A Modular Phase I/II, Open-label, Dose Escalation and Expansion, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Patients With Advanced Non-Hodgkin Lymphoma.
Phase: PHASE1
Conditions: Non-Hodgkin Lymphoma
Sponsor: AstraZeneca

Title: A Modular Phase I/II, Open-label, Dose Escalation and Expansion, Multicentre Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of AZD0466 as Monotherapy or in 
Combination with Anticancer Agents in Patients with Advanced Non-Hodgkin Lymphoma 
 
Sponsor Study Code: D8242C00001 
 
NCT Number: NCT05205161 
 
Date: 01 November 2021 

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Clinical Study Protocol 
Study Intervention
AZD0466
Study Code
D8242C00001
Version
2.0
Date
01 November 2021
A Modular Phase I/II, Open-label, Dose Escalation and 
Expansion, Multicentre Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Efficacy of AZD0466 as 
Monotherapy or in Combination with Anticancer Agents in 
Patients with Advanced Non-Hodgkin Lymphoma
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151 85 Södertälje, Sweden
Regulatory Agency Identifier Numbers: 
IND 142050
EudraCT 2021-003410-39
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: D8242C00001
Amendment Number: 1
Study Intervention: AZD0466
Study Phase: I/II
Short Title: A Phase I/II Study of AZD0466 as Monotherapy or in Combination with 
Anticancer Agents in Advanced Non-Hodgkin Lymphoma
Study Physician Name and Contact Information will be provided separately

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
01 November 2021
Original Protocol
21 July 2021
Amendment 1, Dated 01 November 2021
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The protocol was amended to include FDA recommendations. In addition to the updates based 
on FDA feedback the protocol was also amended to clarify inconsistencies throughout the 
protocol.
Section #
and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.2
Schema
Figure 1 Overall Study Schema 
was updated to correct the number 
of patients in Cohort B2 R/R 
FL/MZL.
Clarification (typographical 
error correction).
Non-substantial
Section 4.5
Criteria for Stopping 
or Pausing the Study 
Recruitment
A new section 'Section 4.5 Criteria 
for Stopping or Pausing the Study 
Recruitment' was added to the 
protocol.
This section has been added 
to include a rule-based, 
study-wide stopping criteria, 
for guidance on when this 
study may stop or pause 
enrolment.
Substantial
Section 5.1
Inclusion Criteria
Inclusion criterion no 6 was
updated to clarify at least one 
measurable FDG-PET avid lesion 
(except for MZL).
Updated for clarity since 
MZL patients have variable 
FDG-PET avidity, this 
criterion may not be 
applicable. Therefore, for 
MZL patients with 
FDG-PET non-avid lesion a 
CT scan is required.
Substantial

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Section #
and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 6.6.6.1
Dose Modifications
The section was updated to clarify 
that dose frequency changes are 
not possible during ramp-up.
Updated to clarify that dose 
frequency changes can only 
occur at the target dose.
Non-substantial
The section was updated to clarify 
permitted dose modifications (dose 
reduction and frequency change) 
and to clarify that a single event of 
CTCAE Grade 3 or 4 haemorrhage 
and any intracranial haemorrhage 
or haematoma, will result in 
discontinuation of study 
intervention.
To specify how many 
recurrences of a particular 
toxicity are permitted before 
the study intervention should 
be discontinued.
Substantial
Table 6 Dose Frequency Changes 
was updated for clarity.
Clarification.
Non-substantial
Section 6.6.6.2
Dose Modifications 
Based on 
Haematologic 
Parameters
The section was updated to clarify 
the requirements for patients prior 
to each cycle. 
Clarification.
Non-substantial
Table 8 Recommended Dose 
Modifications for Haematologic 
Toxicities, was updated to specify 
the actions to be taken with regard 
to dose modification in the event of 
haematologic toxicities, and to 
include the number of recurrences 
of a particular toxicity that are 
permitted before the study 
intervention will be discontinued. 
To specify how many 
recurrences of a particular 
toxicity are permitted before 
the study intervention should 
be discontinued.
To specify to the investigator 
which action (eg, dose 
modification, study 
intervention discontinuation) 
should be taken in the event 
of a specific toxicity.
Substantial
Section 6.6.6.3
Dose Modifications 
Based on 
Non-haematologic 
Parameters
Table 9 Dose Modifications for 
Non-haematologic Toxicities, was 
updated to specify the actions to be 
taken with regards to dose 
modification in the event of 
non-haematologic toxicities, and to 
include the number of recurrences 
of a particular toxicity are 
permitted before the study 
intervention will be discontinued.
To specify how many 
recurrences of a particular 
toxicity are permitted before 
the study intervention should 
be discontinued.
To specify to the investigator 
which action (eg, dose 
modification, study 
intervention discontinuation) 
should be taken in the event 
of a specific toxicity.
Substantial

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Section #
and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 10.1.3
Schedule of 
Activities
Table 13 Schedule of Activities for 
Module 1 Part A and Part B: 
Screening and Cycle 1, was 
updated to include details on 
prophylaxis for Tumour Lysis 
Syndrome.
Clarification regarding the 
management of TLS 
prophylaxis.
Non-substantial
Table 13 Schedule of Activities for 
Module 1 Part A and Part B: 
Screening and Cycle 1, was 
updated to include a footnote to 
clarify that MZL patients with 
FDG-PET non-avid lesion, only 
require a CT scan.
Updated for clarity since 
MZL has variable PET 
avidity, this criterion is not 
applicable.
Substantial
Table 13 Schedule of Activities for 
Module 1 Part A and Part B: 
Screening and Cycle 1, was 
updated to include B-symptoms 
collection at Screening and every 
tumour assessment scan.
Clarification.
Non-substantial
Table 13 Schedule of Activities for 
Module 1 Part A and Part B: 
Screening and Cycle 1, was 
updated to include a footnote to 
clarify that troponin T may be 
collected using a standard assay 
instead of troponin I, provided the 
results remain within normal 
range; However, if an abnormal 
troponin T value is recorded, 
collection of troponin I will be 
required thereafter.
Clarification.
Non-substantial
Section 10.1.3
Schedule of 
Activities
Table 14 Schedule of Activities for 
Module 1 Part A and Part B: Cycle 
2 and Beyond and Follow-up, was 
updated to clarify that safety ECGs 
will be done on Day 1 of every 
even cycle from Cycle 4.
Clarification (typographical 
error correction).
Non-substantial
Table 14 Schedule of Activities for 
Module 1 Part A and Part B: Cycle 
2 and Beyond and Follow-up, was 
updated to include details on 
prophylaxis for Tumour Lysis 
Syndrome.
Clarification regarding the 
management of TLS 
prophylaxis.
Non-substantial

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Section #
and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Table 14 Schedule of Activities for 
Module 1 Part A and Part B: Cycle 
2 and Beyond and Follow-up, was 
updated to include B-symptoms 
collection at Screening and every 
tumour assessment scan.
Clarification.
Non-substantial
Table 14 Schedule of Activities for 
Module 1 Part A and Part B: Cycle 
2 and Beyond and Follow-up, was 
updated to include a footnote to 
clarify that troponin T may be 
collected using a standard assay 
instead of troponin I, provided the 
results remain within normal 
range; However, if an abnormal 
troponin T value is recorded, 
collection of troponin I will be 
required thereafter.
Section 10.5.1.2
Additional Inclusion 
Criteria for Cohort 
B2 (R/R FL or 
MZL)
Inclusion criterion no 1 was 
updated to clarify that patients 
must have a histologically 
confirmed diagnosis of FL Grade 
1, 2, or 3a OR histologically 
confirmed MZL including splenic, 
nodal, and extranodal subtypes, as 
assessed by Investigator or local 
pathologist with documented 
active disease requiring systemic 
treatment.
For patients with indolent 
lymphomas, they must meet 
criteria requiring systemic 
treatment.
Substantial
Section 10.5.1.3
Additional Inclusion 
Criteria for Cohort 
B3 (R/R DLBCL)
Inclusion criterion no 1 was 
updated to clarify that patients 
must have histologically confirmed 
DLBCL (including transformed 
FL) OR FL Grade 3b.
Clarify that Cohort B3 (R/R 
DLBCL) will include 
patients with transformed 
FL.
Substantial
Section 10.5.2.1
Additional 
Exclusion Criteria 
for Part A
Section 10.5.2.1 Additional 
Exclusion Criteria for Part A was 
removed.
The section was removed 
since the addition of 
exclusion criterion no 2 in 
'Section 5.2 Exclusion 
Criteria' made the text 
redundant.
Non-substantial

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Section #
and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 10.8.6.5
Whole Blood for 
Circulating 
Free/Circulating 
Tumour DNA 
Analysis (Part A and 
Part B)
Table 20 Whole Blood for 
 (Part A and 
Part B), was updated to change the 
layout of the table to ensure 
consistency with the rest of the 
tables.
Consistency and clarity.
Non-substantial
Appendix F
Management of 
Specific Adverse 
Events
Table F27 Risk Assessment for 
Tumour Lysis Syndrome, was 
updated for clarity.
Clarification.
Non-substantial
Appendix M
Disease Prognostic 
Scores
Appendix M Disease Prognostic 
Scores was added to the protocol.
Clarity, provide reference for 
all investigators.
Non-substantial
Throughout Protocol
Minor typographical, and editorial 
changes were made throughout the 
clinical study protocol.
Clarity and consistency
Non-substantial
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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS .................................................................................................... 11
1
PROTOCOL SUMMARY – CORE .................................................................. 19
1.1
Synopsis ........................................................................................................... 19
1.2
Schema............................................................................................................. 22
1.3
Schedule of Activities ....................................................................................... 24
2
INTRODUCTION – CORE.............................................................................. 25
2.1
Study Rationale ................................................................................................ 25
2.2
Background ...................................................................................................... 25
2.2.1
Disease Background ......................................................................................... 25
2.2.2
AZD0466.......................................................................................................... 26
2.3
Benefit/Risk Assessment................................................................................... 27
2.3.1
Risk Assessment ............................................................................................... 28
2.3.2
Benefit Assessment........................................................................................... 29
2.3.3
Overall Benefit/Risk Conclusion....................................................................... 29
3
OBJECTIVES AND ENDPOINTS – CORE..................................................... 30
4
STUDY DESIGN – CORE ............................................................................... 32
4.1
Overall Design.................................................................................................. 32
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 32
4.1.2
Modular Protocol Structure............................................................................... 33
4.1.3
Module Naming Conventions ........................................................................... 33
4.1.4
Regulatory Amendment for Additional Modules ............................................... 33
4.1.4.1
Europe and Rest of World ................................................................................. 34
4.1.4.2
United States of America .................................................................................. 34
4.2
Scientific Rationale for Study Design ............................................................... 34
4.3
Justification for Dose........................................................................................ 35
4.4
End of Study Definition.................................................................................... 35
4.5
Criteria for Stopping or Pausing the Study Recruitment .................................... 35
5
STUDY POPULATION – CORE...................................................................... 37
5.1
Inclusion Criteria .............................................................................................. 37
5.2
Exclusion Criteria ............................................................................................. 39
5.3
Lifestyle Considerations ................................................................................... 43
5.3.1
Meals and Dietary Restrictions ......................................................................... 43
5.3.2
Caffeine, Alcohol, and Tobacco......................................................................... 43
5.4
Screen Failures ................................................................................................. 43
6
STUDY INTERVENTION – CORE ................................................................. 44

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6.1
Study Intervention(s) Administered................................................................... 44
6.2
Preparation/Handling/Storage/Accountability ................................................... 45
6.2.1
AZD0466 Preparation and Administration ........................................................ 45
6.2.2
Storage ............................................................................................................. 45
6.2.3
Accountability .................................................................................................. 45
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 46
6.3.1
Methods for Assigning Treatment Groups......................................................... 46
6.4
Study Intervention Compliance......................................................................... 46
6.4.1
Treatment Compliance for AZD0466 ................................................................ 46
6.5
Concomitant Therapy........................................................................................ 47
6.5.1
Permitted Concomitant Medications and Treatments......................................... 47
6.5.2
Prohibited Concomitant Medications and Treatments........................................ 48
6.6
Dose Modification and Toxicity Management................................................... 50
6.6.1
Starting Dose, Dose Escalation Scheme and Stopping Criteria .......................... 50
6.6.2
Dose Expansion................................................................................................ 50
6.6.3
Definition of DLT ............................................................................................. 50
6.6.4
Definition of Maximum Tolerated Dose............................................................ 50
6.6.5
Definition of DLT Evaluable Patient ................................................................. 50
6.6.6
Dose Escalation Committee .............................................................................. 50
6.6.6.1
Dose Modifications........................................................................................... 50
6.6.6.2
Dose Modifications Based on Haematologic Parameters................................... 51
6.6.6.3
Dose Modifications Based on Non-haematologic Parameters............................ 53
6.6.6.4
Dose Modifications for Hepatotoxicity ............................................................. 55
6.6.6.5
Cardiac Findings............................................................................................... 58
6.6.6.6
Infusion Site Reactions ..................................................................................... 58
6.6.6.7
Progressive Disease .......................................................................................... 59
6.6.7
Resumption of Treatment.................................................................................. 59
6.7
Intervention After the End of the Study............................................................. 59
7
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL – CORE............................................. 60
7.1
Discontinuation of Study Intervention............................................................... 60
7.1.1
Procedures for Discontinuation of Study Intervention ....................................... 61
7.2
Patient Withdrawal from the Study.................................................................... 61
7.2.1
Procedures for Withdrawal from Study ............................................................. 62
7.3
Lost to Follow-up ............................................................................................. 62
8
STUDY ASSESSMENTS AND PROCEDURES – CORE................................ 64
8.1
Efficacy Assessments........................................................................................ 65
8.1.1
Bone Marrow Assessments ............................................................................... 66
8.1.2
Imaging Assessments........................................................................................ 66
8.1.3
Disease Response Assessment........................................................................... 68
8.1.3.1
Revised Lugano 2014 Classification for Non-Hodgkin Lymphomas.................. 68
8.1.4
Other Disease-specific Assessments.................................................................. 68
8.1.4.1
Endoscopy........................................................................................................ 68

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9.4.2
Efficacy Analyses ............................................................................................. 85
9.4.3
Safety ............................................................................................................... 87
9.4.3.1
Adverse Events................................................................................................. 87
9.4.3.2
Other Safety Analyses....................................................................................... 89
9.4.4
Pharmacokinetic Analyses ................................................................................ 89
9.5
Interim Analyses............................................................................................... 91
9.6
Data Monitoring Committee ............................................................................. 91
10
MODULE 1: AZD0466 MONOTHERAPY PART A (DOSE ESCALATION) 
AND PART B (DOSE EXPANSION) ............................................................... 92
10.1
Protocol Summary – Module 1.......................................................................... 92
10.1.1
Synopsis ........................................................................................................... 92
10.1.2
Schema............................................................................................................. 92
10.1.3
Schedule of Activities ....................................................................................... 93
10.2
Introduction – Module 1 ................................................................................. 101
10.3
Objectives and Endpoints – Module 1............................................................. 101
10.4
Study Design – Module 1................................................................................ 101
10.4.1
Overall Design................................................................................................ 101
10.4.2
Scientific Rationale for Study Design ............................................................. 101
10.4.3
Justification for Dose...................................................................................... 101
10.4.4
End of Study Definition.................................................................................. 102
10.5
Study Population – Module 1.......................................................................... 102
10.5.1
Inclusion Criteria ............................................................................................ 102
10.5.1.1
Additional Inclusion Criteria for Cohort B1 (R/R MCL) ................................. 102
10.5.1.2
Additional Inclusion Criteria for Cohort B2 (R/R FL or MZL)........................ 103
10.5.1.3
Additional Inclusion Criteria for Cohort B3 (R/R DLBCL)............................. 103
10.5.2
Exclusion Criteria ........................................................................................... 103
10.5.2.1
Additional Exclusion Criteria for Cohort B1 (R/R MCL) ................................ 103
10.5.2.2
Additional Exclusion Criteria for Cohort B2 (R/R FL or MZL)....................... 103
10.6
Study Intervention – Module 1........................................................................ 103
10.6.1
Study Intervention Administration .................................................................. 103
10.6.2
Preparation/Handling/Storage/Accountability ................................................. 103
10.6.3
Measures to Minimise Bias: Randomisation and Blinding............................... 104
10.6.3.1
Methods for Assigning Treatment Groups....................................................... 104
10.6.4
Study Intervention Compliance....................................................................... 104
10.6.5
Concomitant Therapy...................................................................................... 104
10.6.6
Dose Modification and Toxicity Management................................................. 104
10.6.6.1
Starting Dose, Dose Escalation Scheme and Stopping Criteria ........................ 104
10.6.6.2
Dose Expansion.............................................................................................. 107
10.6.6.3
Definition of DLT ........................................................................................... 107
10.6.6.4
Definition of Maximum Tolerated Dose.......................................................... 109
10.6.6.5
Definition of DLT Evaluable Patient ............................................................... 109
10.6.6.6
Dose Escalation Committee ............................................................................ 109
10.6.6.7
Dose Modifications......................................................................................... 110
10.6.6.8
Resumption of Treatment................................................................................ 110

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LIST OF FIGURES
Figure 1
Overall Study Schema ............................................................................. 23
Figure 2
Module 1 Schema .................................................................................... 93
Figure 3
Module 1 Part A Dose Escalation Schema ............................................. 105
LIST OF TABLES
Table 1
AZD0466 Risk Assessment ..................................................................... 28
Table 2
Objectives and Endpoints......................................................................... 30
Table 3
Criteria for Adequate Organ and Marrow Function .................................. 38
Table 4
Investigational Product: AZD0466........................................................... 44
Table 5
Permitted Concomitant Medications and Treatments................................ 47
Table 6
Dose Frequency Changes......................................................................... 51
Table 7
Dose Reduction Modifications................................................................. 51
Table 8
Recommended Dose Modifications for Haematologic Toxicities ............. 52
Table 9
Dose Modifications for Non-haematologic Toxicities .............................. 54
Table 10
Dose Modification for Hepatotoxicity in Patients with Normal Baseline 
Liver Function......................................................................................... 55
Table 11
Dose Modification for Hepatotoxicity in Patients with Abnormal 
Baseline Liver Function........................................................................... 56
Table 12
Laboratory Safety Variables..................................................................... 71
Table 13
Schedule of Activities for Module 1 Part A and Part B: Screening and 
Cycle 1 .................................................................................................... 94
Table 14
Schedule of Activities for Module 1 Part A and Part B: Cycle 2 and 
Beyond and Follow-up............................................................................. 98
Table 15
Decision Rules Based on mTPI-2 for Dose Escalation ........................... 106
Table 16
Module 1 Part A and Part B Safety ECG and Holter ECG Extraction..... 110
Table 17
Pharmacokinetic Timepoints.................................................................. 113
Table 18
114
Table 19
 
................................................................................................... 116
Table 20
....................... 116
Table 21
... 117
Table 22
...... 117
Table 23
......... 118
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Table 24
......... 118
Table 25
 
..................................................................................................... 119
Table 26
Module 1 Part A and Part B Analysis Populations.................................. 121
Table F27
Risk Assessment for Tumour Lysis Syndrome ....................................... 146
Table F28
Recommended Prophylaxis for Tumour Lysis Syndrome....................... 147
Table F29
AZD0466 Dose Modifications for Tumour Lysis Syndrome .................. 148
Table F30
Recommended Management of Electrolyte Abnormalities in Tumour 
Lysis Syndrome..................................................................................... 149
Table G31
Criteria for Laboratory and Clinical Tumour Lysis Syndrome................ 153
Table G32
Grading of Tumour Lysis Syndrome...................................................... 154
Table H33
Drugs with a Known Risk of Torsades de Pointes.................................. 155
Table I34
Highly Effective Methods of Contraception........................................... 156
Table K35
Response Assessment Criteria for Non-Hodgkin Lymphoma ................. 159
Table M36
FLIPI-1 Criteria..................................................................................... 165
Table M37
FLIPI-2 Criteria..................................................................................... 165
Table M38
Simplified MIPI..................................................................................... 166
Table M39
Risk Category According to the MIPI.................................................... 166
Table M40
International Prognostic Index ............................................................... 166
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 123
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 130
Appendix C
Handling of Human Biological Samples ................................................ 135
Appendix D
Optional Genomics Initiative Sample..................................................... 137
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 140
Appendix F
Management of Specific Adverse Events............................................... 146
Appendix G
Classification of Tumour Lysis Syndrome ............................................. 153
Appendix H
Drugs That Prolong QT Interval and/or Induce Torsades De Pointes...... 155
Appendix I
Contraception Guidance......................................................................... 156
Appendix J
New York Heart Association Functional Classification.......................... 157
Appendix K
Response Evaluation Criteria for Non-Hodgkin Lymphoma................... 158
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Appendix L
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 163
Appendix M
Disease Prognostic Scores ..................................................................... 165
Appendix N
Abbreviations ........................................................................................ 168

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1
PROTOCOL SUMMARY – CORE
1.1
Synopsis
Protocol Title:
A Modular Phase I/II, Open-label, Dose Escalation and Expansion, Multicentre Study to 
Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of AZD0466 as 
Monotherapy or in Combination with Anticancer Agents in Patients with Advanced 
Non-Hodgkin Lymphoma
Short Title: 
A Phase I/II Study of AZD0466 as Monotherapy or in Combination with Anticancer Agents in 
Advanced Non-Hodgkin Lymphoma
Rationale:
Non-Hodgkin lymphoma is a heterogeneous group of disorders involving malignant clonal 
proliferation of lymphoid cells in lymphoreticular sites. A subgroup of NHL is B-NHL, which 
includes indolent diseases such as FL and MZL that evolve slowly, with a median survival of 
8 to 10 years. In contrast, more aggressive B-NHL diseases such as DLBCL and MCL, if left 
untreated, have a median survival of 6 months. Despite different available treatment options, a 
subset of patients who receive current therapies relapse.
Overexpression of pro-survival proteins, like Bcl-2 and Bcl-xL have been associated with 
tumour initiation, progression, and resistance to various current therapies. Bcl-2 was first 
identified as an oncogene in a FL cell line with a t(14;18) translocation followed by MCL, 
DLBCL, and MZL. Similarly, Bcl-xL overexpression was reported in FL, DLBCL, and MCL. 
Importantly, recent studies demonstrated Bcl-2 and/or Bcl-xL overexpression in primary 
samples of patients with DLBCL, FL, or MCL to correlate with poor prognosis.
This study will investigate the safety, tolerability, PK, and efficacy of AZD0466, a dual 
Bcl-2/Bcl-xL inhibitor, in patients with advanced B-NHL who have failed prior therapy(ies), 
are not eligible for curative treatment options, and for whom there is no standard therapy 
available. 

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been determined, Part B may open to further explore the preliminary anticancer efficacy of 
AZD0466 monotherapy in patients with selectedlymphoid malignancies, including R/R MCL 
(CohortB1), R/R FL or MZL (Cohort B2), and R/R DLBCL (Cohort B3). 
An SRC (Appendix A5) will review emerging data from evaluable patients in each cohort in 
Module 1 to monitor safety data on an ongoing basis.
This protocol has a modular design with the potential for future treatment arms to be added, as 
described in Section4.1.4. 
Disclosure Statement: 
This is a non-randomised, open-label, dose escalation and expansion study. 
Number of Patients:
In Module 1 Part A, a minimum of patients will be enrolled in a dose cohort and evaluated 
through the DLT evaluation period of 28 days before a dose escalation/dose expansion/de-
escalation decision can be made (unless unacceptable toxicity is encountered prior to 
enrolment of  patients). The maximum number of patients at any given dose cohort will be 
capped at  patients.
In Module 1 Part B, up to 
 patients will be enrolled (
 patients for Cohort B1 and for 
Cohort B2, and 
 patients for Cohort B3).
Intervention Groups and Duration:
All patients will receive AZD0466. Treatment will continue for 2 years or until disease 
progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of 
consent, or other reasons to discontinue study intervention, whichever occurs first. For 
patients who are responding and do not experience unacceptable toxicities, continuation of 
treatment may be considered by the Investigator and Sponsor. 
Patients in Module 1 will receive AZD0466 monotherapy. Patients enrolled into subsequent 
modules incorporated via protocol amendment may receive AZD0466 in combination with 
other anticancer treatments.
Data Monitoring Committee:
This study will utilise an SRC, as described in AppendixA5.
Statistical Methods:
Refer to the relevant individual modules for statistical considerations in this study.
CCI
CCI
CCI
CCI
CCI
CCI

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1.2
Schema 
The overall study schema is shown in Figure 1. Refer to the relevant individual modules for 
additional design information.

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1.3
Schedule of Activities
Refer to the individual SoAs for each study module within the respective protocol section (eg, 
Section 10.1.3 for Module 1).

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2.3.2
Benefit Assessment
AZD0466 has dose-dependent in vivo antitumour activity as a single agent across a range of 
human tumour xenograft and patient-derived models, including haematological malignancies. 
Enhanced nonclinical activity has also been observed for AZD0466 in combination with many 
standard of care anticancer therapies. Refer to Section 4.1 and Appendix A of the AZD0466 
Investigator's Brochure for further details.
2.3.3
Overall Benefit/Risk Conclusion
A high unmet medical need remains for additional treatment options for patients with 
advanced B-NHL. AZD0466 has the potential to provide meaningful clinical benefit. 
Considering the measures taken to minimise risk to patients participating in this study, the 
benefit-risk assessment supports the proposed study.

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4.1.2
Modular Protocol Structure
The structure of the protocol will follow a modular design. Information common 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). 
Module-specific information including design and SoA can be found in subsequent sections.
4.1.3
Module Naming Conventions
Initially, the study will include one module (Module 1) to evaluate the safety, tolerability, PK, 
and preliminary efficacy of AZD0466 monotherapy. Module 1 will include 2 parts; Part A 
dose escalation and Part B dose expansion. Part A will enrol patients with R/R B-NHL and 
once the RP2D has been determined, Part B may open to patients with selected lymphoid 
malignancies, including R/R MCL (Cohort B1), R/R FL or MZL (Cohort B2), and 
R/R DLBCL (Cohort B3).
Module
Tumour type
Intervention
CSP section
Module 1
Advanced NHL
•
Part A dose escalation: R/R B-NHL
•
Part B dose expansion: R/R MCL,
R/R FL and MZL, and R/R DLBCL
AZD0466 
monotherapy
Section 10
4.1.4
Regulatory Amendment for Additional Modules
To support amendment of the CSP for additional modules, the Sponsor will provide a 
summary of all nonclinical and clinical data to support the proposed new combination and 
dosing schedule; this will include updating the following:

Study objectives

Background information providing rationale for the proposed patient population(s) and
the proposed treatment plan(s)

Study eligibility criteria

A detailed description of the proposed study intervention plans

A revised schedule of patient assessments

A summary of safety data from the completed or ongoing cohort(s)/modules(s) and the
proposed toxicity management plans for the proposed new combination

A description of any dose modifications and the data (clinical safety information, clinical
PK data, and 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

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
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
4.1.4.1
Europe and Rest of World
Prior to activating a new module, the Sponsor will provide a substantial amendment to the 
CSP for review and approval by regulatory authorities.
4.1.4.2
United States of America
The Sponsor will provide an amendment to the FDA 60 days in advance of planned enrolment 
into a new module for any combination involving a drug for which the RP2D has not been 
determined for the proposed dosage regimen to be employed, or at least 30 days in advance of 
a planned enrolment into a module for drugs where the RP2D has been determined for the 
proposed dosage regimen to be employed. 
4.2
Scientific Rationale for Study Design
This study will investigate AZD0466 as monotherapy or in combination with other anticancer 
therapies in patients with R/R B-NHL who have failed prior therapy(ies), are not eligible for 
curative treatment options, and for whom there is no standard therapy available. The study is 
modular in design; the core protocol will contain study information applicable to all patients 
in this study. Initially, one module will open (Module 1) and will evaluate the safety, 
tolerability, PK, and preliminary efficacy of AZD0466 as monotherapy. 
Module 1 will consist of Part A dose escalation and Part B dose expansion. Due to its 
mechanism of action, a potential risk of AZD0466 includes TLS (Davids et al 2017). 
Therefore, an intra-patient ramp-up will be incorporated in Part A dose escalation to mitigate 
against the risk of TLS in R/R B-NHL patients. During dose escalation, patients at high risk of 
TLS with high tumour burden and/or bulky disease (> 10 cm) will be excluded. Once a RP2D 
has been determined and with emerging patient data from Part A, Part B dose expansion may 
open to selected lymphoma patients. Part B will consist of 3 cohorts: Cohort B1 will enrol 
R/R MCL patients, Cohort B2 will enrol R/R FL and MZL patients, and Cohort B3 will enrol 
R/R DLBCL patients.
As the mechanism of action of AZD0466 and in vivo data suggest that combining AZD0466 
with other anticancer treatments may result in enhanced activity, it is anticipated that the study 
may evolve to incorporate additional modules to allow further evaluation of AZD0466 in 
combination with anticancer agents.
Refer to the relevant individual modules for details.

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4.3
Justification for Dose
Refer to the relevant individual modules for information on dose justification.
4.4
End of Study Definition
The end of the study is defined as the date of the last visit of the last patient in the study or last 
scheduled procedure shown in the SoA for the last patient in the study globally.
The end of module is defined as the last scheduled visit or contact of the last patient enrolled 
in the module.
Details of planned data analyses are provided in each of the study modules. The results from 
each module will be reported to regulatory authorities within 1 year of the end of each 
module. 
A patient is considered to have completed the study if he/she has completed all phases of a 
study module including last visit or the last scheduled procedure shown in the SoA including 
follow-up for OS.
Patients who continue to demonstrate clinical benefit after a 2-year treatment period will be 
eligible to receive AZD0466 via a roll-over study requiring approval by the responsible health 
authority and ethics committee or through another mechanism at the discretion of the Sponsor.
Patients may be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgement of AstraZeneca, study patients are placed at undue risk because of 
clinically significant findings. The study may be terminated at individual centres if the study 
procedures are not being performed according to ICH GCP or if the recruitment rate does not 
allow for completion of the study in the planned timeframe.
4.5
Criteria for Stopping or Pausing the Study Recruitment
AstraZeneca reserves the right to pause recruitment, temporarily suspend or permanently 
terminate this study or components of the study at any time. AstraZeneca may at any point 
during the study, pause enrolment if at least one of the following occurs:

Fatal event deemed related to study intervention by the Sponsor and in discussion with
the SRC (probable or certain causality based on World Health Organization-The Uppsala
Monitoring Centre [WHO-UMC] after full etiological work-up). This will also result in a
comprehensive review of safety.

Unexpected and life-threatening events deemed related to study intervention by the
Sponsor and in discussion with the SRC. Note: As thrombocytopenia is an on-target
effect it will be further addressed at the time of the SRC (Part A) or the safety interim
analysis (Part B) and will not be considered as stopping criteria.

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Table 3
Criteria for Adequate Organ and Marrow Function
Parameter
Criteria
Haematologic
Haemoglobin
≥ 8.0 g/dL (5.59 mmol/L) with no whole blood transfusions 
within 14 days prior first dose of AZD0466
Platelet count
≥ 75 × 109/L (≥ 100 × 109/L for Module 1 Part A) with no 
platelet transfusions within 7 days prior to first dose of AZD0466
ANC
≥ 1.0 × 109/L. The use of growth factors is not permitted within 
14 days prior to first dose of AZD0466 (long-acting pegylated 
growth factors are not permitted during study intervention). 
Coagulation
INR
< 1.5 × ULN
Hepatic
Total bilirubin
≤ 1.5 × ULN (or ≤ 3.0 × ULN in presence of Gilbert’s syndrome)
≤ 3 × ULN if the patient has Gilbert’s syndrome
ALT and AST
≤ 2.5 × ULN
Pancreatic
Lipase and amylase
≤ 1.5 × ULN and absence of clinical pancreatitis
Renal
Serum creatinine
OR
Calculated creatinine 
clearance
≤ 1.5 × ULN
≥ 50 mL/min by the Cockcroft-Gault equation (Cockcroft and 
Gault 1976) or the estimated glomerular filtration rate 
≥50 mL/min/1.73 m2 using the MDRD formula
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; INR= 
international normalised ratio; MDRD = Modification of Diet in Renal Disease; ULN = upper limit of normal.
9
Adequate cardiac function as demonstrated by left ventricular ejection fraction > 50% on 
screening cardiac multigated acquisition, magnetic resonance imaging, or 
echocardiogram.
Reproduction
10 Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
(a) Female patients:
o
Female patients of childbearing potential must be willing to use 2 forms of highly 
reliable methods of contraception (Appendix I) from the time of screening 
until 6 months after the last dose of study intervention or patients must have 
evidence of an inability to bear children by fulfilling 1 of the following criteria at 
screening:

Postmenopausal, defined as aged > 50 years and amenorrhoeic for at least 
12 months following cessation of all exogenous hormonal treatments.

Documentation of irreversible surgical sterilisation by hysterectomy, 
bilateral oophorectomy, or bilateral salpingectomy, but not tubal ligation.

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o
Female patients must not be lactating, breastfeeding, and must have a negative
pregnancy test (serum) prior to start of dosing.
(b) Male patients:
o
Male patients must be willing to use barrier contraception (ie, condoms) and
refrain from sperm donation from the time of screening until 6 months after the
last dose of study intervention. If not done previously, storage of sperm before
receiving AZD0466 will be advised to male patients with a desire to have
children.
Other
11 Willing and able to participate in all required study evaluations and procedures including 
receiving IV administration of study intervention and admission to the hospital, when 
required, for administration of study intervention and/or monitoring.
12 All patients must be willing to undergo an incisional or excisional lymph node or tissue 
biopsy or to provide a lymph node or tissue biopsy from the most recent available 
archival tissue.
13 For inclusion in the optional genetic component of the study, patients must fulfil the 
following additional criteria:

Provision of signed, written, and dated informed consent for genetic research. If a
patient declines to participate in the genetic component of the study, there will be no
penalty or loss of benefit to the patient. The patient will not be excluded from other
aspects of the study described in this protocol, as long as they consented to the main
study.
5.2
Exclusion Criteria 
Patients are excluded from the study if any of the core criteria below and any criteria from the 
relevant individual modules apply.
Medical Conditions
1
Diagnosis of post-transplant lymphoproliferative disease, Richter’s transformation, 
Burkitt's lymphoma, Burkitt-like lymphoma, lymphoblastic lymphoma/leukaemia, 
chronic lymphocytic leukaemia, small lymphocytic lymphoma. 
2
High risk of TLS according to Howard modification of Cairo-Bishop criteria and/or the 
presence of bulky disease (defined as any lesion ≥ 10 cm on the screening CT scan).
3
Unresolved toxicity from prior anticancer therapy of CTCAE Grade ≥2. Patients with 
Grade 2 neuropathy or Grade 2 alopecia are eligible.
4
Active idiopathic thrombocytopenic purpura.

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5
Active CNS involvement by lymphoma, leptomeningeal disease, or spinal cord 
compression. Patients with a prior history of CNS localisation of lymphoma who received 
treatment are eligible provided that there is no evidence of CNS involvement at study 
entry as documented by cerebrospinal fluid cytology and/or brain MRI.
6
Known history of infection with human immunodeficiency virus.
7
Known serologic status reflecting active hepatitis B or C infection.

Patients who are anti-HBc antibody 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.

Patients who are hepatitis C antibody positive will need to have a negative PCR
result before enrolment. Those who are hepatitis C PCR positive will be excluded.
8
Known concurrent infection with CMV.
9
Patients must be tested for SARS-CoV-2 and those with active infection detected using 
either molecular or antigen tests in accordance with local testing guidelines will be 
excluded. Please note: Fully recovered patients (defined as no ongoing COVID-19 
symptoms, except loss of sense of smell/taste) who present persistence of positive PCR 
test with a negative antigen test and the presence of IgG antibodies, may be included in 
the study.
10 As judged by the Investigator:

Any evidence of severe or uncontrolled systemic diseases, (eg, severe hepatic
impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease]).

Current unstable or uncompensated respiratory or cardiac conditions.

Uncontrolled hypertension.

History of, or active, bleeding diatheses (eg, haemophilia or von Willebrand disease).

Uncontrolled active systemic fungal, bacterial, or other infection (defined as
exhibiting ongoing signs/symptoms related to the infection and without
improvement, despite appropriate antibiotics or other treatment).
11 Any of the following cardiac criteria at screening:

Patients with a history of myocarditis within one year of study entry, or heart failure 
New York Heart Association Functional Classification Class 3 or 4 (Appendix J).

Mean resting corrected QT interval (QTcF) ≥ 470 msec obtained from 3 ECGs, in the 
absence of a cardiac pacemaker.

Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as congenital long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age.

Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG (eg, complete left bundle branch block, third-degree heart block,

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intermittent or persistent bundle branch block, atrioventricular block II to III, or 
clinically significant sinus pause).
12 History of another life-threatening malignancy ≤2 years prior to first dose of study 
intervention. The following are permitted:

Malignancy treated with curative intent and with no evidence of active disease
present for more than 2 years before screening and considered to be at low risk of
recurrence by the treating physician.

Adequately treated lentigo malignant melanoma without current evidence of disease
or adequately controlled non-melanomatous skin cancer.

Adequately treated carcinoma in situ without current evidence of disease.
13 Any of the following procedures or any of the following conditions currently or in the 
6 months prior to the first dose of study intervention:

Coronary artery bypass graft

Angioplasty

Vascular stent

Myocardial infarction

Angina pectoris

Haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any
other CNS bleeding
Prior/Concomitant Therapy
14 Treatment with any of the following: 

Radiotherapy less than 2 weeks prior to the first dose of study intervention. Radiation 
therapy for palliative care to focal sites is allowed.

Any investigational agents or study drugs from a previous clinical study within
≤ 14 days or 5 half-lives (whichever is shorter) prior to the first dose of study 
intervention, with the exception of strong CYP3A inducers or inhibitors as outlined in 
Section 6.5.2. Treatment with high-dose steroids for primary malignancy control is 
permitted, but must be discontinued at least 2 days prior to the first dose of study 
intervention.

Any other chemotherapy, immunotherapy, immunosuppressant medication (other 
than corticosteroids) or anticancer agents within 21 days of the first dose of study 
intervention. A longer washout may be required for drugs with a long half-life (eg, 
biologics) as agreed by the Sponsor.

Prior allogenic HSCT within 6 months from the first dose of study intervention
(patients > 6 months after allogenic HSCT are eligible in the absence of active graft-

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20 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Patients should refrain from consumption of Seville oranges, grapefruit or grapefruit juice, 
pomelos, exotic citrus fruits, grapefruit hybrids from 14 days before the first dose of study 
intervention until 14 days after the last dose of study intervention. 
5.3.2
Caffeine, Alcohol, and Tobacco
Patients should refrain from consumption of red wine, which has components (such as, 
resveratrol) that have been reported to inhibit CYP3A4. There are no caffeine or tobacco 
restrictions.
5.4
Screen Failures
Screen failures are defined as patients who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Only one time of rescreening is allowed in the study. Rescreened patients should 
be assigned the same patient number as for the initial screening. However, rescreening should 
be documented so that its effect on study results, if any, can be assessed. Unused samples will 
be destroyed. 

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6.2
Preparation/Handling/Storage/Accountability 
Only patients enrolled in the study may receive study intervention and only authorised site 
staff may supply or administer study intervention. All study interventions 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.
6.2.1
AZD0466 Preparation and Administration
‘AZD0466 Powder for Concentrate for Solution for Infusion’ and ‘Solvent for AZD0466 
Powder for Concentrate for Solution for Infusion’ should be prepared and administered 
according to the handling instructions available at the study centres.
Preparation of the dosing solutions must occur under aseptic conditions. Preparation and 
dosing of AZD0466 should not occur at temperatures exceeding 25°C (refer to handling 
instructions for allowable excursions). Administration, including 1-hour (+10 minutes) 
infusion time, must be completed within 3 hours of initial reconstitution (ie, addition of 
custom solvent to the powder).
AZD0466 doses must be administered at least 72 hours apart.
The in-use stability period is limited due to the stability of the reconstituted material. Close 
dialogue between the pharmacy and research staff will be required to ensure that the material 
is administered as quickly as possible following reconstitution, and within the in-use 
period/conditions stipulated.
6.2.2
Storage
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.
All study interventions should be kept in a secure place under appropriate storage conditions. 
Refer to the product label for specific storage conditions.
6.2.3
Accountability
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).
The study personnel at the investigational site will account for all drugs dispensed and for 
appropriate destruction of drugs to AstraZeneca. Unused drugs should be destroyed according 
to local guidelines, and the certificate of delivery destruction should be signed. Destruction 

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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.
Further guidance and information for the final disposition of unused study intervention is 
provided in the Pharmacy Manual.
6.3
Measures to Minimise Bias: Randomisation and Blinding
This is an open-label, non-randomised study; no blinding is required. If an unscheduled 
assessment is performed and the patient has not progressed, provided the assessment was 
performed within the visit window, subsequent assessments should be performed at the 
scheduled visits. This schedule is to be followed to minimise any unintentional bias caused by 
some patients being assessed at a different frequency than others.
6.3.1
Methods for Assigning Treatment Groups
Refer to the relevant individual modules for details regarding treatment group assignment.
When the study intervention is provided centrally by AstraZeneca, the IRT will provide the kit 
identification number to be allocated to the patient at the treatment allocation visit and 
subsequent treatment visits.
6.4
Study Intervention Compliance
When patients are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date, and time, 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 patient identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention.
Any changes from the dosing schedule, dose reductions and dose discontinuations should be 
recorded in the eCRF. The reason should also be documented.
Use of doses in excess of that specified in the protocol is considered to be an overdose. 
Overdose procedures to be followed in the event of overdose are described in Section 8.4.
6.4.1 
Treatment Compliance for AZD0466
AZD0466 is administered by IV infusion and patients will receive AZD0466 directly from the 
Investigator or designee, under medical supervision. The date and time of dose administration 
will be recorded in the source documents and in the eCRF. 

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Table 5
Permitted Concomitant Medications and Treatments
Supportive medication/drug class
Usage
G-CSF or GM-CSF
Primary or secondary prophylactic use of G-CSFs 
may be used to treat emergent neutropenia as 
indicated by the current ASCO guideline and 
according to Investigator’s clinical judgement. The 
use of long-acting pegylated G-CSF (eg, 
pegfilgrastim) is not permitted during study 
intervention.
RANKL inhibitors and/or bisphosphonates
Permitted for the treatment of osteopenia, as 
recommended according to practice guidelines
Allopurinol
Mandatory for TLS prophylaxis, with dosing and 
schedule as per institutional guidelines
Rasburicase
Should be considered based on Appendix F and 
institutional guidelines
Diuretics
•
Use with care
•
Prophylactic use should be considered only if
patients have signs of volume overload
Acetaminophen (paracetamol)
Restricted to 3 grams per day or the maximum dose 
approved locally (if < 3 g/day) during the study
Inactivated vaccines or protein/RNA immunogen 
vaccines
Permitted. Note: Use of live attenuated vaccines (eg, 
influenza vaccine delivered as nasal spray) is 
prohibited
Implanted pacemaker (at study entry)
Patient is eligible at Investigator’s discretion
ASCO = American Society of Clinical Oncology; CNS = central nervous system; G-CSF = granulocyte 
colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; RANKL = receptor 
activator of nuclear factor kappa-B ligand; TLS = tumour lysis syndrome.
6.5.2
Prohibited Concomitant Medications and Treatments
AZD0466 is an investigational drug for which no data on in vivo interactions are currently 
available. In vitro data have shown that the principal CYP enzyme responsible for the Phase I 
metabolism of AZD0466 is CYP3A4. In addition, in vitro data suggest AZD0466 has the 
potential to cause drug interactions through inhibition of CYP2B6, CYP2C8, CYP2C9, 
CYP2D6, OATP1B1, OATP1B3, OAT3, OCT2, and BCRP. 

Besides those specified in individual modules, other anticancer agents, investigational
agents, and radiotherapy should not be given while the patient is receiving study
intervention. Radiation therapy for palliative care to focal sites is allowed.

Due to potential drug-drug interactions, the following medications should not be
administered while the patient is receiving AZD0466, and in the 14 days after the
completion of study intervention. In addition, each type of the medications below should
not be given within the specified time prior to starting AZD0466 treatment. For a

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comprehensive list of clinical inhibitors, inducers, and substrates, refer to the FDA 
website (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-
drug-interactions-table-substrates-inhibitors-and-inducers) or contact the AstraZeneca 
Study Team.
5 half-lives of each medication plus 12 days for the medications below:
Strong inducers of CYP3A
Apalutamide, avasimibe, carbamazepine, enzalutamide, lumacaftor, 
mitotane, phenytoin, rifabutin, rifampin, rifapentine, St. John’s wort, and 
ivosidenib
Moderate inducers of CYP3A
Bosentan, dabrafenib, efavirenz, etravirine, genistein, lersivirine, lesinurad, 
lopinavir, modafinil, nafcillin, phenobarbital, primidone, ritonavir, 
semagacestat, talviraline, telotristat ethyl, thioridazine, tipranavir, enasidenib, 
and midostaurin
Mechanism-based strong 
inhibitors of CYP3A
Boceprevir, cobicistat, conivaptan, ritonavir, grapefruit juice, itraconazole, 
ketoconazole, lopinavir, saquinavir, telaprevir, troleandomycin, 
clarithromycin, diltiazem, idelalisib, nefazodone, nelfinavir, montelukast, 
pioglitazone, rosiglitazone, phenytoin, mibefradil, ribociclib, telithromycin, 
and midostaurin
Mechanism-based moderate 
inhibitors of CYP3A
Amprenavir, conivaptan, crizotinib, cyclosporine, erythromycin, imatinib, 
letermovir, nilotinib, tofisopam, and verapamil
5 half-lives of each medication for the following medications:
Reversible strong inhibitors 
of CYP3A
Danoprevir, elvitegravir, indinavir, paritaprevir (ombitasvir and/or 
dasabuvir), posaconazole, tipranavir, and voriconazole
Reversible moderate 
inhibitors of CYP3A
Aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, darunavir, 
dronedarone, faldaprevir, fluconazole, fluvoxamine, isavuconazole, Magnolia 
vine (Schisandra sphenanthera), and netupitant
Substrates of CYP2B6
Bupropion.
Substrates of CYP2C8
Repaglinide
Substrates of CYP2C9
Celecoxib, glimepiride, tolbutamide, and warfarin
Substrates of CYP2D6
Atomoxetine, desipramine, dextromethorphan, eliglustat, nebivolol, 
nortriptyline, perphenazine, tolterodine, venlafaxine, amitriptyline, encainide, 
imipramine, metoprolol, propafenone, propranolol, tramadol, and 
trimipramine.
Substrates of OATP1B1 and 
OATP1B3
Asunaprevir, atorvastatin, bosentan, cerivastatin, danoprevir, docetaxel, 
fexofenadine, glyburide, nateglinide, paclitaxel, pitavastatin, pravastatin, 
repaglinide, rosuvastatin, and simvastatin acid.
Substrates of OAT3
Adefovir, cefaclor, ceftizoxime, famotidine, furosemide, ganciclovir, 
methotrexate, oseltamivir carboxylate, and penicillin G.
Substrates of OCT2
Dofetilide and metformin
Substrates of BCPR
Rosuvastatin and sulfasalazine

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Table 6
Dose Frequency Changes
Table 7
Dose Reduction Modifications
6.6.6.2
Dose Modifications Based on Haematologic Parameters
If a patient experiences a clinically significant and/or unacceptable haematologic toxicity 
(including a DLT) considered by the Investigator to be related to study intervention and not 
attributable to the disease (or to disease-related processes) under investigation, dosing in 
subsequent cycles will be withheld and may subsequently be restarted at one lower dose 
(equivalent to one dose reduction) and supportive therapy (AppendixF) administered as 
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Table 11
Dose Modification for Hepatotoxicity in Patients with Abnormal
Baseline Liver Function
Event
Occurrence
Action with AZD0466
ALT and/or AST ≥ 3 × 
baseline with 
concomitant elevation in 
bilirubin ≥ 2 × baseline
Any 
occurrence
•
Discontinue AZD0466, refer to Appendix E for process to
follow in order to identify and appropriately report episodes
of potential Hy’s Law
ALT and/or AST > 20 × 
ULN
Any 
occurrence
•
Discontinue AZD0466
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology 
Criteria for Adverse Events; ULN = upper limit of normal; Q2W = every 2 weeks.
6.6.6.5
Cardiac Findings
AZD0466 should be withheld if any of the following occur at any time during study 
intervention: 

Symptomatic tachycardia

Symptomatic hypotension

QTcF shortening by 60 milliseconds compared to baseline, or interval value
< 340 milliseconds, confirmed on at least 2 separate ECGs recorded 5 minutes apart

QTcF prolongation of > 500 milliseconds or QTcF prolongation from baseline by
60 milliseconds, confirmed on at least 2 separate ECGs recorded 5 minutes apart

Any other cardiac findings of CTCAE Grade ≥ 2 or considered by the Investigator to be
clinically significant.

AZD0466 should be permanently discontinued if a CTCAE Grade ≥ 3 cardiac AE of any
duration occurs during study intervention, if considered by the Investigator to be related
to study intervention.
Further investigation of the cardiac findings should be considered, including referral to a 
cardiac specialist. Patients should be monitored closely. AZD0466 may be restarted after 
resolution of cardiac findings to the patient’s baseline at the discretion of the Investigator and 
after discussion with the Study Physician.
6.6.6.6
Infusion Site Reactions
As with other drugs administered intravenously, local infusion site reactions (eg infusion pain, 
infusion site reaction, skin irritation, or vein irritation) may occur. For CTCAE Grade ≥2 
reactions, the infusion of AZD0466 should be stopped; if the patient recovers without issue, a 
full dose may be considered at the next scheduled infusion. For CTCAE Grade 1 or transient 
reactions with recovery within 15 minutes, AZD0466 infusion may be restarted if timings 
permit it to be completed within the 3-hour window of stability.

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
Should the patient continue to be unreachable, he/she will be considered to have
withdrawn from the study.

Site personnel, or an independent third party, will attempt to collect the vital status of the
patient within legal and ethical boundaries for all patients enrolled in the study, including
those who did not get study intervention. Public sources may be searched for vital status
information. If vital status is determined as deceased, this will be documented and the
patient will not be considered lost to follow-up. Sponsor personnel will not be involved in
any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.

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8
STUDY ASSESSMENTS AND PROCEDURES – CORE
The study assessments listed in this section apply to all modules. Safety assessments specific 
to each module will be listed in the respective sections. Study procedures and their timing are 
summarised in the SoA of each individual module. Protocol waivers or exemptions are not 
allowed.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
intervention.
Adherence to the study requirements, including those specified in the SoA for each module, is 
essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
Procedures conducted as part of the patient’s routine clinical management (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.
Enrolment and Screening
At enrolment, each potential patient will provide informed consent prior to starting any study-
specific procedures (see Appendix A 3). Screening will occur for up to 28 days from the date 
of enrolment. Every effort should be made to minimise the time between treatment assignment 
and dosing, preferably within 14 days. Patients who fail to meet the eligibility criteria will be 
recorded as a “screen failure”. Each potential patient is assigned a unique patient number. If a 
patient withdraws from the study, the patient number cannot be reused. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all core and module-specific eligibility criteria. The Investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable. The common screening forms will be considered 
as core protocol in the EDC system.
Procedures conducted as part of the patient’s routine clinical management (eg, blood count) 
and obtained before signing the ICF may be utilised for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
appropriate time frame relative to the first dose of study intervention, as defined in the SoA.

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8.1.1
Bone Marrow Assessments
For all patients, a baseline (before first dose of study intervention) bone marrow biopsy and/or 
aspirate is required at screening to assess bone marrow involvement by lymphoma. The 
baseline bone marrow aspirate/biopsy will be used to confirm disease status and profiling 
utilising technologies including, but not limited to, genomics, cytogenetics, transcriptomics, 
epigenomics, proteomics, and/or imaging. A portion of bone marrow sample may be used for 
assessing 
. 
Bone marrow biopsies/aspirates will be read at each site’s local laboratory and will be 
performed as clinically indicated while on study (ie, to confirm CR [if bone marrow was 
involved by lymphoma at baseline, within 14 days after the respective radiological 
assessment] and/or per standard of care). If bone marrow involvement before the start of the 
study was unknown, a bone marrow evaluation must be conducted to confirm a CR. 
Patients with a negative bone marrow aspirate/biopsy (ie, no lymphoma involvement) at 
screening, and patients with a PR, SD, or PD at any disease response assessment timepoint do 
not require a follow-up bone marrow aspirate/biopsy. Locally obtained results should be 
entered into the eCRF. 
 
Further details on sample processing, handling and shipment are provided in the Laboratory 
Manual.
8.1.2
Imaging Assessments
During the screening period, an FDG-PET scan covering the whole body from base of skull to 
mid-thigh will be performed to assess the measurability of disease and will serve as baseline 
(Day -28 to Day -1). Information on extranodal involvement will also be recorded.
Any imaging assessments performed as part of standard of care within 5 weeks of the ICF 
signature, may be considered as baseline assessments for the study, provided that no 
anticancer treatment has been administered between the date of the assessment and the start of 
study intervention (with the only exception of low-dose steroids given for symptom control) 
and in the absence of significant clinical worsening of the patient based on the Investigator’s 
opinion.
Subsequent radiological assessment, ie, CT scans with contrast (unless contraindicated)
covering neck, chest, abdomen, and pelvis and any other disease sites will be performed every 
8 weeks (± 7 days) until Week 24 (ie, Weeks 8, 16, and 24), every 12 weeks (± 7 days) until 
Week 48 (ie, Weeks 36 and 48), and thereafter every 16 weeks (± 7 days) for R/R DLBCL and 
R/R MCL, and every 24 weeks (± 7 days) for R/R FL and MZL.
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Positron emission tomography scans covering whole body from base of skull to mid-thigh (or 
PET/CT scans) are mandatory on Week 8 (± 7 days), Week 24 (± 7 days), and Week 48 
(± 7 days), and thereafter once a year to confirm CR or as clinically indicated. Newly 
documented CT-based CR should be confirmed by a negative PET scan within a window of 
14 days; patients with confirmed CR can be subsequently followed up with CT with IV 
contrast only. More frequent PET-CT scans can be performed when clinically indicated at the 
Investigator’s discretion.
Efficacy assessments will be performed until disease progression or relapse, start of a new 
anticancer therapy, death, lost to follow-up, or withdrawal of consent, following the schedule 
indicated in the SoA in the relevant individual modules. If clinically indicated, unscheduled 
imaging assessments can be performed at any timepoint during the study.
If a PET/CT is not available, an independent PET and a diagnostic-quality CT scan can be 
used. If PET and CT scans are done on the same day, the PET must be performed prior to the 
contrast-enhanced CT not to compromise the PET read-out. The CT portion of a PET/CT may 
be submitted in lieu of a dedicated CT; however, certain radiographic requirements are needed 
for acceptance, as described in the Site Radiology Manual, provided separately from this CSP.
Magnetic resonance imaging may be used for imaging assessments if a contrast CT scan is 
contraindicated or unobtainable (in cases where MRI is desirable, the MRI must be obtained at 
baseline and at all subsequent response evaluations).
Brain MRI or brain CT with contrast (if possible) will be performed at screening only if there 
is a prior history of CNS involvement or if there are neurologic signs or symptoms present 
and/or as clinically indicated during the study.
No anticancer treatment other than study intervention can be implemented between the earliest 
date of baseline scans or bone marrow assessment and the start of study intervention. Patients 
should have radiographic tumour measurements done at the participating study centre or an 
acceptable alternate imaging facility using an identical imaging protocol and similar 
equipment. The same imaging equipment should be used for all scans whenever possible. The 
same radiologist should be assigned to read all the scans for a given patient throughout the 
study.
Sites will be required to store electronic copies of all scans, and the Sponsor will arrange for 
centralised storage of all imaging data. All imaging assessments, including unscheduled visit 
scans, will be collected on an ongoing basis, and sent to the Sponsor or designee for storage.
The centralised storage of imaging data would be for possible independent centralised 
third-party blinded review of disease assessments. At the discretion of the Sponsor, an 
independent central review of all scans used in the assessment of tumours may be conducted. 

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8.2.4.1
Troponin I and Brain Natriuretic Peptide 
Blood samples for troponin I and BNP or NTproBNP measurements will be collected, as 
specified in the SoA within the relevant module and below:

Screening

Target dose pre-infusion (C1D8 – pre-infusion)

As clinically indicated

EoT visit
Troponin T may be collected using a standard assay instead of troponin I, provided the results 
remain within normal range. However, if an abnormal troponin T value is recorded, collection 
of troponin I will be required thereafter, as it is more cardiac-specific. Dosing with AZD0466 
must not occur until results are obtained and are normal. If an unscheduled ECG is performed, 
an electrolyte panel (ie, calcium, magnesium, potassium, and troponin I) must be done to 
coincide with the ECG assessment, including referral to a cardiac specialist. Isolated troponin 
elevations are not sufficient to trigger dosing changes and should be evaluated in the context 
of other cardiac findings.
8.2.5
Other Safety Assessments
8.2.5.1
Cardiac MUGA/MRI/ECHO
A cardiac MUGA/MRI/ECHO to assess LVEF will be conducted. The modality of the cardiac 
function assessments must be consistent within a patient ie, if ECHO is used for the screening 
assessment then ECHO should also be conducted at subsequent assessments. A 28-day 
follow-up assessment will be required if an on treatment assessment was abnormal at the time 
of discontinuation of study intervention, to confirm reversibility of the abnormality. The 
patients should also be examined using the same machine and operator whenever possible. 
Unscheduled assessments should be performed as clinically indicated, including after a 
clinically significant ECG finding (T wave inversion/flattening, significant QRS amplitude 
changes or symptomatic patient, etc). In case of any T wave abnormality, the ECHO, MRI, or 
MUGA should be repeated at the EoT visit to address the question of recovery during the 
off-treatment period. 
Cardiac MUGA/MRI/ECHO should be performed as specified in the SoA. 

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If the Investigator becomes aware of an SAE with a suspected causal relationship to study 
intervention that occurs after the end of the clinical study in a patient treated by him/her, the 
Investigator shall, without undue delay, report the SAE to the Sponsor.
8.3.2
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient
at subsequent visits/contacts. All SAEs and non-SAEs will be followed until resolution, 
stabilisation, the event is otherwise explained, or the patient is lost to follow-up.
Any AEs that are unresolved at the patient’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated 
(this may be beyond the 28 days after the last dose of study intervention), but without further 
recording in the eCRF. AstraZeneca retains the right to request additional information for any 
patient with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse Event Variables
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

CTCAE grade/changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the investigational product(s) (yes or no)

Action taken with regard to investigational product

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of SAE

AE is serious due to

Date of hospitalisation

Date of discharge

Causality assessment in relation to study procedure(s)

Causality assessment to other medication

Description of the SAE

Probable cause of death

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
Date of death

Autopsy performed
The grading scales found in the revised NCI CTCAE v5.0 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 v5.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov).
8.3.3
Causality Collection
The Investigator should assess causal relationship between each study intervention (AZD0466 
and combination treatment) and each AE, and answer ‘yes’ or ‘no’ to the question ‘Do you 
consider that there is a reasonable possibility that the event may have been caused by the 
study intervention?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to CSP.
8.3.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5
Adverse Events Based on Examinations and Tests
The results from the CSP mandated laboratory tests, vital signs, and ECGs will be summarised 
in the CSR.
Deterioration as compared to baseline in protocol-mandated laboratory values or vital signs 
should therefore only be reported as AEs if they fulfil any of the SAE criteria, DLT criteria, 
are the reason for discontinuation of study intervention, or are considered to be clinically 
relevant as judged by the Investigator (which may include but is not limited to consideration 
as to whether treatment or non-planned visits were required or other action was taken with the 
study intervention, eg, dose adjustment or dose interruption).

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8.3.8
Disease Progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new, or progression of existing lesions to the primary disease under study 
should be considered as disease progression and not an AE. Events, which are unequivocally 
due to disease progression, should not be reported as an AE during the study.
8.3.9
Disease Under Study
Symptoms of disease under study are those that might be expected to occur as a direct result 
of the advanced haematologic malignancy. Events that are unequivocally due to disease under 
study should not be reported as an AE during the study unless they meet SAE criteria or lead 
to discontinuation of the study intervention.
8.3.10
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the Investigator or other study site staff reports an 
SAE to the appropriate AstraZeneca representative by telephone. The AstraZeneca 
representative will advise the Investigator/study site staff on how to proceed.

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The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes an SAE and is to be reported as such. 
For further guidance on the definition of a SAE, refer to Appendix B of the CSP.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug. 
Where hospitalisation for longer than 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.
8.3.11
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy that is discovered before the study patient has received any study
intervention.
8.3.11.1 
Maternal Exposure
If a patient becomes pregnant during the course of the study, study intervention should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital anomaly/birth defect) should be followed up and documented even 
if the patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.10) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.

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When the eCRF module is used include the following: The PREGREP module in the eCRF is 
used to report the pregnancy and the paper-based PREGOUT module is used to report the 
outcome of the pregnancy.
8.3.11.2
Paternal Exposure
The outcome of any conception occurring from the date of the first dose until 6 months after 
the last dose of study intervention should be followed up and documented. Information on the 
pregnancy of a patient’s partner must be obtained directly from the patient’s partner. 
Therefore, prior to obtaining information on the pregnancy, the Investigator must obtain the 
consent of the patient’s partner.
Pregnancy of the patient’s partners is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth,
or congenital anomaly), occurring from the date of the first dose until 6 months after the last 
dose of study intervention 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 pregnancy occurs in a patient’s partner within the timeframe specified above, 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. Detailed instructions on 
reporting pregnancies are provided in the Investigator manual separate from this CSP.
8.3.12
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study intervention and have been identified after the patient’s inclusion 
in this study.
8.3.13
Deaths
All deaths that occur during the study or within the protocol-defined follow-up period after the 
administration of the last dose of study intervention should be reported as follows:

Death, which is unequivocally due to disease progression, should be communicated to the
Study Physician at the next monitoring visit and should be documented in the eCRF
module, but should not be reported as a SAE during the study.

Where death is not clearly due to disease progression of the disease under study the AE
causing the death should be reported to the Study Physician as an SAE within 24 hours. It
should also be documented in the eCRF module. The SAE report should contain a

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Samples for determination of AZD4320 concentrations in plasma (and/or urine) will be 
analysed by a suitable vendor on behalf of AstraZeneca, using an appropriate bioanalytical 
method. Full details of the analytical method used will be described in a separate Bioanalytical 
Report.
All samples still within the known stability of the analytes of interest at the time of receipt by 
the bioanalytical laboratory will be analysed.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the clinical study 
report but separately in a Bioanalytical Report.
Refer to the relevant individual modules for details of collection schedule and procedures for 
PK sample collection.
8.5.2
Pharmacodynamics
Refer to the relevant individual modules for details of collection schedule and procedures for 
pharmacodynamic sample collection.
8.6
Human Biological Sample Biomarkers
8.6.1
Refer to the relevant individual modules for details.
8.6.2
 
.
8.6.3
Other Study-related 
Refer to the relevant individual modules for details.
8.7
 research is also part of this study as 
specified in the SoA of the relevant individual module and is subject to agreement in the ICF 
addendum.
A 
 will be collected from patients who have consented to 
participate in the 
 component of the study. Participation is optional. Patients 
who do not wish to participate in the
 may still participate in the study. The 
mandatory saliva sample for 
 is separate to this 
 
.
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9
STATISTICAL CONSIDERATIONS – CORE
9.1
Statistical Hypotheses
No formal statistical hypothesis testing is planned.
9.2
Sample Size Determination
Refer to relevant individual modules for details of sample sizes.
9.3
Populations for Analyses
Refer to relevant individual modules for details of populations for analysis.
9.4
Statistical Analyses
The SAP 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 that will be 
applicable across all modules.
9.4.1
General Considerations
Analyses will be performed by AstraZeneca or its representatives, including CROs. A 
comprehensive SAP will be developed and will describe the patient populations to be included 
in the analyses, the analyses including any subgroup analyses or sensitivity analyses, and the 
procedures to account for missing, unused, and spurious data.
Unless stated otherwise, each module and cohort will be analysed separately.
Descriptive statistics will be used for all variables. Continuous variables will be summarised 
by the number of observations, mean, standard deviation, median, minimum, and maximum. 
Categorical variables will be summarised by frequency counts and percentages for each 
category. Unless otherwise stated, percentages will be calculated out of the population total. 
All data collected will be listed. 
Demographic and exposure data will be summarised on the safety population set. Safety data 
will be summarised on the safety population set. Pharmacokinetic data will be summarised 
based on the PK analysis set. 
In general, the last observed measurement prior to first dose of study intervention will be 
considered the baseline measurement. For assessments on the day of first dose where time is 
not captured, a nominal pre-dose indicator, if available, will serve as sufficient evidence that 
the assessment occurred prior to first dose. Assessments on the day of first dose, when neither 
time nor a nominal pre-dose indicator are captured, will be considered prior to first dose if 
such procedures are required by the protocol to be conducted before the first dose.

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Depending on the extent of any impact, summaries of data relating to patients diagnosed with 
COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, delayed or 
discontinued study intervention, and other protocol deviations) may be generated. More detail 
will be provided in the SAP.
Demographic Data
Characteristics of the patients, including medical history and disease characteristics at baseline 
will be listed for each patient and summarised by dose group where appropriate. Reasons for 
discontinuation of study intervention will be listed including the study day of treatment 
discontinuation and will be summarised by dose group if appropriate.
Exposure
Exposure to study intervention, ie, total amount of study intervention received will be listed 
for all patients. Total exposure and total time on study (date of last dose minus date of first 
dose) will be summarised by the following: mean, standard deviation, minimum, maximum, 
median, and number of observations.
9.4.2
Efficacy Analyses 
The efficacy endpoints for tumour response (ORR, DoR, and TTR) will be summarised on the 
evaluable for response population set. The efficacy endpoints for OS and PFS will be 
summarised on the Intent-to-treat Population Set.
Clinical responses will be listed and summarised by dose group and by appropriate response 
category. Clinical responses for ORR will be derived by applying revised Lugano 
classification 2014 response criteria (Cheson et al 2014). 
Objective Response Rate
Objective response rate is defined as the proportion of patients achieving either CR or PR. 
Data obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR, regardless of whether the patient withdraws from 
therapy. Patients who discontinue treatment without a response or progression, receive 
subsequent anti-lymphoma therapy and then respond will not be included as responders in the 
ORR.
The ORR will include data of all scans, regardless of whether it was scheduled or not. 
ORR will be presented by the number and percentage of patients with a response (CR/PR) 
including 95% CIs based on exact binomial proportions.
Best objective response will also be summarised by n (%) for each category, with no formal 
statistical analysis presented.

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Duration of Response
Duration of response will be defined as the time from the date of first documented response 
until the date of documented progression or death due to any cause in the absence of disease 
progression. The end of response should coincide with date of progression or death from any 
cause used for the PFS endpoint. The time of the initial response will be defined as the latest 
of the dates contributing towards the first visit that was CR or PR.
The analysis will include all patients in the response-evaluable analysis set who had a 
response, regardless of whether the patient withdraws from therapy.
If a patient does not progress following a response, then their DoR will use the PFS censoring 
time.
Kaplan-Meier plots of DoR will be presented. Median DoR, including 95% CIs, will also be 
presented, calculated from the Kaplan-Meier curve. In addition, the number of patients still 
responding at 3, 6, and 12 months after initial response will also be presented. Swimmer plots 
that clearly show the profile of each patient who responds will also be produced.
Progression-free Survival
Progression-free survival is defined as the time from date of first dose to date of objective 
disease progression or death (by any cause in the absence of progression) regardless of 
whether the patient withdraws from treatment or receives another anti-lymphoma therapy 
prior to progression.
Patients who have not progressed or died at the time of analysis will be censored at the time of 
the latest date of assessment from their last evaluable assessment. The PFS time will always 
be derived based on scan/assessment dates and not on visit dates. 
Kaplan-Meier plots of PFS will be presented. Summaries of the number and percentage of 
patients experiencing a PFS event, and the type of event (progression or death) will be 
provided along with the median PFS, its 95% CI, and the proportion of patients who were 
progression-free at 6, 12, and 18 months.
The treatment status at progression of patients at the time of analysis will be summarised. This 
will include the number and percentage of patients who were on treatment at the time of 
progression, the number and percentage of patients who discontinued study intervention prior 
to progression, the number and percentage of patients who have not progressed and were on 
treatment or discontinued treatment. This will also provide a distribution of number of days 
prior to progression for the patients who have discontinued treatment.

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Overall Survival
Overall survival is defined as the time from date of first dose until death due to any case 
regardless of whether patient withdraws from treatment or receives another anti-lymphoma 
therapy. Any patient not known to have died at the time of analysis will be censored on the last 
recorded date on which the patient was known to be alive.
Note: Survival follow-up phone calls will be made in the week following the date of DCO for 
the analysis, if patients are confirmed to be alive or if the death date is after the DCO date 
these patients will be censored at the date of DCO.
Overall survival data will be presented similarly to the presentation described for PFS.
Time to Objective Response
Time to objective response is defined as the time from date of first dose until the date of first 
documented objective response and will include all patients in the response-evaluable analysis 
set who had a response.
The TTR will be summarised (ie, number of patients [%] based upon the number of 
responders) by scheduled assessment timepoint that the response was first observed.
Additionally, descriptive summary statistics will also be presented. Associated Kaplan-Meier 
curves may also be presented.
9.4.3
Safety 
Safety and tolerability will be assessed in terms of AEs, laboratory data, vital signs, and ECG 
changes. These will be collected for all patients. Safety will be presented using descriptive 
statistics unless otherwise stated. 
All patients receiving a particular dose level within each part of the study will be grouped for
summary and analysis and defined as a dose group.
9.4.3.1
Adverse Events
All patients who receive at least one dose of AZD0466 will be included in the assessment of 
the safety profile (safety analysis set). At the end of the study, appropriate summaries of all 
safety data will be produced, as defined below.
Adverse events will be coded using the most recent version of Medical Dictionary for 
Regulatory Activities that will have been released for execution at AstraZeneca/designee.
Adverse events will be presented by system organ class and/or preferred term, covering 
number and percentage of patients reporting at least one event and number of events, where 
appropriate.

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Only treatment-emergent AEs will be presented. Adverse events occurring prior to start of 
study intervention and post-treatment AEs will only be listed.
An overview of AEs will present the number and percentage of patients with any AE, AEs 
with outcome of death, SAEs, and AEs leading to discontinuation of treatment, AESIs, as well 
as AEs leading to withdrawal from study, as well as the number of individual occurrences in 
these categories.
Separate AE tables will be provided taking into consideration relationship as assessed by the 
Investigator, maximum CTCAE grading, seriousness, death and events leading to 
discontinuation of treatment as well as other action taken related to treatment, events of 
special interest, other significant AEs and timing of events.
An additional table will present number and percentage of patients with most common AEs. 
Most common (eg, frequency of > x%, ≥ x%) will be defined in the SAP.
Key patient information will be presented for patients with AEs with outcome of death, SAEs, 
AEs leading to discontinuation of treatment and AEs leading to treatment delay.
An AE listing for the safety analysis set will cover details for each individual AE.
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to treatment discontinuation. 
Based on the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered OAEs and reported as 
such in the CSR. A similar review of laboratory/vital signs/ECG data will be performed for 
identification of OAEs.
Examples of these are marked haematologic and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 
Treatment-emergent Adverse Events
The following events are considered treatment-emergent:

AEs with an onset date on or after the first dose of study intervention and within 30 days
after last dose of study intervention or up to the day prior to start of subsequent therapy,
whichever comes first.

Worsening of pre-existing events on or after first dose of study intervention and within
30 days after last dose of study intervention or up to the day prior to start of subsequent
therapy.

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Full details of AE analyses will be provided in the SAP.
9.4.3.2
Other Safety Analyses
Detailed analyses will be provided in the SAP. Haematology, clinical chemistry, vital signs, 
ECG data (including QTc as calculated by Fridericia’s formulae), and concomitant 
medications will be listed individually by patient and summarised. For all laboratory 
variables, which are included in the current version of CTCAE, the CTCAE grade will be 
calculated. Summary statistics of mean, median, standard deviation, minimum, maximum, and 
number of observations will be used. Details of any deaths will be listed for all patients.
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.
9.4.4
Pharmacokinetic Analyses 
Calculation or Derivation of Pharmacokinetic Variables
Pharmacokinetic analysis of the plasma concentration data for total and released AZD4320 
and its metabolites (if available and appropriate), when applicable, will be derived using non-
compartmental methods in Phoenix® WinNonlin® Version 8.1 or higher (Certara) performed 
by Covance on behalf of the Sponsor. The PK parameters are calculated/estimated according 
to AstraZeneca standards.
Pharmacokinetic analysis will, where data allow, be carried out using actual elapsed times 
determined from the PK sampling and dosing times recorded will be used 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. 
Where data allow, the following PK parameters for total and released AZD4320 will be 
derived from plasma and urine concentrations:
Plasma
Cmax
Maximum observed plasma (peak) drug concentration
tmax
Time to reach peak or maximum observed concentration or response following drug 
administration
z
Terminal rate constant, estimated by log-linear least squares regression of the 
terminal part of the concentration-time curve
t1/2λz
Half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve

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Cmax
Maximum observed plasma (peak) drug concentration
AUC0-24
Partial area under the plasma concentration-time curve from time 0 to 24 hours after 
the start of infusion
AUC0-72
Partial area under the plasma concentration-time curve from time 0 to 72 hours after 
the start of infusion
AUClast
Area under the plasma concentration-curve from time 0 to the last quantifiable 
concentration
tlast
Time of last observed (quantifiable) concentration
Ctrough
Concentration prior to dosing
Dose normalised 
AUClasta
Area under the plasma concentration-time curve from time 0 to time of last 
quantifiable analyte concentration divided by the dose administered
Dose normalised 
AUC0-72a
Area under the plasma concentration-time curve from time 0 to 72 hours after the 
start of infusion
Dose normalised Cmaxa
Maximum observed plasma (peak) drug concentration divided by the dose 
administered
a
Calculated for total AZD4320 only.
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)
Additional PK parameters may be calculated as appropriate.
Pharmacokinetic Summary Statistics
Plasma concentrations of AZD4320 will be summarised by nominal sample time. Plasma 
concentrations and derived PK parameters will be summarised by dose level and cohort. 
Plasma concentrations at each timepoint will be summarised according to dose and cohort by 
the following summary statistics:

The geometric mean (gmean, calculated as exp [μ], where μ is the mean of the data on a
logarithmic scale)

Coefficient of variation (calculated as 100 √ [exp(s2)-1], where s is the standard deviation
of the data on a log scale)

Gmean ± standard deviation (calculated as exp[μ±s])

Arithmetic mean calculated using untransformed data

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
Standard Deviation calculated using untransformed data

Minimum

Maximum

Number of observations
The following summary statistics will be presented for the estimated PK parameters, as 
appropriate: 

Gmean, calculated as exp[μ], where μ is the mean of the data on a logarithmic scale)

Coefficient of variation (calculated as 100 √ [exp(s2)-1], where s is the standard deviation
of the data on a log scale)

Arithmetic mean calculated using untransformed data

Standard deviation calculated using untransformed data

Minimum

Maximum

Number of observations
The PK data for AZD4320 will also be displayed graphically. Displays will include AZD4320 
(total and released) plasma concentration patient profiles (on the linear and log scale) versus 
time and Gmean concentration (±standard deviation) versus time, stratified by dose. 
Scatter plots of PK parameters versus dose, or log-dose, may also be considered to assess dose 
proportionality.
9.5
Interim Analyses 
Refer to the relevant individual modules for details.
9.6
Data Monitoring Committee
This study will utilise an SRC, as described in Appendix A 5.

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Table 13
Schedule of Activities for Module 1 Part A and Part B: Screening and Cycle 1
Procedure
Screening
Cycle 1 (28 days)
Details in 
CSP section 
or appendix
Ramp-up
Target dose
Day
-28 to -1
1
2
4
5
8
9
10 
11 
15
22
Visit window
± 2 days (unless indicated otherwise)
Informed consent
X
A 3
Inclusion and exclusion criteria
X
5.1, 5.2, 
10.5.1, 
10.5.2
Demography
X
8
Medical history
X
8
Disease characteristics
X
NA
Disease prognostic scores
X
Appendix M
Physical examination
X
X
X
X
X
X
X
X
8.2.1
Height
X
8.2.1
Weight
X
X
X
X
8.2.1
Vital signs
X
X
X
X
X
X
X
X
X
8.2.2
ECOG performance status
X
X
8.2.5.2
Concomitant medication
X
X
X
X
X
X
X
X
6.5
Adverse events
X
X
X
X
X
X
X
X
X
8.3
Safety ECGs (triplicate)
X
X
X
X
X
X
X
X
X
8.2.3, 
10.8.2.3
24-hour continuous 12-lead 
ECG (Holter) recording for PK 
purpose 
X a
8.2.3, 
10.8.2.3
Cardiac MUGA/MRI/ECHO
X
8.2.5.1
Fresh or archival tumour sample
X
As clinically indicated
10.8.6.3

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Table 14
Schedule of Activities for Module 1 Part A and Part B: Cycle 2 and Beyond and Follow-up
Procedures
Cycle 2 (28 days)
Cycle 3 and beyond (28 days)
EoT
Follow-up
Details in CSP 
section or 
appendix
Day
1
8/15/22
1
8/15/22
Post-treatment 
FU visit (28 days 
after last dose)
Q3M after post-
treatment FU 
visit
Visit window
± 2 days
± 7 days
Physical examination
X
X
X
X
X
8.2.1
Weight
X
D15
X
D15
X
8.2.1
Vital signs
X
X
X
X
X
8.2.2
ECOG performance status
X
X
X
8.2.5.2
Concomitant medication
X
X
X
X
X
X
6.5
Adverse events
X
X
X
X
X
X
8.3
Safety ECGs (triplicate)
X
D8
Even cycles only 
beginning at C4
X
8.2.3, 10.8.2.3
Cardiac MUGA/MRI/ECHO
D8
D8, every 3 cycles 
from C5
X
8.2.5.1
Fresh tumour sample
As clinically indicated
10.8.6.3
Survival status
X
X
NA
Laboratory test
SARS-CoV-2 test
X
X
8.2.4
Pregnancy test (WOCBP)
X
X
X
8.2.4
Haematology
X
X
X
X
X
8.2.4
Clinical chemistry
X
X
X
X
X
8.2.4
Serum immunoglobulins
X
8.2.4
Beta-2 microglobulin
X
8.2.4
Amylase and lipase
X
X
X
X
X
8.2.4
Coagulation
X
X
X
X
X
8.2.4
Cortisol, ACTH, TSH
X
8.2.4

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Table 14
Schedule of Activities for Module 1 Part A and Part B: Cycle 2 and Beyond and Follow-up
Procedures
Cycle 2 (28 days)
Cycle 3 and beyond (28 days)
EoT
Follow-up
Details in CSP 
section or 
appendix
Day
1
8/15/22
1
8/15/22
Post-treatment 
FU visit (28 days 
after last dose)
Q3M after post-
treatment FU 
visit
Visit window
± 2 days
± 7 days
Troponin I a
X
8.2.4
BNP (or NTproBNP)
X
8.2.4
Urinalysis
X
X
X
X
X
8.2.4
Disease assessments
CT scan
Weeks 8, 16, 24, 36, 48 and thereafter every 24 weeks for R/R FL and MZL, and every 16 weeks for R/R MCL and R/R 
DLBCL, until disease progression
8.1.2
FDG-PET scan 
Week 8, 24 and 48 and thereafter once a year. If confirmed CR, no further PET scans are required.
8.1.2
Bone marrow biopsy/aspirate 
To confirm CR (if prior bone marrow involvement) or as clinically indicated
8.1.1
Endoscopy/histology 
To confirm CR (if prior gastrointestinal involvement), or as clinically indicated
8.1.4.1
Brain MRI/CT scan
Only if clinically indicated
8.1.2
B-symptoms
To be collected at Screening, and every tumour assessment scan
8.1.4.3
Study intervention
Administer AZD0466
X
X
X
X
6.1, 10.6.1
Prophylaxis for Tumour Lysis Syndrome
Prophylaxis for TLS
X b
(based on risk 
profile)
X b
(based on risk 
profile)
X b
(based on risk 
profile)
X b
(based on risk 
profile)
Appendix F
Pharmacokinetic assessments
Blood samples for plasma PK
X c
C3D1 c, C5D1 c
10.8.5.1

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Table 14
Schedule of Activities for Module 1 Part A and Part B: Cycle 2 and Beyond and Follow-up
Procedures
Cycle 2 (28 days)
Cycle 3 and beyond (28 days)
EoT
Follow-up
Details in CSP 
section or 
appendix
Day
1
8/15/22
1
8/15/22
Post-treatment 
FU visit (28 days 
after last dose)
Q3M after post-
treatment FU 
visit
Visit window
± 2 days
± 7 days
Exploratory and biomarkers assessments
Blood samples for 
X
D15 
(Part B only)
C3D1, C5D1, C7D1, C9D1
(and at every tumour assessment scan)
X
8.1.4.2, 10.8.6.4
Blood samples for 
X
D15 
(Part B only)
C3D1, C5D1, C7D1, C9D1
(and at every tumour assessment scan)
X
10.8.6.5
Blood samples for 
 
X
C3D1, C5D1
(and at every tumour assessment scan 
during Part B only)
X
10.8.6.6
Blood samples for 
X
C3D1, C5D1
(and at every tumour assessment scan 
during Part B only)
X
10.8.6.7
Blood samples for 
 
X
C3D1, C5D1
(and at every tumour assessment scan)
X
10.8.6.8, 10.8.6.9
Blood samples for
 
X
D15
C3D1, C5D1, C7D1, C9D1
(and at every tumour assessment scan)
X
10.8.6.10
a
Troponin T may be collected using a standard assay instead of troponin I, provided the results remain within normal range; However, if an abnormal troponin T value is 
recorded, collection of troponin I will be required thereafter, as it is more cardiac-specific.
b
Prophylaxis for TLS (hydration and anti-hyperuricaemic agents) is required for all patients receiving study intervention and should be implemented according to the TLS risk 
level. Prophylaxis is not provided by the study, is not given at the same frequency as the study intervention, and varies based on risk. See Appendix F, Appendix F 1.2 for 
details.
c
More than one assessment to be performed at the visit.
ACTH = adrenocorticotropic hormone; C = Cycle;
; CSP = clinical study protocol; CR = complete response; 
CT = computed tomography; D = Day; DLBCL = diffuse large B-cell lymphoma; FDG = fluorodeoxyglucose; FL = follicular lymphoma; BNP = brain natriuretic peptide; 
ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EoT = end of treatment; FU = follow-up; MCL = mantle cell lymphoma; 
; MRI = magnetic resonance imaging; MUGA = multigated acquisition scan; MZL = marginal zone lymphoma; NA = not applicable; 
NTproBNP = N-terminal pro brain natriuretic peptide; PBMC = peripheral blood mononuclear cell; PET = positron emission tomography; PK = pharmacokinetics; Q3M = every 3 
months; R/R = relapsed/refractory; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TLS = Tumour Lysis Syndrome; TSH = thyroid-stimulating hormone; 
WOCBP = women of childbearing potential.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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10.6.6.2
Dose Expansion
Cohorts may open either in parallel or sequentially at the Sponsor’s discretion. The dose 
expansion part of the study (Part B) will enrol up to approximately 
 patients. After 
determining the RP2D in Module 1 Part A (dose escalation), the following separate cohorts 
may be opened at the RP2D in Module 1 Part B. 
!
Cohort B1: Approximately 
response-evaluable patients with R/R MCL
!
Cohort B2: Approximately 
response-evaluable patients with R/R FL or MZL
!
Cohort B3: Approximately 
response-evaluable patients with R/R DLBCL
Following an initial ramp-up during Week 1, AZD0466 will be administered based on a 
weekly dosing schedule for 2 years or until disease progression, initiation of alternative 
anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to 
discontinue study intervention, whichever occurs first. In the event of liver or haematologic 
toxicities, a 2-weekly dosing schedule may be considered. In the absence of toxicities, a 
2-weekly dosing schedule may also be considered after discussion with the Sponsor. For
patients who are responding and do not experience unacceptable toxicities, continuation of
treatment may be considered by the Investigator and Sponsor.
All patients should be followed for survival every 3 months until death. Patients who 
discontinue treatment due to unacceptable AEs should be followed until resolution or 
stabilisation of the AE, then for response and survival. Patients who achieve a CR will be 
followed for relapse of disease until death.
If the interim analysis of Part B meets the pre-set target value for monotherapy expansion in 
Cohorts B1 and B2, additional patients will be enrolled in these cohorts.
10.6.6.3
Definition of DLT
A DLT will be defined as the occurrence of any of the following during the 28-day DLT 
evaluation period in Cycle 1, unless unequivocally due to underlying malignancy or an 
extraneous cause:
!
Haematologic toxicity:
∀
CTCAE Grade 3 thrombocytopenia of any duration, associated with Grade ≥ 2
bleeding or requiring platelet transfusion
∀
CTCAE Grade 4 thrombocytopenia lasting > 7 days
∀
CTCAE Grade 4 anaemia
∀
CTCAE Grade 4 neutropenia lasting > 7 days
∀
CTCAE Grade ≥ 3 febrile neutropenia (ANC < 1.0 × 109/L, fever > 100.9°F [or
> 38.3°C]) of any duration despite supportive care
CCI
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10.6.6.7
Dose Modifications
Refer to Section 6.6.6.1 of the core protocol for AZD0466 dose modification and toxicity 
management guidelines.
10.6.6.8
Resumption of Treatment
Refer to Section 6.6.7 of the core protocol.
10.7
Discontinuation of Study Intervention and Patient 
Discontinuation/Withdrawal – Module 1
Refer to Section 7 of the core protocol.
10.8
Study Assessments and Procedures – Module 1
10.8.1
Efficacy Assessments
Refer to Section 8.1 of the core protocol.
10.8.2
Safety Assessments
10.8.2.1
Physical Examinations
Refer to Section 8.2.1 of the core protocol.
10.8.2.2
Vital Signs
Refer to Section 8.2.2 of the core protocol.
10.8.2.3
Electrocardiograms
Refer to Section 8.2.3 of the core protocol and to the Module 1-specific information below.
Twelve-lead centrally-read digital ECGs will be performed in triplicate, however, if safety 
ECGs are being collected at a matched timepoint as Holter ECGs (ECGs for PK purpose), 
single safety ECG is sufficient. If a single safety ECG is abnormal, triplicate safety ECGs are 
recommended.
Electrocardiograms will be performed at timepoints specified in the SoA and as indicated in 
Table 16 below.
Table 16
Module 1 Part A and Part B Safety ECG and Holter ECG Extraction
Study period
Day
Timepoint
Holter ECG 
extraction (for PK) a
Triplicate ECG 
(for safety)
Screening
-28 to -1
Baseline
--
X
Cycle 1
Day 1
Pre-infusion
--
X b
End of the infusion (+ 10 min)
--
X b

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Table 16
Module 1 Part A and Part B Safety ECG and Holter ECG Extraction
Study period
Day
Timepoint
Holter ECG 
extraction (for PK) a
Triplicate ECG 
(for safety)
Day 2
24 hours after the start of the 
Day 1 infusion (± 2 hours)
--
X
Day 4
Pre-infusion
--
X b
End of the infusion (+ 10 min)
--
X b
Day 5
24 hours after the start of the 
Day 4 infusion (± 2 hours)
--
X
Day 8
Pre-infusion
X
X b
30 min after start of infusion 
(± 5 min)
X
-
End of the infusion (+ 10 min)
X
X b
2 hours from start of Day 8 
infusion (± 15 min)
X
-
6 hours from start of Day 8 
infusion (± 30 min)
X
-
9 hours from start of Day 8 
infusion (± 1 hour)
X
-
Day 9
24 hours after the start of the 
Day 8 infusion (± 2 hours)
X
X b
Day 15
Pre-infusion
--
X
End of the infusion (+ 10 min)
--
X
Day 22
Pre-infusion
--
X
End of the infusion (+ 10 min)
--
X
Cycle 2
Day 1
Pre-infusion 
--
X
End of the infusion (+ 10 min)
--
X
Day 8
Pre-infusion
--
X
End of the infusion (+ 10 min)
--
X
Cycle 4 and 
beyond
Day 1
Pre-infusion 
--
See footnote c
End of the infusion (+ 10 min)
--
See footnote c
EoT
--
--
X
a
Patients enrolled in cohorts for which the treatment dose has not been cleared by the SRC in previous 
AZD0466 clinical studies will require continuous recordings of 12-lead ECGs (Holter device) for PK 
modelling (see Section 10.8.5.1 for PK assessment timepoints)
b
Triplicate ECGs will be collected before the PK sample is taken (see Section 10.8.5.1 for PK assessment 
timepoints).
c
Beyond Cycle 4 ECGs will be collected on even Cycles only ie, Cycle 4, 6, 8 etc; Day 1: pre-infusion 
and at the end of the infusion (+10 minutes).
ECG = electrocardiogram; PK = pharmacokinetics; SRC = Safety Review Committee.

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Continuous 12-lead ECG Recordings (Holter)
Patients enrolled in cohorts for which the treatment dose has not been cleared by the SRC in 
previous AZD0466 clinical studies will require continuous recordings of 12-lead ECGs 
(12-lead Holter devices) for the purpose of PK modelling. When electrocardiogram Holter 
monitoring is performed, extractions will capture PR, QRS, QT, QTcF, and RR intervals.
Recording should be performed as specified in Table 13 of the SoA and Table 16 above, with 
recording commencing on C1D8 pre-infusion to cover the 24-hour timepoint (prior to PK 
sampling). The timing of ECGs may be altered depending on the emerging PK profile. The 
standardised 12-lead Holter device will be provided by the central ECG vendor who 
will provide the central ECG reads.
The 12-lead Holter devices will always be fitted and safely removed by the Investigator or a 
trained designee.
The schedule of continuous ECG recordings may be increased, reduced, or stopped at any 
time during the study, if supported by emerging data and with the agreement of the SRC.
10.8.2.4
Clinical Safety Laboratory Assessments
Refer to Section 8.2.4 of the core protocol.
10.8.2.5
Other Safety Assessments
Refer to Section 8.2 of the core protocol.
10.8.3
Adverse Events and Serious Adverse Events
Refer to Section 8.3 of the core protocol.
10.8.4
Overdose
Refer to Section 8.4 of the core protocol.
10.8.5
Human Biological Samples
10.8.5.1
Pharmacokinetics
Pharmacokinetic samples may be subjected to further analyses in order to further investigate 
the presence and/or identity of drug metabolites. These samples will be separate from the 
primary PK samples sent to the bioanalytical laboratory for analysis. Any results from such 
analyses will be reported separately from the CSR.
Blood Samples for Plasma Pharmacokinetics
Blood samples should be taken from a different part of body than where study intervention is 
being infused to prevent erroneous drug concentration readings. For example, if AZD0466 is 

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being infused into the patient’s right arm, then the blood sample should be collected from the 
left arm. 
Blood samples for plasma PK will be collected as outlined in Table 17 (collection time begins 
from start of infusion). The date and time of collection of each sample as well as sample 
processing time will be recorded. Details will be provided in Laboratory Manual.
Table 17
Pharmacokinetic Timepoints 
Blood sample for plasma PK
Cycle
Day
Timepoint
Part A
Part B
1
1
Pre-infusion
X
X
End of the infusion (+ 10 min)
X
X
4
Pre-infusion
X
X
End of the infusion (+ 10 min)
X
X
8
Pre-infusion
X
X
30 min after start of infusion (± 5 min)
X
X
End of the infusion (+ 10 min)
X
X
2 hours from start of Day 8 infusion (± 15 min)
X
X
6 hours from start of Day 8 infusion (± 30 min)
X
X
9 hours from start of Day 8 infusion (± 1 hour)
X
X
9
24 hours after the start of the Day 8 infusion (± 2 hours)
X
X
10
48 hours after the start of the Day 8 infusion (± 3 hours)
X
11
72 hours after the start of the Day 8 infusion (± 7 hours)
X
2
1
Pre-infusion 
X
X
End of the infusion (+ 10 min)
X
X
2 hours from start of infusion (± 15 min)
X
X
6 hours from start of infusion (± 30 min)
X
X
9 hours from start of infusion (± 1 hour)
X
X
2
24 hours after the start of the Day 1 infusion (± 2 hours)
X
X
3 & 5
1
Pre-infusion 
X
X
End of the infusion (+ 10 min)
X
X
PK = pharmacokinetics.
10.8.5.2
Pharmacodynamics
Whole Blood Samples for Locally Collected PBMCs (Part A and Part B)
Mandatory whole blood samples will be collected from all patients at the timepoints indicated 
in the SoA (Table 13 and Table 14) and as shown in Table 18 below. Assays will include, but 
are not limited to, pro-apoptotic:anti-apoptotic proteins complex disruption and caspase 3 

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cleavage assays. Peripheral blood mononuclear cell isolation should occur within 30 minutes 
of whole blood sample collection. Note: Collection time begins with the start of infusion.
Table 18
10.8.6
Human Biological Sample Biomarkers
10.8.6.1
Per local regulations, a
 
. It is important to assess whether 
 in the patient 
are 
. The sample should be 
collected from patients before receiving study intervention. Details on sample processing, 
handling, and shipment are provided in the Laboratory Manual.
10.8.6.2
Bone Marrow (Part A and Part B)
Refer to Section 8.1.1 of the core protocol.
10.8.6.3
Tumour Tissue Samples (Part A and Part B)
The provision of an archival tumour biopsy sample FFPE tumour block is mandated, with 
sufficient material to produce approximately 20 slides. The sample age should be less than 
3 months before the first dose of study intervention. If archival tumour biopsy FFPE blocks 
are not available, archival tumour biopsy FFPE unstained slides (20 unstained slides 
preferable, minimum 15 slides acceptable) must be provided that were obtained from the 
FFPE block generated that should not be older than 3 months prior to the first dose of study 
intervention. Archival tissues must have been obtained as a core 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 patients enrolled into the study. 
CCI
CCI
CCI
CCI
CCI
CCI

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10.9.4.2
Efficacy Analyses
Refer to Section 9.4.2 of the core protocol. 
10.9.4.3
Safety Analyses
Refer to Section 9.4.3 of the core protocol. 
10.9.4.4
Pharmacokinetic Analyses
Refer to Section 9.4.4 of the core protocol.
10.9.5
Interim Analyses
An interim analysis will be performed for Module 1 Part B when the last patient per criteria 
above has had the opportunity to complete 2 cycles of treatment and is response-evaluable as 
per population definition. This analysis will include evaluation of clinical response and AEs 
leading to discontinuation. 
10.9.6
Data Monitoring Committee
Refer to Section 9.6 of the core protocol.

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11 SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and Council for International Organisations of Medical
Sciences International Ethical Guidelines

Applicable ICH 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 patients.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the
study from the concerned Regulatory Authority. This responsibility may be delegated to a
CRO but the accountability remains with AstraZeneca.

The Investigator will be responsible for providing oversight of the conduct of the study at
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC,
European Regulation 536/2014 for clinical studies (if applicable), European Medical
Device Regulation 2017/745 for clinical device research (if applicable), and all other
applicable local regulations.
Regulatory Reporting Requirements for SAEs

Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal
obligations and ethical responsibilities towards the safety of patients and the safety of a
study intervention under clinical investigation are met.

The Sponsor has a legal responsibility to notify both the local regulatory authority and
other regulatory agencies about the safety of a study intervention under clinical
investigation. The Sponsor will comply with country-specific regulatory requirements
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators.

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
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.

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 [Investigator’s Brochure 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
patient or his/her legally authorised representative and answer all questions regarding the
study.

Patients must be informed that their participation is voluntary and they are free to refuse
to participate and may withdraw their consent at any time and for any reason during the
study. Patients or their legally authorised representative “an individual, juridical, or other
body authorised under applicable law to consent, on behalf of a prospective subject, to the
subject’s participation in the clinical trial”, per ICH GCP E6(R2) will be required to sign
a statement of informed consent that meets the requirements of 21 CFR 50, local
regulations, ICH guidelines, Health Insurance Portability and Accountability Act
requirements, where applicable, and the IRB/IEC or study centre.

The medical record must include a statement that written informed consent was obtained
before the patient was enrolled in the study and the date the written consent was obtained.
The authorised person obtaining the informed consent must also sign the ICF.

Patients must be reconsented to the most current version of the ICF(s) during their
participation in the study.

A copy of the ICF(s) must be provided to the patient or the patient’s legally authorised
representative.
Patients who are rescreened are required to sign a new ICF.

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If a patient declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the patient and he/she will not be 
excluded from other aspects of the study.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The Investigator or authorised 
designee will explain to each patient the objectives of the analysis to be done on the samples 
and any potential future use. Patients will be told that they are free to refuse to participate in 
any optional samples or the future use and may withdraw their consent at any time and for any 
reason during the retention period.
The patient will give a separate agreement to allow any remaining specimens to be used for 
exploratory research. Patients who decline to participate in this optional research will indicate 
this in the ICF. If a patient withdraws consent to the use of donated biological samples, the 
samples will be disposed of/destroyed, and the action documented. If samples already have 
been analysed at the time of the request, AstraZeneca will not be obliged to destroy the results 
of this research. 
A 4
Data Protection
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. In some cases, such wording will be in a separate accompanying document. 
AstraZeneca will not provide individual genotype results to patients, their family members, 
their general physician, any insurance company, any employer, or any other third party, unless 
required to do so by law; however, AstraZeneca may share data and biosamples with research 
partners. 
Precautions are taken to preserve confidentiality and prevent genetic data from being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and might also have access to his or her genetic data. Also, regulatory authorities may 
require access to the relevant files. Even so, the patient’s medical information and the genetic 
files would remain physically separate.
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets 
that are transferred to the Sponsor will contain the identifier only; patient names or any 
information which would make the patient identifiable will not be transferred.
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure and use of their 
data must also be explained to the patient in the informed consent.

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The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
A study-specific SRC will review the emerging data from the study and will monitor safety 
data on an ongoing basis.
The SRC will consist of:

Study Chair, who will chair the committee, or delegate

Principal Investigator or delegate from the investigational sites that have enrolled patients

Study Physician for the study or delegate

Medical Science Director or delegate
In addition, one other physician from the following may be invited:

Global Safety Physician or delegate

Senior Physician from another project.
The Study Pharmacokineticist, Study Statistician, Patient Safety Scientist, Clinical Project 
Manager, and other experts may also be invited as appropriate. The SRC Charter document for 
this study will define the exact membership, and who should be present for decisions to be 
made, how reviews will be performed and how the discussions will be documented.
Further internal or external experts may be consulted by the SRC, as necessary. The Global 
Safety Physician or delegate should always be present at the SRC if there are safety issues for 
discussion.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com, https://www.clinicaltrialsregister.eu and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical study and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.

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A 7
Data Quality Assurance

All patient data relating to the study will be recorded on eCRF unless transmitted to the
Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible
for verifying that data entries are accurate and correct by electronically signing the eCRF.

The Investigator must maintain accurate documentation (source data) that supports the
information entered in the eCRF.

The Investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as Risk Management and Mitigation Strategies and Analytical Risk-Based
Monitoring), methods, responsibilities, and requirements, including handling of
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring)
are provided in the Monitoring Plan.

The Sponsor or designee is responsible for the data management of this study including
quality checking of the data.

The Sponsor assumes accountability for actions delegated to other individuals (eg,
CROs).

Study monitors will perform ongoing source data verification to confirm that data entered
into the eCRF by authorised site personnel are accurate, complete, and verifiable from
source documents; that the safety and rights of patients are being protected; and that the
study is being conducted in accordance with the currently approved protocol and any
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study
must be retained by the Investigator for 15 years after study completion unless local
regulations or institutional policies require a longer retention period. No records may be
destroyed during the retention period without the written approval of the Sponsor. No
records may be transferred to another location or party without written notification to the
Sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the patient and substantiate the
integrity of the data collected. Source documents are filed at the Investigator’s site.

Data 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.

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
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 construction
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 
patients.
The first act of recruitment is the first site activated and will be the study start date.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC
or local health authorities, the Sponsor’s procedures, or GCP guidelines

Inadequate recruitment of patients by the Investigator

Discontinuation of further study 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 CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. 
The Investigator shall promptly inform the patient and should assure appropriate patient 
therapy and/or follow-up.
Patients from terminated sites will have the opportunity to be transferred to another site to 
continue the study.

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

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

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The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 
is being treated by the Investigational Product under study and is not the development of new 
or progression of existing metastasis to the tumour under study). Malignant tumours that – as 
part of normal, if rare, progression – undergo transformation (eg, Richter’s transformation of 
B-cell chronic lymphocytic leukaemia into diffuse large B-cell lymphoma) should not be
considered a new malignant tumour.
Life-threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself 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 patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability, or incapacity but may jeopardise the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical
judgement must be used.

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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In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
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 patient or 
has the potential to cause harm to the patient. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient.
Medication error includes situations where an error. 

Occurred

Was identified and intercepted before the patient received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to
the patient

Drug not administered as indicated, for example, wrong route or wrong site of
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a
solid tablet

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

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
patients while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent.
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of, destroyed, or repatriated, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The Investigator:

Ensures patient’s withdrawal of informed consent to the use of donated samples is
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that patient, if stored at the study
site, are immediately identified, disposed of as appropriate, and the action documented.

Ensures that the patient and AstraZeneca are informed about the sample disposal.

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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 
 to explore how 
variations may affect 
, and the 
. This 
 may lead to better understanding of 
, better
 or 
, and to the discovery of new
, or 
. Therefore, where local regulations and IRB/IEC
allow, a 
 will be collected for DNA analysis from consenting patients.
!
This 
 may consist of the analysis of the structure of the patient´s
DNA, ie, the entire genome.
!
The results of 
 may be reported in a separate study summary.
!
The Sponsor will store the DNA samples in a secure storage space with adequate
measures to protect confidentiality.
D 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population
All patients will be asked to participate in this genetic research. Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit. The patient will 
not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described 
in the main body of the CSP 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:
Withdrawal of Consent for Genetic Research 
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7.2 of the main 
CSP.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Patient Data Protection
!
AstraZeneca will not provide individual genotype results to patients, any insurance
company, any employer, their family members, general physician unless required to do so
by law.
!
Extra precautions are taken to preserve confidentiality and prevent genetic data being
linked to the identity of the patient. In exceptional circumstances, however, certain
individuals might see both the genetic data and the personal identifiers of a patient. For
example, in the case of a medical emergency, an AstraZeneca Physician or an Investigator
might know a patient’s identity and also have access to his or her genetic data. Regulatory
authorities may require access to the relevant files, though the patient’s medical
information and the genetic files would remain physically separate.
Data Management
!
Any genetic data generated in this study will be stored at a secure system at AstraZeneca
and/or designated organisations to analyse the samples.
!
AstraZeneca and its designated organisations may share summary results (such as genetic
differences from groups of individuals with a disease) from this
 with
other researchers, such as hospitals, academic organisations, or health insurance
companies. This can be done by placing the results in scientific databases, where they can
be combined with the results of similar studies to learn even more about health and
disease. The researchers can only use this information for health-related research
purposes. Researchers may see summary results but they will not be able to see individual
patient data or any personal identifiers.
!
Some or all of the clinical datasets from the main study may be merged with the genetic
data in a suitable secure environment separate from the clinical database.
CCI

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

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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
Local Laboratories Being Used:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative

Determine whether the patient meets PHL criteria (see Section E 2 for definition) by
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria Not Met
If the patient does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the patient has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in
the CSP.
E 4.2
Potential Hy’s Law Criteria Met
If the patient does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
intervention (see Section E 6)

Notify the AstraZeneca representative who will then inform the central Study Team

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
Within one 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

For patients that met PHL criteria prior to starting IMP, the Investigator is not required to
submit a PHL SAE unless there is a significant change# in the patient’s condition

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an
approach for patient follow-up (including any further laboratory testing), and the
continuous review of data

Subsequent to this contact the Investigator will:

Monitor the patient until liver biochemistry parameters and appropriate clinical
symptoms and signs return to normal or baseline levels, or as long as medically
indicated. Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as
discussed with the Study Physician

Complete the 3 Liver eCRF Modules as information becomes available
#A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days from 
date PHL criteria was met. The AstraZeneca 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.

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

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At the first on study intervention occurrence of PHL criteria being met the Investigator will 
determine if there has been a significant change in the patients’ 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 patient meets PHL criteria on study intervention and has 
already met PHL criteria at a previous on study intervention visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found 
to be the disease under study eg, chronic or progressing malignant disease, severe 
infection or liver disease, or did the patient meet PHL criteria prior to starting study 
intervention and at their first on study intervention visit as described in Section E 6 of 
this Appendix?
If No: follow the process described in Section E 4.2 for reporting PHL as an SAE
If Yes: Determine if there has been a significant change in the patient’s condition# compared 
with when PHL criteria were previously met#

If there is no significant change no action is required

If there is a significant change follow the process described in Section E 4.2 for reporting
PHL as an SAE
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.

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E 8
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory. The list may be modified based on clinical judgement. Any 
test results need to be recorded.
Hy’s Law Lab Kit for 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.

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F 2
Guidance for Management of Haematologic Changes
F 2.1
Thrombocytopenia and Haemorrhage
Platelet transfusions are permitted as per institutional standards. However, due to the 
mechanism of action of AZD0466, platelet transfusion may have limited efficacy within 24 to 
48 hours after AZD0466 infusion.
AZD0466 should be withheld in presence of significant bleeding events with or without 
thrombocytopenia, such as:

Grade 3 or 4 haemorrhage

Any grade serious haemorrhage event

Any grade intracranial haemorrhage or haematoma
However, if there is evidence that the patient is experiencing clinical benefit with AZD0466, 
restarting at a reduced dose may be considered following discussion with the Study Physician. 
AZD0466 should be discontinued if significant bleeding reoccurs.
Anticoagulants and aspirin are not allowed during the study; other anti-aggregants may be 
used with caution.
F 2.2
Neutropenia and Febrile Neutropenia
The use of G-CSF (eg, filgrastim) or GM-CSF (eg, sargramostim) may be used for 
management of severe neutropenia or febrile neutropenia, as indicated by the current 
American Society of Clinical Oncology guideline and according to Investigator’s clinical 
judgement. The use of long-acting pegylated G-CSF (eg, pegfilgrastim) is not permitted 
during study intervention.
F 2.3
Anaemia
Patients already receiving erythropoietin at screening may continue to receive it during study 
intervention, provided they have been receiving erythropoietin for > 1 month at the time study 
intervention is started. 
Prophylaxis in Cycle 1: Prophylactic erythropoietin should not be started during Cycle 1.
Prophylaxis in Cycle 2 and beyond: Prophylactic erythropoietin may be started during 
Cycle 2 or in subsequent cycles.
Use of the long-acting erythropoiesis-stimulating agent, darbepoetin, is not permitted during 
study intervention.

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Blood transfusions may be administered at the discretion of the Investigator.
F 3
References
Cairo and Bishop 2004
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. 
Br J Haematol. 2004;127(1):3-11.
Coiffier et al 2008
Coiffier et al 2008. University of Texas MD Anderson Cancer Center 2018 Tumor lysis 
syndrome (TLS) in adult patients. 2018. Copyright University of Texas MD Anderson Cancer 
Center 2018.
Howard et al 2011
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 
2011;364(19):1844-54.

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Table G32
Grading of Tumour Lysis Syndrome
Cairo-Bishop Grading for TLS
Abnormality Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Laboratory 
TLS
Absent
Present
Present
Present
Present
Present
Serum 
creatinine a
≤ 1.5 x ULN 1.5 x ULN
1.5 – 3.0 x ULN
> 3.0 – 6.0 x
ULN
> 6.0 x ULN
Death b
Cardiac 
arrhythmia a
None
Intervention 
not 
indicated
Nonurgent 
medical 
intervention 
indicated
Symptomatic 
and incompletely 
controlled 
medically, or 
controlled with 
device (eg, 
defibrillator) 
Life-threatening 
(eg, arrhythmia 
associated with 
CHF, 
hypotension, 
syncope, shock)
Death b
Seizure a
None
--
One brief 
generalised 
seizure; seizures 
well controlled 
by 
anticonvulsants; 
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 and 
prolonged, 
repetitive, or 
difficult to 
control (eg, 
status 
epilepticus, 
intractable 
epilepsy)
Death b
a
Not directly or probably attributable to therapeutic agent.
b
Probably or definitely attributable to clinical TLS.
Modified from Cairo and Bishop 2004. 
ADL = activities of daily living; CHF = congestive heart failure; TLS = tumour lysis syndrome; ULN = upper 
limit of normal.
G 3
References
Cairo and Bishop 2004
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. 
Br J Haematol. 2004;127(1):3-11.
Cheson et al 2017
Cheson BD, Enschede SH, Cerri E, Desai M, Potluri J, Lamanna N et al. Tumor lysis 
syndrome in chronic lymphocytic leukemia with novel targeted agents. Oncologist. 
2017;22(11):1283-91.
Howard et al 2011
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364(19):1844-
54.

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Appendix H
Drugs That Prolong QT Interval and/or Induce Torsades De 
Pointes
Drugs with known or possible risk of Torsades de Pointes (cardiac arrhythmia due to 
drug-induced QTc prolongation) are withheld for 5 half-lives prior to the first dose of study 
intervention and will continue to be withheld during the study, and for 14 days after the last 
dose of AZD0466. 
Table H33
Drugs with a Known Risk of Torsades de Pointes
Contraindicated drug
Withdrawal period prior to 
the start of study intervention
Aclarubicin, anagrelide, ciprofloxacin, clarithromycin, cocaine, droperidol, 
erythromycin, levofloxacin, ondansetron, papaverine hydrochloride, 
procainamide, sulpiride, sultopride, terfenadine, terlipressin.
2 days
Cilostazol, cisapride, disopyramide, dofetilide, domperidone, flecainide, 
gatifloxacin, grepafloxacin, ibutilide, moxifloxacin, oxaliplatin, propofol, 
quinidine, sotalol, roxithromycin, sevoflurane, sparfloxacin, thioridazine
7 days
Azithromycin, bepridil, chlorpromazine, halofantrine, haloperidol, 
mesoridazine, citalopram, dronedarone, escitalopram, fluconazole, 
levomepromazine, levosulpiride
14 days
Donepezil, terodiline
3 weeks
Levomethadyl, methadone, pimozide
3 weeks b
Arsenic trioxide a, ibogaine
3 weeks b
Pentamidine
3 weeks b
Astemizole, probucol, vandetanib
3 weeks b
Amiodarone, chloroquine
1 year
a
Estimated value, as pharmacokinetics of arsenic trioxide have not been studied.
b
The withdrawal period for these drugs will be 3 weeks prior to the start of study treatment, after discussion 
with the Study Physician regarding the risk/benefit ratio.
CredibleMeds® (www.crediblemeds.org) is the standard reference for drugs with known or 
possible risk of Torsades de Pointes. Since CredibleMeds® constantly assesses new drug 
information and updates its lists, sites should go directly to the crediblemeds.org website in 
real-time for reference. Patients receiving drugs listed in the “known” or “possible” categories 
at the time of eligibility assessment are prohibited from 14 days before the start of treatment 
until permanent discontinuation of treatment.
Some of the medications listed as a possible risk of Torsades de Pointes may be allowed at the 
Investigator’s discretion after approval by the Study Physician when the patient has unmet 
medical need to continue receiving prohibited medication(s), no suitable alternative treatments 
are available, and the benefit-risk ratio is acceptable in the Investigator’s opinion.

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Appendix J
New York Heart Association Functional Classification
Class
Patient Symptoms
Class
Objective Assessment
I
No limitation of physical activity. 
Ordinary physical activity does not 
cause undue fatigue, palpitation, 
dyspnea (shortness of breath).
A
No objective evidence of cardiovascular 
disease. No symptoms and no limitation 
in ordinary physical activity.
II
Slight limitation of physical activity. 
Comfortable at rest. Ordinary 
physical activity results in fatigue, 
palpitation, dyspnea (shortness of 
breath).
B
Objective evidence of minimal 
cardiovascular disease. Mild symptoms 
and slight limitation during ordinary 
activity. Comfortable at rest.
III
Marked limitation of physical 
activity. Comfortable at rest. Less 
than ordinary activity causes fatigue, 
palpitation, or dyspnea.
C
Objective evidence of moderately severe 
cardiovascular disease. Marked 
limitation in activity due to symptoms, 
even during less-than-ordinary activity. 
Comfortable only at rest.
IV
Unable to carry on any physical 
activity without discomfort. 
Symptoms of heart failure at rest. If 
any physical activity is undertaken, 
discomfort increases.
D
Objective evidence of severe 
cardiovascular disease. Severe 
limitations. Experiences symptoms even 
while at rest.
Source: https://www heart.org/en/health-topics/heart-failure/what-is-heart-failure/classes-of-heart-failure adapted 
from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria 
Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, 
MA: Lippincott Williams and Wilkins; March 1, 1994.

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Table K35
Response Assessment Criteria for Non-Hodgkin Lymphoma
Response and site
PET-CT-based response
CT-based response
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but 
should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result 
of chemotherapy of myeloid growth factors).
b
PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 
4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of 
uptake unlikely to be related to lymphoma.
Adapted from Table 3: Cheson et al 2014
5PS = Deauville 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; GI = gastrointestinal; 
IHC = immunohistochemistry; LDi = longest transverse diameter of a lesion; MRI = magnetic resonance 
imaging; PET = positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; 
SDi = shortest axis perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for 
multiple lesions.
K 2
Assessment of New Lesions
Appearance of any new lesions > 1.5 cm in any axis during or at the end of therapy, even if all 
other lesions are decreasing should be considered progression. Increased FDG uptake in a 
previously unaffected site should only be considered progression after confirmation with other 
modalities (eg, CT, MRI, biopsy).
In patients with no history of pulmonary lymphoma, new nodules identified by CT are benign 
and should be considered negative for lymphoma. These lesions typically represent infectious 
or inflammatory lesions; therefore, if FDG positive, should not be considered positive for 
lymphoma in the absence of confirmatory tests, (eg, histology).
The presence or absence of new lesions will be recorded in the eCRF.
K 3
Overall Response Assessment
The efficacy endpoints are based on the overall response assessment, which is combining the 
radiological response from PET/CT scans, the bone marrow findings (if applicable) and any 
additional clinical finding, including cytologic or histopathologic findings for each disease 
response assessment during the study. The possible outcomes for ORR as CR, PR, SD, PD, 
Unknown. The Investigator-assessed ORR and respective date will be captured on the eCRF.
K 4
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):3059-68.

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L 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service may visit the patient’s home/or other 
remote location as per local standard operating procedures, as applicable. Supplies will be 
provided for a safe and efficient visit. The qualified HCP will be expected to collect 
information per the CSP.
L 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the patients will allow AEs, concomitant medication, and ECOG performance status to be 
reported and documented.
L 5
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site or TPV service in the source documents, or by the patient themselves.

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M 4
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Appendix N
Abbreviations
Abbreviation or special term
Explanation
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
Bcl-2
B-cell lymphoma 2
Bcl-xL
B-cell lymphoma-extra large
BCRP
breast cancer resistance protein
B-NHL
B-cell non-Hodgkin lymphoma
CAR-T
chimeric antigen receptor T cell
cfDNA
circulating free deoxyribonucleic acid
CFR
Code of Federal Regulations
CI
confidence interval
Cmax
maximum observed concentration
CMV
cytomegalovirus
CNS
central nervous system
COVID-19
coronavirus disease 2019
CR
complete response
CRO
contract research organisation
CSP
clinical study protocol
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumour deoxyribonucleic acid
CTEP
Cancer Therapy Evaluation Program
CYP
cytochrome P450
DCO
data cutoff
DILI
drug-induced liver injury
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DoR
duration of response
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group

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Abbreviation or special term
Explanation
eCRF
electronic case report form
EDC
electronic data capture
EoT
end of treatment
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose
FFPE
formalin-fixed paraffin-embedded
FL
follicular lymphoma
GCP
Good Clinical Practice
HCP
healthcare provider
HL
Hy’s Law
HSCT
haematopoietic stem cell transplantation
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous(ly)
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MCL
mantle cell lymphoma
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
MZL
marginal zone lymphoma
NCI
National Cancer Institute
NHL
non-Hodgkin lymphoma
OAE
other significant adverse event
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease
CCI
CCI

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Abbreviation or special term
Explanation
PET
positron emission tomography
PFS
progression-free survival
PHL
Potential Hy’s Law
PK
pharmacokinetic(s)
PR
partial response
RP2D
recommended Phase II dose
R/R
relapsed/refractory
QTcF
QTc corrected by Fridericia’s formula
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCT
stem cell transplantation
SD
stable disease
SoA
Schedule of Activities
SRC
Safety Review Committee
TBL
total bilirubin
TLS
tumour lysis syndrome
TPV
third-party vendor
TTR
time to response
ULN
upper limit of normal
US
United States

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