addition, ALCL participants must have received BV as part of 
prior therapy.
(ii) NKTCL: Prior treatment must have included asparaginase and/or a platinum 
agent.
(b) cHL: Participants must have failed at least 2 prior therapies for the treatment of cHL 
(including BV and anti-PD1) except where unable to receive BV or anti-PD1 due to 
neuropathy or autoimmune disease.
9
Presence of at least 1 radiographically measurable, FDG-avid lymphoma disease lesion
>1.5cm (according to the Lugano criteria [Cheson et al 2014]).
10 Uric acid level < ULN at screening. If hyperuricaemia is present at screening, SoC 
therapy should be administered (including IV fluid and rasburicase or allopurinol) to 
reduce the uric acid levels to < ULN before the start of study intervention.
11 Willing and able to participate in all required evaluations and procedures in this study 
protocol including receiving IV administration of study drug and being admitted, if
required, for at least 24 hours during study drug administration.


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12 Fresh tumour tissue or archival tumour tissue must be confirmed to be available at 
screening. 
13 Adequate haematologic function at screening (Table 5).
(a) No growth factor support within 14 days prior to the date of the screening laboratory 
assessment.
(b) No transfusions within 7 days prior to the date of the screening lab assessment.
Table 5
Criteria for Adequate Haematological Function
Category
Parameter
Value
Haematologic
Haemoglobin
≥ 8.0 g/dL
Absolute neutrophil count
≥ 1000 cells/mm3 (1.0 × 109/L)
Platelet count
≥75000 cells/mm3 (75 × 109/L) 
without bone marrow involvement
≥50000 cells/mm3 (50 × 109/L) 
with bone marrow involvement
14 Adequate organ function at screening as defined below in Table 6.
Note that 1 rescreen is permitted for participants if required, in line with Section 5.4. 
Table 6
Criteria for Adequate Organ Function
Category
Parameter
Value
Hepatic
Bilirubin
≤ 1.5 × ULN in the absence of 
Gilbert’s syndromea
≤ 3 × ULN if the participant has 
Gilbert’s syndromea
Alanine transaminase and 
aspartate transaminase
≤3 × ULN
Renal
Calculated creatinine clearance by 
Cockcroft Gault equation 
[(140-Age) • Mass (kg)/(72 • 
creatinine mg/dL) • multiply by 
0.85 if female])
≥ 60 mL/minute
Coagulation
INR
< 1.5 × ULN
Pancreatic
Lipase
≤ 3 × ULN and no ongoing
pancreatitis
Amylase
≤ 3 × ULN and no ongoing 
pancreatitis
Cardiac
LVEF as assessed by 
echocardiography MUGAb
≥ 40%
a
Gilbert’s syndrome = ratio between total and direct bilirubin > 5.


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b
Appropriate correction to be used, if a MUGA is performed.
Abbreviations: INR, International Normalised Ratio; LVEF, left ventricular ejection fraction; MUGA, multi-
gated acquisition scan; ULN, upper limit of normal.
15 PTCL Only: All participants with PTCL must be willing and able to provide mandatory 
baseline bone marrow aspirate and/or biopsy no older than 3 months, and agree to 
undergo post-treatment bone marrow biopsy when required to confirm response.
Reproduction
16 Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
(a) Male participants:
(i)
Male participants must be willing to use barrier contraception (ie, condoms) for 
the duration of the study plus a further 4 months after discontinuing AZD4573. 
Non-pregnant WOCBP partners of male participants should use highly effective 
methods of contraception (defined below) for the duration of the study and for a 
washout period of 4 months after discontinuing AZD4573.
(ii) Male participants should refrain from donating sperm from the start of dosing 
until 4 months after discontinuing AZD4573. If male participants wish to father 
children, they should be advised to arrange for freezing of sperm samples before 
the start of receiving AZD4573.
(b) Female participants:
(i)
Female participants must be either women not of childbearing potential (defined 
below), or must use one highly effective form of birth control (defined below)
from 3 months prior to enrolment (the participant should have been stable on 
their chosen method of birth control for a minimum of 3 months before entering 
the study), throughout the study, and until 7 months after last dose of study 
intervention.
(ii) All WOCBP must have a negative serum pregnancy test result at Visit 1.
(iii) Female participants must not donate, or retrieve for their own use, ova from the 
time of start of dosing and throughout the study treatment period, and for at least 
7 months after the final study drug administration.

Women not of childbearing potential are defined as women who are either 
permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Women will be considered 
postmenopausal if they have been amenorrhoeic for 12 months prior to first 
dose of study drug without an alternative medical cause. The following age-
specific requirements apply:


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
Women < 50 years old would be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more following cessation of exogenous 
hormonal treatment and follicle stimulating hormone levels in the 
postmenopausal range.

Women ≥50 years old would be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more following cessation of all 
exogenous hormonal treatment.
(iv) Women of childbearing potential must use one highly effective form of birth 
control. A highly effective method of contraception is defined as one that can 
achieve a failure rate of less than 1% per year when used consistently and 
correctly. Women of childbearing potential who are sexually active with a non-
sterilised male partner must agree to use 1 highly effective method of birth 
control, as defined below, from enrolment throughout the study and until at least 
7 months after last dose of study intervention. Cessation of contraception after 
this point should be discussed with a responsible physician. Periodic abstinence 
(calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception. Female condom and male condom should 
not be used together. 
(v) Highly effective birth control methods include: sexual abstinence (note that 
periodic abstinence methods are not acceptable methods of contraception [eg, 
calendar, ovulation, symptothermal, post-ovulation methods, declaration of 
abstinence for the duration of exposure to IMP, and withdrawal)], a 
vasectomised partner, Implanon®, bilateral tubal occlusion, intrauterine 
device/levonorgestrel intrauterine system, Depo-Provera™ injections, oral 
contraceptive, and Evra Patch™, Xulane™, or NuvaRing®. 
Genomics Initiative Research Study (Optional):
17 For inclusion in the optional Genomics Initiative component of the study, participants 
must fulfil the following additional criteria:
(a) Provision of signed and dated written Optional Genetic Research Information 
informed consent prior to collection of samples for optional genetic research that 
supports Genomic Initiative. If a participant declines to participate in the genetic 
component of the study, there will be no penalty or loss of benefit to the participant. 
The participant will not be excluded from other aspects of the study described in this 
protocol, so long as they consented to the main study.


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Bone Marrow Aspirate / Tumour Biopsy at Progression (Optional):
18 For inclusion in the optional bone marrow aspirate/tumour biopsy component of the 
study, participants must fulfil the following additional criteria:
(a) Provision of signed, written, and dated informed consent for a bone marrow aspirate 
or tumour biopsy at disease progression. If a participant declines to participate in the 
bone marrow aspirate/tumour biopsy component of the study, there will be no penalty 
or loss of benefit to the participant. The participant will not be excluded from other 
aspects of the study described in this protocol, so long as they consented to the main 
study. 
(b) Having an accessible tumour/lymphadenopathy and a stable clinical condition that 
will allow the participant to tolerate the procedure, if deemed safe and feasible by the 
investigator.
5.2
Exclusion Criteria
The below are the core exclusion criteria for all modules of the study; all participants must
meet the criteria described in the relevant module in addition to those described below. Where 
module-specific criteria are more stringent than core study criteria, the module-specific 
criteria take precedent. 
Participants are excluded from the study if any of the following criteria apply:
Type of Participant and Disease Characteristics
1
PTCL only: Presence of bulky disease (defined as largest lymphoma lesion ≥10 cm) or a 
LDH value > 3 x ULN.
2
PTCL only: Diagnosis of any of the following:
(a) Lymphoblastic/precursor T-cell lymphoma or leukaemia
(b) T-cell prolymphocytic leukaemia
(c) T-cell large granular lymphocytic leukaemia
(d) Cutaneous T-cell lymphoma (eg, primary cutaneous type ALCL, mycosis 
fungoide/Sezary syndrome).
Medical Conditions
3
With the exception of alopecia and neuropathy, presence of any unresolved 
non-haematological toxicities from prior therapy greater than CTCAE Grade 1 at the time 
of starting study treatment.
4
Presence of, or history of, CNS lymphoma, leptomeningeal disease, or spinal cord 
compression.
5
History of prior non-haematological malignancy except for the following:


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(a) Malignancy treated with curative intent and with no evidence of active disease 
present for more than 1 year prior to screening and felt to be at low risk for 
recurrence by treating physician. 
(b) Adequately treated lentigo maligna melanoma without current evidence of disease or 
adequately controlled non-melanomatous skin cancer.
(c) Adequately treated carcinoma in situ without current evidence of disease.
6
As judged by the investigator, any evidence of: 
(a) Severe or uncontrolled systemic disease (eg, severe hepatic impairment, interstitial 
lung disease [bilateral, diffuse, parenchymal lung disease]).
(b) Current unstable or uncompensated respiratory or cardiac conditions.
(c) Uncontrolled hypertension.
(d) Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as 
exhibiting ongoing signs/symptoms related to the infection and without 
improvement, despite appropriate antibiotics or other treatment).
(e) IV anti-infective treatment within 1 week before first dose of study drug.
7
Known history of infection with HIV.
8
Serologic status reflecting active hepatitis B or C infection:
(a) Participants who are hepatitis B core antibody (anti-HBc) positive and who are 
surface antigen negative will need to have a negative PCR result before enrolment. 
Those who are hepatitis B surface antigen positive or hepatitis B PCR-positive will 
be excluded.
(b) Participants who are hepatitis C antibody positive will need to have a negative PCR 
result before enrolment. Those who are hepatitis C PCR-positive will be excluded.
9
Any of the following cardiac criteria:
(a) Resting QT interval corrected using Fridericia’s formula (QTcF) ≥ 470 msec 
obtained from a single ECG.
(b) Any clinically important abnormalities in rhythm (except for participants with a 
pacemaker in place), conduction or morphology of resting ECG (e.g., complete left 
bundle branch block, third degree heart block).
(c) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, congenital long QT syndrome, family history of long QT 
syndrome or unexplained sudden death under 40 years of age.
10 Documented confirmation and ongoing treatment of adrenal gland insufficiency or 
pancreatitis.
11 Undergone any of the following procedures or experienced any of the following 
conditions within 6 months prior to first dose:
(a) Coronary artery bypass graft


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(b) Angioplasty
(c) Vascular stent: 
(i)
A participant who has had a cardiac stent or arterial stent implanted within 6 
months prior to first dose, is not eligible for the study.
(ii) A participant who has had a venous stent implanted within 6 months prior to first 
dose, is eligible for the study.
(d) Myocardial infarction
(e) Angina pectoris
(f) CHF (New York Heart Association Class ≥ 2)
(g) Ventricular arrhythmias requiring continuous therapy
(h) Atrial fibrillation, which is judged as uncontrolled by the treating physician
(i)
Haemorrhagic or thrombotic stroke, including transient ischemic attacks or any other 
CNS bleeding.
Prior/Concomitant Therapy
12 Treatment with any of the following:
(a) Received major surgery (as defined by the investigator) or immunotherapy 
(specifically immune checkpoint inhibitors) within 28 days.
(b) Received cytotoxic chemotherapy, standard anti-lymphoma therapy, or radiation 
therapy within 14 days of receiving the first dose of study treatment. 
(c) Received adoptive cellular therapy such as autologous or donor NK cell or 
T lymphocyte infusions [eg, CAR-T cells]) within 90 days.
(d) Received an investigational drug within 14 days of the first scheduled dose or not 
recovered from associated toxicities.
(e) Participants who have previously received an autologous SCT are excluded if less 
than 90 days have elapsed from the time of transplant or the participant has not 
recovered from transplant-associated toxicities prior to the first scheduled dose.
(f) Participants with a history of allogeneic SCT are excluded UNLESS the following 
eligibility criteria are met: 
(i)
Transplant was > 180 days prior to the first scheduled dose
(ii) Participant has no history of liver GVHD
(iii) Participant has no active GVHD
(iv) Participant has not taken immunosuppressive medications for at least 1 month
prior to first scheduled dose; low-dose steroids (≤ 10 mg of prednisone or 
equivalent per day) are permitted as therapy for comorbid conditions other than 
GVHD.


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13 Requires ongoing immunosuppressive therapy, including systemic (eg, intravenous or 
oral) corticosteroids for treatment of lymphoid cancer or other conditions. 
Note: Participants may use topical or inhaled corticosteroids or low-dose steroids 
(≤10 mg of prednisone or equivalent per day) as therapy for comorbid conditions, but use 
of corticosteroids as therapy for lymphoid cancer is not permitted. Short courses of 
steroids before study entry are allowed. During study participation, participants may 
receive systemic corticosteroids as needed for treatment-emergent comorbid conditions.
14 Receipt of live, attenuated vaccine within 28 days before the first dose of study 
treatment(s).
Prior/Concurrent Clinical Study Experience
15 Participation in another clinical study with an IP administered in the last 5 half-lives of 
that IP.
16 Participants with a known hypersensitivity to AZD4573 or any of the excipients of the 
product.
Other Exclusions
17 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
18 Judgment 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.
19 Previous enrolment in the present study. 
20 For women only - currently pregnant (confirmed with positive pregnancy test) or 
breastfeeding.
5.3
Lifestyle Considerations
There are no dietary/activity restrictions for this study. For restrictions around reproduction
and contraception, refer to the inclusion criteria (Section 5.1).
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 CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened. Only 1 rescreening is allowed in the study. Rescreened participants should be 
assigned the same participant number as for the initial screening.


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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to or medical device(s) utilised by a study participant
according to the study protocol.
6.1
Study Intervention(s) Administered
Please refer to the relevant module for information on study intervention(s).
6.2
Preparation/Handling/Storage/Accountability
1
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.
2
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.
3
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).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual.
5
The study personnel at the investigational site will account for all study intervention
dispensed and where appropriate, for all destruction of study intervention or delivery of 
intervention to sponsor for destruction. Unused study intervention should be destroyed 
according to local guidelines, and the certificate of delivery/destruction should be signed. 
Destruction should not take place until approved by the responsible person at 
AstraZeneca. All study supplies and associated documentation will be regularly reviewed 
and verified by the site monitor before destruction.
6.3
Measures to Minimise Bias: Randomisation and Blinding
This is an open-label study. Each potential participant is assigned a unique participant 
enrolment number. If a participant withdraws from the study, then the enrolment number 
cannot be reused. Study intervention will be dispensed at the study visits summarised in the 
relevant module. Returned study intervention should not be re-dispensed to the participants.
If an unscheduled assessment is performed, and the participant has not progressed, every 
attempt should be made to perform the subsequent assessments at their scheduled visits. This 
schedule is to be followed to minimise any unintentional bias caused by some participants 


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being assessed at a different frequency than other participants.
6.4
Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff.
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
Information on any medication or vaccine that the participant is receiving at the time of 
enrolment, or has received in at least the 30 days before starting IP, as well as all concomitant 
treatments given during the study (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) must be recorded in the eCRF along with:

Reason for use/indication

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.
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential 
enzyme inducer) or 5 half-lives (whichever is longer) before the start of study intervention 
until completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, 
the medication will not interfere with the study.
Given the proposed clinical dosing regimen of AZD4573, an IV infusion over 2 hours (once 
weekly), and the observed short half-life of approximately 4 to 7 hours, the risk of clinically 
meaningful drug interactions with AZD4573 is considered to be low. No AEs suggestive of a 
drug-drug interaction have been reported so far in clinical studies with AZD4573. 
Pharmacokinetic drug interaction data based on in vitro studies only is available in the IB.
Prohibited concomitant therapies are listed in Table 7 and permitted concomitant therapies are 
listed in Table 8. Concomitant medication additional to those listed in Table 8 may be 
considered on a case-by-case basis by the investigator in consultation with the Study 


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Physician if required.
Table 7
Prohibited Concomitant Therapies
Prohibited medication/class of drug
Usage
Any other 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 through 30 days after the last 
dose of investigational products.
Immunosuppressive medications such as
methotrexate, azathioprine, and tumour necrosis 
factor-α blockers. 
Should not be given concomitantly or used for 
premedication.
Table 8
Permitted Concomitant Therapies (Conditional)
Supportive medication/class of drug
Usage
Premedication for prophylaxis of diarrhoea, nausea, 
vomiting, TLS, and infection.
Permitted as per protocol and as deemed required by 
the investigator.
Blood transfusions
During the study, blood and platelet transfusions are 
allowed as clinically indicated at any time during the 
study and can be given as per local institutional 
guidelines.
G-CSF
G-CSF should not be used prophylactically from 
Cycle 1, Day 1 but can be started when medically 
indicated.
Corticosteroids
At study entry, participants may be using topical or 
inhaled corticosteroids or low-dose steroids (≤10 mg 
of prednisone or equivalent per day) as therapy for 
comorbid conditions, but use of corticosteroids as 
therapy for lymphoid cancer is not permitted. 
Doses of systemic corticosteroid > 10 mg/day may be 
used during the study if clinically indicated (eg, for 
treatment of an AE/SAE), but the dose must be 
tapered back down to no greater than 10 mg/day upon 
resolution of the event, to avoid chronic use.


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Table 8
Permitted Concomitant Therapies (Conditional)
Supportive medication/class of drug
Usage
Concomitant drugs that have the potential to prolong 
QTc
Concomitant drugs that have the potential to prolong 
QTc should not be used around the time of the 
scheduled ECG assessments during this study.
Strong CYP3A4 inducers/inhibitors
It is recommended that treatment with strong 
CYP3A4 inducers is avoided, unless it is deemed 
clinically warranted in the opinion of the investigator. 
If potent CYP3A4 inhibitors are administered, it is 
recommended to avoid administering them on the 
same day as AZD4573 administration where possible. 
Alternatively, such inhibitors should be administered 
8 to 12 hours after the completion of the AZD4573 
infusion, if deemed clinically warranted in the 
opinion of the investigator.
Best supportive care (including recombinant growth 
factor support, bisphosphonates, 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, after discussion 
with the study physician and in accordance with local 
institutional guidelines.
Inactivated viruses, such as those in the influenza 
vaccine and COVID-19 vaccines.
The sponsor recommends avoiding administering 
COVID-19 vaccinations during the 72 hours prior to 
administration of the first dose of IP, or during Cycle 
1, to avoid biases in the interpretation of safety data 
due to the potential overlap of vaccine-related AEs 
with IP AEs. 
Abbreviations: AE, adverse event; ECG, electrocardiogram; G-CSF, granulocyte colony stimulating factor; IP, 
investigational product; SAE, severe adverse event; TLS, tumour lysis syndrome.
6.6
Dose Modification
If, in the opinion of the investigator, a participant experiences a clinically significant and/or 
unacceptable adverse reaction, then the dose may be temporarily or permanently halted or 
reduced. 
Supportive therapy will be administered as required. Relevant reporting and discussion with 
the Study Physician will take place before resumption of dosing.
See the relevant module for detail on dose modification.
6.7
Intervention after the End of the Study
No intervention is planned after the end of the study. However, provisions will be in place for 
participants still enrolled at the end of the trial to continue to receive study intervention if, in 


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the opinion of the investigator, they are continuing to receive benefit from treatment. Such 
participants will continue to be monitored for all SAEs up to 30 days after the last dose of the 
intervention therapy.
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, participants currently receiving treatment with study intervention may 
be transitioned to such a study, and the current study would reach its end. The roll-over or 
safety extension study would ensure treatment continuation with visits and assessments per its 
protocol. Any participant who would be proposed to move to such a study would be asked to 
sign a new ICF.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is permanently discontinued, the participant will
remain in the study to be evaluated for safety and efficacy during the 30-day follow-up period 
(Section 8.2.1), or until documented disease progression during the long term follow-up 
period (Section 8.2.2). See the SoA for data to be collected at the time of discontinuation of 
study intervention and follow-up and for any further evaluations that need to be completed.
Note that discontinuation from study intervention is NOT the same as a withdrawal from the 
study.
The participant should continue attending subsequent study visits and data collection should 
continue according to the study protocol. If the participant does not agree to continue 
in-person study visits, a modified follow-up must be arranged to ensure the collection of 
endpoints and safety information. This could be a telephone contact with the participant for
the follow-up visit, a contact with a relative or treating physician, or information from medical 
records. The approach taken should be recorded in the medical records. A participant who 
agrees to modified follow-up is not considered to have withdrawn consent or to have 
withdrawn from the study.
Participants may be discontinued from study intervention in the following situations:

Objective disease progression assessed by investigator

Adverse event as defined in Section 8.3

Participant or investigator decision. The participant is at any time free to discontinue 
treatment, without prejudice to further treatment

Pregnancy (See Section 8.3.10)


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
Non-compliance with the CSP (investigator or participant)

Participant incorrectly initiated on study treatment

When the reason does not impact safety, the Study Physician together with the 
investigator will consider the risk/benefit to the participant of stopping treatment.

The Study Physician is responsible for ensuring all such contacts are appropriately 
documented.

Unexpected, significant, or unacceptable risk to the participants enrolled in the study.

Sponsor termination of study for reasons including but not limited to unfavourable
risk/benefit or change in drug development plan.
See the SoA for the relevant module for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed.
Restarting of study intervention may only occur in line with the dose modification and 
discontinuation guidelines described in the relevant module. Participants who have had 
investigative treatment discontinued for safety reasons may not be restarted on this treatment 
during the study.
7.1.1
Criteria for stopping or pausing the study recruitment
At any time point during the trial, the study recruitment may be paused if at least one of the 
following events occurs:

Fatal event deemed related to study therapy by the Sponsor and in discussion with the 
SRC (probable or certain causality based on WHO-UMC after full etiological work-up). 
This will also result in a comprehensive review of safety.

Confirmed true Hy’s law event as assessed by the Sponsor and in discussion with the 
SRC.

A CTCAE grade 4 or higher TLS event that is not reversible within 48 hours as assessed 
by the Sponsor and in discussion with the SRC.

Unexpected and life-threatening non-haematological event deemed related to study 
therapy by the Sponsor and in discussion with the SRC.

Sponsor decision that study participants are placed at undue safety risk.

Sponsor decision to discontinue the development of the study treatment in the proposed 
indications.
If, on an ongoing basis, > 25% of participants experience any AEs related to study 
intervention that result in discontinuation of study treatment, the study data will be evaluated 
by the SRC. Enrolment may be paused until the safety data review by the SRC has been 
completed.


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7.2
Participant Withdrawal from the Study
All participants will be followed for survival until death, lost to follow-up, sponsor
closes the study or withdrawal of consent, whichever occurs first.

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).

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation The 
investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.
Participants that are withdrawn from the study but are evaluable per the definition in the 
Populations for Analyses section of the relevant module will not be replaced. Any participant 
that is withdrawn and is not evaluable will be replaced to ensure a minimum number of 
evaluable participants.
In addition, participants will be withdrawn from the study in the event that the sponsor
terminates this study.
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,


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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. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA for the relevant module.
Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the 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 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, is not anticipated to exceed
436.5 mL in Cycle 1 (cycle duration of 5 weeks) and 124 mL in each subsequent cycle 
(cycle duration of 3 weeks). Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples.

All efficacy assessments should continue until progression, including when a participant’s 
study treatment has been stopped. 
8.1
Efficacy Assessments
Efficacy assessments are detailed in the relevant module.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the relevant module.


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8.2.1
30-Day Follow-up Visit
A follow-up visit will be performed 30 (± 7) days from the time that all study intervention is
permanently discontinued (see the SoA for the relevant module). Tumour assessments 
(including PET-CT) will be repeated at this visit if they have not been performed within 
9 weeks if the participant discontinued before Week 26, or 12 weeks if the participant 
discontinued after Week 26.
8.2.2
Long-term Follow-up Visit
Participants who discontinue all study intervention before documented disease progression 
will be followed according to standard of care until documented disease progression. Disease 
progression or start of new anticancer therapy will be captured in the eCRF. During this 
period, only information on any SAEs considered related to IP or study procedures will be 
collected. If a participant is unable to attend site for this visit, the LTFU may be performed via 
phone call. LTFU visits will cease at disease progression. The long-term follow up will not 
apply to participants who withdraw consent or are lost to follow-up.
8.2.3
Survival Follow-up
All participants will be followed for survival until death, lost to follow up, AstraZeneca closes 
study, or withdrawal of consent, whichever occurs first. Participants will be followed for 
survival by telephone calls or clinic visits approximately every 3 months. During this period, 
information will be collected in the eCRF on survival status and any new anticancer therapies, 
and on any SAEs considered related to study drug(s) or study procedures.
8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE and an SAE can be found in Appendix B.
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.
All AEs (including SAEs) must be entered into the Clinical Database which will be used to 
generate the CSR. SAEs are also to be entered into the Global Patient Safety database which is 
used for expedited and periodic regulatory safety reporting and safety surveillance activities. 
Regular reconciliation of SAEs between these 2 databases will be conducted by the clinical 
team as per the Reconciliation Plan on a periodic basis. 


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8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events and SAEs will be collected from time of signature of the ICF, throughout the 
treatment period and including the follow-up period of 30 days (± 7 days) after last dose of 
study intervention.
A formal assessment of AEs will occur at the visits marked in the SoA of the relevant module, 
but AEs reported at any time during the study must also be recorded in the eCRF.
If the investigator becomes aware of a SAE with a suspected causal relationship to the IMP(s)
that occurs after the end of the clinical trial in a study participant, 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 assessment in the study are followed up 
by the investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and non-serious AEs will be followed until
resolution, stabilisation, the event is otherwise explained, or the participant is lost to follow-
up.
Adverse event variables
The following variables will be collected for each AE:

AE (verbatim)

The capture of diagnoses is preferred over all associated signs and symptoms. For 
example: laboratory TLS, clinical TLS, cytokine release syndrome. Provisional 
diagnoses (eg, PHL) must be updated as soon as possible.

The date when the AE started and stopped

When the onset of an AE in relation to dosing is rapid, for example TLS, it is
important to record the exact time of the start of infusion dosing and the time of 
AE onset in addition to the dates.

CTCAE grade/changes in CTCAE grade

For TLS events: Adverse events of TLS shall be graded according to CTCAE. The AE 
verbatim shall discriminate between laboratory and clinical TLS. In addition, TLS events 
will be graded according to Howard modification of the Cairo-Bishop grading system 
(see Appendix G) on the TLS monitoring eCRF form.

Whether the AE is serious or not


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
Investigator causality rating against the IP(s) (yes or no)

Action taken with IP(s) in response to the AE (for example: no action, dose reduced, 
treatment temporarily stopped, treatment permanently discontinued).

Outcome of the event
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

The date of start of first signs and symptoms should be captured together with the 
date the event became serious. 

Date investigator became aware of SAE

Reason AE is classified as serious

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed (yes/no)

Causality assessment in relation to Study procedure(s)

Causality assessment to other medication
8.3.3 Causality Collection
The investigator should assess causal relationship between IP and each Adverse Event, 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 IP?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the CSP.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 


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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 protocol-mandated physical examinations, laboratory 
values, vital signs, ECGs or B symptoms should therefore only be reported as AEs if they 
fulfil any of the SAE criteria, are the reason for discontinuation of treatment with the IP, or are 
considered to be clinically relevant as judged by the investigator (which may include but not 
limited to consideration as to whether treatment or non-planned visits were required or other 
action was taken with the study treatment, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the DUS.
8.3.6 Adverse Events of Special Interest
For AESIs associated with combination treatments, see the relevant module.
The following events are AESIs for participants who receive AZD4573 and must be reported 
to the sponsor expeditiously irrespective of seriousness criteria or causality:

Neutropenia, including Febrile neutropenia, Neutropenic sepsis, Neutrophil count 
decrease

Thrombocytopenia, including Platelet count decrease

Hepatotoxicity, including PHL, Drug-induced liver injury, Bilirubin increase with 
transaminase (ALT or AST, or both ALT and AST) increase

Pyrexia

TLS


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
Myocardial ischaemia
8.3.7
Potential Hy’s Law Cases
Cases where a participant shows elevations in liver transaminases and bilirubin levels require 
further evaluation. Occurrences of AST and/or ALT ≥ 3 × ULN together with total bilirubin 
≥2 × ULN must be reported as SAEs due to medical significance. The PHL page of the 
eCRF form must also be completed without delay. The verbatim of 'Potential Hy's Law' 
is a provisional diagnosis and must be updated as soon as possible. All PHL cases must 
be reported by the Sponsor to the USA FDA as a SUSAR in an expedited manner (even 
before all other possible causes of liver injury have been excluded). Please refer to 
Appendix E for more details.
For all PHL events, expedited safety reporting is required. The investigator must inform the 
sponsor as soon as more information is available on the event.
Please refer to the toxicity management and dose modification guidance in the relevant 
module. Discussions regarding treatment discontinuation due to increased liver transaminases 
and/or bilirubin increases should be documented. All PHL cases should be captured in the 
study PHL log by the central study team.
8.3.8 Disease Progression and Disease Under Study
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the treatment is being studied. It may be an increase in the severity of 
the DUS 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.
Symptoms of DUS are those which might be expected to occur as a direct result of r/r PTCL 
or r/r cHL. Events which are unequivocally due to DUS should not be reported as an AE 
during the study unless they meet SAE criteria or lead to discontinuation of the study 
treatment. Death clearly resulting from disease progression should not be reported as an SAE.
8.3.9
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IP, the study 
procedure(s) or other medication. All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.


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The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
For all PHL events, expedited safety reporting is required. The investigator must inform the 
sponsor as soon as more information is available on the event.
Once the investigators or other site personnel indicate an AE is serious in the eCRF, an 
automated email alert is sent to the designated AstraZeneca representative.
If the eCRF system is not available, then the investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by an alternative method.
The AstraZeneca representative will advise the investigator/study site staff how to proceed. 
For further guidance on the definition of a SAE, see Appendix B of the CSP.
The reference document for definition of expectedness/listedness is the IB for the AZD4573. 
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.
If a pregnancy is reported, the investigator should inform AstraZeneca within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.10.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Elective abortions 
without complications should not be handled as AEs. The outcome of all pregnancies 


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(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.
Congenital anomalies/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. 
If any pregnancy occurs in a female participant during exposure to IP or in the 7 months after 
discontinuing the AZD4573, then the investigator or other site personnel informs the 
appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.9) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
8.3.10.2
Paternal Exposure 
Male participants should refrain from fathering a child or donating sperm during the study and 
for 4 months following the last dose (see Inclusion Criteria Section 5.1).
Pregnancy of a participant’s partner is not considered to be an AE. However, any conception 
occurring from the date of dosing until 4 months after discontinuation of dosing should be 
reported to AstraZeneca and followed up for its outcome. 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 4 months after the last dose 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. 
If a pregnancy occurs in a participant’s partner within the timeframe specified above, then 
investigators or other site personnel will inform the appropriate sponsor representative 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The same timelines apply when outcome information is available.
8.3.11
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at least 
1 of the seriousness criteria. New primary cancers are those that are not the primary reason for 


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the administration of the study intervention and have been identified after the participant’s 
inclusion in this study. They do not include metastases of the original cancer.
8.3.12
Deaths
All deaths that occur during treatment period, including the follow-up period, must be 
reported as follows:

Death clearly resulting from disease progression should be reported to the study 
monitor/physician at the next monitoring visit and should be documented in the relevant
eCRF module. It should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the DUS, the AE causing the 
death must be reported as an SAE within 24 hours. It should also be documented in the 
eCRF. The report should contain a comment regarding the co-involvement of disease 
progression, if appropriate, and should assign single main cause of death together with 
any contributory causes. Autopsies should be requested if available.

Death with an unknown cause should always be reported as an SAE, but every effort 
should be made to establish a cause of death. It should also be documented in the eCRF. 
A postmortem may be helpful in the assessment of the cause of death, and if performed, a 
copy of the postmortem results (with translation of important parts into English) should 
be forwarded to AstraZeneca Patient Safety or its representative within the usual time 
frames.

Deaths that occur after the treatment period during the survival follow-up period should 
be reported on the survival log on the eCRF. If the death occurred as a result of an event 
that started after the defined follow-up period and the event is considered by the 
investigator to be due to a late-onset toxicity to study intervention, then it should also be 
reported as an SAE. 
8.3.13
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.9) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 4.


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8.4
Overdose
Overdose information for AZD4573 is below; refer to relevant module for information on 
overdose for combination therapies.
For this study, any dose of AZD4573 greater than the dose intended to be delivered will be 
considered an overdose.
All overdoses should be recorded as follows:

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.
For overdoses associated with a SAE, the standard reporting timelines apply.
For AZD4573, no data on overdosing are available. There is no known antidote for AZD4573. 
Investigators should be advised that any participant who receives a higher dose than that 
intended should be monitored closely, managed with appropriate supportive care under local 
institutional guidelines, and followed up expectantly.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples see Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 


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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
Refer to relevant module for information on PK.
8.5.2
Pharmacodynamics
Refer to relevant module for information on pharmacodynamics.
8.5.3
Immunogenicity Assessments
Refer to relevant module for information on immunogenicity assessments.
8.6
Refer to relevant module for information on 
.
8.7
Optional Genomics Initiative Sample
Collection of optional samples for genomics initiative research is also part of this study as 
specified in the SoA and is subject to agreement in the ICF addendum. A 
 sample for 
DNA isolation will be collected from participants who have consented to participate in the 
genetic analysis component of the study. Participation is optional. Participants who do not 
wish to participate in the genetic research may still participate in the study. This 
sample 
will be taken from consenting participants prior to AZD4573 dosing.
See Appendix D for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found either in 
the appendices or in the Laboratory Manual. 
For storage and destruction of genetic samples see Appendix D. 
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8.8
Health Economics
Not applicable for study. 
9
STATISTICAL CONSIDERATIONS
The statistical analyses will be performed by AstraZeneca or CRO under the direction of the 
Early Biometrics Oncology, AstraZeneca. A comprehensive SAP will be prepared.
9.1
Statistical Hypotheses
Not applicable.
9.2
Sample Size Determination
Refer to relevant module for information on sample size determination.
9.3
Populations for Analyses
Refer to relevant module for information on populations for analyses.
9.4
Statistical Analyses
The SAP will be finalised prior to database lock and 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 this plan will be reported in the CSR. 
9.4.1
General Considerations
Unless stated otherwise, each module and cohort will be analysed separately. Data will be 
presented by cohort. 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. Geometric mean and coefficient of variation may be presented as 
applicable. Categorical variables will be summarised by frequency counts and percentages for 
each category. Unless otherwise stated, percentages will be calculated from the population 
total, by cohort and by timepoint as appropriate. Time to event variables will be presented 
using the KM methodology where appropriate, including median time calculated from the KM
curves. SAS® version 9.4 (as a minimum) will be used for analyses presented in the CSR.
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 treatment, and other protocol deviations) may be generated. 
More details will be provided in the SAP.
Refer to the relevant Module for details on analyses and cut-off triggers.


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9.4.2
Efficacy Analyses
Analysis of Primary Endpoint (Efficacy)
The primary objective of this study is to assess the efficacy of the module-defined study 
treatment in participants with r/r PTCL or r/r cHL. Endpoints for this objective are specific to 
each module.
For information on efficacy analyses and endpoints, refer to the relevant module.
9.4.3
Safety Analyses
Safety and tolerability will be assessed in terms of AEs, laboratory data, vital signs, and ECG 
changes. These variables will be collected for all participants. All safety data listings and 
summaries will be created using the safety analysis set.
Adverse events will be listed individually by cohort and participant. The number of 
participants experiencing each AE will be summarised by the MedDRA system organ class, 
MedDRA preferred term, and CTCAE grade (in line with NCI CTCAE Version 5.0). TLS will 
be graded by CTCAE grade and Howard’s modification of Cairo-Bishop grading 
(Appendix G; Howard et al 2011). The number and percentage of participants experiencing 
each AE, and the number and percentage of participants with AEs in different categories 
(eg, causally related and CTCAE Grade ≥3) will be summarised by cohort, and events in each 
category will be further summarised by MedDRA system organ class and preferred term. 
SAEs will be summarised separately if a sufficient number occur.
Adverse event summary tables will include only treatment-emergent AEs. Adverse events will 
be defined as treatment-emergent if they have an onset or worsen (by investigator report of a 
change in intensity/severity), during the study treatment until the follow-up period (as defined 
in the individual study Modules), but prior to subsequent cancer therapy. AEs occurring 
outside of this period will be listed but not summarised. 
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 of study 
treatment. Based on the expert’s judgement, AEs of particular clinical importance may, after 
consultation with the Global Safety Physician, be considered OAEs and reported as such in 
the CSR. A similar review of laboratory values, vital signs, ECGs, and other safety 
assessments will be performed for identification of 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. Duration of exposure will be summarised.


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Haematology, serum chemistry, vital signs, ECG data, and other laboratory values will be 
listed individually by cohort and participant, and suitably summarised. For all laboratory 
variables, which are included in the current version of CTCAE, the CTCAE grade will be 
calculated.
Details of any deaths will be listed for all participants.
Graphical presentations of safety data will be presented as is deemed appropriate. This may 
include, but is not restricted to, presentation of parameters against time, concentration or shift 
plots. Appropriate scatter plots will also be considered to investigate trends in parameters 
compared to baseline level. 
9.4.4
Pharmacokinetic Analyses
Assessment of the plasma PK of AZD4573 as monotherapy and in combination with other 
module-defined anti-cancer agents when given in combination is a secondary objective for the 
study.
The endpoints for these analyses are plasma concentrations and derived PK parameters for 
AZD4573 summarised by cohort for the PK analysis set. Plasma/serum concentrations and 
derived PK parameters for other anti-cancer agents may be summarised by cohort for the PK 
analysis set, as applicable.
For details on PK analyses, please refer to the separate Bioanalytical Report.
9.4.5
Pharmacodynamics 
 Analyses
Assessment of pharmacodynamics
 analyses are exploratory objectives for 
this study. 
For details on pharmacodynamic analyses
 analyses refer the relevant 
module. 
9.5
Interim Analyses 
See relevant module for information on planned interim analyses.
9.6
Data Monitoring Committee
There will be no formal data monitoring committee for this study. See relevant module for 
information regarding the use of a SRC for this study.
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10.1.2
Schedule of Activities
Table 9
Schedule of Activities: Module 1 (AZD4573 Monotherapy)
Procedure
Screeninga
Cycle 1,
Weeks 1-5
(includes intra-
participant
Dose ramp-up)
Cycle 2 to 12
(Cycle = 21 Days)
Cycles 13+ 
(Cycle = 
21 days)
Disease 
Assessment
30-Day
FUe
LTFU
Details in 
Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(± 2 Days)
(± 2 Days)
(± 7 Days)
(± 7 Days)
(± 7 Days)
Informed consentb
X
Appendix A
Inclusion/exclusion
X
5 and 
10.4.3
Medical history and 
demographics
X
5 and 
10.4.3
Physical examination
X
X
X
X
X
X
X
10.8.2.1
ECOG performance 
status
X
X
X
X
X
X
X
10.8.2.1
B symptoms
X
X
X
X
X
X
X
10.8.2.2
Vital signs and weight
X
X
X
X
X
X
X
10.8.2.3
12-lead ECG
X
Refer to Section 10.8.2.4 for schedule
X
10.8.2.4
ECHO/MUGA
X
As clinically indicated
X
10.8.2.4
Cardiac troponin
X
X
X
X
X
10.8.2.5
T4, Cortisol, ACTH 
and TSH
X
X
10.8.2.5
EBV
Prior to receiving study 
treatment
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Table 9
Schedule of Activities: Module 1 (AZD4573 Monotherapy)
Procedure
Screeninga
Cycle 1,
Weeks 1-5
(includes intra-
participant
Dose ramp-up)
Cycle 2 to 12
(Cycle = 21 Days)
Cycles 13+ 
(Cycle = 
21 days)
Disease 
Assessment
30-Day
FUe
LTFU
Details in 
Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(± 2 Days)
(± 2 Days)
(± 7 Days)
(± 7 Days)
(± 7 Days)
Haematologyc
X
X
X
X
X
X
X
10.8.2.5
Coagulation
X
X
X
X
X
X
X
10.8.2.5
Clinical chemistryc
X
X
X
X
X
X
X
10.8.2.5
Urinalysis
X
X
X
X
X
10.8.2.5
TLS monitoring 
(for at least 24 hours
post SOI)
X
X
10.6.2.1.2
Pregnancy testing 
(WOCBP)
X
Pre-dose Week 
1, Day 1 
Prior to initiating a new cycle 
(once every 21 days)
X
10.8.2.5
Lipase/amylase
X
X
X
X
X
X
X
10.8.2.5
Hepatitis serology
X
10.8.2.5
Liver chemistry tests
X
10.8.2.5
Whole blood samples 
for 
X
Per Section 10.8.8.4
X
X
10.8.8.4
 sample for 
 
Prior to receiving study 
treatment
10.8.9.4
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Table 9
Schedule of Activities: Module 1 (AZD4573 Monotherapy)
Procedure
Screeninga
Cycle 1,
Weeks 1-5
(includes intra-
participant
Dose ramp-up)
Cycle 2 to 12
(Cycle = 21 Days)
Cycles 13+ 
(Cycle = 
21 days)
Disease 
Assessment
30-Day
FUe
LTFU
Details in 
Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(± 2 Days)
(± 2 Days)
(± 7 Days)
(± 7 Days)
(± 7 Days)
Serum 
immunoglobulins 
(IgA, IgM, IgG)
X
Day 1 of Cycles 3, 6 and 9 
(pre-dose)
Cycle 13 
(± 7 days) 
and every 
6 months 
thereafter
X
10.8.2.6
Concomitant 
medication
X
X
X
X
X
X
X
X
5.2, 6.5
Adverse event 
evaluation
X
X
X
X
X
X
X
8.3
AZD4573 plasma PK
Refer to Section 10.8.6 for schedule
10.8.6
 
X
10.8.6
Pharmacodynamic 
samples (blood) for 
AZD4573
Weeks 1 to 3
10.8.7
 
X
Weeks 1 to 3
If elevated liver chemistry tests/bilirubin
10.8.9.3
Exploratory analyses 
samples
X
Refer to Section 10.8.8 for schedule
10.8.8
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Table 9
Schedule of Activities: Module 1 (AZD4573 Monotherapy)
Procedure
Screeninga
Cycle 1,
Weeks 1-5
(includes intra-
participant
Dose ramp-up)
Cycle 2 to 12
(Cycle = 21 Days)
Cycles 13+ 
(Cycle = 
21 days)
Disease 
Assessment
30-Day
FUe
LTFU
Details in 
Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(± 2 Days)
(± 2 Days)
(± 7 Days)
(± 7 Days)
(± 7 Days)
Genomics Initiative 
sample (optional)
X
8.7
Bone marrow biopsy 
& aspirate 
(PTCL only)d
X
As 
clinically 
indicated 
and to 
confirm CR
10.8.9.1.1
Fresh or archival 
tumour tissue sample
X
10.8.9.1.2
Additional tumour 
biopsy sample 
(optional)
At disease 
progression
(X)
10.8.9.1.2
Disease 
assessments/radiologic 
scans
X
After Cycle 2 (+/- 1 week), then Q9W 
until W26 (Cycle 8, Week 3), then Q12W 
(+/- 1 week)
X
10.8.1
AZD4573 (IV; once
weekly)c
X
X
X
X
X
10.6
Disease progression 
follow-up (SoC)
X
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Table 9
Schedule of Activities: Module 1 (AZD4573 Monotherapy)
Procedure
Screeninga
Cycle 1,
Weeks 1-5
(includes intra-
participant
Dose ramp-up)
Cycle 2 to 12
(Cycle = 21 Days)
Cycles 13+ 
(Cycle = 
21 days)
Disease 
Assessment
30-Day
FUe
LTFU
Details in 
Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(± 2 Days)
(± 2 Days)
(± 7 Days)
(± 7 Days)
(± 7 Days)
Survival FUe
X
8.2.3
a
Screening tests should be performed within 30 days before the first administration of study drug, unless otherwise indicated.
b
Informed consent must be obtained ≤ 30 days before first dose of study drug and must be obtained before any protocol-defined screening tests are done.
c
Results of safety laboratory testing (haematology and clinical chemistry at a minimum) must be available within 72 hours prior to dosing and must be 
reviewed by the investigator prior to each administration of AZD4573. To initiate Cycle 1 and subsequent cycles, haematology and chemistry criteria in 
inclusion criteria 10, 13, and 14 shall be met. In addition, during AZD4573 treatment, dose modification and discontinuation guidelines are provided in 
Section 10.6.1.
d
Mandatory exploratory 
 analysis will be performed any time a bone marrow analysis is performed.
e
The follow-up visit will be performed 30 days (± 7 days) after the last dose of all study drug. Disease assessments will be repeated at this visit if they have 
not been performed within 9 weeks if the participant discontinued before Week 26, or 12 weeks if the participant discontinued after Week 26.
Abbreviations: ACTH, adrenocorticotropic hormone; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; FU, 
follow-up; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; IV, intravenous; LTFU, long-term follow-up; MUGA, multigated 
acquisition; PK, pharmacokinetic; PTCL, peripheral T-cell lymphoma; SoC, standard of care; SOI, start of infusion; TLS, tumour lysis syndrome; TSH, thyroid 
stimulating hormone; WOCBP, women of childbearing potential.
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
AZD4573 will be administered intravenously as a monotherapy to participants with 
r/r PTCL or r/r cHL, including an intra-participant dose ramp-up. For dose regimen, see 
Section 10.4.1 below.

For details on study design applying to all modules, including information on the SRC 
and the definitions for end of study, refer to the core protocol study design (Section 4.4).
10.4.1
Module 1 Design: AZD4573 monotherapy
Module 1 is non-randomised and will consist of 2 r/r PTCL cohorts and 1 r/r cHL cohort; see 
Figure 5 and Table 10 below for planned participant numbers. 
Each cohort will include an intra-participant dose ramp-up, starting at 6 mg AZD4573 
(Figure 6). The target dose following the ramp-up is 12 mg attained on Week 3 of Cycle 1. 
During the first cycle, participants will receive a single dose of AZD4573 once weekly 
beginning with 6 mg Week 1, 9 mg Week 2, and 12 mg for each of Weeks 3 to 5. 
Every cycle beyond Cycle 1 will be 3 weeks in length and participants will receive 12 mg 
infusions of AZD4573 once weekly until progression.
Figure 6
Module 1 AZD4573 Monotherapy Dosing Regimen in PTCL and cHL 
including Intra-Participant Dose Ramp-Up
Abbreviations: cHL, classical Hodgkin Lymphoma; D, day; PTCL, peripheral T-cell lymphoma; Q1W, once 
weekly.
A comprehensive initial review of all safety and PK/PD data will be conducted in 
approximately the first 6 participants of each cohort (safety run-in), with separate SRCs for 
each cohort executed independently. The safety assessment will be undertaken by the SRC and 
is detailed in Section 10.4.4. The study procedures and safety assessments undertaken for the 
first cycle will be as per the SoA (Table 9). Each cohort will have a separate dose 
confirmation, assessed independently by the SRC, to assess safety and PK/PD data compared 
to the known profiles in the first time in human study (Study D8230C00001) lymphoma 
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10.4.2
Justification for Dose
The planned starting and target doses of AZD4573 for Module 1 are as per the RP2D already 
determined for lymphoma in the ongoing Phase I monotherapy study of AZD4573 
(D8230C00001). 
 
 
 
 
 
 
 
 
 
 
 These Grade 4 AST elevations met the definition of DLT in 
versions 2 and 5 of the protocol (dated 7 July 2017 and 18 April 2019), but were transient (less 
than 4 days duration) and were not accompanied by clinical signs and symptoms of significant 
hepatic dysfunction. Review of the data (December 2019) by AstraZeneca’s Hepatic Safety 
Knowledge Group and external industry and academic experts concluded that isolated 
asymptomatic reversible Grade 4 enzyme elevations should not be regarded as DLTs unless 
prolonged and accompanied by other clinical changes. Study investigators concurred with this 
interpretation and the protocol was amended accordingly to update the DLT definition. The 
protocol version including the revised DLT definition has been approved by competent 
authorities in the United Kingdom, Netherlands, and Germany. 
 
 
 
 
 
Furthermore, exploratory data from 
 samples collected from ongoing Phase I 
monotherapy study support target engagement 
 at all doses 
tested to date (ie, 6 mg and above), with a median 
 of 
 (range: 
 
) observed following the 12 mg weekly regimen (based on preliminary PK/PD 
modelling). Corresponding biological effects, eg, 
 
 have also been observed.
In addition, based on exposure versus safety analysis conducted for the Phase I monotherapy 
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study, 
 
 
Overall, these analyses support the evaluation of AZD4573 12 mg, once weekly, monotherapy 
regimen in the treatment of patients with r/r PTCL or r/r cHL.
The clinical data will be used to refine a PK/pharmacodynamics/efficacy model, and future 
decisions on dose regimens and escalations will be based on the observed clinical data to date 
and this refined model.
10.4.3
End of Module Definition
Refer to Section 4.4 in the core protocol for the end of study definition.
The end of module is defined as the last scheduled visit or contact of the last participant
enrolled in the module.
All participants will continue to be followed for survival after objective disease progression 
until death, lost to follow-up, AstraZeneca closes the Module, or withdrawal of consent, 
whichever occurs first, up to the final analysis DCO.
Any participants still receiving study intervention at the completion of the final analysis will 
be able to continue to receive the intervention at the sponsor’s discretion for up to 2 years, if 
the participant is still considered to be deriving clinical benefit and the sponsor is continuing 
development of the IP. Such participants will continue to be monitored for all SAEs up to 30 
days after the last dose of the intervention therapy. Participants who continue to demonstrate 
clinical benefit after this 2 year treatment period will be eligible to receive AZD4573 as 
monotherapy or as part of a combination therapy via a rollover study requiring approval by the 
responsible Health Authority and ethics committee or through another mechanism at the 
discretion of the sponsor. 
10.4.4
Safety Review Committee
A study-specific SRC will provide ongoing safety surveillance of the study, with regularly 
scheduled reviews of safety, PK, and other relevant data. 
The SRC will be responsible for making recommendations for dose confirmation or
modification All participants will be followed for safety through the entire duration of 
treatment.
A comprehensive initial review of all safety data will be conducted in approximately the first 
6 participants of each cohort (safety run-in), with separate SRCs for each cohort executed 
independently. Recruitment will not be paused during this review. These participants will be 
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followed until all have completed Cycle 1, to ensure the treatment schedule is safe and 
tolerable. The SRC will review the totality of all relevant data (eg clinical, laboratory, safety) 
prior to providing decisions on study conduct. All decisions by this committee will be 
documented and shared in writing with all participating sites.
If, on an ongoing basis, > 25% of participants experience any AEs related to study 
intervention that result in discontinuation of study treatment, study data will be evaluated by 
the SRC. Enrolment may be paused until the safety data review by the SRC has been 
completed. Following this SRC review, additional monitoring may be implemented and/or
enrolment and dosing may resume at a lower dose level or on a modified schedule. The SRC 
will meet at least every 6 months to review the overall safety and clinical data from the study.
At any time point during the study, the occurrence of a fatal AE deemed related to study 
therapy (after full etiological work-up and in discussion with the SRC) will result in study 
drug interruption and a comprehensive review of safety.
10.5
Study Population – Module 1
Refer to Section 5.1 and Section 5.2 in core protocol for inclusion and exclusion criteria, 
respectively.
10.6
Study Intervention – Module 1
AZD4573 is administered as an absolute (flat) dose, 2-hour (± 15 minutes) intravenous 
infusion on a once weekly schedule.
 
 
Arm name
N/A
Intervention name
AZD4573
Type 
Drug
Dose formulation
Concentrate for solution for infusion
Unit dose strength(s)
1.5 mg/ml
Dosage level(s)
6 mg AZD4573 (starting dose)
9 mg AZD4573
12 mg AZD4573 (target dose)
Route of administration
IV infusion
Use
Experimental
IP or NIP
IP
Sourcing
Provided centrally by the sponsor
Packaging and labelling
Study Intervention will be provided in a clear glass vial. Each vial will be 
labelled as required per country requirement.
Former names
AZ13810325
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IP, investigational product; IV, intravenous; NIP, non-investigational product.
10.6.1
Dose Modification
Dose modification and discontinuation guidelines for haematological and non-haematological 
toxicities (excluding abnormal liver chemistry test results) are shown below in Table 11. Dose 
modifications for AZD4573 for abnormal liver chemistry test results are described in Table 12.
In general, if a participant experiences a Grade 1 or Grade 2 haematological or 
non-haematological toxicity, no dose modification is required. If a participant experiences a 
Grade 3 or Grade 4 toxicity, not attributable to the disease or disease-related processes under 
investigation, dosing will be interrupted and/or the dose reduced (see Table 11 for 
recommended dose modifications for AZD4573) and supportive therapy administered as 
required. If the toxicity resolves or reverts in line with the dose modification guidelines below
and the participant was showing clinical benefit, treatment with study treatment(s) may be 
restarted.
If the toxicity does not resolve in line with the dose modification guidelines below, then the 
participant should be discontinued from the study treatment and observed until resolution of 
the toxicity. Maximal drug interruption allowed for AZD4573 is 21 consecutive days; in cases 
where more than 21 days are needed, a decision to continue, modify, or discontinue study 
treatment will be made on a case-by-case basis in consultation with the principal investigator 
and the Study Physician.
Table 11
Recommended Dose Modifications for AZD4573
Eventa
Occurrence
Action with AZD4573
Tumour Lysis Syndrome (TLS)
Changes in uric 
acid, potassium, 
phosphorus, 
creatinine or 
calcium, or 
symptoms 
suggestive of TLS
Any
For any abnormal changes present before dosing, initiate supportive 
therapy and hold drug for up to 7 days. If not resolved, reduce by 1 
dose level.
For events of Howard Grade 1 or 2 TLS, resume at same dose level 
upon resolution.
For first occurrence of Howard Grade 3 TLS resume at the same 
dose upon resolution to Grade 1.
For second occurrence of Howard Grade 3 TLS, after resolution to 
Grade 1, reduce dose by 1 dose level when re-starting AZD4573 
except events that in the opinion of the investigator, in consultation 
with the Study Physician, are not dose limiting.
For subsequent occurrences of Howard Grade 3 TLS, further re-
challenge and dose level to be discussed with the Study Physician.
For events of Howard Grade 4 TLS, discontinue AZD4573.
Non-haematological toxicities (except liver dysfunction and TLS)


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Eventa
Occurrence
Action with AZD4573
Grade 3 or 4 
non-haematological 
toxicities
First 
occurrence 
Withhold dosing with AZD4573 until the toxicity has resolved to 
Grade 1, but no longer than 21 daysb. 
Adequate supportive therapy as per Institutional guidelines should be 
given. 
After resolution of Grade 3 event to Grade 1, AZD4573 therapy may 
be resumed at the same dose. No dose modification is required.
After resolution of Grade 4 event to Grade 1, reduce dose by one dose 
level when re-starting AZD4573.
Second 
occurrence
Withhold dosing AZD4573 up to 21 daysb.
Adequate supportive therapy as per Institutional guidelines should be 
given.
After resolution to Grade 1, reduce dose by one dose level when re-
starting AZD4573. 
If no resolution within 21 days discontinue AZD4573b.
Third 
occurrence
Discontinue AZD4573.
Haematological Toxicities
Grade 3 or 4 
neutropenia without 
fever or infection, 
lasting ˃ 7 days 
despite growth 
factor support
First
occurrence
Withhold dosing AZD4573 until Grade ≤2 or baseline level.
Restart at same dose level following resolution.
Second and 
subsequent 
occurrences
Withhold dosing AZD4573 until Grade ≤2 or baseline level.
Restart with 1 dose level reduction following resolution.
In case of subsequent occurrences, dosing may be modified to skip 
weekly dose(s) (eg, 2 weeks on/1 week off or to 1 week on/1 to 2 
weeks off), after discussing with the Study Physician.
Grade 3 or 4 
neutropenia with 
infection or fever
First 
occurrence
Withhold dosing AZD4573. 
To reduce the infection risks associated with neutropenia, G-CSF may 
be administered with AZD4573 if clinically indicated/required as per 
Institutional practice. 
Consider secondary prophylaxis with G-CSF as per ASCO/ESMO 
guidelines. Once the toxicity has resolved to ≤Grade 2 or to baseline 
level, AZD4573 therapy may be resumed at the same dose.
Second
occurrence
Withhold dosing AZD4573.
Consider using G-CSF as clinically indicated/as per Institutional 
practice. Follow dose reduction guidelines when resuming treatment 
with AZD4573 after resolution.
Reduce dose by 1 dose level. 


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Eventa
Occurrence
Action with AZD4573
Third
occurrence
Discontinue AZD4573.
Grade 3 
thrombocytopenia 
without bleeding
Any
Withhold AZD4573 until Grade ≤2 or baseline level.
Restart AZD4573 at the same dose level.
Grade 4 
thrombocytopenia 
without bleeding 
requiring blood or 
platelet transfusion
First
occurrence
Withhold AZD4573 until Grade ≤2 or baseline level.
Restart AZD4573 at the same dose level.
Second
occurrence
Withhold AZD4573 until Grade ≤2 or baseline level.
Restart AZD4573 with 1 level dose reduction.
If not recovered to Grade ≤2 or baseline level discontinue.
Third
occurrence
Discontinue AZD4573.
Grade 3 or 4 
thrombocytopenia 
with bleeding 
requiring blood or 
platelet transfusion
First
occurrence
Withhold AZD4573 until Grade ≤2 or baseline level.
Restart AZD4573 with 1 level dose reduction.
If not recovered to Grade ≤2 or baseline level discontinue.
Second
occurrence
Discontinue AZD4573.
a
Adverse reactions are graded using NCI CTCAE version 5.0.
b
In cases where more than 21 days are needed, a decision to continue, modify, or discontinue study treatment 
will be made on a case-by-case basis in consultation with the principal investigator and the Study Physician.
Abbreviations: ANC, absolute neutrophil count; ASCO, American Society of Clinical Oncology; ESMO,
European Society for Medical Oncology; G-CSF, granulocyte-colony stimulating factor.
Dose modifications for AZD4573 for abnormal liver chemistry test results are described in 
Table 12.
Table 12
Recommended Dose Modifications for AZD4573 for Abnormal Liver 
Chemistry Test Results
Eventa
Action
Isolatedb elevations in ALT, AST, or bilirubin
Grade 1
Isolated ALT/AST ≤3 × ULN 
or
Isolated Bilirubin ≤1.5 × ULN
Maintain current dose level.
Monitor ALT, AST, ALP, and bilirubin at least 1x per 
week.


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Eventa
Action
Grade 2
Isolated ALT/AST > 3 to ≤5 × ULN
or
Isolated Bilirubin > 1.5 to ≤3 × ULN
After 7 days if hepatic enzymes resolve to Grade ≤1, re-
challenge at same dose level.
Grade 3
Isolated ALT/AST > 5 to 20 × ULN
If recovered to Grade ≤1 within 7 days, allow re-challenge 
at same dose level.
If not recovered to baseline level within 7 days, discontinue 
AZD4573.
Grade 3
Isolated Bilirubin > 3 to 10 × ULN
If recovered to baseline level within 96 hours (-2/+12 
hours) of start of dose allow re-challenge at same dose 
level.
If not, discontinue AZD4573.
Grade 4
Isolated ALT > 20 × ULN
or
Isolated Bilirubin > 10 × ULN
Discontinue AZD4573.
Grade 4
Isolated elevation (≥ 20 × ULN) in
AST without concomitant elevation in ALT ≥ 
20 × ULN or concomitant elevation in TBL 
≥2 × ULN that fails to return to baseline level 
within 7 days from start of dosing
Discontinue AZD4573.
Grade 4c
Isolated AST elevation ≥20 × ULN without 
concomitant elevation in ALT ≥20 × ULN or 
TBL ≥2 × ULN
First occurrence
If recovered to Grade ≤1 or baseline level within 7 days of 
start of dose allow re-challenge at same dose level.
Second occurrence
If recovered to Grade ≤1 or baseline level within 7 days of 
start of dose allow re-challenge with 1 dose level reduction.
Third occurrence
Discontinue AZD4573.
Concurrent elevations in ALT, AST, or bilirubin
(Please also refer to the HL appendix in the CSP for actions to be taken in the event of PHL)
ALT or AST ≥3 × ULN with TBL ≥2 × ULN 
(PHL) AND INR ≥1.5 × ULN (or ≥1.5 × 
baseline if elevated at baseline) of any duration
Discontinue AZD4573.


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Eventa
Action
ALT or AST ≥3 × ULN with the appearance of 
fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or 
eosinophilia > 5%
Discontinue AZD4573.
ALT or AST ≥ 3 × ULN and TBL
≥ 2 × ULN where TBL does not return to 
baseline level within 96 hours (-2/+12 hours) 
from start of dose and/or AST or ALT do not 
return to baseline level within 7 days from start 
of dose
Discontinue AZD4573.
Grade 3 elevation (≥ 5 × ULN) in
ALT or AST with TBL elevation
above baseline level or ULN, but
< 2 × ULN that do not return to baseline level 
within 7 days
Discontinue AZD4573.
ALT and AST ≥ 3 × ULN with concomitant 
TBL ≥ 2 × ULN, NO increase in INR ≥ 1.5 × 
ULN (or 1.5 × baseline), and NO fatigue, 
nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or 
eosinophilia > 5%
If recovered to Grade ≤1 or baseline level within 96 
(-2/+12) hours, re-challenge at same dose levelc.
a
Adverse reactions are graded using NCI CTCAE version 5.0.
b
Elevations in ALT or AST are considered isolated if bilirubin remains below Grade 1, and elevations in 
bilirubin are considered isolated if ALT and AST remain below Grade 1.
c
Participants who are considered for re-challenge in the event of Grade 4 transaminase increases or PHL 
must discuss possible risk of hepatotoxicity with the treating physician, who will document this discussion 
and participant agreement for continued treatment in the medical records.
Adequate supportive therapy as per Institutional guidelines should be given for all toxicities.
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
CTCAE, Common Terminology Criteria for Adverse Events; HL, Hy’s Law; INR, international normalised ratio; 
PHL, Potential Hy’s Law; TBL, total bilirubin; ULN, upper limit of normal.
10.6.2
Prevention and Toxicity Management of Risks for AZD4573
Monotherapy
This section provides recommendations for treatment of potential toxicities associated with 
AZD4573, and guidance about modifying the dose of AZD4573 due to those toxicities. For 
complete safety information refer to the IB for AZD4573. 
Generally, Grade 1 or 2 non-haematological and/or haematological toxicities do not require 
AZD4573 dose reductions and should be managed as medically indicated (with or without 
short dose interruptions) by the treating physician. Grade 3 and 4 toxicities require dose 
modifications, temporary treatment interruptions, or discontinuation of AZD4573. These are 
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10.6.2.1
Tumour Lysis Syndrome (TLS)
Tumour lysis syndrome is an important identified risk for AZD4573. TLS prophylaxis is 
mandatory for all participants starting 3 days before the first dose of AZD4573, which 
should be followed in addition to institutional guidelines.
Tumour lysis syndrome is characterised by the rapid and/or massive release of intracellular 
constituents (potassium, phosphorus and nucleic acids that can be metabolised to uric acid) 
following tumour cell lysis, resulting in life-threatening complications including acute kidney 
injury, arrhythmias, and neurological complications. While TLS can be seen in solid tumours, 
it is most prevalent in haematological malignancies. Prevention and management of TLS is 
dependent on risk stratification, and risk-based prophylaxis and management (Howard et al 
2016). Participants identified with TLS potential per published risk guidelines (Coiffier et al 
2008; Table 13) should be provided with adequate hydration, pharmacological pretreatment 
with allopurinol or rasburicase, and be carefully monitored for development of TLS. The risk 
of TLS associated with AZD4573 is anticipated to be lower for participants with PTCL or cHL 
compared to participants with DLBCL, as TLS is less often seen in these populations (Gopal 
et al 2015; Chen et al 2017; Coiffier et al 2014; O’Connor et al 2015; O’Connor et al 2011) .
The Howard modification of the Cairo-Bishop definitions of clinical and laboratory TLS are 
included in Appendix G. Laboratory or clinical TLS may trigger dose modification in 
accordance with guidelines provided in Table 11.
10.6.2.1.1
TLS Prophylaxis
Tumour lysis syndrome (TLS) prophylaxis is mandatory for all participants starting 3 days 
before the first dose of AZD4573. TLS prophylaxis is mandatory for all infusions as outlined 
below in Table 13 which provides TLS prophylaxis guidance, which should be followed in 
addition to institutional guidelines. In the event of a discrepancy between the protocol 
guidelines for the management of TLS and the Institutional guidelines of a given 
investigator/centre, the investigator should discuss with the Study Physician.
In addition to the criteria outlined in Table 13 below, any participant with creatinine clearance 
(CrCL) < 80 mL/min must be considered at higher risk of developing TLS and managed 
appropriately.
TLS prophylaxis/management with rasburicase and IV fluid is permitted at any time during 
screening and treatment, however rasburicase and allopurinol must not be co-administered 
(Jones et al 2015).
It is strongly recommended that for all participants with elevated uric acid (hyperuricaemia) 
and intermediate/high risk of TLS, rasburicase (0.20 mg/kg/d IV over 30 minutes) should be 
administered as prophylaxis prior to AZD4573 and repeated as clinically indicated thereafter 
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NOTE: If hyperuricaemia is present at screening and/or during ramp-up, SoC therapy 
should be administered (including IV fluid and rasburicase or allopurinol) to reduce the 
uric acid levels to < ULN before each administration of AZD4573. Rasburicase and 
allopurinol must not be co-administered.
Table 13
Mandatory TLS Prophylaxis Guidance (in Addition to Institutional 
Guidance)
Intermediate to High Risk
LDH > ULN OR any lymph node ≥5 cm
Prophylaxis
Hydrationa
Oral (1.5-2 L/day) plus additional IV fluid: Normal saline 500 mL over 2 to 4 hours
prior to AZD4573, then 100 to 175 mL/h as tolerated to maintain urine output.
Antihyperuricemics
Allopurinol 300 mg orally twice daily beginning 3 days prior to AZD4573 and 
continuing at least through the end of Week 1b.
Consider prophylactic rasburicasec if baseline uric acid is elevated above ULNd, 
LDH > 2 × ULN, or high tumour burden.
a
Administer more aggressive IV fluid hydration for any participant who cannot tolerate or maintain oral 
hydration.
b
After the end of Week 1, or upon discussion and agreement with the Study Physician, the dose or frequency 
of allopurinol may be reduced. Note: The dose of allopurinol should be reduced for renal insufficiency.
c
The recommended dose for rasburicase is 0.20 mg/kg IV over 30 minutes. Rasburicase is contraindicated in 
participants with G6PD deficiency, so participants at higher risk for G6PD deficiency (eg, African or 
Mediterranean ancestry) should be screened for this condition prior to starting rasburicase. Rasburicase and 
allopurinol must not be co-administered.
d
Uric acid levels should be < ULN before each dosing of AZD4573.
Adequate supportive therapy as per Institutional guidelines should be given for all toxicities. 
NOTE: TLS prophylaxis/management with rasburicase and IV fluid is permitted at any time during screening 
and treatment. Rasburicase and allopurinol must not be co-administered.
Abbreviations: h, hour; IV, intravenous; LDH, serum lactate dehydrogenase; ULN, upper limit of normal.
Modified from Coiffier et al 2008.
10.6.2.1.2
TLS Monitoring and Management
Please refer to Appendix G for the definition of TLS and the TLS grading criteria to be used in 
this study.
All participants will receive TLS prophylaxis during the intra-participant dose ramp-up and be 
monitored for TLS during the first 24 hours post start of infusion during the intra-participant 
dose ramp-up (see Sections 10.6.2.1.1 and 10.6.2.1.2). If there are no signs of TLS at the 
6 hour TLS monitoring assessment, the participant can be managed as an outpatient at the 
discretion of the investigator and return to the clinic the next day to complete the 24 hour TLS 
monitoring assessment. Participants showing signs of TLS at 6 hours after the start of infusion 
must remain admitted for inpatient TLS monitoring approximately every 6 hours (or more 
frequently if clinically indicated) until the 24 hour TLS monitoring assessment.


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Where hospitalisation for longer than the mandated 24 hours is required it should be noted that 
if this is due to occurrence of an AE then the event must be reported as an SAE, per definition.
However, if it is purely for the purposes of extended observation then this does not qualify as 
an SAE and does not need to be reported.
For all participants, results of safety laboratory testing (haematology and clinical chemistry at 
a minimum) must be available within 72 hours prior to dosing and must be reviewed by the 
investigator prior to each administration of AZD4573. For each TLS monitoring timepoint, a 
TLS Monitoring page in the eCRF is to be filled out.
In particular, the uric acid level must be < ULN prior to the start of each AZD4573 infusion.
It is strongly recommended that for all participants with elevated uric acid (hyperuricaemia) 
and intermediate/high risk of TLS, prophylaxis should be administered prior to AZD4573 per 
Section 10.6.2.1.1 and repeated as clinically indicated thereafter as per local standard. 
Monitoring for TLS includes checking potassium, calcium, phosphate, uric acid, and 
creatinine. Fluid balance must be monitored according to institutional standards.
Any participant developing laboratory TLS must be treated promptly for electrolyte 
abnormalities (such as hyperkalaemia) to prevent arrhythmias/seizures and for elevated uric 
acid (hyperuricaemia) with rasburicase (0.20 mg/kg/d IV over 30 minutes for up to 5 days) to 
prevent acute renal failure and monitored closely for signs of progression to clinical TLS. 
If these measures are inadequate, then haemodialysis represents definitive therapy and 
should be initiated promptly.
Any participant with hyperkalaemia should receive cardiac monitoring with continuous 
telemetry for ECG changes associated with potentially life-threatening arrhythmias.
Participants with TLS or suspicion of TLS will remain in hospital to undergo additional 
investigations until the TLS has resolved.
10.6.2.1.3
Management of Hydration
Adequate fluid intake for all participants enrolled into the study is mandatory, in particular, 
around the times of AZD4573 dosing.
All participants are mandated to receive IV fluid hydration with normal saline (NaCl 0.9%). 
For participants at intermediate or high risk for TLS (per Table 13), normal saline 500 mL 
should be administered over 2 to 4 hours prior to AZD4573 and then continued at a rate of 100 
to 175 mL/hr as tolerated to maintain urine output at least until the 6 hour TLS monitoring lab 
assessment, and thereafter if medically indicated.


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In case of diarrhoea/nausea/vomiting, more aggressive IV fluid hydration may be needed as 
clinically indicated. Participants are also encouraged to drink enough fluid before and after 
each dosing. Please use diuretics carefully; do not use them prophylactically, only if 
participants have signs of hyper-hydration.
10.6.2.2
Transaminases Increase With or Without Concomitant Bilirubin Increase
and the Risk of Liver Injury
Transaminase elevations are an important identified risk for participants treated with 
AZD4573. Evidence of abnormal liver function should be monitored as per the protocol 
guidelines. Increased levels of AST, ALT, or serum bilirubin should trigger an investigation of 
the cause, which may include viral infection or disease progression with liver infiltration. The 
investigator should consider whether the abnormal liver chemistry test results meet the criteria 
for expedited reporting.
Bilirubin increase with transaminase increase (ALT or AST or both) is included as an 
important identified risk for AZD4573. Biochemical changes of increased transaminases with 
concomitant increase in bilirubin fulfilling criteria for potential Hy's law have been observed 
in participants treated with AZD4573. These events resolved rapidly and have to date not been 
associated with any adverse clinical sequelae or lasting liver damage. Upon re-challenge with 
AZD4573, there is no consistent pattern of recurrence, nor is there any consistent increase in 
severity of the events. As such, whilst the events follow the biochemical definition of Hy's 
law, the clinical pattern is rapidly self-limiting and does not seem to predict any lasting liver 
damage.
Liver injury is classified as an important potential risk for AZD4573. Participants who 
experience increases in transaminases or bilirubin levels after AZD4573 dosing must be 
monitored in line with Section 10.8.2.5. Please refer to Section 10.6.1 (dose modification and 
re-treatment) for additional information on how to manage a participant with increases in 
transaminases/bilirubin. 
Additional 
 will also be collected for central analysis (see Section 
10.8.9.3).
If bilirubin fails to resolve within 96 (-2/+12) hours or transaminases fail to resolve within 
7 days, or if the event is associated with significant clotting abnormality or clinical symptoms 
of liver disease, study treatment must be permanently discontinued (the participant remains on 
study for the 30-day Follow-up and LTFU visits), and the event must be immediately 
communicated to AstraZeneca.
For guidance on treating liver toxicity, please refer to Section 10.6.2, Table 12.
During the course of the study the investigator will remain vigilant for increases in liver 
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biochemistry. The investigator is responsible for determining whether a participant meets PHL 
criteria at any point during the study.
Appendix E describes the process to be followed to identify and appropriately report cases of 
PHL. It is not intended to be a comprehensive guide to the management of elevated liver 
biochemistries. 
The investigator will participate, together with the Study Physician, in review and assessment 
of cases meeting PHL criteria to agree whether HL criteria are met. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
Available transcriptomic and clinical pathology data from the FIH study of AZD4573 
monotherapy suggests the presence of an acute phase response in participants showing signs 
of liver injury. Thus, anti-inflammatory prophylaxis with steroids (eg, dexamethasone) could 
be expected to have a beneficial effect on the incidence and severity of adverse effects on the 
liver related to AZD4573. While, in the absence of a suitably-sized control group without 
prophylactic steroid administration, there is no confirmatory evidence for a positive effect of 
dexamethasone on liver safety profiled from available FIH study clinical data as yet. 
Assessment of ALT changes from baseline versus cumulative dexamethasone dose suggests a 
possible trend towards a negative correlation, ie, high dexamethasone doses being associated 
with smaller increases in ALT post-baseline. 
10.6.2.3
Diarrhoea
Diarrhoea is an important identified risk for AZD4573, based on monkey preclinical 
toxicology studies and clinical data accumulated to date. 
Participants with diarrhoea during therapy should be managed per Institutional guidelines with 
maximal supportive care and diagnostic evaluations as clinically indicated. After excluding 
infectious aetiologies, symptomatic management should be considered. Participants 
experiencing prolonged or severe diarrhoea should be closely monitored and managed as 
appropriate if dehydration and/or electrolyte abnormalities are observed.
Prophylaxis for diarrhoea with atropine is strongly recommended for all participants enrolled 
into the study as an anticholinergic drug, administered at 0.5 mg subcutaneously 15 to 
30 minutes prior to all scheduled AZD4573 infusions. In the event of multiple episodes of 
diarrhoea despite atropine prophylaxis, 1 additional atropine dose may be considered and 
administered as outlined above. In addition, in the event of diarrhoea, participants should 
remain fully hydrated with additional intravenous fluids.


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10.6.2.4
Nausea and Vomiting
Nausea and/or vomiting are important identified risks for AZD4573. Participants with nausea 
and/or vomiting during therapy should be managed per Institutional guidelines with maximal 
supportive care and diagnostic evaluations as clinically indicated. Participants experiencing 
prolonged or severe vomiting should be closely monitored and managed as appropriate if 
dehydration and/or electrolyte abnormalities are observed. 
Events of nausea and vomiting have been observed in approximately half of all participants 
dosed with AZD4573, and have occurred at all dose levels tested to date (except 3 mg). 
Prophylaxis with a 5-HT3 antagonist (e.g. ondansetron +/- dexamethasone) has been 
implemented in the Phase I study (D8230C00001) to help alleviate this toxicity. 
Therefore, prophylaxis for nausea and vomiting is recommended as follows: administer 
dexamethasone 8 mg (IV administration preferable but orally also permitted) plus a 5-HT3 
antagonist (eg, ondansetron initially 8 mg to be taken before treatment, then 8 mg every 12 
hours for up to 3 days) as anti-emetics for all participants, approximately 30 to 60 minutes 
prior to all scheduled AZD4573 infusions. Additional doses of 8 mg dexamethasone may be 
administered if deemed clinically warranted. In addition, in the event of vomiting, participants 
should remain fully hydrated with additional fluids. Participants experiencing prolonged or 
severe nausea and vomiting should be closely monitored and managed as appropriate if 
dehydration and/or electrolyte abnormalities are observed.
10.6.2.5
Neutropenia and Febrile Neutropenia
Neutropenia and febrile neutropenia are important identified risks for participants treated with 
AZD4573. In the presence of CTCAE Grade 3/4 neutropenia, participant’s blood counts 
should be monitored, using local laboratories, at least every 48 hours until recovery.
In the clinical setting to date, Grade 3/Grade 4 neutropenia (~ 45% to 50%) has been observed 
in several participants with an onset around 24 hours after dosing AZD4573 monotherapy. 
Usually, neutrophils recovered spontaneously even without G-CSF. However, colony-
stimulating factors including G-CSF or pegylated G-CSF has been shown to work rapidly and 
may be used according to each investigator site’s institutional guidelines. Anti-infective 
prophylaxis including anti-fungal prophylaxis should be used according to institutional 
guidelines. Anti-viral or cotrimoxazole prophylaxis may not be used unless CD4 helper cell 
counts are less than 100 to 200 per microlitre.
Primary prophylaxis with G-CSF is not generally recommended. Anti-infective 
prophylaxis (antibiotics and antifungals) should be given in accordance with local hospital 
guidelines and International National Comprehensive Cancer Network/European Society for 
Medical Oncology/American Society of Clinical Oncology guidelines.


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10.6.2.6
Infection/Bone Marrow Toxicity with Peripheral Effect/Lymphoid Tissue 
Hypocellularity
Infection/Bone marrow toxicity with peripheral effect/lymphoid tissue hypocellularity is an 
important potential risk for AZD4573, based on findings in preclinical toxicology studies. As 
observed in preclinical studies, this important potential risk refers to haematological changes 
(decreased platelets, red blood cell count/haematocrit, reticulocytes, neutrophils, lymphocytes) 
that may be/may not be accompanied by secondary infections. AEs of thrombocytopenia 
should be managed as deemed appropriate by the investigator as per standard Institutional 
guidelines and in some cases, management of thrombocytopenia may require platelet 
transfusions; again, these should be done according to local hospital guidelines.
Common treatable causes of anaemia (e.g., iron, vitamin B12, or folate deficiencies and 
hypothyroidism) should be excluded. In some cases, management of anaemia may require 
blood transfusions which should be given as per local Institutional guidelines.
10.6.2.7
Pancreatic and Cortical Adrenal Injury (as well as Surveillance for Renal, 
Thymus, and Spleen Toxicity)
Pancreatic injury and cortical adrenal injury are potential risks for AZD4573 based on 
preclinical observations, however, to date, there are no clinical data suggestive of these risks, 
but safety surveillance will continue. Regular complete blood counts, clinical chemistry, and 
coagulation tests will be performed throughout the conduct of the study to monitor for any 
abnormal laboratory parameters, for example: monitoring of lipase and amylase levels for 
potential pancreas toxicity, creatinine values and regular urinalysis testing for kidney function, 
potassium, sodium, cortisol levels along with adrenocorticotropic hormone levels for adrenal 
glands and TSH for any thyroid toxicity.
10.6.2.8
Drug-Drug Interactions
Drug-drug interactions is a potential risk for AZD4573 and refers to interactions with potent 
CYP3A4 inhibitors. Specific drug-drug interaction studies have not yet been performed for 
AZD4573.
Given the proposed clinical dosing regimen of AZD4573, a short IV infusion over 2 hours 
(once weekly), and the observed short half-life of approximately 4 to 7 hours, the risk of 
clinically meaningful drug interactions with AZD4573, is considered to be low.
In vitro studies suggest AZD4573 could reversibly inhibit cytochrome P450 (CYP)3A4/5, 
CYP2C8, CYP2C9, CYP2C19, organic anion transporting polypeptide (OATP)1B1, 
OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2 and 
multi-antimicrobial extrusion protein. However, clinical studies have not yet been performed 
to access the drug-drug interaction. Based on the static model recommended (FDA 2017),
exposure increase of CYP3A sensitive substrates caused by AZD4573 will be 1.06, making it 
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AZD4573 is not a strong inducer of CYP1A2, CYP2B6, or CYP3A, based on in vitro studies. 
If potent CYP3A4 inhibitors are administered, it is recommended to avoid administering them 
on the same day as AZD4573 administration where possible. Alternatively, such inhibitors 
could be administered 8 to 12 hours after the completion of the AZD4573 infusion, if deemed 
clinically warranted in the opinion of the investigator. It is recommended that treatment with 
strong CYP3A4 inducers is avoided, unless it is deemed clinically warranted in the opinion of 
the investigator.
10.6.2.9
Myocardial Ischaemia and Heart Rate Increase
Myocardial ischaemia and heart rate increased are considered potential risks for AZD4573. 
There has been an isolated case report of possible myocardial infarction in association with 
AZD4573, but positive causality could not be established. The same patient experienced heart 
rate increase during the event of ST-segment elevation myocardial infarction. A thorough 
evaluation of all participants dosed to date has not revealed any further cases suggestive of 
myocardial ischaemia or other cardiovascular toxicity causally related to AZD4573 
administration.
Safety surveillance related to this potential toxicity will include ECG and troponin 
measurements for all participants as described in Section 10.8.2. ECG and troponin 
measurements must be performed for all participants who develop symptoms suggestive of 
myocardial ischaemia.
10.6.3 Criteria for Restarting Treatment
The criteria to be met before a participant receives further study drug infusions following a 
pause in treatment, either within 1 cycle or between cycles, is as below:
All participants:
1
Participant has recovered from all treatment-related non-haematological toxicity to 
CTCAE Grade ≤2.
2
Recovery of neutrophils > 1000/μL and platelets > 75000/μL or > 50000/μL with bone 
marrow involvement.
3
Participant has recovered from all hepatic toxicity events within the timeframes described 
in Table 12 above. If biochemical changes in transaminase(s) and total bilirubin are 
consistent with the definition of HL, the participant may continue to receive study drug 
only if all abnormalities have resolved within the timeframes specified in Table 5 above, 
there are no symptoms of liver injury and INR has not increased above 1.5 × ULN (or 1.5 
× baseline). In these circumstances the participant must be made aware of the unknown 
potential for liver damage with continued exposure to AZD4573 prior to retreatment.
Documentation of continued consent is required.


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4
Recovery of uric acid to < ULN.
5
Recovery of changes in uric acid, potassium, phosphorus, creatinine or calcium, or 
symptoms suggestive of TLS as defined in Table 11.
10.7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal – Module 1
See the SoA (Section 10.1.2) for data to be collected at the time of intervention discontinuation
and follow-up and any further evaluations that need to be completed.
Please refer to Section 7 (Core protocol) for information on discontinuation of study
intervention and participant discontinuation/withdrawal.
10.8
Study Assessments and Procedures – Module 1

Study procedures and their timing are summarised or linked to 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 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, is not anticipated to exceed 
436.5 mL in Cycle 1 (cycle duration of 5 weeks) and 124 mL in each subsequent cycle 
(cycle duration of 3 weeks).
10.8.1
Efficacy Assessments
10.8.1.1
Disease Assessment Criteria
Disease assessments for PTCL and HL will be done by the investigator using the Lugano 
Response Criteria (Cheson et al 2014). 


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Table 14
The Lugano Response Criteria
Response and 
Site
PET-CT-Based Response
CT-Based Response
Complete:
Complete metabolic response:
Complete radiologic response 
(all of the following):
Lymph nodes 
and extra-
lymphatic 
sites
Score 1, 2, 3a with or without a residual 
mass on 5PSb
It is recognised that in Waldeyer’s ring or 
extra-nodal sites with physiologic uptake 
or with activation within spleen or marrow 
(eg, with chemotherapy or myeloid 
colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or 
liver. In this circumstance, complete 
metabolic response may be inferred if 
uptake at sites of initial involvement is no 
greater than surrounding normal tissue 
even if the tissue has high physiologic 
uptake
Target nodes/nodal masses must regress to 
≤1.5 cm in LDi
No extra-lymphatic sites of disease
Non-
measured 
lesion
Not applicable
Absent
Organ 
enlargementc
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if indeterminate, 
IHC negative
Partial:
Partial metabolic response:
Partial remission (all of the following):
Lymph nodes 
and extra-
lymphatic 
sites
Score 4 or 5b with reduced uptake 
compared with baseline and residual 
mass(es) of any size
At interim, these findings suggest 
responding disease
At end of treatment, these findings indicate 
residual disease
≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extra-nodal sites
When a lesion is too small to measure on 
CT, assign 5 mm x 5 mm as the default value
When no longer visible, 0 x 0 mm
For a node > 5 mm x 5 mm, but smaller than 
normal, use actual measurement for 
calculation
Non-
measured 
lesions
Not applicable
Absent/normal, regressed, but no increase
Organ 
enlargement
Not applicable
Spleen must have regressed by > 50% in 
length beyond normal
New lesions
None
None


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Table 14
The Lugano Response Criteria
Response and 
Site
PET-CT-Based Response
CT-Based Response
Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan
Not applicable
No response or 
stable disease:
No metabolic response:
Stable disease:
Target 
nodes/nodal 
masses, extra-
nodal lesions
Score 4 or 5b with no significant change in 
FDG uptake from baseline at interim or 
end of treatment
< 50% decrease from baseline in SPD of up 
to 6 dominant, measurable nodes and extra-
nodal sites; no criteria for progressive 
disease are met
Non-
measured 
lesions
Not applicable
No increase consistent with progression
Organ 
enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive 
disease:
Progressive metabolic disease:
Progressive disease requires at least 1 of 
the following PPD progression:
Individual 
target 
nodes/nodal 
masses Extra-
nodal lesions
Score 4 or 5b with an increase in intensity 
of uptake from baseline and/or 
New FDG-avid foci consistent with 
lymphoma at interim or end of treatment 
assessment
An individual node/lesion must be abnormal 
with:
LDi > 1.5 cm and
Increase by ≥ 50% from PPD nadir and
An increase in LDi or SDi from nadir
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the splenic 
length must increase by > 50% of the extent 
of its prior increase beyond baseline (eg, a 
15 cm spleen must increase to > 16 cm). If 
no prior splenomegaly, must increase by at 
least 2 cm from baseline
New or recurrent splenomegaly


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Table 14
The Lugano Response Criteria
Response and 
Site
PET-CT-Based Response
CT-Based Response
Non-
measured
lesions
None
New or clear progression of pre-existing 
non-measured lesions
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another aetiology 
(eg, infection, inflammation). If uncertain 
regarding aetiology of new lesions, biopsy 
or interval scan may be considered
Regrowth of previously resolved lesions;
A new node > 1.5 cm in any axis;
A new extra-nodal site > 1.0 cm in any axis; 
if < 1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma;
Assessable disease of any size unequivocally 
attributable to lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
a
A score 3 in many participants indicates a good prognosis with standard treatment, especially if at the time 
of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid under treatment). Measured dominant 
lesions: Up to 6 of the largest dominant nodes, nodal masses, and extra-nodal lesions selected to be clearly 
measurable in 2 diameters. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid 
organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. 
Non-measured lesions: Any disease not selected as measured, dominant disease and truly assessable disease 
should be considered not measured. These sites include any nodes, nodal masses, and extra-nodal sites not 
selected as dominant or measurable or that do not meet the requirements for measurability but are still
considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would 
be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, 
leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by 
imaging. In Waldeyer’s ring or in extra-nodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be 
greater than in the mediastinum with complete metabolic response, but should be no higher than 
surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid 
growth factors).
b
PET 5PS: 1 = no uptake above background; 2 = uptake ≤ mediastinum; 3 = uptake > mediastinum but 
≤liver; 4 = uptake moderately > liver; 5 = uptake markedly higher than liver and/or new lesions; X = new 
areas of uptake unlikely to be related to lymphoma.
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC,
immunohistochemistry; LDi, longest transverse diameter; MRI, magnetic resonance imaging; PET, 
positron-emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis 
perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions.
Cheson et al 2014
10.8.1.2
Disease Assessment Schedule
Baseline tumour assessments will be performed using radiologic imaging by CT with contrast 
and PET-CT during the screening period. CT scans with contrast will cover neck, chest, 
abdomen, pelvis and any other disease sites; PET scans will cover the whole body from base 
of skull to mid-thigh.
Radiologic scans (ie, contrast CT) and PET scans will be performed as specified in Table 15




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all subsequent response evaluations. 
All response assessments will be made by the investigator. All images for the assessment of 
response will be collected and stored for central review. 
Participants should have radiographic tumour measurements done at the participating study 
centre or an acceptable alternate imaging facility using an identical imaging protocol and 
similar equipment. The same imaging equipment should be used for all scans whenever 
possible. The same radiologist should be assigned to read all the scans for a given participant
throughout the study.
Participants who discontinue study intervention for reasons other than PD will continue to be 
scanned for disease response following the same schedule until documented PD, regardless of 
the start of new anti-lymphoma treatment.
10.8.2
Safety Assessments
Planned time points for all safety assessments are provided in the Module 1 SoA (Section
10.1.2) and are detailed below.
10.8.2.1
Physical Examinations
Baseline/screening:
A complete physical examination, including a standard neurological examination, should be 
completed at screening and will include, at a minimum: the general appearance of the 
participant, height, weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, 
abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system. 
Investigators should pay special attention to clinical signs related to previous serious illnesses 
and new or worsening abnormalities that may qualify as AEs. 
Post first dose of AZD4573: 
From the first dose of AZD4573 onwards, symptom-directed physical examinations will be 
performed before each infusion and at the 30-day follow-up visit as specified in the Module 1 
SoA (Section 10.1.2). 
ECOG performance status:
Performance status will be assessed at screening, before each dose of AZD4573 and at the 
30-day follow-up according to ECOG criteria as follows:
0 = Fully active, able to carry out all pre-disease activities without restrictions.
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a 


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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.
10.8.2.2
B symptoms 
Information on B symptoms (e.g., unintentional weight loss, fevers and night sweats) will be 
collected at each visit. 
10.8.2.3
Vital Signs
Vital signs (body temperature, blood pressure [BP], heart [pulse] rate and body weight) will be 
performed at timelines specified below.

Blood pressure and pulse/heart rate measurements will be assessed in supine position 
with a completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 10 minutes of 
rest for the participant in a quiet setting.

Vital signs are to be taken before any blood collection.

Body temperature will be taken prior to all infusions (within 2 hours before start of 
the infusion). 

Weight will be measured at screening, prior to infusions on Day 1 of each cycle, and 
at the 30-day follow-up visit.
Blood pressure and pulse rate will be measured at the following timepoints:

Screening

On Day 1 of each AZD4573 dose in Cycle 1

Cycle 2 Day 1 at the following timepoints: 

Pre-dose (up to 2 hours prior to infusion)

1 hour after the start of the infusion (± 10 minutes) 

At end of infusion (up to 10 minutes post-dose)

4 hours (± 30 minutes) after end of infusion
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
For all subsequent infusions:

Pre-dose (up to 30 minutes prior to infusion)

At the end of infusion (up to 30 minutes post-dose)

At the 30-day follow-up visit.
10.8.2.4
Electrocardiograms
ECG will be performed at timepoints specified below.
Twelve-lead digital ECGs will be obtained after the participant has been resting semi-supine 
for at least 10 minutes. All ECGs should be recorded with the participant in the same physical 
position where possible.
If an abnormal ECG finding at screening or baseline is considered to be clinically significant 
by the investigator, it should be reported as a concurrent condition. If a clinically significant 
abnormal ECG finding occurs on study, contact the Study Physician.
Single ECGs will be collected for central analysis at the timepoints below:

Screening 

During Cycle 1, all weeks: 

Pre-dose (up to 2 hours prior to infusion) 

End of infusion (within 30 minutes of the end of infusion)

Cycle 2 Day 1 

Pre-dose (up to 2 hours prior to infusion)

End of infusion (within 30 minutes of the end of infusion)

Cycle 3+: End of infusion (within 30 minutes of the end of infusion)

30-day follow-up visit
The ECG parameters to be determined will include (but will not be limited to) the following:

Heart rate

RR interval: duration in msec between 2 R peaks of 2 consecutive QRS complexes

PR interval: duration in msec from the beginning of wave P to onset of ventricular
depolarisation (Q and R)

QRS interval: duration in msec of the QRS complex

QT interval: duration in msec from the beginning of Q wave to the end of the T-wave

QTcF: QT interval corrected for heart rate using Fridericia’s formula
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Any abnormal finding in the ECG tracing will be evaluated by the investigator and will be
specifically documented and registered in the eCRF. Throughout the study, clinically relevant 
new findings or worsening of a pre-existing finding in the ECGs (parameters or abnormal
findings in the tracing) must be considered an AE and must be recorded in the AE eCRF form.
If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, 
potassium, and troponin) must be done to coincide with the ECG testing (see Section 
10.8.2.5).
Echocardiograms: In addition to screening, an ECHO should be done within 14 days after an 
abnormal ECG finding (T wave inversion/flattening) or as soon as possible when clinically 
indicated. If an ECHO cannot be taken, a MUGA scan to assess LVEF will be done. In case of 
any T wave abnormality, the ECHO (or MUGA) should be repeated at the 30-day follow-up
visit to address the question of recovery, during the off-treatment period.
10.8.2.5
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation,
and urinalysis will be taken at the timepoints indicated below.
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The clinical chemistry, haematology and urinalysis will be performed at a local laboratory at 
or near to the investigator site. Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site.
For all participants, results of safety laboratory testing (haematology and clinical chemistry at 
a minimum) must be available within 72 hours prior to dosing and must be reviewed by the 
investigator prior to administration of AZD4573. To initiate Cycle 1 and subsequent cycles, 
haematology and chemistry criteria in inclusion criteria 10, 13, and 14 shall be met. 
In addition, during AZD4573 treatment, dose modification and discontinuation guidelines are 
provided in Section 10.6.1. For each TLS monitoring timepoint, a TLS Monitoring page in the 
eCRF is to be filled out. If clinically indicated, additional clinical laboratory tests and 
evaluations may be performed by the investigator and these need to be entered into the eCRF. 
The laboratory variables to be measured for haematology/haemostasis, clinical chemistry, 
urinalysis, coagulation, and pregnancy testing are listed in Table 16. 

Haematology: should be measured at screening, during Cycles 1 to 3 before AZD4573 
dosing and 24 hours post start of infusion, before dosing for Cycles 4+, and at the 30-day 


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follow-up. From Cycle 4 onwards, a 24-hour sample is only required where clinically 
indicated.

Clinical chemistry: blood samples should be taken during Cycles 1 to 3 before AZD4573 
dosing and 24 hours post start of infusion, before dosing for Cycles 4+, and at the 30-day 
follow-up. From Cycle 4 onwards, a 24-hour sample is only required where clinically 
indicated.

In addition, GLDH and CPK will be measured at screening for all participants. For 
any participant on study who experiences elevated ALT or AST ≥ 3 × ULN and/or 
total bilirubin ≥ 2 × ULN after dosing, repeated measurements of liver chemistry 
tests are required at least every 48 hours (-2/+12 hours) post start of infusion until 
resolution of the event to baseline level.

Note that additional samples are required for TLS monitoring at baseline and prior to 
infusion, 6 hours after start of infusion, and 24 hours after start of infusion during the 
intra-participant ramp-up; see TLS monitoring below for further details.  

If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, 
magnesium, potassium, and troponin) must be done to coincide with the ECG testing. 

Coagulation: should be measured at screening, during Cycles 1 to 3 before AZD4573 
dosing and 24 hours post start of infusion, before dosing for Cycles 4+, and at the 30-day 
follow-up. From Cycle 4 onwards, a 24-hour sample is only required where clinically 
indicated. 

INR/PT and fibrinogen (and D-dimer where available at local institution) should be 
measured at 96 (-2/+12) hours and 7 days post start of infusion for any participant 
experiencing ALT or AST elevations ≥ 3 × ULN with concomitant elevation in total 
bilirubin ≥ 2 × ULN, then as clinically indicated until resolution of the liver 
chemistry test abnormality to baseline level.

Urinalysis: should be done at screening, up to 30 minutes prior to infusion on Day 1 of 
each cycle, and at the 30-day follow-up. 

Supra-renal glands: T4, cortisol, adrenocorticotropic hormone and TSH should be 
measured at screening and at the 30-Day FU.

Pancreas: Lipase and amylase measurements are required at screening, pre-dose on each 
AZD4573 dosing day, and at the 30-Day FU. 

Hepatitis serology: will be conducted at screening. Hepatitis serology must include 
hepatitis B surface antigen (HbsAg), hepatitis B surface antibody (anti-HBs), anti-HBc, 
and hepatitis C (HCV) antibody. Participants who are anti-HBc positive, or have a known 
history of HBV infection, should be monitored every 3 months with a quantitative PCR 
test for HBV DNA. Any participants testing positive for any hepatitis serology must have 
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
Pregnancy: a urine or serum sample for a pregnancy test will be collected from all 
female participants of childbearing potential at the following timepoints:

Screening

Pre-dose on Cycle 1, Day 1

Prior to initiating a new cycle (once every 21 days)

At the 30-day follow-up visit. 
Urine β-hCG and quantitative serum β-hCG tests are permitted. If a urine β-hCG test is 
positive or indeterminate, quantitative serum β-hCG will be performed for confirmation. 
Additional testing may be performed at investigator discretion for example in the event of 
suspected contraception failure.

Cardiac: Cardiac troponin measurements are required at:

Screening.

Cycle 1: pre-dose (up to 2 hours prior to infusion) and at 24 hours after start of 
infusion.

Cycle 2+: pre-dose (up to 2 hours prior to infusion).

30-Day follow-up visit.

TLS monitoring: potassium, calcium, phosphate, uric acid, and creatinine at baseline, 
then at the following timepoints for each infusion: prior to infusion, 6 hours after start of 
infusion, and 24 hours after start of infusion during the intra-participant ramp-up. 
Participants showing signs of laboratory TLS at 6 hours after infusion must be admitted 
for inpatient TLS monitoring for 24 hours and monitored every 4 to 6 hours during this 
time (or more frequently if clinically indicated); see Section 10.6.2.1.2.

Liver chemistry tests: GLDH and CPK, will be measured at screening for all 
participants.
For any participant on study who experiences elevated ALT/AST (≥ 3 × ULN) and/or 
elevated total bilirubin (≥ 2 × ULN), repeated liver chemistry tests are required 
including: total and direct/indirect bilirubin, ALT, AST, ALP, C-reactive protein, CPK, 
GLDH, INR/PT, fibrinogen, D-dimer (where available at local institution). Liver chemistry 
tests should be measured at least every 48 hours (-2/+12 hours) post start of infusion until 
resolution of the event to baseline (or Grade 1) levels.
If liver chemistry tests are still elevated after 96 hours, then additional testing should be done 
with each subsequent chemistry panel test until resolution for each incidence of the elevated 
ALT and/or AST. During the course of the study the investigator will remain vigilant for 
increases in liver biochemistry. The investigator participates in review and assessment of these 
cases together with the sponsor. HL criteria are met if there is no alternative explanation for 
the elevations in transaminases and total bilirubin levels. If a participant is assessed as meeting 
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biochemistry and evaluation of HL’, for further instructions. 
The following laboratory variables for haematology/haemostasis, clinical chemistry, 
urinalysis, and pregnancy testing will be measured.
Table 16
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Full blood count with differential
S/P-Creatinine
S/P-Chloride
B-Hb
S/P-Bilirubin total
S/P-Magnesium
B-White blood cell count with differential
S/P-Direct and indirect bilirubin 
(where required)
S/P-Phosphorus
B-Platelet count
S/P-Alkaline phosphatise
S/P-Cholesterol
B-Haemocrit
S/P-Aspartate transaminase
S/P-Amylase
B-Absolute neutrophil count
S/P-Alanine transaminase
S/P-Lactate 
dehydrogenase
B-Absolute lymphocyte count
S/P-Albumin
S/P-Lipase
B-Blast Cells
S/P-Potassium
S/P-Bicarbonate
Urinalysis (dipstick)
S/P-Carbonate
S/P-glutamate 
dehydrogenase
U-Hb/Erythrocytes/Blood 
U-pH
S/P-Calcium, total
S/P-Blood urea nitrogen
U-Protein/Albumin
U-Bilirubin
S/P-Sodium
S/P-Glucose (fasting 
preferred)
U-Glucose 
U-Ketones
S/P-Creatine phosphokinase
S/P-Total protein
U-Specific gravity
U-Drug 
screeninga
S/P-Uric acid
S/P-GGT
U-Microscopy including white blood cells 
/high-power field, red blood cells/high-power 
field
S/P-Triglycerides
S/P-Ferritin
Coagulation
S/P-C-reactive protein
S/P-Urea
International normalised ratio
S/P-Triglycerides
S/P-Phosphate
Activated partial thromboplastin time, 
absolute or relative
S/P-Troponin
Prothrombin time
S/P-Ammonia (where available at local institution; to be 
tested every 2 weeks)
Fibrinogen
D-Dimer (where available at local institution)
Pregnancy Test (women of childbearing potential only)
U-hCG
S-beta hCG (at screening only)
a
Mandated at screening visit only; for all other urinalysis tests, drug screening may be performed at 
investigator discretion.
Abbreviations: B, blood; GGT, gamma-glutamyl transferase; Hb, haemoglobin; hCG, human chorionic 
gonadotropin; P, plasma; S, serum; U, urinalysis.


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10.8.2.6
Other Safety Assessments
Monitoring for TLS per the SoA (Section 10.1.2) and prophylaxis for TLS are outlined in 
detail in Section 10.6.2.1.2.
Blood samples for 
 will be collected per the SoA (Section 10) and as 
outlined in Section 10.8.9.3.
Additional testing requirements (refer to the SoA [Section 10] for timing) include:

Echocardiograms: In addition to screening, an ECHO should be done within 14 days after 
an abnormal ECG finding (T wave inversion/flattening) or as soon as possible when
clinically indicated. If an ECHO cannot be taken, a MUGA scan to assess LVEF will be 
done. In case of any T wave abnormality, the ECHO (or MUGA) should be repeated at 
the 30-day follow-up visit to address the question of recovery, during the off-treatment
period.

Serum immunoglobulins (IgA, IgM, IgG): Screening, pre-dose on Day 1 of Cycles 3, 6, 9, 
13, every 6 months thereafter and at the 30-Day FU.
10.8.3
Adverse Events and Serious Adverse Events
Refer to Section 8.3 in the core protocol.
10.8.4
Overdose
Refer to core protocol Section 8.4 for information on AZD4573 overdose.
10.8.5
Human Biological Samples
See core protocol Section 8.5 for detail on human biological samples.
10.8.6
Pharmacokinetics
Pharmacokinetics is a secondary objective for Module 1. Plasma samples will be used to 
analyse the PK of AZD4573 (and metabolites, if applicable). Samples collected for analyses of 
AZD4573 concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study.
10.8.6.1
Pharmacokinetics Sampling Schedule
Plasma samples will be collected for measurement of plasma concentrations of AZD4573 at 
the following timepoints on Cycle 1, Day 1 of Weeks 1 through 3 and Cycle 2, Day 1: 

Pre-dose (up to 2 hours prior to AZD4573 administration)

Following the start of infusion at the following timepoints:
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
1 hour (± 15 minutes)

2 hours (± 15 minutes)

4 hours (± 30 minutes)

7 hours (± 1 hour)

24 hours (± 1 hour) (ie, Cycle 1 Day 2).
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. 
 





Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
10.8.6.2
Determination of Drug Concentration
Samples for determination of drug concentration in plasma
will be assayed by 
bioanalytical test sites operated by or on behalf of AstraZeneca, using an appropriately 
validated bioanalytical method. Full details of the analytical method used will be described in 
a separate Bioanalytical Report.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
10.8.7
Pharmacodynamics
Whole blood samples will be collected and immediately processed (within 30 minutes) on-site 
for 
. The objective of these studies is to evaluate whether AZD4573 is 
 
 as expected, and to gain an 
understanding of kinetics and dose response. 
 
 
10.8.7.1
Collection of Samples
Mandatory pharmacodynamic (whole blood) samples will be collected at the following 
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timepoints:

Screening

Week 1 (6 mg AZD4573; starting dose)

C1D1 predose (up to 2 hours prior to dosing)

C1D1 2 hours (± 15 minutes) after start of infusion

C1D1 4 hours (± 30 minutes) after start of infusion

C1D1 7 hours (± 1 hour) after start of infusion 

C1D2 24 hours (± 2 hours) after start of infusion 

Week 2 (9 mg AZD4573)

C1D8 predose (up to 2 hours prior to dosing)

C1D8 2 hours (± 15 minutes) after start of infusion

C1D8 4 hours (± 30 minutes) after start of infusion

C1D8 7 hours (± 1 hour) after start of infusion 

C1D9 24 hours (± 2 hours) after start of infusion 

Week 3 (12 mg AZD4573; target dose)

C1D15 predose (up to 2 hours prior to dosing)

C1D15 2 hours (± 15 minutes) after start of infusion

C1D15 4 hours (± 30 minutes) after start of infusion

C1D15 7 hours (± 1 hour) after start of infusion 

C1D16 24 hours (± 2 hours) after start of infusion 
Note: The timing of these samples may be adjusted dependent upon ongoing PK and 
pharmacodynamic analysis and interpretation.
 must be collected at each pharmacodynamic timepoint once 
participants have reached the target dose.
Further details on sample processing, handling and shipment will be provided in the 
Laboratory Manual.
For storage, re-use and destruction of pharmacodynamic samples see Section 8.5 and 
Appendix C. 
10.8.8
Exploratory Whole Blood Analyses Samples
Mandatory whole blood samples will be collected from all participants as per the schedule in 
Table 17 and the sections below.
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10.8.8.1
Whole blood for Exploratory 
(all 
participants)
Mandatory whole blood samples to enable exploratory 
analysis will be collected as 
specified below. Note: Collection time begins with the start of infusion.

Screening

C1D1 predose (up to 2 hours prior to dosing)

C1D15 predose (up to 2 hours prior to dosing)

C1D29 predose (up to 2 hours prior to dosing)

C2D1 predose (up to 2 hours prior to dosing)

C2D15 predose (up to 2 hours prior to dosing)

C3D1 predose (up to 2 hours prior to dosing)

C5D1 predose (up to 2 hours prior to dosing)

C6D1 predose (up to 2 hours prior to dosing)

C7D1 predose (up to 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, collect 
pre-infusion)

Disease progression/End of treatment
10.8.8.2
Whole Blood for 
 Analysis (All Participants)
Mandatory whole blood samples to isolate plasma for 
 and 
 analysis will be collected to 
 
 
Note: Collection time begins with the start of infusion.

Screening

C1D1 predose (up to 2 hours prior to dosing)

C1D15 predose (up to 2 hours prior to dosing)

C1D29 predose (up to 2 hours prior to dosing)

C2D1 predose (up to 2 hours prior to dosing)

C2D15 predose (up to 2 hours prior to dosing)

C3D1 predose (up to 2 hours prior to dosing)

C5D1 predose (up to 2 hours prior to dosing)

C6D1 predose (up to 2 hours prior to dosing)

C7D1 predose (up to 2 hours prior to dosing)
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
Every scheduled or unscheduled tumour assessment scan (if on day of infusion, collect 
pre-infusion)

Disease progression/End of treatment
10.8.8.3
Whole Blood Samples for 
 (All Participants)
Mandatory whole blood samples will be collected from all participants at the timepoints 
indicated below. 
 
 Note: Collection time 
begins with the start of infusion.

Screening

C1D1 predose (up to 2 hours prior to dosing)

C1D15 predose (up to 2 hours prior to dosing)

C1D16 24 hours (± 2 hours) after start of infusion 

C2D1 predose (up to 2 hours prior to dosing)

C3D1 predose (up to 2 hours prior to dosing)

C5D1 predose (up to 2 hours prior to dosing)

C7D1 predose (up to 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, collect 
pre-infusion)

Disease progression/End of treatment
10.8.8.4
Whole Blood Samples for 
 (All Participants)
Mandatory whole blood samples will be collected from all participants at the timepoints 
indicated below. 
 
 Note: Collection time begins with the start of 
infusion.

Screening

C1D1 predose (up to 2 hours prior to dosing)

C1D15 predose (up to 2 hours prior to dosing)

C1D16 24 hours (± 2 hours) after start of infusion 

C2D1 predose (up to 2 hours prior to dosing)

C3D1 predose (up to 2 hours prior to dosing)

C5D1 predose (up to 2 hours prior to dosing)

C7D1 predose (up to 2 hours prior to dosing)
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
Every scheduled or unscheduled tumour assessment scan (if on day of infusion, collect 
pre-infusion)

Disease progression/End of treatment
10.8.8.5
Whole Blood for 
 Exploratory Analysis (All Participants)
Mandatory whole blood samples will be collected from all participants in 
 at the timepoints indicated below to 
 Note: 
Collection time begins with the start of infusion.

Screening

C1D1 predose (up to 2 hours prior to dosing)

C2D1 predose (up to 2 hours prior to dosing)

C3D1 predose (up to 2 hours prior to dosing)

C5D1 predose (up to 2 hours prior to dosing)

C7D1 predose (up to 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, collect 
pre-infusion)

Disease progression/End of treatment
10.8.8.6
Whole Blood for 
 Exploratory Analysis (All Participants)
Mandatory whole blood samples will be collected in 
 from all 
participants at the timepoints indicated below.
 
 
 Note: Collection time begins with the start of 
infusion.

Screening

Week 1 (6 mg AZD4573; starting dose)

C1D1 predose (up to 2 hours prior to dosing)

C1D1 2 hours (± 15 minutes) after start of infusion

C1D2 24 hours (± 2 hours) after start of infusion

Week 2 (9 mg AZD4573)

C1D8 predose (up to 2 hours prior to dosing)

C1D8 2 hours (± 15 minutes) after start of infusion
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
C1D9 24 hours (± 2 hours) after start of infusion

Week 3 (12 mg AZD4573; target dose)

C1D15 predose (up to 2 hours prior to dosing)

C1D15 2 hours (± 15 minutes) after start of infusion

C1D16 24 hours (± 2 hours) after start of infusion

C2D1 predose (up to 2 hours prior to dosing)

C3D1 predose (up to 2 hours prior to dosing)

C5D1 predose (up to 2 hours prior to dosing)

C7D1 predose (up to 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on the day of infusion,
collect pre-infusion)

Disease progression/End of treatment
10.8.9
10.8.9.1
Tissue Samples
10.8.9.1.1
Bone Marrow
All PTCL participants must be willing and able to provide mandatory baseline bone marrow 
aspirate and/or biopsy no older than 3 months, and agree to undergo post-treatment bone 
marrow biopsy when required to confirm response.
Where bone marrow biopsy is performed on a dosing day, it must be done at least 2 hours 
post-infusion.
For all participants, any time a bone marrow analysis is performed, mandatory exploratory 
 analysis will be performed.
 
10.8.9.1.2
Tumour Tissue
Tumour tissue samples will be utilised to confirm cHL and PTCL histological subtype and for 
 
 
. The tumour biopsy samples may also be used as 
part of the 
 assessments.
Fresh tumour tissue or archival tumour tissue must be confirmed to be available at screening.
This should be provided as a fresh biopsy (preferable) where available and clinically feasible,
or where a fresh biopsy is unavailable, an archival tumour biopsy sample FFPE tumour block 
may be provided. Where an archival tumour biopsy FFPE tumour block is unavailable, 
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archival tumour biopsy FFPE unstained slides must be provided.
For quantities, refer to the laboratory manual.
Archival tissues must have been obtained as a core biopsy or excisional node biopsy and meet 
the specified criteria detailed in the Laboratory Manual. Associated pathology report(s) for 
archival tissue samples must be obtained at screening for all participants enrolled into the 
study.
Where clinically feasible, participants may also consent to provide an additional optional 
biopsy at end of treatment/disease progression for analysis of candidate resistance 
mechanisms. Informed consent must be obtained from any participant who agrees to provide 
tissue for optional tumour tissue sample testing. This optional sample may be taken at the 
30-day follow-up visit if not collected previously.
The tumour biopsy procedure will be performed by core needle, under radiological guidance, 
or surgically if the site of disease is superficial and palpable or visible (eg, palpable lymph 
node). Tumour biopsies should be preferentially obtained from tumour tissues that are safely 
accessible, as determined by the investigator, and are not obtained from sites that require 
significant risk procedures. Participants will undergo 6 core image-guided needle biopsies. It 
is mandated that the core biopsy be removed directly from the tumour in situ and not cored 
from a surgically removed tumour. This is to ensure the best possible quality of the biopsy, as 
the blood/nutrient supply to the tumour is not disrupted prior to biopsy collection. Fine-needle 
aspirate specimens are not acceptable. Failure to obtain sufficient tumour sample after making 
best efforts to biopsy the tumour will not be considered a protocol deviation.
Sites should confirm adequacy of tumour biopsy material at the time of the procedure. The 
exact time that the biopsy was taken should be clearly noted in the associated documentation. 
For mandatory and optional biopsy participants, the associated pathology report(s) for fresh 
tumour samples will be required at screening and requested on-treatment for all participants 
enrolled into the study.
Instructions on tumour biopsies processing, storage, and shipping will be provided in the 
Laboratory Manual.
10.8.9.2
Blood samples
EBV serology will be conducted at screening. EBV serology must include IgM and IgG. Any 
participants testing positive for EBV must also have EBV viral load (PCR) performed at 
screening. For participants with positive EBV serology at baseline, sites should enter 
historical EBV-encoded RNA in situ hybridisation and/or latent membrane protein 1 
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10.8.9.3
Plasma samples will be collected from all participants to assess exploratory 
.
These samples will be collected as per the timepoints in Table 18 below.
Table 18
Sampling Schedule (All Participants)
Day
Timing for blood samples
Window
Screening
At any screening visit
Not applicable
Cycle 1, Weeks 1-3
Predose
Within 2 hours before start of 
infusion
4 hours post start of infusion
± 30 minutes
7 hours post start of infusion
± 1 hour
24 hours post start of Day 1 infusion
± 1 hour
In cases of increased liver 
chemistry tests/bilirubin at 24h 
post start of infusion
96 hours post start of infusion
-2/+12 hours
Pre-dose the following infusion
Within 4 hours before start of 
infusion
Each timepoint where chemistry 
panel testing is performed
N/A
Any visit from Cycle 1, Week 4 
onwards where increased liver 
chemistry tests/bilirubin is 
observed (post dose chemistry 
panel test)
Same schedule as Cycle 1, 
Weeks 1-3
N/A
For all participants, plasma samples will be collected during Cycle 1, Weeks 1 to 3. In 
addition, if a participant has increases in liver chemistry tests/bilirubin (defined as any 
elevated transaminases of Grade 3 or above or fulfilling PHL criteria), samples should also be 
taken at 96 hours post start of infusion (-2/+12 hours), pre-dose the following infusion (within 
4 hours) and whenever chemistry panel testing is being performed, until resolution of the 
event.
For any elevated liver chemistry tests/bilirubin that is observed with subsequent dosing with 
AZD4573, 
 should be performed using the timepoints outlined 
above (excluding screening sample).
10.8.9.4
Other Study Related 
 Research
 Sample for 
Per local regulations, a mandatory 
 sample for 
will be collected 
from participants in this module. It is important to assess 
 
 will be used to discriminate this. The sample 
should be collected from participants before receiving study treatment.
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Details on sample processing, handling, and shipment are provided in the Laboratory Manual. 
For storage, re-use and destruction of 
 samples see Section 8.5. 
10.8.10
Optional Genomics Initiative Sample
See core protocol Section 8.7.
10.9
Statistical Considerations – Module 1
10.9.1
Statistical Hypotheses
Not applicable.
10.9.2
Sample Size Determination
Table 19
Sample Size: Module 1
Indication
Primary Analysis Sample Size
PTCL
Cohort 1: Non-NK PTCL, 
N = 21 response-evaluable
Cohort 2: NKTCL, 
N = 21 response-evaluable
cHL
Cohort 3: cHL, 
N = 21 response-evaluable
Abbreviations: cHL, classical Hodgkins lymphoma; NKTCL, natural killer T-cell lymphoma; non-NK PTCL; 
non-natural killer peripheral T-cell lymphoma; PTCL, peripheral T-cell lymphoma; 
 
 
Module 1 will include approximately 21 response-evaluable PTCL participants excluding 
NKTCL in Cohort 1, 21 response-evaluable NKTCL participants in Cohort 2, and
21 response-evaluable cHL participants in Cohort 3.
 
This may 
enable the sponsor to continue enrolling participants, beyond the initial 21 response-evaluable 
per cohort, while considering further clinical development options based on an early 
suggestion of positive benefit-risk for participants with r/r PTCL treated with AZD4573 
monotherapy. 
 
 
 This 
may enable the sponsor to continue enrolling participants, beyond the initial 
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21 response-evaluable participants, while considering further clinical development options 
based on an early suggestion of positive benefit-risk for participants with r/r cHL treated with 
AZD4573 monotherapy.
 
 
In Module 1 the primary objective is to evaluate efficacy of AZD4573 monotherapy in 
non-NK PTCL (excluding NKTCL), NKTCL and cHL. For primary ORR endpoint analyses 
approximately 21 RP2D-treated response-evaluable participants will be incorporated per 
cohort. These sample sizes are large enough to give a reasonable chance of detecting an 
efficacy signal.
Historical response rates for drugs approved for r/r PTCL 2L are in the range of 25% to 30% 
(Zain 2019). 
The following examples give an indication of the level of precision that will be achieved at the 
primary analysis for PTCL within and across Module 1 Cohorts 1 and 2 of this study:
Table 20
In addition to ORR, the criteria for success will take into account the observed safety and 
tolerability data, and the other efficacy endpoints, in particular the DoR.
The DCO for the primary analysis for each Module 1 PTCL cohort will occur after 
21 response-evaluable participants in the cohort have had the opportunity to be followed for at 
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least 6 months since their first dose or have progressed or have initiated other anticancer 
therapy, or when 75% of participants have progressed or died, whichever occurs first. If one 
cohort reaches its planned primary analysis DCO ahead of the other, then the slower enrolling 
cohort may be evaluated for efficacy responses at the same time. The purpose of evaluating 
the slower cohort early would be for internal planning and to review continued development 
of the AZD4573 in one or both r/r PTCL groups. When both cohorts have reached their 
primary analysis DCOs the efficacy and safety data may be pooled for analysis. Additional 
data cuts may also be performed, if required.
Historical response rates in r/r cHL 3L (excluding BV and anti-PD1) have been in the range of 
10% to 50% (Vassilakopoulos et al 2020).
The following examples give an indication of the level of precision that will be achieved for 
cHL in Module 1 Cohort 3 of this study:
Table 21
In addition to ORR, the criteria for success will take into account the observed safety and 
tolerability data, and the other efficacy endpoints, in particular the DoR.
The DCO for primary analysis of Module 1 Cohort 3 will occur after 21 response-evaluable 
participants in the cohort have had the opportunity to be followed for at least 6 months since 
their first dose or have progressed or have initiated other anticancer therapy, or when 75% of 
participants have progressed or died, whichever occurs first. Additional data cuts may also be 
performed, if required.
In Module 1 cohorts a secondary objective is to confirm if the lymphoma RP2D is safe and 
tolerable or if additional dose optimisation at a revised dose is indicated. Up to a maximum of 
approximately 60 r/r PTCL participants and 30 r/r cHL participants will be treated with 
AZD4573 monotherapy in Module 1. The data from these approximately 90 new lymphoma 
participants would supplement safety data collected for participants treated at this dose level 
in D8230C00001. Module 1 will also provide further data for PK/PD modelling.
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At the end of the module a final analysis will be conducted to incorporate all data (up to and 
beyond the primary analysis) from all participants.
10.9.3
Populations for Analyses
For purposes of analysis, the study populations are defined as provided in Table 22. For the 
safety and PK analyses, participants will be classified according to the dose schedule they 
actually received. For all efficacy analyses, and for baseline and demography, participants will 
be classified according to the dose they were assigned to (ie, the planned dose schedule).
Table 22
Populations for Analyses
Population/Analysis set
Description
Enrolled
All participants who sign the ICF.
Safety
All participants who receive at least 1 dose of any study intervention.
Full analysis set/ITT
All participants who receive any amount of any study intervention. 
This is for efficacy, baseline and demography. 
Response evaluable
All dosed participants who have measurable disease at baseline.
PK
All participants who receive any amount of study intervention with at 
least 1 reportable concentration.
Abbreviations: ICF, informed consent form; ITT, intention-to-treat; PK, pharmacokinetics.
10.9.4
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 this plan will be reported in the CSR.
10.9.4.1
General Considerations
Refer to Section 9.4.1 for core study details on statistical analyses.
The primary endpoint for Module 1 is ORR; other efficacy endpoints are secondary.
10.9.4.2
Efficacy Analyses 
The efficacy endpoints of ORR, CR rate and DoR will be summarised on the response 
evaluable set. The efficacy endpoints of PFS and OS will be summarised on the full analysis 
set (ITT).
Additional subgroup analysis of efficacy may be performed as specified in the SAP.
The response criteria for malignant lymphoma (Cheson et al 2014) will be used, as assessed 
by investigators, to derive the endpoints (ORR, CR rate, DoR and PFS).
10.9.4.2.1
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is ORR, defined as the proportion of participants who have a 


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tumour response (CR and PR).
Overall Response Rate and Complete Response Rate
Overall response rate (and CR rate) will be presented with corresponding 80% and 95% 
2-sided CIs.
10.9.4.2.2
Secondary Efficacy Endpoint(s)
The secondary efficacy endpoints are CR rate, DoR, PFS and OS.
Duration of Response
Duration of response is defined as the time from the first objective response of CR or PR to 
the time of documented disease progression or death (in the absence of disease progression). It 
will be summarised using descriptive statistics and KM plots where there are sufficient 
numbers of responders.
Progression Free Survival
PFS is defined as the time from first dose date to documented disease progression, or death 
(by any cause in the absence of progression), regardless of whether the participant withdraws 
from study treatment 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 assessment. 
The PFS time will always be derived, based on scan/assessment dates, not visit dates.
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.
KM plots and estimates will be provided.
Overall Survival
Overall survival is defined as the time from first dose until the date of death from any cause. 
Any participant not known to have died by the analysis DCO date will be censored based on 
the last recorded date on which the participant was known to be alive. KM plots and estimates
will be provided.


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10.9.4.3
Safety Analyses
See core protocol Section 9.4.3 for safety analyses.
10.9.4.4
Pharmacokinetic Analyses
The secondary endpoints for PK are plasma concentrations and derived PK parameters for 
AZD4573. Additional details on PK analyses will be provided in the SAP.
10.9.4.5
Pharmacodynamics 
analyses
Detail on exploratory endpoints will be contained in the SAP.
 status will be assessed for participants in each cohort according to pre-specified 
criteria that may be detailed in the SAP. 
 assessments may include, but are not 
limited to, pharmacodynamic analysis of 
 
 
 
 exploratory analyses may be described in a separate analysis plan and may be 
reported outside the CSR in a separate report or publication. The results of this 
 
assessment may be pooled with 
 data from other studies with the study intervention 
to generate hypotheses to be tested in future research.
10.9.5
Interim Analyses
No interim analyses are planned for this module. 
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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study 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.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

For all studies except those utilising medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.


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
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations

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 or state other documents] 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.

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.
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date.
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 


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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.
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.
A 5
Committees Structure
Not applicable.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical study and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the 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 electronically 
signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.


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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,
Contract Research Organisations).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the 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 the first site open and will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.


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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines.

Inadequate recruitment of participants by the investigator.

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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


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Intensity Rating Scale:

mild (awareness of sign or symptom, but easily tolerated)

moderate (discomfort sufficient to cause interference with normal activities)

severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
The grading scales found in the revised National Cancer Institute CTCAE version 5.0 will be 
utilised for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

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 judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant


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
Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IRT/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTMS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTMS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each centre keeps full traceability of collected biological samples from the 
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.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent.
If a 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.


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


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Appendix D
Optional Genomics Initiative Sample
D 1
Use/Analysis of DNA

AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments or medications. Therefore, where local regulations and IRB/IEC 
allow, a 
sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome. 

The results of genetic analyses may be reported in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
D 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population

All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: Provide informed consent for 
the Genomics Initiative sampling and analyses.
Exclusion Criteria

Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:

Previous allogeneic bone marrow transplant

Healthy Volunteers and paediatric participant samples will not be collected for the 
Genomics Initiative.
Withdrawal of Consent for Genetic Research

Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 
CCI


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withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
section 7.2 of the main Clinical Study Protocol.
Collection of Samples for Genetic Research

The 
sample for this genetic research will be obtained from the participants after 
randomisation at the visit specified in the relevant module SoA. Although DNA is stable, 
early sample collection is preferred to avoid introducing bias through excluding 
participants who may withdraw due to an AE. If for any reason the sample is not drawn at 
the planned visit, it may be taken at any visit until the last study visit. Only one sample 
should be collected per participant for genetics during the study.
Coding and Storage of DNA Samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years, from the date of last participant last visit, after which they will be destroyed. 
DNA is a finite resource that is used up during analyses. Samples will be stored and used 
until no further analyses are possible or the maximum storage time has been reached.

An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organisation. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organisations working with the DNA).

The link between the participant enrolment/randomisation code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organisations. The link will be used to identify the relevant 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent.
Ethical and Regulatory Requirements

The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A.
Informed Consent

The genetic component of this study is optional and the participant may participate in 
other components of the main study without participating in this genetic component. To 
CCI


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participate in the genetic component of the study the participant must sign and date both 
the consent form for the main study and the addendum for the Genomics Initiative 
component of the study. Copies of both signed and dated consent forms must be given to 
the participant and the original filed at the study centre. The principal investigator(s) is 
responsible for ensuring that consent is given freely and that the participant understands 
that they may freely withdrawal from the genetic aspect of the study at any time.
Participant Data Protection

AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law.

Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, an AstraZeneca Physician or an 
investigator might know a participant’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate.
Data Management

Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organisations to analyse the samples.

AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organisations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results but they will not be able to see individual 
participant data or any personal identifiers. 

Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.


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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
Specific guidance on managing liver anomalies can be found in the Dose Modification section 
of each module in the Clinical Study Protocol.
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 PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca, in review and assessment of cases 
meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. HL criteria are met if 
there is no alternative explanation for the elevations in liver biochemistry. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3 × Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).
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


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cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
Central Laboratories Being Used:
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the investigator (also sent to 
AstraZeneca representative). 
The investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the investigator will:

Notify the AstraZeneca representative.

Request a repeat of the test (new blood draw) by the central laboratory without delay.

Complete the appropriate unscheduled laboratory eCRF module(s) with the original local 
laboratory test result.
When the identification criteria are met from central or local laboratory results the investigator
will without delay:

Determine whether the participant meets PHL criteria (see Section E 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results).
Local Laboratories Being Used:
The investigator will without delay review each new laboratory report and if the identification 
criteria are met will:


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
Notify the AstraZeneca representative.

Determine whether the participant meets PHL criteria (see Section E 2 for definition) by 
reviewing laboratory reports from all previous visits.

Promptly enter the laboratory data into the laboratory eCRF.
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria. 

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
E 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (see Section E 6).

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting.

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 Liver/PHL eCRF Modules/forms as information becomes available.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.


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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, to ensure timely analysis and 
SUSAR reporting to health authorities in an expedited manner. 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.

If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE 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 alternative explanation for the ALT or AST and TBL elevations:

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 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:

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.


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E 6
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Treatment 
This section is applicable to participants with liver metastases who meet PHL criteria on study 
treatment, having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on-study treatment occurrence of PHL criteria being met the investigator will 
determine if there has been a significant change in the participants’ condition compared with 
the last visit where PHL criteria were met.

If there is no significant change, no action is required.

If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Section E 4.2.
E 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit (Section E 6).
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?
If No: follow the process described in Section E 4.2 for reporting PHL as an SAE.
If Yes: Determine if there has been a significant change in the participant’s condition 
compared with when PHL criteria were previously met.

If there is no significant change, no action is required.

If there is a significant change follow the process described in Section E 4.2 for reporting 
PHL as an SAE.


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E 8
Laboratory Tests
Hy’s Law Lab Kit for Central Laboratories 
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
HBsAg
IgM and IgG anti-HBc 
HBV DNA a
IgG anti-HCV
HCV RNA b
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin)c
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin c
Transferrin saturation
a
HBV DNA is only recommended when IgG anti-HBc is positive
b
HCV RNA is only recommended when IgG anti-HCV is positive or inconclusive 
c
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly
E 9
References
Aithal et al, 2011Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation


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Appendix F
Abbreviations
Abbreviation or special term
Explanation
1QW
once weekly dosing
ADA
anti-drug antibody 
AE
adverse event
AESI
adverse event of special interest
AITL
angioimmunoblastic T-cell lymphoma
ALCL
anaplastic large cell lymphoma
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid lymphoma
AST
aspartate aminotransferase
β-HCG
beta-human chorionic gonadotropin
BV
brentuximab vedotin
CAR-T
chimeric antigen receptor T-cell
CDK9
cyclin dependent kinase 9
CHF
congestive heart failure
cHL
classical Hodgkin Lymphoma
CI
confidence interval
CLL
chronic lymphocytic leukaemia
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CPK
creatine phosphokinase
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
DCO
data cut-off 
DLBCL
diffuse large B-cell lymphoma
DLT
dose limiting toxicity
DoR
duration of response
DUS
disease under study
EBV
Epstein–Barr virus
CCI
CCI


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Abbreviation or special term
Explanation
ECG
electrocardiogram
ECHO
echocardiograms
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EMA
European Medicines Agency
FDA
US Food and Drug Administration
FDG
fluorodeoxyglucose
FFPE
formalin-fixed paraffin embedded
FIH
first-in-human
FU
follow-up
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
GLDH
glutamic dehydrogenase
GVHD
graft-versus-host disease
HBV
hepatitis B virus
HCP
Health Care Professional
HIV
human immunodeficiency virus
HL
Hy’s Law
HSCT
haematopoietic stem cell transplantation
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgA
immunoglobulin A
IgG
immunoglobulin G
IgM
immunoglobulin M
IMP
investigational medicinal product
INR
International Normalised Ratio
IP
investigational product
IRB
Institutional Review Board
IRT/RTSM
Interactive Response Technology System/Randomisation and Trial 
Supply Management
ITT
intention-to-treat
IV
intravenous
KM
Kaplan-Meier


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Abbreviation or special term
Explanation
LDH
serum lactate dehydrogenase
LTFU
long-term follow-up
LVEF
left ventricular ejection fraction
MCL1
myeloid cell leukaemia 1
MedDRA
Medical Dictionary for Regulatory Activities 
MM
multiple myeloma
MTD
maximum tolerated dose
MUGA
multigated acquisition
NCI
National Cancer Institute
NK
natural killer
NKTCL
natural killer/T-cell lymphoma
OAE
other significant adverse event
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PET
positron emission tomography
PFS
progression free survival
PHL
potential Hy's Law
PK
pharmacokinetic
PK/PD
pharmacokinetic/pharmacodynamic
PR
partial response
PTCL
peripheral T-cell lymphoma
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase II dose
r/r
relapsed/refractory
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SCT
stem cell transplantation
SD
stable disease
SoA
schedule of activities
SoC
standard of care
SOI
start of infusion
CCI
CCI
CCI
CCI
CCI
CCI


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Abbreviation or special term
Explanation
SRC
Safety Review Committee
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin
TEAE
treatment emergent adverse event
TLS
tumour lysis syndrome
TPV
third-party vendor
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
Unites States
WOCBP
women of childbearing potential


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Appendix G
Cairo-Bishop Tumour Lysis Syndrome Definition and 
Grading Criteria (Howard Modification)
Laboratory tumour lysis syndrome (TLS) is defined as a level above or below normal, as 
defined below, for any 2 or more serum values of uric acid, potassium, phosphate, and calcium 
within 3 day before or 7 day after the initiation of anti-cancer therapy. This assessment 
assumes that a participant has or will receive adequate hydration and a hypouricaemic 
agent(s).
Cairo-Bishop Definition of Laboratory Tumour Lysis Syndrome (Howard Modification)
Element 
Value
Uric Acid 
≥476 µmol/L (8 mg/dL)
Potassium
≥6.0 mmol/L (6 mg/L)
Inorganic phosphorus
≥1.45 mmol/L (4.5 mg/dL)
Calcium
≤1.75 mmol/L (7.0 mg/dL)
Howard et al 2011
Cairo-Bishop Definition of Clinical Tumour Lysis Syndrome
Clinical tumour lysis syndrome assumes the laboratory evidence of metabolic changes and 
significant clinical toxicity that requires clinical intervention. Clinical tumour lysis syndrome 
is defined as the presence of laboratory tumour lysis syndrome and any 1 or more of the 
below-mentioned criteria. Maximal clinical tumour lysis syndrome manifestation (renal, 
cardiac, neuro) defines the grade.
(1) Creatinine ≥1.5 × ULN (age > 12 years or age adjusted)
(2) Cardiac arrhythmia/sudden death
(3) Seizure
Cairo-Bishop Clinical Tumour Lysis Syndrome Grading Criteria
Grade
Complication
0
1
2
3
4
5
Creatinine*,†
≤1.5 × 
ULN
1.5 × ULN
1.5 – 3.0 × ULN
> 3.0 – 6.0 × 
ULN
> 6.0 × ULN
Death
Cardiac 
Arrhythmia*
None
Intervention 
not indicated
Nonurgent 
medical 
intervention 
indicated
Symptomatic 
and 
incompletely 
controlled 
Life-
threatening 
(eg, 
arrhythmia 
Death


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medically or 
controlled with 
devise (eg, 
defibrillator) 
associated 
with CHF, 
hypotension, 
syncope, 
shock)
Seizure*
None
None
One brief, 
generalised 
seizure; 
seizure(s) well 
controlled by 
anticonvulsants 
or infrequent 
focal motor 
seizures not 
interfering with 
ADL
Seizure in 
which 
consciousness 
is altered; 
poorly 
controlled 
seizure 
disorder; with 
breakthrough 
generalised 
seizures 
despite 
medical 
intervention 
Seizure of 
any kind 
which are 
prolonged, 
repetitive or 
difficult to 
control (eg, 
status 
epilepticus, 
intractable 
epilepsy)
Death
ADL = activities of daily living; CHF = congestive heart failure; CTLS = clinical tumour lysis syndrome; 
LTLS = laboratory tumour lysis syndrome; ULN = upper limit of normal
Clinical tumour lysis syndrome (CTLS) requires one or more clinical manifestations along with criteria for 
LTLS. Maximal CTLS manifestation (renal, cardiac, neuro) defines the grade.
*Not directly or probably attributable to therapeutic agent (eg, rise in creatinine after amphotericin 
administration).
†If no institutional ULN is specified, age/sex ULN creatinine may be defined as 105.6 μmol/L for female 
participants ≥16 years of age and 114.4 μmol/L for male participants ≥16 years of age. 
Modified from Cairo and Bishop 2004.


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Appendix H
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions and other measures implemented to ensure the 
participant’s safety. If in doubt, please contact the AZ Study Physician.
H 1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections H 2 to H 6. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
H 2
Rescreening of Participants To Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
study physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with IP. If this delay 
is outside the screening window specified in the schedule of assessments for the relevant 
module, the participant will need to be rescreened to reconfirm eligibility before commencing 
study procedures. This will provide another opportunity to re-screen participants in addition to 
that detailed in Section 5.4. The procedures detailed in the schedule of assessments for the 
relevant module must be undertaken to confirm eligibility using the same randomisation 


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number as for the participant.
H 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service will visit the participant’s home / or other 
remote location as per local SOPs, as applicable. Supplies will be provided for a safe and 
efficient visit. The qualified HCP will be expected to collect information per the clinical study 
protocol (CSP).
H 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the 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 medication to be reported and 
documented.
H 5
At-home or Remote Location IP Administration Instructions
If a site visit is not possible, at-home or remote location administration of IP may be 
performed by a qualified HCP, provided this is acceptable within local regulation/guidance. 
The option of at-home or remote location IP administration ensures participants safety in cases 
of a pandemic where participants may be at increased risk by traveling to the site/clinic. This 
will also minimise interruption of IP administration during other study disruptions, eg, site 
closures due to natural disaster. 
H 5.1
At-home or Remote Location IP Administration by the Participant or 
His/Her Caregiver
Prior to at-home or remote location IP administration the investigator must assess the 
participant or his/her caregiver to determine whether they are appropriate for at-home or 
remote location administration of IP. Once the participant or his/her caregiver is deemed 
appropriate for at-home or remote location administration, he/she must receive appropriate 
training. All necessary supplies and instructions for administration and documentation of IP 
administration will be provided. More information related to the visit can be obtained via a 
telemedicine or home / remote visit.
H 6
Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home / remote visits will be captured by the qualified 
HCP from the study site or TPV service.


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12
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SAP_001.pdf: 
A Modular Phase II, Open-label, Multicentre 
Study to Assess AZD4573 Efficacy and
Safety as Monotherapy or in Combination 
with Anti-cancer Agents in Patients with
Relapsed/Refractory Peripheral T-cell
Lymphoma or classical Hodgkin Lymphoma
ClinicalTrials.gov Identifier: NCT05140382
Statistical Analysis Plan: version 3.0, dated 12 Dec 2023
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STATISTICAL ANALYSIS PLAN
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STATISTICAL ANALYSIS PLAN
Study Code
D8231C00001
Edition Number
3.0
Date
12-Dec-2023
A Modular Phase II, Open-label, Multicentre Study to Assess 
AZD4573 Efficacy and Safety as Monotherapy or in 
Combination with Anti-cancer Agents in Patients with 
Relapsed/Refractory Peripheral T-cell Lymphoma or classical 
Hodgkin Lymphoma


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TABLE OF CONTENTS...................................................................................................... 2
LIST OF ABBREVIATIONS ............................................................................................... 5
AMENDMENT HISTORY................................................................................................... 7
1
INTRODUCTION............................................................................................ 10
2
STUDY DETAILS ........................................................................................... 10
2.1
Module 1 .......................................................................................................... 10
2.1.1
Study Objectives............................................................................................... 10
2.1.2
Study Design .................................................................................................... 12
3
CHANGES TO PROTOCOL PLANNED ANALYSIS..................................... 13
4
DATA ANALYSIS CONSIDERATIONS ........................................................ 13
4.1
Core.................................................................................................................. 13
4.1.1
Timing of Analyses........................................................................................... 13
4.1.2
Analysis Populations......................................................................................... 14
4.1.3
General Considerations..................................................................................... 14
4.1.3.1
General Study Level Definitions ....................................................................... 14
4.1.3.2
Timepoint Windows ......................................................................................... 16
4.1.3.3
Handling of Unscheduled Timepoints ............................................................... 16
4.1.3.4
Multiplicity/Multiple Comparisons ................................................................... 16
4.1.3.5
Handling of Protocol Deviations in Study Analysis........................................... 16
4.1.3.6
Missing Dates................................................................................................... 17
4.1.3.7
Sample Size...................................................................................................... 18
4.2
Module 1 .......................................................................................................... 18
4.2.1
Timing of Analyses........................................................................................... 18
4.2.2
Analysis Populations......................................................................................... 19
4.2.3
General Considerations..................................................................................... 20
4.2.3.1
General Study Level Definitions ....................................................................... 20
4.2.3.2
Timepoint Windows ......................................................................................... 20
4.2.3.3
Handling of Unscheduled Timepoints ............................................................... 20
4.2.3.4
Multiplicity/Multiple Comparisons ................................................................... 20
4.2.3.5
Handling of Protocol Deviations in Study Analysis........................................... 20
4.2.3.6
Missing Dates................................................................................................... 20
4.2.3.7
Sample size....................................................................................................... 20
5
STATISTICAL ANALYSIS............................................................................. 22
5.1
Study Population............................................................................................... 22
5.1.1
Subject Disposition and Completion Status....................................................... 22
5.1.1.1
Definitions and Derivations .............................................................................. 22
5.1.1.2
Presentation ...................................................................................................... 22
5.1.2
Analysis Sets .................................................................................................... 23
5.1.2.1
Definitions and Derivations .............................................................................. 23


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5.1.2.2
Presentation ...................................................................................................... 23
5.1.3
Protocol Deviations........................................................................................... 23
5.1.3.1
Definitions and Derivations .............................................................................. 23
5.1.3.2
Presentation ...................................................................................................... 24
5.1.4
Demographics................................................................................................... 24
5.1.4.1
Definitions and Derivations .............................................................................. 24
5.1.4.2
Presentation ...................................................................................................... 24
5.1.5
Baseline Characteristics .................................................................................... 24
5.1.5.1
Definitions and Derivations .............................................................................. 24
5.1.5.2
Presentation ...................................................................................................... 24
5.1.6
Disease Characteristics ..................................................................................... 25
5.1.6.1
Presentation ...................................................................................................... 25
5.1.7
Medical History and Concomitant Disease........................................................ 25
5.1.7.1
Definitions and Derivations .............................................................................. 25
5.1.7.2
Presentation ...................................................................................................... 25
5.1.8
Prior and Concomitant Medications .................................................................. 26
5.1.8.1
Definitions and Derivations .............................................................................. 26
5.1.8.2
Presentation ...................................................................................................... 27
5.2
Endpoint Analyses – Module 1 ......................................................................... 27
5.2.1
Primary Endpoint – Objective Response Rate (ORR) by Lugano ...................... 28
5.2.1.1
Definition and Derivations................................................................................ 28
5.2.1.2
Primary Analysis of Primary Endpoint: ORR.................................................... 29
5.2.1.3
Supportive Data: Change in Target Lesion Tumour Size................................... 29
5.2.2
Secondary Endpoint: Complete Response Rate (CR Rate)................................. 30
5.2.2.1
Definition and Derivations................................................................................ 31
5.2.2.2
Primary Analysis of Secondary Endpoint: CR Rate........................................... 31
5.2.3
Secondary Endpoint: Duration of Response (DoR)............................................ 31
5.2.3.1
Definition ......................................................................................................... 31
5.2.3.2
Derivations ....................................................................................................... 31
5.2.3.3
Primary Analysis of Secondary Endpoint: DoR................................................. 31
5.2.4
Secondary Endpoint: Progression-free Survival (PFS)....................................... 31
5.2.4.1
Definition ......................................................................................................... 31
5.2.4.2
Derivations ....................................................................................................... 32
5.2.4.3
Primary Analysis of Secondary Endpoint: PFS ................................................. 34
5.2.4.4
Sensitivity Analysis of PFS Endpoint................................................................ 34
5.2.5
Secondary Endpoint: Overall Survival (OS)...................................................... 34
5.2.5.1
Definition ......................................................................................................... 34
5.2.5.2
Derivations ....................................................................................................... 35
5.2.5.3
Handling of Dropouts and Missing Data ........................................................... 36
5.2.5.4
Primary Analysis of Secondary Endpoint (Overall Survival)............................. 36
5.2.5.5
Sensitivity Analysis of OS Endpoint ................................................................. 36
5.3
Pharmacodynamic Endpoints 
......................................... 37
5.4
Pharmacokinetics – Module 1 ........................................................................... 37
5.4.1
Definition and Derivations................................................................................ 37
5.4.1.1
Plasma .............................................................................................................. 37
5.4.1.2
................................................................................................................ 39
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5.4.2
Primary Analysis of Pharmacokinetics.............................................................. 39
5.4.2.1
Plasma .............................................................................................................. 39
5.4.2.2
................................................................................................................ 42
5.5
Immunogenicity................................................................................................ 42
5.6
Safety Analyses ................................................................................................ 42
5.6.1
Exposure........................................................................................................... 42
5.6.1.1
Definitions and Derivations .............................................................................. 42
5.6.1.2
Presentation ...................................................................................................... 44
5.6.2
Adverse Events................................................................................................. 44
5.6.2.1
Definitions and Derivations .............................................................................. 44
5.6.2.2
Presentation ...................................................................................................... 46
5.6.3
Deaths .............................................................................................................. 47
5.6.3.1
Presentation ...................................................................................................... 47
5.6.4
Clinical Laboratory, Blood Sample ................................................................... 47
5.6.4.1
Definitions and Derivations .............................................................................. 47
5.6.4.2
Presentations..................................................................................................... 49
5.6.5
Clinical Laboratory, Urinalysis ......................................................................... 50
5.6.5.1
Definitions and Derivations .............................................................................. 50
5.6.5.2
Presentations..................................................................................................... 50
5.6.6
Vital Signs........................................................................................................ 50
5.6.6.1
Definitions and Derivations .............................................................................. 50
5.6.6.2
Presentations..................................................................................................... 50
5.6.7
Weight.............................................................................................................. 50
5.6.7.1
Presentations..................................................................................................... 50
5.6.8
B symptoms...................................................................................................... 50
5.6.8.1
Presentations..................................................................................................... 50
5.6.9
Tumour lysis syndrome..................................................................................... 51
5.6.9.1
Definitions and Derivations .............................................................................. 51
5.6.9.2
Presentations..................................................................................................... 51
5.6.10
Electrocardiogram............................................................................................. 51
5.6.10.1
Definitions and Derivations .............................................................................. 51
5.6.10.2
Presentations..................................................................................................... 52
5.6.11
Echocardiogram................................................................................................ 52
5.6.11.1
Presentations..................................................................................................... 52
5.6.12
Other Safety Assessments................................................................................. 52
5.6.12.1
Presentations..................................................................................................... 52
6
INTERIM ANALYSIS ..................................................................................... 52
7
REFERENCES................................................................................................. 53
8
APPENDICES.................................................................................................. 54
Appendix A Time windows for Module 1 – Efficacy assessments....................................... 54
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LIST OF ABBREVIATIONS
Abbreviation 
or Specialized 
Term
Definition
3L
Third-line
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutical Chemical
BMI
Body mass index
BOR
Best Overall Response
BSR
Baseline scaled ratio
BV
Brentuximab vedotin
cHL
Classical Hodgkin Lymphoma
CI
Confidence interval
COVID-19
Coronavirus disease 2019
CR
Complete response
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DCO
Data cut-off
DoR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
FAS
Full analysis set
gCV
Geometric coefficient of variation
gMean
Geometric mean
gSD
Geometric standard deviation
IP
Investigational Product
IPD
Important protocol deviation
IPI
International Prognostic Index
ITT
Intent-to-Treat
IV
Intravenous


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Abbreviation 
or Specialized 
Term
Definition
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NA
Not applicable
NC
Not calculable
NE
Not evaluable
NK
Natural killer
NKTCL
Natural killer T-cell lymphoma
NS
No sample
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD1
Anti-programmed cell death-1
PFS
Progression-free survival
PK
Pharmacokinetics
PR
Partial response
PT
Preferred term
PTCL
Peripheral T-cell Lymphoma
r/r
Relapsed/refractory
RDI
Relative dose intensity
RP2D
Recommended phase 2 dose
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Stable disease
SOC
System Organ Class
Std Dev
Standard deviation
TEAE
Treatment emergent adverse event
TFL
Tables, figures and listings
TLS
Tumour lysis syndrome
ULN
Upper limit of normal
WHO
World Health Organisation
WHODrug
World Health Organisation Drug Dictionary


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AMENDMENT HISTORY
CATEGORY
Change refers to:
Date
Description of change
In line with CSP?
Rationale
N/A
15-Mar-2022
Initial approved SAP
N/A
N/A
Data presentation
20-Nov-2023
Added the interim response 
evaluable set in Section 4.2.2
N/A
This analysis set is currently 
not planned to be used for 
any outputs to be presented 
in the CSR. This analysis set 
will only be used for 
presentation in conferences 
and publications.
Data presentation
20-Nov-2023
Mention that SAP is for 
conference and publication 
purposes as well in Section 1
N/A
Details added to mention that 
this SAP is not only to 
describe CSR analyses, but 
also analyses performed for 
conferences and publications.
Data presentation
20-Nov-2023
Swimmer plot for response 
assessment added in Section 
5.2.1.2
Yes
Visual representation of 
disease assessment results 
over time added for better 
understanding of the results.
Derivation of secondary 
endpoint(s)
20-Nov-2023
Added formula to derive QTcB 
in Section 5.6.10.1
Yes
QTcB was required for 
presentation per Version 1.0 
of this document, but the 
formula was never provided.
Derivation of secondary 
endpoint(s)
20-Nov-2023
Clarified that duration of 
follow-up in overall survival 
should be derived for all 
participants and not just for 
censored participants in 
Section 5.2.5.2
Yes
Clarification provided to 
derivation provided in 
Version 1.0 of this 
document.
Derivation of secondary 
endpoint(s)
20-Nov-2023
Updated TLS monitoring 
derivations in Section 5.6.9
Yes
Consistency of text within 
the compound.
Other
20-Nov-2023
Removed imputation for 
missing best percentage change 
Yes
Imputation does not make 
clinically sense.


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CATEGORY
Change refers to:
Date
Description of change
In line with CSP?
Rationale
in target lesion in Section 
5.2.1.3.1
Data presentation
20-Nov-2023
Removed requirement to 
present ramp-up dosing in 
disposition Section 5.1.1.2
Yes
Not required per protocol 
and not adding any value in 
presentations.
Data presentation
20-Nov-2023
Update derivation of actual 
exposure in Section 5.6.1
Yes
Updated to be in line with 
standards as current 
derivations caused actual 
exposure to be longer than 
intended exposure.
Data presentation
20-Nov-2023
Update derivation of RDI and 
dose delays in Section 5.6.1 to 
account for windows around 
dosing
Yes
Added a statement that RDI 
should consider the ± 2 days 
window around doses.
Dose delays were determined 
using 7 days between doses. 
Per a dosing window of ± 2 
days around doses the 
calculation is updated to use 
9 days instead of 7 days.
Data presentation
20-Nov-2023
Clarified that where we have 
missing post-baseline target 
lesions that these should not be 
presented in figures or 
summaries in Section 5.2.1.3
Yes
Missing target lesions 
underrepresent the target 
lesion sizes and changes at 
post-baseline timepoints.
Data presentation
20-Nov-2023
Clarified that highest ATC 
level should be used in 
summaries in Section 5.1.8.2
Yes
Clarification on what should 
be presented in summaries.
N/A
20-Nov-2023
Approved SAP Version 2.0
N/A
N/A
Data presentation
12-Dec-2023
Removed timepoint window 
derivations for safety endpoints 
from Section 4.1.3.2.
Yes
Due to the schedule of 
assessments in this study, it 
makes more sense to present
results as recorded in the 
database as reassignment of 


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CATEGORY
Change refers to:
Date
Description of change
In line with CSP?
Rationale
visits caused confusion in 
interpretation of results.
N/A
12-Dec-2023
Approved SAP Version 3.0
N/A
N/A








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Figure 1 Module 1 AZD4573 Monotherapy Dosing Regimen in PTCL and cHL including 
Intra-Participant Dose Ramp-Up
3
CHANGES TO PROTOCOL PLANNED ANALYSIS
The CSP defines Cycle 1 as having a duration of 5 weeks. Section 2.1.2 of this SAP clarifies 
that Cycle 1 will only be considered completed once the participant has received 5 doses of 
AZD4573 (at any dose level).
Section 10.9.3 of the CSP defines the safety set as all participants who receive at least one 
dose of investigational product (IP) (study intervention). Participants who are exposed to any 
amount of IP, may have safety events, even if the full dose were not received (eg, dose 
interruption). Therefore, the safety population definition is updated to include all participants 
who received any amount of IP (Section 4.2.2).
A survival sweep for the purpose of analysing overall survival (OS) is currently not included 
in the CSP but is included in this version of the SAP (Section 5.2.5). 
4
DATA ANALYSIS CONSIDERATIONS
4.1
Core
4.1.1
Timing of Analyses
The timing of analyses is specific to each module and are discussed separately for each 
module.

Module 1: Section 4.2.1


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4.1.2
Analysis Populations
The analysis populations are specific to each module and are discussed separately for each 
module.

Module 1: Section 4.2.2
4.1.3
General Considerations
Unless stated otherwise, each module and cohort will be analysed separately. Data will be 
presented by cohort.
The general principles described below will be followed throughout the study:

Continuous endpoints will be summarised by the number of observations, mean, standard 
deviation (Std Dev), median, upper and lower quartiles (as applicable), minimum, and 
maximum. For data that requires log-transformation, it is more appropriate to present 
geometric mean (gMean), coefficient of variation (CV), median, minimum, and 
maximum. Categorical endpoints will be summarised by frequency counts and 
percentages for each category.

Unless otherwise stated, percentages will be calculated out of the analysis set total, by 
cohort as appropriate. Percentages will not be presented for zero counts.

For continuous data (except for pharmacokinetics [PK]), descriptive summary statistics 
(mean, median, quartiles, Std Dev, standard error, confidence intervals [CIs]) will be 
rounded to one additional decimal place compared to the original data. Minimum and 
maximum will be displayed with the same accuracy as the original data. Decimal 
precision for PK is described in Section 5.4.2.

For categorical data, percentages will be rounded to one decimal place. 

Time to event variables will be presented using the Kaplan-Meier methodology where 
appropriate, including median time calculated from the Kaplan-Meier curves.

For summaries at the participant level, all values will be included, regardless of whether 
they appear in a corresponding timepoint-based summary.

SAS® version 9.4 (as a minimum) will be used for analyses presented in the CSR. PK 
parameters will be calculated using Phoenix® WinNonlin® Version 8.1 (as a minimum).
4.1.3.1
General Study Level Definitions
Baseline is the last non-missing value obtained prior to the first dose/administration of any IP 
and any information taken after first dose/administration of IP is regarded as post-baseline 
information. If 2 timepoints are equally eligible to assess participant status at baseline (eg, 
screening and baseline assessments both on the same date prior to first dose/administration 


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with no washout or other intervention in the screening period), the average is taken as the 
baseline value. For non-numeric laboratory tests (ie, some of the urinalysis parameters) where 
taking an average is not possible then the best value is taken as baseline as this is the most 
conservative. In the scenario where there are 2 assessments on Day 1 prior to first dose, one 
with time recorded and the other without time recorded, the one with time recorded is selected 
as baseline. Where safety data are summarised over time, study day is calculated in relation to 
date of first intervention of IP. For assessments on the day of first dose where time is not 
captured, a nominal pre-dose indicator, if available, serves as sufficient evidence that the 
assessment occurred prior to first dose. Assessments on the day of the first dose where neither 
time nor a nominal pre-dose indicator are captured is considered prior to the first dose. If no 
value exists before the first dose/administration, then the baseline value is treated as missing.
In all summaries, change from baseline variables will be calculated as the post-baseline value 
minus the value at baseline. The percentage change from baseline will be calculated as (post-
baseline value – baseline value) / baseline value x100. For any endpoint subjected to log 
transformation, the change from baseline calculated and summarised on the log scale are 
back-transformed and presented as a ‘baseline scaled ratio’ (BSR). Percentage change is then 
calculated as (BSR – 1) x 100.
Study Day 1 is defined as the date of the first dose of IP (Cycle 1 Day 1). For timepoints (or 
events) that occur on or after first dose of IP, Study Day is derived as (date of timepoint 
[event] – date of first dose of IP +1). For timepoints (or events) that occur prior to first dose, 
Study Day is defined as (date of timepoint [event] – day of first dose of IP). There is no Day 0 
defined for this study.
For listings (such as adverse events [AEs]) that include the derivation of “days since last 
dose”, this is defined as (event date – date of last dose) where “date of last dose” is defined as 
the date of dosing immediately preceding the event occurrence. Events that occur on the same 
day as the last dose of IP will therefore be described as occurring 0 days from last dose of IP.
Study periods for the purpose of safety summaries will be defined as follows:

Pre-treatment: Any result prior to first dose of IP.

On-treatment: Any result from first dose of IP up to 30 days after last dose of IP, and 
prior to start of any subsequent cancer therapy.

Follow-up: Any result after 30 days after last dose of IP, or after start of any subsequent 
cancer therapy.
For the purpose of summarising safety data assessed at timepoints, in addition to baseline 
data, only on-treatment data (as defined above) will be included in the summary tables.


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Naming conventions of timepoints for inclusion in summary tables will be defined separately 
for each module.

Module 1: Section 4.2.3.1
4.1.3.2
Timepoint Windows
For tumour assessments:

The protocol assigned windows for tumour assessments will be used to assign the result 
to a particular timepoint.

Examples applicable to each module will be defined separately for that module.

Module 1: Section 4.2.3.2
For safety assessments:

Results will be presented as recorded in the database and no windowing to assign the 
result to a particular timepoint will be done.
4.1.3.3
Handling of Unscheduled Timepoints
Unscheduled timepoints will be included in listings but will not be included in by-timepoint 
summaries. Unscheduled timepoints have the potential to be included in summaries showing 
the maximum or minimum values while on IP.
4.1.3.4
Multiplicity/Multiple Comparisons
The handling of multiplicity/multiple comparisons is specific to each module and are 
discussed separately for each module.

Module 1: Section 4.2.3.4
4.1.3.5
Handling of Protocol Deviations in Study Analysis
Important protocol deviations (IPDs) are those deviations from the protocol likely to have an 
impact on the perceived efficacy and/or safety of study intervention.
The following general deviation categories will be defined. These deviations will be reviewed 
on a case-by-case basis by AstraZeneca to determine importance. Deviations considered to be 
important will be listed and discussed in the CSR as appropriate. All decisions on importance 
will be made ahead of database lock and will be documented prior to the primary analysis 
being performed.

Patients who deviate from entry criteria per CSP


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
No baseline Lugano assessments on or before the date of first dose

Received prohibited concomitant medications or therapies

Participants deviating from prescribed dosing regimen

Missed timepoints, assessments, or treatments that, in the opinion of the investigator, 
were due to Coronavirus Disease 2019 (COVID-19) global pandemic, and where there 
was a significant effect on either completeness, accuracy and/or reliability of the 
participant’s data, or the participant’s rights, safety or wellbeing

Missing scheduled efficacy assessments

Deviation from Good Clinical Practice as determined by medical review (for example 
insufficient informed consent)
A detailed list of protocol deviations to be considered are defined in the study specific 
protocol deviation specifications.
Participants with no baseline Lugano assessments will be excluded from the response 
evaluable set. None of the other deviations defined in this study will lead to participants being 
excluded from any analysis populations described in this SAP. If a deviation is serious enough 
to have a potential impact on the primary analysis, sensitivity analyses may be performed. The 
need for such a sensitivity analysis will be determined following review of the protocol 
deviations ahead of database lock and will be documented prior to the analysis being 
conducted.
A list of all protocol deviations will be reviewed and decisions regarding how to handle these 
deviations in the analyses will be documented by the study team physician, medical scientist, 
clinical pharmacology scientist and statistician prior to database lock.
4.1.3.6
Missing Dates
Generally, the imputation of dates is used to decide if an observation is treatment emergent for 
AEs or concomitant medications. The imputed dates should not be used to calculate durations, 
where the results would be less accurate.
The following are the guidelines used when partial dates are detected in the study:

For missing diagnostic dates (eg, disease diagnosis), if the day and/or month are missing 
use 01 and/or January. If year is missing, put the complete date to missing.

For missing AE and concomitant medication start dates, the following is applied:

Missing day – impute the 1st of the month unless month is the same as month of the 
first dose of the study drug then impute first dose date.

Missing day and month – impute 1st Januaryunless year is the same as first dose date 
then impute first dose date.


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
Completely missing – impute first dose date unless the end date suggests it could 
have started prior to this in which case impute the 1st of January of the same year as 
the end date.

Imputed start date should be no later than the end date.

For missing AE and concomitant medication end dates, the following is applied:

Missing day – impute the last day of the month unless both the month and year are 
the same as the last dose date or the primary analysis date cut-off (DCO) date then 
impute the last dose date or the primary analysis DCO date.

Missing day and month – Impute 31st December unless the year is the same as the 
last dose date or the primary analysis DCO date then impute the last date or the 
primary analysis DCO date. 

Completely Missing – before imputing a date, consider whether the AE/medication is 
still ongoing and also when it started in relation to study drug. If the ongoing flag is 
missing then assume that AE is still present/ medication is still being taken (ie, do not 
impute a date). If the AE/medication has stopped and start date is prior to first dose 
date, then impute first dose date. Or if it started on or after first dose date then impute 
a date that is after the last dose of study drug date.

Flags will be retained in the database indicating where any programmatic imputation has 
been applied, and in such cases for AEs and concomitant medications, any durations will 
not be calculated.
4.1.3.7
Sample Size
Sample size is specific to each module and is discussed separately for each module.

Module 1: Section 4.2.3.7
4.2
Module 1
4.2.1
Timing of Analyses
The DCO for the primary analysis for each Module 1 PTCL cohort (Cohorts 1 and 2) will
occur after 21 response-evaluable participants in the cohort have had the opportunity to be 
followed for at least 6 months since their first dose or have progressed or have initiated other 
anticancer therapy, or when 75% of participants have progressed or died, whichever occurs 
first. If one cohort reaches its planned primary analysis DCO ahead of the other, then the 
slower enrolling cohort may be evaluated for efficacy responses at the same time. The purpose 
of evaluating the slower cohort early would be for internal planning and to review continued 
development of the AZD4573 in one or both r/r PTCL groups. When both cohorts have 
reached their primary analysis DCOs the efficacy and safety data may be pooled for analysis. 
Additional data cuts may also be performed, if required.


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The DCO for primary analysis of the Module 1 cHL Cohort (Cohort 3) will occur after 21 
response-evaluable participants in the cohort have had the opportunity to be followed for at 
least 6 months since their first dose or have progressed or have initiated other anticancer 
therapy, or when 75% of participants have progressed or died, whichever occur first. 
Additional data cuts may also be performed, if required.
At the end of the module a final analysis will be conducted to incorporate all data (up to and 
beyond the primary analysis) from all participants.
4.2.2
Analysis Populations
For purposes of analysis, the study populations are defined as provided in Table 2. 
All participants who received any amount of IP will be included in the safety population. 
The following populations are defined: 
Table 2 Populations for Analyses
Population/Analysis set
Description
Endpoint/Output
Enrolled
All participants who sign the ICF.
Disposition
Safety
All participants who receive any 
amount of any IP.
Exposure
Safety
PK concentrations and parameters 
listings
Full analysis set/ITT
All participants who receive any 
amount of any IP. 
Baseline and demography
PFS
OS
Response evaluable
All dosed participants who have 
measurable disease at baseline.
ORR
CR
DoR
Interim response evaluable
All dosed participants with 
measurable disease at baseline that 
have had their first post-baseline 
disease assessment performed or 
have discontinued study treatment 
before the first post-baseline disease 
assessment.
This analysis set will not be used for 
presentation in the CSR and is only 
defined for conferences and 
publications.
ORR at interim
DoR at interim
PK
All participants who receive any 
amount of IP with at least one 
reportable concentration.*
PK concentrations
PK parameters


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Abbreviations: ICF, informed consent form; IP, investigational product; ITT, intention-to-treat; PK, pharmacokinetics; PFS, 
progression free survival; OS, overall survival; DoR, duration of response; ORR, objective response rate; CR, complete 
response.
* Individual PK concentration and parameter data values that are excluded from the descriptive summary tables and/or figures 
eg, due to important protocol deviations that might effect PK – are included in the listings and are flagged with an appropriate 
footnote.
4.2.3
General Considerations
4.2.3.1
General Study Level Definitions
Refer to Section 4.1.3.1.
Timepoint naming conventions are defined separately for efficacy and non-efficacy data.
Timepoints for efficacy summaries will be named according to the time from first dose as 
defined in the CSP. Examples are:

After 8 weeks

After 17 weeks

After 26 weeks

End of Treatment

30-day follow-up visit
Non-efficacy data will be named as in the database.
4.2.3.2
Timepoint Windows
Refer to Section 4.1.3.2.
4.2.3.3
Handling of Unscheduled Timepoints 
Refer to Section 4.1.3.3.
4.2.3.4
Multiplicity/Multiple Comparisons
Not applicable.
4.2.3.5
Handling of Protocol Deviations in Study Analysis
Refer to Section 4.1.3.5.
4.2.3.6
Missing Dates
Refer to Section 4.1.3.6.
4.2.3.7
Sample size
Refer to Section 10.9.2 of the CSP for detailed information on the sample size for module 1.






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tables, figures and listings (TFL) standards. The number and percentage of participants for the 
following will be summarised:

Participants screened;

Screen failures;

Participants assigned to IP;

Participants assigned to IP, but who were not treated;

Participants who received IP and participants who did not receive IP;

Participants ongoing IP at DCO;

Participants who discontinued IP;

Participants ongoing study at DCO;

Participants who terminated study.
Summaries on disposition due to COVID-19 will be added to the disposition table if 
applicable. The number and percentage of participants for the following summaries will be 
added if applicable:

Participants who discontinue IP due to COVID-19;

Participants who withdrew from study due to COVID-19.
The number and percentages of participants with confirmed or suspected COVID-19 infection 
will be presented separately, including details on COVID-19 related interruptions impacting 
on timepoints and IP administration. Listings of participants affected by the COVID-19 
pandemic will be presented detailing any affect and impact on the study. Issues reported in the 
Clinical Trial Management System will be considered for presentation in listings as well.
5.1.2
Analysis Sets
5.1.2.1
Definitions and Derivations 
For the definitions of each analysis set, refer to Section 4.1.2.
5.1.2.2
Presentation
The analysis sets will be summarised by cohort. Any exclusions from analysis sets will be 
listed.
5.1.3
Protocol Deviations
5.1.3.1
Definitions and Derivations
Protocol deviations are defined in Section 4.1.3.5.


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5.1.3.2
Presentation
The incidence of IPDs will be summarised for the full analysis set (FAS) by deviation 
categories. The number and percentage of participants in the following categories will be 
summarised:

Number of participants with at least one IPD

Number of participants with at least one COVID-19 related IPD

Number of participants with at least one IPD, excluding COVID-19 related IPDs.
A listing will be provided with IPD details.
5.1.4
Demographics
5.1.4.1
Definitions and Derivations
Age will be grouped accordingly in the following categories: ≥18 – 64, ≥65 – 74, ≥75 – 84, 
and ≥85. Each race category counts participants who selected only that category.
5.1.4.2
Presentation
Demographics will be summarised and listed based on the FAS by cohort as defined by the 
current relevant TFL standards. The following will be summarised: age, age group, sex, race, 
and ethnicity.
Demographics will further be summarised separately for all participants in the FAS who had 
confirmed or suspected COVID-19 infection. If less than 5 participants have confirmed or 
suspected COVID-19 infection, this will be presented in a listing rather than being 
summarised.
The number of participants recruited in each country and each center will be presented by 
analysis populations.
5.1.5
Baseline Characteristics
5.1.5.1
Definitions and Derivations
Body mass index (BMI) will be derived as:
BMI(kg/m2)= weight(kg)
height(m)2
5.1.5.2
Presentation
Baseline characteristics will be listed and summarised for the FAS by cohort as defined by the 
current relevant TFL standards. The following will be summarised: height, weight and BMI.


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Participant characteristics will further be summarised separately for all participants in the FAS 
who had confirmed or suspected COVID-19 infection. If less than 5 participants have 
confirmed or suspected COVID-19 infection, this will be presented in a listing rather than 
being summarised.
5.1.6
Disease Characteristics
5.1.6.1
Presentation
Disease characteristics at baseline will be summarised and listed for all participants in the 
FAS by cohort as defined by the current relevant TFL standards. 
Summaries will be produced that present: 

Eastern Cooperative Oncology Group (ECOG) performance status 

Lymphoma diagnosis:

Primary tumour location (lymph node/ extranodal) 

Histology type (lymphoma) 

Lymphoma type 

Location of involvement (brain, spleen, bone marrow, liver and extranodal) 

Presence of bulky nodal disease 

Ann Arbor Lymphoma staging 

Ann Arbor Lymphoma symptoms 

International Prognostic Index (IPI) score 

cHL pathology

Primary tumour location (axilla/ inguinal region/ mediastinum/ mesenteric/ 
naso-oropharynx/ neck/ para-aortic/ Waldeyer’s ring or tonsil/ other) 

Ann Arbor Lymphoma staging

Ann Arbor Lymphoma symptoms
5.1.7
Medical History and Concomitant Disease
5.1.7.1
Definitions and Derivations
Medical and surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 24.1 (as a minimum).
5.1.7.2
Presentation
Medical history, surgical history and concomitant disease will be listed and summarised for 
the FAS by cohort as defined by the current TFL standards.


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Summaries of the number and percentage of participants who have had previous 
disease-related treatments will be presented for each type of modality (immunotherapy, 
cytotoxic chemotherapy, platinum chemotherapy, biologic therapy, experimental therapy, 
autologous haematopoietic stem cell transplantation, antibody-drug conjugate therapy, 
allogeneic haematopoietic stem cell transplantation and other). 
The number and percentage of participants who have had prior cancer therapies will be 
summarised by Anatomical Therapeutic Chemical (ATC) classification and generic drug 
name, coded by World Health Organization (WHO) – Drug dictionary (WHO Drug Global B3 
Sep 2021 or later).
Summaries for the number and percentage of participants who had a certain number of 
previous lines of therapies and the best response on most recent line of therapy will be 
produced.
Summaries on participants’ medical history by System Organ Class (SOC) and Preferred 
Term (PT) will be produced.
A separate summary on medical history will be presented for participants who had confirmed 
or suspected COVID-19 infection. If less than 5 participants have confirmed or suspected 
COVID-19 infection, this will be presented in a listing rather than being summarised.
5.1.8
Prior and Concomitant Medications
5.1.8.1
Definitions and Derivations
For the purpose of inclusion in prior and/ or concomitant medication or therapy summaries, 
incomplete dates will be imputed as detailed in Section 4.1.3.6.
Prior medications, concomitant and post-treatment medications will be defined based on 
imputed start and stop dates as follows:

Prior medications are those taken prior to IP with a stop date prior to the first dose of 
study intervention.

Concomitant medications are those with a stop date on or after the first dose date of IP 
and must have started prior to or during IP so there is at least one day in common with the 
IP.

Post-treatment medications are those with a start date after the last dose date of IP.
Disallowed medications will be identified through medical review prior to any analysis of 
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responders in the ORR (ie, the timepoint contributing to a response must be prior to 
subsequent therapy for the participant to be considered as a responder).
The ORR will be based on the investigator assessment using all scans, regardless of whether 
the scan was scheduled or not.
In addition, best overall response will be calculated based on overall timepoint responses from 
Lugano assessments by the investigator recorded in the eCRF. It is the best response a 
participant has had following start of IP, but prior to starting any subsequent cancer therapy 
and up to and including Lugano progression or the latest evaluable assessment in the absence 
of Lugano progression. Categories of BOR will be based on Lugano criteria using the 
following response criteria (CR, PR, stable disease [SD], progressive disease [PD], not 
evaluable [NE], and unknown).
5.2.1.2
Primary Analysis of Primary Endpoint: ORR
Summaries will be produced that present the number and percentage of participants with a 
tumour response (CR/PR) based upon the number of participants in the response evaluable 
analysis set. ORR will be calculated and binomial exact 2-sided CIs at 80% and 95% will be 
presented for participants in the response evaluable set. For the purpose of conferences and 
publications, outputs may also be presented for the interim response evaluable set.
A swimmer plot will be presented showing disease assessment results for each assessment 
performed, including treatment duration and treatment status.
In addition, BOR will be summarised by number of participants and percentage for each 
category (CR, PR, SD, PD, and NE). No formal statistical analyses are planned for BOR.
5.2.1.3
Supportive Data: Change in Target Lesion Tumour Size
Change in target lesion tumour size will be analysed as supportive to the primary endpoint and 
is not a specified endpoint of this study.
5.2.1.3.1
Definition and Derivation: Change in Target Lesion Tumour Size
Target lesions are measurable tumour lesions. Baseline is defined to be the last evaluable 
assessment prior to starting intervention.
Target lesion tumour size for the target measurable nodes and extra-nodal sites at any 
timepoint is defined as the sum of the product of the perpendicular diameters for multiple 
lesions. When a lesion is too small to measure, 5 mm x 5 mm will be assigned as the product 
of the perpendicular diameters. 
If target lesion measurements are missing post-baseline then the sum of the product of 
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measurements. Subsequent percentage changes will consequently not be calculated using 
post-baseline measurements where any target lesion measurement is missing.
The percentage change in target lesion size at each timepoint for which data are available will 
be obtained for each participant.
The best change in tumour size from baseline (ie, depth of response) is the largest decrease 
from baseline or the smallest increase from baseline in the absence of a reduction and includes 
all assessments:

up to and including the first timepoint at which the overall timepoint response is a PD,

prior to death in the absence of progression,

prior to the start of subsequent anti-cancer therapy,

or up to and including the last evaluable tumour assessment if the participant has not died, 
progressed or stated subsequent anti-cancer therapy.
5.2.1.3.2
Primary Analysis of Supportive Data: Change in Target Lesion Tumour Size 
Only participants included in the response evaluable analysis set will be included in 
summaries of change in tumour size. For the purpose of conferences and publications, this 
may be presented for participants in the interim response evaluable set.
The target lesion tumour size and percentage change from baseline in target lesion tumour size 
will be summarized using descriptive statistics and presented at each scheduled timepoint 
(refer to efficacy naming conventions in Section 4.2.3.1 and Section 8 Appendix A). 
Participants who progress before the scheduled assessment at 8 weeks should have had a 
tumour assessment performed at the time of progression prior to treatment discontinuation. 
The tumour size from their latest progression assessment is used instead of the 8-week 
assessment for these participants.
Additionally, using all scheduled and unscheduled tumour assessments, ‘spider’ plots of 
percentage change from baseline in target lesion size by participants will be presented. A 
graphical summary of the best percentage change in target lesion tumour size will be
presented in a vertical bar chart with each participant’s best percentage change from baseline 
to nadir displayed as a vertical bar, with colour coding that indicates best response obtained 
(“waterfall” plot).
5.2.2
Secondary Endpoint: Complete Response Rate (CR Rate)
CR is a secondary endpoint.


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5.2.2.1
Definition and Derivations
CR rate is defined as the proportion of participants who achieve CR, according to the response 
criteria for malignant lymphoma reported by the investigator. 
5.2.2.2
Primary Analysis of Secondary Endpoint: CR Rate
CR rate will be calculated and binomial exact 2-sided CIs at 80% and 95% will be presented 
for participants in the response evaluable set.
5.2.3
Secondary Endpoint: Duration of Response (DoR)
DoR is a secondary endpoint.
5.2.3.1
Definition
DoR is defined as the time from the date of first documented objective response (CR or PR) 
until date of first documented disease progression per Lugano classification as assessed by 
investigator at local site or death (by any cause in the absence of disease progression).
5.2.3.2
Derivations
DoR (months) = (date of progression free survival [PFS] event [progression/death] or 
censoring – date of first objective response + 1) / (365.25/12).
The end of response should coincide with the date of progression or death from any cause 
used for the PFS endpoint. The time of the initial response is defined as the latest of the dates 
contributing towards the first timepoint response of CR or PR. If a participant does not 
progress following a response, then their DoR is censored on the PFS censoring date. Only 
participants who have achieved objective response are evaluated for DoR.
5.2.3.3
Primary Analysis of Secondary Endpoint: DoR
Only participants who achieved objective response (CR or PR) will be included in the 
summaries of DoR. If number of responders allow, Kaplan-Meier plots of DoR will be 
presented. The median DoR and 2-sided 80% and 95% CIs will be estimated using the 
Kaplan-Meier method.
Swimmer plots by participant (including non-responders) will be created to visualise when 
response begins and ends and when study intervention is withdrawn.
5.2.4
Secondary Endpoint: Progression-free Survival (PFS)
PFS is a secondary endpoint.
5.2.4.1
Definition
PFS is defined as the time from first dose until the date of first documented disease 
progression, per Lugano classification as assessed by the investigator at local site, or death (by 


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any cause in the absence of disease progression), regardless of whether the participant 
withdraws from therapy or receives another anti-cancer therapy prior to Lugano progression.
5.2.4.2
Derivations
PFS (months) = (date of PFS event [progression/death] or censoring – date of first dose + 1) / 
(365.25/12).
Participants who have not progressed or died at the time of analysis, or have unknown status, 
are censored at the time of the latest date of assessment from their last evaluable disease 
assessment. However, if the participant progresses or dies immediately after 2 or more 
consecutive missed timepoints, the participant is censored at the time of the latest evaluable 
disease assessment prior to the 2 missed timepoints. Note: a NE timepoint is not considered as 
a missed timepoint. 
Given the schedule timepoint assessment scheme (ie, 9-weekly for the first 26 weeks then 
12-weekly thereafter) the definition of 2 missed timepoints will change. 
If the previous assessment is less than study day 113 (ie, week 16) then 2 missing timepoints 
will equate to 20 weeks since the previous assessment, allowing for early and late timepoints 
(ie, 2 x 9 weeks + 1 week for an early assessment + 1 week for a late assessment= 20 weeks). 
If the 2 missed timepoints occur over the period when the scheduled frequency of assessment 
changes from nine-weekly to twelve-weekly this will equate to 23 weeks (ie, take the average 
of 9 and 12 weeks which gives 10.5 weeks and then apply the same rationale, hence 2 x 10.5 
weeks + 1 week for early assessment + 1 week for late assessment =23 weeks). The time 
period for the previous assessment is from study days 113 to 175 (ie, week 16 to week 25).
From week 25 onwards (when the scheduling changes to 12-weekly assessments), 2 missing 
timepoints equates to 26 weeks (ie, 2 x 12 weeks + 1 week for an early assessment + 1 week 
for a late assessment = 26 weeks). 
If the participant has no evaluable disease assessments post-baseline or does not have baseline 
assessment data, they will be censored at Day 1 unless they die within 2 timepoints of baseline 
(19 weeks plus 1 week allowing for a late assessment within the timepoint window) when the 
death date qualifies as a PFS event.
A summary of censoring rules and the date of PD/death or censoring are given in Table 7.Note 
that censoring overrides event in certain specified cases and that this table does not indicate 
the order for programming.


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Table 7 Summary of Censoring Rules for PFS
Situation
Date of PD/Death or Censoring
PFS Outcome
Documented Progressive Disease (PD) or death 
in the absence of progression
Date of earliest documentation of 
PD or date of death in the absence 
of progression
Event
Either no assessment at baseline or no 
evaluable assessments post-baseline AND 
death prior to second scheduled post-baseline 
disease assessment
Date of death
Event 
Either no assessment at baseline or no 
evaluable assessments post-baseline AND no 
death prior to second scheduled post-baseline 
disease assessment
Date of first dose (Day 1)
Censored
PD or death (in the absence of progression) 
immediately after ≥ 2 consecutive missed 
disease assessments as per the protocol 
specified assessment schedule
Last evaluable progression-free 
disease assessment prior to missed 
assessments
Censored
On-going with neither PD nor death at the time 
of analysis or lost to follow-up or withdrawn 
consent
Date of last evaluable disease 
assessment
Censored
Initiation of subsequent anti-cancer therapy 
prior to PD or death
Date of last evaluable disease 
assessment prior to initiation of 
subsequent anti-cancer therapy
Censored for 
sensitivity analysis 
only
Abbreviations: PD, progressive disease; PFS, progression-free survival
The PFS time is always derived based on scan/assessment dates, not timepoint dates.
Disease assessments/scans contributing towards a particular timepoint may be performed on 
different dates. The following rules are applied:

The date of progression is determined based on the earliest of the dates of the component 
that triggered the progression.

When censoring a participant for PFS the participant is censored at the latest of the dates 
contributing to a particular overall timepoint assessment. 
Note: for target lesions only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions and similarly for non-target lesions only the latest scan date is 
recorded out of all scans performed at that assessment for the non-target lesions.


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Duration of follow-up for PFS is applicable only for PFS censored participants and is defined 
as follows:
Duration of follow-up for PFS in censored participants (months) = (date of PFS censoring –
date of first dose + 1) / (365.25/12).
5.2.4.3
Primary Analysis of Secondary Endpoint: PFS
The main analysis of PFS is based on the FAS. The number and percentage of participants 
experiencing a PFS event (broken down by type of event/censoring) and Kaplan-Meier plots 
of PFS will be presented. The median PFS and its 2-sided 80% and 95% CIs will be estimated 
using the Kaplan-Meier method (if participant numbers allow).
The IP status at progression of participants at the time of analysis will be summarised. This 
includes the number (%) of participants who were on IP at the time of progression, the number 
(%) of participants who discontinued IP prior to progression, the number (%) of participants 
who have not progressed and were on IP or discontinued IP.
A summary of the duration of follow-up for PFS is included using median (range) for 
censored participants (including all types of PFS censoring).
The proportion of participants alive and progression free at every 3 months (3, 6, 9, 12, etc.) 
and associated 2-sided 80% and 95% CIs will be estimated using the Kaplan-Meier method. 
5.2.4.4
Sensitivity Analysis of PFS Endpoint
A sensitivity analysis will be performed censoring PFS at the date of the last progression-free 
disease assessment prior to initiation of subsequent anticancer intervention.
Separately, a sensitivity analysis will also be conducted to assess the impact of COVID-19 
related deaths on PFS. That is, participants who had a PFS event due to death where the 
primary or secondary cause of death was COVID-19 infection or COVID-19 infection was 
reported as a fatal AE, will be censored on the last available tumour assessment prior to 
COVID-19 infection related death. This sensitivity analysis will only be performed if 5 or 
more participants have confirmed or suspected COVID-19 death events.
5.2.5
Secondary Endpoint: Overall Survival (OS)
OS is a secondary efficacy endpoint.
5.2.5.1
Definition
OS is defined as the time from the date of first dose until death due to any cause regardless of 
whether the participant withdraws from study therapy or receives another anti-cancer therapy.


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5.2.5.2
Derivations
OS (months) = (date of death or censoring – date of first dose + 1) / (365.25/12).
Any participant not known to have died at the time of analysis will be censored based on the 
last recorded date on which the participant was known to be alive. Participants known to be 
alive or dead after the DCO for analysis will be censored at the DCO. Participants lost to 
follow-up will be censored at the date the participant is last known to have been alive. At 
study closure, any participant still alive after last patient last visit for the study will be 
censored at the date of last patient last visit.
Note: Survival calls will be made in the week following the date of DCO for the analysis, and 
if participants are confirmed to be alive or if the death date is after the DCO date these 
participants will be censored at the date of DCO. The status of ongoing, withdrawn (from the 
study) and “lost to follow-up” participants at the time of the final OS analysis should be 
obtained by the site personnel by checking the participant’s notes, hospital records, contacting 
the participant’s general practitioner and checking publicly-available death registries. In the 
event that the participant has actively withdrawn consent to the processing of their personal 
data, the vital status of the participant can be obtained by site personnel from publicly 
available resources where it is possible to do so under applicable local laws.
Note: For any OS analysis performed in the absence of survival calls being made, it may be 
necessary to use all relevant eCRF fields to determine the last recorded date on which the 
participant was known to be alive for those participants still on intervention (since the 
SURVIVE module is only completed for participants off IP if a survival sweep is not 
performed). The last date for each individual participant is defined as the latest among the 
following dates recorded on the eCRFs:

AE start, stop and change in severity dates

Admission and discharge dates of hospitalization

Study IP date

End of IP date

Concomitant medication start and stop dates

Laboratory test dates

Date of vital signs

Disease assessment dates on eCRF

Start and stop dates of alternative anticancer intervention

Date last known alive on survival status eCRF

End of study date


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Duration of follow-up for OS is reported separately for censored participants and 
non-censored participants as well as combined for all participants and is defined as follows:
Duration of follow-up for OS (months) = (date of death or censoring [date last known to be 
alive]) – date of first dose + 1) / (365.25/12).
5.2.5.3
Handling of Dropouts and Missing Data
If a participant is known to have died where only a partial death date is available, then the date 
of death is imputed as the latest of the last date known to be alive +1 from the database and 
the death date using the available information provided:

For Missing day only – using the 1st of the month of death. 

For Missing day and Month – using the 1st of January of the year of death.
If there is evidence of death but the date is entirely missing, it is treated as missing, ie, 
censored at the last known alive date.
5.2.5.4
Primary Analysis of Secondary Endpoint (Overall Survival)
The analysis of OS is based on the FAS. The number and percentage of participants 
experiencing an OS event and Kaplan-Meier plots of OS will be presented. The median OS 
and 2-sided 80% and 95% CIs will be estimated using the Kaplan-Meier method (if 
participant numbers allow).
Summaries of the number and percentage of participants who have died, those still in survival 
follow-up, those lost to follow-up and those who have withdrawn consent will be provided.
A summary of the duration of follow-up for OS will be included using median (range). This is 
presented separately for censored and non-censored participants.
The proportion of participants alive at every 3 months (3, 6, 9, 12, etc.) and associated 2-sided 
80% and 95% CIs will be estimated using the Kaplan-Meier method. 
5.2.5.5
Sensitivity Analysis of OS Endpoint
A sensitivity analysis will also be conducted to assess the impact of COVID-19 related deaths 
on OS. That is, participants who had an OS event due to death where the primary or secondary 
cause of death was COVID-19 infection or COVID-19 infection was reported as a fatal AE, 
will be censored on the date of their COVID-19 infection related death. This sensitivity 
analysis will only be performed if 5 or more participants have confirmed or suspected 
COVID-19 death events.


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5.3
Pharmacodynamic Endpoints 
Analysis on pharmacodynamic 
 will be described in a separate analysis 
plan.
5.4
Pharmacokinetics – Module 1
This section covers details related to PK endpoints and analyses. PK is a secondary endpoint 
for Module 1.
5.4.1
Definition and Derivations
5.4.1.1
Plasma
The PK parameters of the concentration data for AZD4573 and its metabolites (if applicable) 
will be derived using non-compartmental methods in Phoenix® WinNonlin® Version 8.1 or 
higher (Certara) as data applicable.
The PK parameters will be calculated/estimated according to AstraZeneca standards.
PK analysis will, where data allow, be carried out using actual elapsed times determined from 
the PK sampling and dosing times recorded in the database. If actual elapsed times are 
missing, nominal times may be used. Nominal sampling times may be used for any agreed 
interim PK parameter calculations and PK parameters will be derived using standard 
non-compartmental methods.
For AZD4573 (intravenous [IV] infusion) the following PK parameters will be calculated 
using the PK concentration vs. time data from Cycle 1, Day 1 of Weeks 1 through 3 and Cycle 
2, Day 1.
Cmax
Maximum observed plasma (peak) drug concentration
tmax
Time to reach peak or maximum observed concentration following IP 
administration
λz
Terminal rate constant, estimated by log-linear least squares regression of 
the terminal part of the concentration-time curve
t1/2
Half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve
AUC(0-24)
Area under the plasma concentration-time curve from 0 to time 24 hours
AUClast
Area under the plasma concentration-time curve from zero to last 
quantifiable concentration
CCI
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AUCinf
Area under plasma concentration-time curve from zero to infinity
CL
Total body clearance of drug from plasma after a single IV infusion dose
Vz
Volume of distribution after a single IV infusion (based on terminal 
phase)
Vss
Volume of distribution at steady-state after a single IV infusion
tlast
Time of last observed (quantifiable) concentration
Cmax/D
Dose-normalised Cmax
AUClast/D
Dose-normalised AUClast
AUCinf/D
Dose-normalised AUCinf
Additional PK parameters may be determined where appropriate.
The following diagnostic parameters for plasma PK analysis will be provided:
λz lower
Lower (earlier) t used for λz determination
λz upper
Upper (later) t used for λz determination
λzN
Number of data points used for λz determination
Rsq
Statistical measure of fit for the regression used for λz determination
Rsq adj
Statistical measure of fit for the regression used for λz determination 
adjusted for the number of used data points (n obs)
λz span ratio
Time period over which λz was determined as a ratio of t1/2λz
AUCextr
Extrapolated area under the curve from tlast to infinity (%)
The time period used for the estimation of apparent terminal elimination half-lives, where 
possible, should be over at least 2 half-lives. For t1/2 estimates where λz was calculated over a 
time period less than twice their resultant half-life, the reliability of t1/2 and any PK 
parameters derived from λz will be discussed in the CSR.


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5.4.1.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.4.2
Primary Analysis of Pharmacokinetics
5.4.2.1
Plasma
Plasma concentrations will be listed by actual and relative (to dose administration) sampling 
time. The following summary statistics will be presented for concentrations and PK 
parameters at each time point:

n below LLOQ (only for concentrations)

gMean (calculated as exp[µ], where µ is the mean of the data on a logarithmic scale)
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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
Geometric CV% (gCV, calculated as 100×exp(s2) -1 where s is the standard deviation 
of the data on a natural log scale)

Gmean + gSD (gSD calculated as exp[s] where s is the standard deviation of the data on 
the natural log scale. Gmean + gSD calculated as exp(μ+s)) 

Gmean – gSD (calculated as exp(μ-s))

Arithmetic mean

Arithmetic Std Dev

Minimum

Median

Maximum

Number of observations
In listings, concentrations below the LLOQ will be presented as BLQ. In listings and tables 
where terms BLQ or LLOQ are included, the LLOQ (numerical value) will be included in a 
footnote.
For the calculation of statistics, concentrations that are BLQ will be handled as follows at each 
timepoint:

If ≤ 50% of the concentrations are BLQ, all BLQ values will be set to LLOQ, and all 
descriptive statistics will be calculated.

If > 50%, but not all, of the concentrations are BLQ, the gMean, gCV, arithmetic mean, 
and arithmetic Std Dev will be reported as “NC” (not calculable). The maximum value 
will be reported from the individual data, and the minimum and median will be set as 
“BLQ”.

If all concentrations are BLQ, no descriptive statistics will be calculated. “NA” (not 
applicable” will be presented for gCV and arithmetic SD, and “BLQ” will be presented 
for gMean, arithmetic mean, median, minimum, and maximum.
For PK concentration and parameter data, if there are < 3 values available at a timepoint, only 
the maximum, minimum and n will be reported; the remaining descriptive statistics will be 
reported as “NC”. Concentrations that are BLQ are considered a value.
Missing samples will be reported as “NS” (no sample) and excluded from analysis.
Source data will be used in all derived PK concentrations without prior rounding.
The following figures, in black and white, will be produced:

Participant Profiles, Plasma Concentration Time Data – Linear Scale


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
Participant Profiles, Plasma Concentration Time Data – Semi-logarithmic Scale

Gmean (± gSD), Plasma Concentration Time Data

Gmean, Plasma Concentration Time Data – Semi-logarithmic scale
Individual and spaghetti figures will be plotted using concentration versus actual time, and 
mean figures will be plotted using concentration time versus nominal time by PK day as 
needed.
The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings for PK parameters:

Individual PK parameters will be presented to 4 significant digits, with the exception of 
tmax, which will be presented to 2 decimal places.

Parameters derived directly from source data (eg, Cmax) will be reported with the same 
precision as the source data (if this is not 4 significant digits).

The mean, gMean, median and Std Dev values will be reported to 4 significant digits, all 
other descriptive statistics will be reported to 3 significant digits except for gCV% which 
will be presented to one decimal place.

For tmax, the minimum and maximum will be presented to 2 decimal places and all other 
descriptive statistics will be presented to 3 decimal places.

Estimates and confidence intervals in the form of percentages will be presented to 2 
decimal places.
Criteria for Handling Concentrations Below the Limit of Quantification or Missing 
Concentrations in Pharmacokinetic Analysis
For the non-compartmental analysis and individual plots, if a BLQ value occurs before the 
first measurable concentration, it will be assigned the value of 0, otherwise it will be treated as 
missing. The following rules apply with special situations defined below:

Where 2 or more consecutive concentrations are BLQ at the end of the profile the profile 
will be deemed to have terminated and any further quantifiable concentrations will be set 
to missing for the calculation of PK parameters, unless they are considered to be a true 
characteristic of the profile of the drug.

If an entire concentration-time profile is BLQ, the profile will be excluded from the PK 
analysis.

If a pre-dose measurement for the first dose of Cycle 1 is missing, the value will be set to 
zero.


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Treatment of Outliers in Pharmacokinetic Analysis
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, exclusion 
of data must have a strong justification and will be documented in the CSR.
Quantifiable predose concentration values in the first dosing of Cycle 1 will be considered 
anomalous and set to missing for the PK analysis.
5.4.2.2
 
5.5
Immunogenicity
No immunogenicity analysis will be conducted for Module 1.
5.6
Safety Analyses
The domain safety covers exposure, adverse events, clinical laboratory, vital signs, 
electrocardiograms (ECGs), B symptoms, and tumour lysis syndrome (TLS). 
Tables will be provided for the safety analysis set; listings will be provided for All participants 
or the safety set depending on the availability of data.
All safety analysis will be presented by cohort.
5.6.1
Exposure
Exposure amounts, durations and dose modifications and interruptions/delays will be 
summarised for the following periods:

Overall treatment period

Cycle 1

Up to first tumour assessment

Cycle 2 onwards
5.6.1.1
Definitions and Derivations

Total duration of exposure is defined by the last date of actual AZD4573 dosing (ie, a 
dose > 0 mg was given) plus 6 days (due to the fact that AZD4573 is ordinarily dosed on 
a weekly schedule) minus the date of first AZD4573 dose (> 0 mg) plus 1.

For participants who die whilst on study treatment or if a DCO occurs, duration of 
exposure (months/weeks) is defined as date of death/DCO (whichever occurs first) 
minus the date of first treatment plus 1 day.
CCI
CCI


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
Therefore: Duration of exposure (weeks) = [min(last dose date where dose > 0 mg + 
6, date of death, date of DCO) – first dose date + 1]/7.

Actual duration of exposure (weeks) = [duration of exposure (days) – total duration of 
dose delays (days)]/7. Duration of exposure is calculated as above, and dose delays are 
defined as any length of time where the subject has not taken any of the planned dose in 
accordance with the protocol. The actual exposure calculation makes no adjustment for 
any dose reductions that may have occurred. 

Dose intensity of study intervention is addressed by considering relative dose intensity 
(RDI), where RDI is the percentage of the actual dose delivered relative to the intended 
dose through to treatment discontinuation. More specifically, RDI is defined as follows:

RDI (%) = 100 × d/D, where d is the actual cumulative dose delivered up to the 
actual last day of dosing and D is the intended cumulative dose up to the actual last 
day of dosing. D is the total dose that would be delivered, if there were no 
modification to dose or schedule. Note: When accounting for the calculation of 
intended cumulative dose 2 days should be added to the date of last dose to reflect the 
protocol allowed window for dosing.

 
 
 
 
 
 
 
 
 
 

Duration of dose delays will be derived for doses indicated as being delayed on the eCRF. 
For each individual dose, the duration of dose delay is the number of days the dose was
received outside of the original planned dosing schedule. Overall duration of dose delays 
will be calculated as the sum of all individual dose delays during the study. For example, 
assume the eCRF indicate that there was a treatment delay (question “Treatment delayed” 
indicated as “Y” by investigator) then the duration of the individual delay will be [date 
first dose received after delay – date last dose received before delay – 9]. For example, if 
dose is given on days 1 and 15 with the eCRF indicating a delay, the duration of the 
delay = 15 – 1 – 9 = 5 days.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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5.6.1.2
Presentation
Total and actual duration of exposure to study intervention in weeks will be summarised by 
descriptive statistics. Dose intensity will be summarised by descriptive statistics. Exposure to
IP (ie, total amount of IP received) will be listed and summarised for all subjects. Exposure 
swimmer plot(s) will be produced, with a line presented for each subject to display relevant 
exposure and disposition details. 
Dosing deviations for IP will be summarized with reasons for deviations for the following 
categories: reductions and interruptions. The number of subjects with dosing delays and total 
dose delays will be summarised. Dose delays will also be summarised for number of delays 
with a duration < 7 days and number of delays with a duration ≥7 days. 
The following additional summaries will also be produced:

Number of participants that completed Cycle 1 (ie, received 5 doses of AZD4573), 
including number of participants that did not complete Cycle 1.

Number of doses received per participant in Cycle 1.

Total and actual duration of exposure, specific to Cycle 1.

Number of participants that initiated Cycle 2.
5.6.2
Adverse Events
5.6.2.1
Definitions and Derivations
The MedDRA (version 24.1 at a minimum) will be used to code AEs. AEs will be graded 
according to the National Cancer institute Common Terminology Criteria for AEs (CTCAE) 
(using the CTCAE version 5.0).
AEs are defined as treatment emergent adverse events (TEAEs) if they onset or worsen (by 
investigator report of a change in intensity/severity), during the treatment emergent phase 
defined below. Worsening is determined by comparison with the pre-intervention severity of 
the AE recorded closest to the start of dosing.
When assigning AEs to the relevant phase of the study the following rules apply and any 
deviations must be agreed by the study team:

Pre-treatment phase – All AEs with a start date after signing the informed consent form, 
prior to the first administration of IP that do not subsequently go on to worsen during the 
treatment emergent phase.

Treatment emergent phase – All AEs starting or worsening in severity following the first 
administration of IP for the duration of the treatment period, up to and including 30 days 
after the last dose of IP as per the study safety follow-up period but prior to subsequent 


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cancer therapy. AEs with missing start time which occur on the same day as first IP 
administration will be reported as treatment emergent.

Post-treatment phase – All AEs starting more than 30 days after last dose of IP or once 
subsequent cancer therapy is started, whichever is earlier. This period is defined for the 
purpose of possible causally related SAEs.
Serious Adverse Events (SAEs)
A serious adverse event (SAE) is any AE that:

Results in death

Is immediately life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalisation

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect in offspring of the participant

Is an important medical event that may jeopardize the participant
AEs of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the IP and may require close monitoring and rapid communication by the 
investigator to the sponsor.
The following events will be considered to be AESIs:

Neutropenia, including Febrile neutropenia, Neutropenic sepsis, neutrophil count decrease

Thrombocytopenia, including platelet count decrease

Hepatoxicity, including potential Hy’s Law, Drug-induced liver injury, Bilirubin increase 
with transaminase (alanine aminotransferase [ALT] or aspartate aminotransferase [AST], 
or both ALT and AST) increase

Pyrexia

TLS

Myocardial ischaemia
Other categories may be added, or existing terms may be modified as necessary. An 
AstraZeneca medically qualified expert after consultation with the Global Patient Safety 
Physician has reviewed the AEs of interest and identified which higher-level terms and which 
preferred terms contribute to each AESI. Further reviews may take place prior to database 


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lock to ensure any further terms not already included are captured within the categories. 
Preferred terms used to identify AESIs will be listed prior to database lock.
Other significant adverse events (OAE)
No OAEs are defined for this study.
5.6.2.2
Presentation
All TEAEs will be summarised and listed. AEs which are not treatment emergent will be 
listed for the Safety set.
TEAEs will be counted once for each participant for calculating percentages of participants 
experiencing TEAEs. In addition, if the same TEAE occurs multiple times within a particular 
participant, the highest severity and level of relationship observed will be reported. For tables 
by MedDRA SOC and MedDRA PT, participants with multiple TEAEs will be counted once 
for each SOC/PT.
An overall summary table of the number of participants experiencing each category of AEs 
will be produced. The number of participants experiencing TEAEs by MedDRA SOC and PT 
will be summarised and the severity, and relationship to IP will be summarised. Further splits 
by CTCAE grade, causal relationship to IP and AEs with Grade 3-4 will also be also 
summarised.
Separate tables present AEs leading to discontinuation of IP, IP-related AEs, IP-related AEs 
leading to discontinuation of IP, AEs leading to dose reduction, AEs leading to dose delay, 
and AEs leading to dose interruption.
AEs leading to death will also summarised.
SAEs
SAEs will be summarised as described above for the TEAEs. 
AEs of special interest
Grouped summary tables of certain MedDRA PTs will be produced and may also show the 
individual PTs which constitute each AESI grouping. Groupings will be based on PTs 
provided by the medical team prior to database lock, and a listing of the PTs in each grouping 
will be provided.
Summaries of the above-mentioned grouped AE categories include number and percentage 
(%) of participants who have:

At least one AESI presented by event outcome


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
At least one AESI causally related to IP

At least one AESI leading to discontinuation of study intervention.
A summary of total duration (days) of AESI will be provided for events which have an end 
date, and this may be supported by summaries of ongoing AESIs at death and, separately, at 
data cut-off.
5.6.3
Deaths
5.6.3.1
Presentation
A summary of deaths will be provided with the number and percentage of participants 
categorised as:

Related to disease under investigation only

AE outcome = death only

Both related to disease under investigation and with AE outcome = death

AE with outcome = death > 30 days after last study intervention

Other deaths
A corresponding listing will also be produced.
5.6.4
Clinical Laboratory, Blood Sample
5.6.4.1
Definitions and Derivations
Laboratory tests will be grouped according to chemistry, haematology and coagulation. 
Listings will be provided for all laboratory results. Laboratory parameters will be assessed at 
baseline as well as throughout the study.
For chemistry and haematology parameters, laboratory abnormalities with toxicity grades 
according to the NCI CTCAE version 5.0 will be derived.
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Table 8 Laboratory Safety Variables
. 


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Table 8 Laboratory Safety Variables
Haematology/Haemostasis (whole 
blood)
Clinical Chemistry (serum or plasma)
B-Full blood count with differential
S/P-Creatinine
S/P-Chloride
B-Hb
S/P-Bilirubin total
S/P-Magnesium
B-White blood cell count with differential
S/P-Direct and indirect bilirubin 
(where required)
S/P-Phosphorus
B-Platelet count
S/P-Alkaline phosphatase
S/P-Cholesterol
B-Haemocrit
S/P-Aspartate transaminase
S/P-Amylase
B-Absolute neutrophil count
S/P-Alanine transaminase
S/P-Lactate 
dehydrogenase
B-Absolute lymphocyte count
S/P-Albumin
S/P-Lipase
B-Blast Cells
S/P-Potassium
S/P-Bicarbonate
Urinalysis (dipstick)
S/P-Carbonate
S/P-glutamate 
dehydrogenase
U-Hb/Erythrocytes/Blood 
U-pH
S/P-Calcium, total
S/P-Blood urea nitrogen
U-Protein/Albumin
U-Bilirubin
S/P-Sodium
S/P-Glucose (fasting 
preferred)
U-Glucose 
U-Ketones
S/P-Creatine phosphokinase
S/P-Total protein
U-Specific gravity
U-Drug 
screeninga
S/P-Uric acid
S/P-GGT
U-Microscopy including white blood cells 
/high-power field, red blood cells/high-power 
field
S/P-Triglycerides
S/P-Ferritin
Coagulation
S/P-C-reactive protein
S/P-Urea
International normalised ratio
S/P-Troponin
S/P-Phosphate
Activated partial thromboplastin time, 
absolute or relative
S/P-Ammonia (where available at local institution; to be 
tested every 2 weeks)
Prothrombin time
Fibrinogen
D-Dimer (where available at local institution)
Pregnancy Test (women of childbearing potential only)
U-hCG
S-beta hCG (at screening only)
a
Mandated at screening visit only; for all other urinalysis tests, drug screening may be performed at 
investigator discretion.
Abbreviations: B, blood; GGT, gamma-glutamyl transferase; Hb, haemoglobin; hCG, human chorionic 
gonadotropin; P, plasma; S, serum; U, urinalysis.
Change from baseline in haematology, clinical chemistry and coagulation endpoints will be 
calculated for each post-baseline timepoint. CTCAE grade is calculated at each timepoint for 


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tests with CTCAE grading defined. Maximum on-treatment CTCAE will be also calculated. 
Absolute values will be compared to the local laboratory reference range and classified as low 
(below range), normal (within range or on limits of range) and high (above range). All values 
classified as high or low will be flagged on the listings.
Liver Function Parameters
Participants with elevated post-baseline ALT, AST, or Total Bilirubin will be identified. 
5.6.4.2
Presentations
The absolute values and change in each laboratory parameter from baseline to each 
post-baseline timepoint will be summarised graphically in box plots.
Laboratory abnormalities occurring during the on-treatment period to the last assessment on 
treatment will be presented. Worst toxicity grade, rates of grade 3-4 toxicity, and grade shifts 
of 2 or more from baseline to the maximum grade will be presented. Summaries indicating 
hyper- and hypo- directionality of change will be produced, where appropriate. Laboratory 
parameters that cannot be graded via NCI CTCAE will be summarised with frequencies of 
post-baseline laboratory values categorized as low (L), normal (N), or high (H) using 
laboratory normal ranges compared to baseline.
Listings will be provided for all laboratory results.
Liver Function Parameters
Number and percentage of participants with elevated post-baseline ALT, AST, or Total 
Bilirubin will be tabulated.
For participants with “Potential Hy’s law”, the change in the following laboratory parameters 
from baseline to each post-baseline timepoint will be summarised: ALT, AST, alkaline 
phosphatase, glutamate dehydrogenase, lactate dehydrogenase, gamma-glutamyl transferase, 
and international normalised ratio. Individual participant data for these laboratory parameters 
will be listed as well.
Plots for both maximum on-treatment ALT and AST versus the maximum on-treatment 
bilirubin (expressed as multiples of their upper limit of normal [ULN] reference range) will be 
produced, with reference lines at 3 x ULN for ALT and AST and 2 x ULN for total bilirubin.
Liver biochemistry test results over time for participants with elevated ALT or AST 
(≥3 x ULN) and elevated bilirubin (≥2 x ULN) regardless of whether or not these elevations 
coincide, or ALT or AST ≥5 x ULN will be plotted.


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5.6.5
Clinical Laboratory, Urinalysis
5.6.5.1
Definitions and Derivations
Urinalysis variables that will be measured are detailed in 


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Table 8 Laboratory Safety Variables
. 
5.6.5.2
Presentations
Shift tables (“Negative”, “Trace”, “Positive”, “0”, “+”, “++”, “+++”) from baseline to worst 
on-treatment results will be produced for urinalysis.
Listings will be provided for all laboratory results including urinalysis.
5.6.6
Vital Signs
5.6.6.1
Definitions and Derivations
Temperature, blood pressure and heart rate will be assessed.
5.6.6.2
Presentations
Vital signs will be assessed at baseline and throughout the study. Vital signs will be 
summarised by study timepoint including descriptive statistics for the value of the parameters 
and the changes from baseline. 
Absolute values and change from baseline for vital signs data at each timepoint will be 
presented using box plots. 
5.6.7
Weight
5.6.7.1
Presentations
Weight will be assessed at baseline and throughout the study. Weight will be summarised by 
study timepoint including descriptive statistics for the value and changes from baseline.
Absolute values and change from baseline for weight at each timepoint will be presented 
using box plots.
5.6.8
B symptoms
5.6.8.1
Presentations
Information on B symptoms (unintentional weight loss, disease related intermittent fevers >38 
C, drenching sweats especially at night, significant fatigue, worsening of B-symptoms 
compared to baseline, worsening of B-symptoms compared to prior timepoint, and comments) 
will be listed for all subjects and timepoints.


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5.6.9
Tumour lysis syndrome
5.6.9.1
Definitions and Derivations
Tumour lysis syndrome (TLS) is an important identified risk for AZD4573. TLS prophylaxis 
is mandatory for all participants starting 3 days before the first dose of AZD4573, which 
should be followed in addition to institutional guidelines.
There are 2 data sources to report TLS: AEs of TLS and TLS monitoring data. One TLS AE 
per infusion per participant will be counted. For participants with multiple TLS AEs recorded 
after one infusion, only the TLS AE with maximum CTCAE grade will be counted for 
reporting purposes. Similar rules apply to TLS monitoring data. According to the TLS 
monitoring schedule in the CSP, participants could have multiple TLS monitoring episodes 
after one infusion, if counting TLS monitoring assessments at each unique date and time per 
participant as an episode. For reporting purposes, a maximum of one TLS per infusion per 
participant will be counted. The highest Cairo-Bishop grade of each clinical characteristic 
(creatinine abnormality, cardiac arrythmia, seizure) and overall grading will be computed for 
each infusion and participant.
Overall Cairo-Bishop grading for Clinical TLS is defined as the maximum overall on 
treatment Cairo-Bishop grading, derived from the highest contributing grade (creatinine 
abnormality, cardiac arrythmia, seizure) for a specific episode of clinical TLS.
5.6.9.2
Presentations
The number and percentage of participants with AE LLTs involving clinical TLS and 
laboratory TLS by maximum CTCAE grade will be presented, including the total number of 
AEs. Figures for laboratory TLS and clinical TLS will be presented. Bar charts showing the 
number of TLS AEs and the number and percentage of participants having TLS AEs by week 
since AZD4573 administration will be presented. TLS-associated AEs will be listed with other 
AEs.
Time from infusion to onset of TLS after first AZD4573 administration and after subsequent 
doses will be summarised using TLS monitoring data. Listing of TLS monitoring will be 
presented including uric acid, potassium, phosphate, calcium, urea nitrogen, creatinine, 
creatinine elevation due to TLS, cardiac arrhythmia due to TLS, seizure due to TLS and 
Cairo-Bishop grades for clinical TLS.
5.6.10
Electrocardiogram
5.6.10.1
Definitions and Derivations
Electrocardiogram (ECG) parameters will be assessed at baseline as well as throughout the 
study. ECG parameters include PR, RR, QRS, QT, QTcB, and QTcF. The QTcF is considered 
as the primary correction method to assess participant cardiac safety.


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From these resting 12-lead ECGs values of the QT and RR intervals the QTcF and QTcB will 
be derived using the following formulae:
QTcF = QT/RR^ (1/3) where RR is in seconds 
QTcB = QT/RR^ (1/2) where RR is in seconds
The values of QTcF (milliseconds) and QTcB (milliseconds) will be re-derived from the 
values of RR and QT during the creation of the reporting database.
The notable ECG interval values while on intervention are:

Maximum QTcF and QTcB intervals 470 milliseconds, > 480 milliseconds, and > 500 
milliseconds. 

Maximum changes from baseline in QTcF and QTcB 30, >60, and 90 milliseconds. 
5.6.10.2
Presentations
ECG parameters will be summarised using descriptive statistics by timepoint and change from 
baseline for each post-baseline timepoint. Absolute values and change from baseline for ECG 
data at each timepoint will be presented using boxplots.
The number and percentage of participants having notable ECG interval values on 
intervention will be summarised.
5.6.11
Echocardiogram
5.6.11.1
Presentations
Left ventricular ejection fraction results will be presented in listings.
5.6.12
Other Safety Assessments
5.6.12.1
Presentations
Serum immunoglobulins (IgA, IgM, IgG) will be listed and summarised descriptively. 
Absolute values and change from baseline values at each timepoint will be presented.
6
INTERIM ANALYSIS
There will be no interim analysis for Module 1.


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7
REFERENCES
Cheson et al 2014
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al.
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and 
non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068. 
doi: 10.1200/JCO.2013.54.8800. 
Vassilakopoulos et al 2020
Vassilakopoulos TP, Asimakopoulos JV, Konstantopoulos K, Angelopoulou MK. Optimizing 
outcomes in relapsed/refractory Hodgkin lymphoma: a review of current and forthcoming 
therapeutic strategies. Ther Adv Hematol. 2020;11:2040620720902911. doi: 
10.1177/2040620720902911.
Zain 2019
Zain JM. Aggressive T-cell lymphomas: 2019 updates on diagnosis, risk stratification, and 
management. Am J Hematol. 2019;94(8):929-946. doi: 10.1002/ajh.25513.


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8
APPENDICES
Appendix A Time windows for Module 1 – Efficacy assessments 
Timepoint
Tumour assessments
After 8 weeks a
49 – 63
After 17 weeks
112 – 126
After 26 weeks
175 – 189
a Participants who progress before the “After 8 weeks” timepoint should have had a tumour assessment 
performed at the time of progression. This tumour assessment will be used for the “After 8 weeks” timepoint.


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