Clinical trial NCT05205161
Conditions: Non-Hodgkin Lymphoma
Keywords: Open-label, Dose Escalation Dose Expansion, Multicentre Study Anticancer Pegylated poly-L-lysine dendrimer
Sponsor: AstraZeneca
Start date: 2022-07-05; Completion date: 2023-08-17
Enrollment: 7 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study evaluates the safety, tolerability, PK, and preliminary efficacy of AZD0466 as monotherapy or in combination with other anticancer agents in patients with advanced NHL

Detailed description:
This is a modular Phase I/II, open-label, dose escalation and expansion, multicentre Study. The study consists of individual modules, each evaluating the safety and tolerability of AZD0466 as monotherapy or with a specific combination treatment. The initial components are the core protocol, which contains information applicable to all modules, and Module 1.

Module 1 will evaluate the safety, tolerability, PK, and preliminary efficacy of AZD0466 monotherapy and will include 2 parts. Part A dose escalation and Part B dose expansion cohorts. Part A will enrol patients with advanced B-NHL and once the RP2D has been determined, Part B may open to further explore the preliminary anticancer efficacy of AZD0466 monotherapy in patients with selected lymphoid malignancies.

Part A: Phase 1 dose setting to assess the safety and tolerability and determine dose(s) and schedule(s) to be evaluated in Part B.

Part B: Phase 1b/2a dose expansion to assess the efficacy of AZD0466 in 3 select patient populations: relapsed/refractory (R/R) mantle cell lymphoma (MCL) (Cohort B1), R/R follicular lymphoma (FL) or marginal zone lymphoma (MZL) (Cohort B2), and R/R diffuse large B-cell lymphoma (DLBCL) (Cohort B3).

Arms: arm 1: Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 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. arm 2: Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 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. arm 3: Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 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. arm 4: Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 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. arm 5: Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 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. arm 6: Participants with advanced R/R MCL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 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. arm 7: Participants with advanced R/R FL or MZL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 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. arm 8: Participants with advanced R/R DLBCL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 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.
Interventions: intervention 1: AZD0466
Intervention descriptions: intervention 1: All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.

Protocol documents:
Prot_000.pdf: 
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 


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
1 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
2 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
3 of 174
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




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
5 of 174
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




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
7 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
8 of 174
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




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
10 of 174
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
CCI


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
11 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
12 of 174
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




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
14 of 174
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




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
16 of 174
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
CCI
CCI
CCI
CCI
CCI
CCI


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
17 of 174
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
CCI
CCI


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
18 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
19 of 174
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. 




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
21 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
22 of 174
1.2
Schema 
The overall study schema is shown in Figure 1. Refer to the relevant individual modules for 
additional design information.




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
24 of 174
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).










Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
29 of 174
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.








Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
33 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
34 of 174

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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
35 of 174
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.






Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
38 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
39 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
40 of 174
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,


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
41 of 174
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-




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
43 of 174
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. 




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
45 of 174
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 


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
46 of 174
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. 




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
48 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
49 of 174
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




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
51 of 174
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 
CCI
CCI














Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
58 of 174
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.










Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
63 of 174

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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
64 of 174
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.




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
66 of 174
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.
CCI
CCI


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
67 of 174
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. 










Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
72 of 174
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. 




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
74 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
75 of 174

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).




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
77 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
78 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
79 of 174
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






Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
82 of 174
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 
 
.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
84 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
85 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
86 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
87 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
88 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
89 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
90 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
91 of 174

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.






Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
94 of 174
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








Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
98 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
99 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
100 of 174
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














Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
107 of 174
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
CCI
CCI
CCI






Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
110 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
111 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
112 of 174
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 


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
113 of 174
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 


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
114 of 174
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
















Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
122 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
123 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
124 of 174

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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
125 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
126 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
127 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
128 of 174

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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
129 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
130 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
131 of 174
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




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
133 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
134 of 174

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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
135 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
136 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
137 of 174
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




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
139 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
140 of 174
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. 


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
141 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
142 of 174

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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
143 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
144 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
145 of 174
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.












Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
151 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
152 of 174
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.




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
154 of 174
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.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
155 of 174
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.




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
157 of 174
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.










Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
162 of 174
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.




Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
164 of 174
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.






Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
167 of 174
M 4
References
Federico et al 2009
Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U, et al.
Follicular lymphoma international prognostic index 2: a new prognostic index for follicular
lymphoma developed by the international follicular lymphoma prognostic factor project. J
Clin Oncol 2009;27(27):4555-62.
Hoster et al 2008 
Hoster E, Dreyling M, Klapper W, Gisselbrecht C, van Hoof A, Kluin-Nelemans HC, et al. A 
new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 
(2008) 111 (2): 558–565.
International Non-Hodgkin's Lymphoma Prognostic Factors Project
International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for 
aggressive non-Hodgkin's lymphoma. N Engl J Med. 1993 Sep 30;329(14):987-94. doi: 
10.1056/NEJM199309303291402. PMID: 8141877.2008;111(2):558-65.
NCCN Guidelines
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) B-Cell Lymphomas. 
Version 1.2021. Available from https://www.nccn.org/professionals/physician_gls/pdf/bcell. 
pdf (accessed 11 February 2021).
Solal-Céligny et al 2004
Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, et al. Follicular 
lymphoma international prognostic index. Blood 2004;104(5):1258–65.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
168 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
169 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
170 of 174
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


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
171 of 174
12 REFERENCES
Bray et al 2018
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 
2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 
countries. CA Cancer J Clin. 2018;68(6):394-424.
Cairo and Bishop 2004
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. 
Br J Haematol. 2004;127(1):3-11.
Chapuy et al 2018
Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA et al. Molecular subtypes of 
diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and 
outcomes. Nat Med. 2018;24(5):679-90.
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.
Cheson et al 2017
Cheson BD, Heitner Enschede S, 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.
Correia et al 2015
Correia C, Schneider PA, Dai H, Dogan A, Maurer MJ, Church AK et al. BCL2 mutations are 
associated with increased risk of transformation and shortened survival in follicular 
lymphoma. Blood. 2015;125(4):658-67.
Czabotar et al 2014
Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein 
family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014;15(1):49-63.
Davids et al 2017
Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG et al. Phase I First-in-
Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin 
Lymphoma. J Clin Oncol. 2017;35(8):826-33.
Delbridge and Strasser 2015
Delbridge AR, Strasser A. The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell 
Death Differ. 2015;22(7):1071-80.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
172 of 174
Denlinger et al 2018
Denlinger NM, Epperla N, William BM. Management of relapsed/refractory marginal zone 
lymphoma: focus on ibrutinib. Cancer Manag Res. 2018;10615-24.
DiNardo et al 2018
DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M et al. Safety and preliminary 
efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously 
untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet 
Oncol. 2018;19(2):216-28.
DiNardo et al 2019
DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS et al. Venetoclax 
combined with decitabine or azacitidine in treatment-naive, elderly patients with acute 
myeloid leukemia. Blood. 2019;133(1):7-17.
Frewer et al 2016
Frewer P, Mitchell P, Watkins C, Matcham J. Decision-making in early clinical drug 
development. Pharm Stat. 2016;15(3):255-63.
Guo et al 2017
Guo W, Wang SJ, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design 
addressingOckham's razor: mTPI-2. Contemp Clin Trials. 2017;5823-33.
Hanahan and Weinberg 2000
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.
Howard et al 2011
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 
2011;364(19):1844-54.
Howlader 2020
Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics 
Review, 1975-2017, National Cancer Institute. Bethesda, MD, 
https://seer.cancer.gov/csr/1975_2017/, based on November 2019 SEER data submission, 
posted to the SEER web site, April 2020. https://seer.cancer.gov/statfacts/html/nhl.html. 
Accessed 29 December 2020. 2020.
Ji et al 2010
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-finding 
trials. Clin Trials. 2010;7(6):653-63.
Kerr et al 1972
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging 
implications in tissue kinetics. Br J Cancer. 1972;26(4):239-57.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
173 of 174
Lynch and Acharya 2021
Lynch DT, Acharya U. Mantle Cell Lymphoma. StatPearls. Treasure Island (FL)2021.
Meda et al 2003
Meda BA, Frost M, Newell J, Bohling SD, Huebner-Chan DR, Perkins SL et al. BCL-2 is 
consistently expressed in hyperplastic marginal zones of the spleen, abdominal lymph nodes, 
and ileal lymphoid tissue. Am J Surg Pathol. 2003;27(7):888-94.
Monni et al 1999
Monni O, Franssila K, Joensuu H, Knuutila S. BCL2 overexpression in diffuse large B-cell 
lymphoma. Leuk Lymphoma. 1999;34(1-2):45-52.
NCI 2017
NCI. National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) 
Program. Cancer Stat Facts: Non-Hodgkin Lymphoma. 2017. 
http://seer.cancer.gov/statfacts/html/nhl.html. Accessed October 4, 2017. 2017.
Rimokh et al 1993
Rimokh R, Berger F, Delsol G, Charrin C, Bertheas MF, Ffrench M et al. Rearrangement and 
overexpression of the BCL-1/PRAD-1 gene in intermediate lymphocytic lymphomas and in 
t(11q13)-bearing leukemias. Blood. 1993;81(11):3063-7.
Roberts et al 2016
Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF et al. Targeting 
BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 
2016;374(4):311-22.
Rummel et al 2004
Rummel MJ, de Vos S, Hoelzer D, Koeffler HP, Hofmann WK. Altered apoptosis pathways in 
mantle cell lymphoma. Leuk Lymphoma. 2004;45(1):49-54.
Siegel et al 2020
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
Tsuyama et al 2017
Tsuyama N, Sakata S, Baba S, Mishima Y, Nishimura N, Ueda K et al. BCL2 expression in 
DLBCL: reappraisal of immunohistochemistry with new criteria for therapeutic biomarker 
evaluation. Blood. 2017;130(4):489-500.
Vaux et al 1988
Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates 
with c-myc to immortalize pre-B cells. Nature. 1988;335(6189):440-2.


Clinical Study Protocol - 2.0
AstraZeneca
AZD0466 - D8242C00001
CONFIDENTIAL AND PROPRIETARY
174 of 174
Xerri et al 1996
Xerri L, Parc P, Brousset P, Schlaifer D, Hassoun J, Reed JC et al. Predominant expression of 
the long isoform of Bcl-x (Bcl-xL) in human lymphomas. Br J Haematol. 1996;92(4):900-6.
Yi et al 2015
Yi S, Zou D, Li C, Zhong S, Chen W, Li Z et al. High incidence of MYC and BCL2 
abnormalities in mantle cell lymphoma, although only MYC abnormality predicts poor 
survival. Oncotarget. 2015;6(39):42362-71.


6,*1$785(3$*(
7KLVLVDUHSUHVHQWDWLRQRIDQHOHFWURQLFUHFRUGWKDWZDVVLJQHG
HOHFWURQLFDOO\DQGWKLVSDJHLVWKHPDQLIHVWDWLRQRIWKHHOHFWURQLFVLJQDWXUH
'RFXPHQW1DPHGFFVSDPHQGPHQWY
'RFXPHQW7LWOH
'&&OLQLFDO6WXG\3URWRFRO9HUVLRQ$PHQGPHQW
'RFXPHQW,'
'RF,'
9HUVLRQ/DEHO
&855(17/$7(67$33529('
6HUYHU'DWH
GG000\\\\++PPµ87&¶=
6LJQHGE\
0HDQLQJRI6LJQDWXUH
1RY87&
&RQWHQW$SSURYDO
1RY87&
4XDOLILHG3HUVRQ$SSURYDO
1RY87&
4XDOLILHG3HUVRQ$SSURYDO
1RWHV'RFXPHQWGHWDLOVDVVWRUHGLQ$1*(/DQ$VWUD=HQHFDGRFXPHQWPDQDJHPHQWV\VWHP
PPD
PPD
PPD

SAP_001.pdf: 
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: 15 June 2022 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
1 of 65
STATISTICAL ANALYSIS PLAN
Study Code
D8242C00001
Edition Number
1.0
Date
15-Jun-2022
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


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
2 of 65
TABLE OF CONTENTS
TITLE PAGE................................................................................................................1
TABLE OF CONTENTS..............................................................................................2
LIST OF ABBREVIATIONS .......................................................................................6
AMENDMENT HISTORY...........................................................................................8
1
INTRODUCTION......................................................................................9
2
STUDY OBJECTIVES - CORE ...............................................................10
2.1
Objectives.................................................................................................10
3
CHANGES TO PROTOCOL PLANNED ANALYSES - CORE ..............12
4
DATA ANALYSIS CONSIDERATION - CORE.....................................12
4.1
Timing of Analyses...................................................................................12
4.2
Analysis Populations.................................................................................12
4.3
General Considerations.............................................................................12
4.3.1
Data Quality Assurance ............................................................................12
4.3.2
General Presentation Considerations.........................................................12
4.3.3
General Study Level Definitions ...............................................................13
4.3.4
Visit Window ...........................................................................................14
4.3.5
Handling of Unscheduled Visits................................................................15
4.3.6
Multiplicity/Multiple Comparisons ...........................................................15
4.3.7
Handling of Protocol Deviations in Study Analysis...................................15
4.3.8
Missing Dates...........................................................................................16
4.3.9
Sample Size..............................................................................................17
5
STATISTICAL ANALYSIS - CORE .......................................................17
5.1
Study Population.......................................................................................17
5.1.1
Patient Disposition and Completion Status................................................17
5.1.1.1
Definitions and Derivations ......................................................................17
5.1.1.2
Presentation ..............................................................................................17
5.1.2
Analysis Sets ............................................................................................18
5.1.2.1
Definitions and Derivations ......................................................................18
5.1.2.2
Presentation ..............................................................................................18
5.1.3
Protocol Deviations...................................................................................18
5.1.3.1
Definitions and Derivations ......................................................................18
5.1.3.2
Presentation ..............................................................................................18
5.1.4
Demographics...........................................................................................19
5.1.4.1
Definitions and Derivations ......................................................................19
5.1.4.2
Presentation ..............................................................................................19
5.1.5
Baseline Characteristics ............................................................................19
5.1.5.1
Definitions and Derivations ......................................................................19
5.1.5.2
Presentation ..............................................................................................19
5.1.6
Disease Characteristics .............................................................................19
5.1.6.1
Presentation ..............................................................................................19


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
3 of 65
5.1.7
Medical History and Concomitant Disease................................................20
5.1.7.1
Definitions and Derivations ......................................................................20
5.1.7.2
Presentation ..............................................................................................20
5.1.8
Prior and Concomitant Medications ..........................................................21
5.1.8.1
Definitions and Derivations ......................................................................21
5.1.8.2
Presentation ..............................................................................................21
5.2
Endpoint Analyses....................................................................................22
5.2.1
Primary Endpoint – Objective Response Rate ...........................................22
5.2.1.1
Definition and Derivations........................................................................22
5.2.1.2
Primary Analysis of Primary Endpoint: ORR............................................23
5.2.1.3
Sensitivity Analysis of ORR Endpoint ......................................................23
5.2.2
Secondary Endpoint: Complete Response .................................................23
5.2.2.1
Definition and Derivations........................................................................23
5.2.2.2
Primary Analysis of Secondary Endpoint: CR...........................................23
5.2.3
Secondary Endpoint: Duration of Response ..............................................23
5.2.3.1
Definition .................................................................................................24
5.2.3.2
Derivations ...............................................................................................24
5.2.3.3
Primary Analysis of Secondary Endpoint: DoR.........................................24
5.2.4
Secondary Endpoint: Time to Objective Response ....................................24
5.2.4.1
Definition .................................................................................................24
5.2.4.2
Derivations ...............................................................................................24
5.2.4.3
Primary Analysis of Secondary Endpoint: TTR.........................................24
5.2.5
Secondary Endpoint: Progression-free Survival (PFS)...............................25
5.2.5.1
Definition .................................................................................................25
5.2.5.2
Derivations ...............................................................................................25
5.2.5.3
Primary Analysis of Secondary Endpoint: PFS .........................................28
5.2.5.4
Sensitivity Analysis of PFS Endpoint........................................................28
5.2.6
Secondary Endpoint: Overall Survival ......................................................28
5.2.6.1
Definition .................................................................................................28
5.2.6.2
Derivations ...............................................................................................28
5.2.6.3
Handling of Dropouts and Missing Data ...................................................30
5.2.6.4
Primary Analysis of Secondary Endpoint: OS...........................................30
5.2.6.5
Sensitivity Analysis of OS Endpoint .........................................................30
5.3
Pharmacodynamic Endpoint(s) .................................................................30
5.4
Pharmacokinetics......................................................................................30
5.4.1
Pharmacokinetic Concentrations...............................................................31
5.4.2
Pharmacokinetic Parameters Calculation and Summary ............................32
5.4.3
Criteria for Handling Concentrations Below the Limit of Quantification or 
Missing Concentrations in Pharmacokinetic Analysis ...............................33
5.4.4
Treatment of Outliers in Pharmacokinetic Analysis...................................33
5.5
Immunogenicity........................................................................................33
5.6
Safety Analyses ........................................................................................33
5.6.1
Exposure...................................................................................................34
5.6.1.1
Definitions and Derivations ......................................................................34
5.6.1.2
Presentation ..............................................................................................34


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
4 of 65
5.6.2
Adverse Events.........................................................................................35
5.6.2.1
Definitions and Derivations ......................................................................35
5.6.2.2
Presentation ..............................................................................................36
5.6.3
Death........................................................................................................38
5.6.3.1
Presentations.............................................................................................38
5.6.4
Clinical Laboratory, Blood Sample ...........................................................38
5.6.4.1
Definitions and Derivations ......................................................................38
5.6.4.2
Presentations.............................................................................................40
5.6.5
Clinical Laboratory, Urinalysis .................................................................41
5.6.5.1
Definitions and Derivations ......................................................................41
5.6.5.2
Presentations.............................................................................................42
5.6.6
Vital Signs................................................................................................42
5.6.6.1
Definitions and Derivations ......................................................................42
5.6.6.2
Presentations.............................................................................................42
5.6.7
B symptoms..............................................................................................42
5.6.7.1
Presentations.............................................................................................42
5.6.8
Tumour lysis syndrome.............................................................................42
5.6.8.1
Definitions and Derivations ......................................................................42
5.6.8.2
Presentations.............................................................................................42
5.6.9
Electrocardiogram.....................................................................................43
5.6.9.1
Definitions and Derivations ......................................................................43
5.6.9.2
Presentations.............................................................................................43
5.6.10
Echocardiogram (ECHO)..........................................................................43
5.6.10.1
Definitions and Derivations ......................................................................43
5.6.10.2
Presentations.............................................................................................44
5.6.11
Other Safety Assessments.........................................................................44
6
INTERIM ANALYSIS - CORE................................................................44
7
STUDY OBJECTIVES – MODULE 1......................................................44
8
STUDY DESIGN – MODULE 1..............................................................45
8.1
Schema.....................................................................................................45
8.2
Overall Design..........................................................................................46
9
CHANGES TO PLANNED PROTOCOL ANALYSES – MODULE 1 ....46
10
DATA ANALYSIS CONSIDERATION – MODULE 1 ...........................46
10.1
Timing of Analyses...................................................................................46
10.2
Analysis Populations.................................................................................47
10.3
General Considerations.............................................................................48
10.3.1
Visit Window ...........................................................................................48
10.3.2
Handling of Unscheduled Visits................................................................48
10.3.3
Multiplicity/Multiple Comparisons ...........................................................48
10.3.4
Handling of Protocol Deviations in Study Analysis...................................49
10.3.5
Sample Size..............................................................................................49
10.3.5.1
Modified toxicity probability interval-2 (mTPI-2).....................................49
10.3.5.2
Dose Escalation ........................................................................................49


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
5 of 65
10.3.5.3
Dose Expansion........................................................................................49
11
STATISTICAL ANALYSIS – MODULE 1..............................................50
11.1
Study Population.......................................................................................50
11.1.1
Patient Disposition and Completion Status................................................50
11.1.2
Analysis Sets ............................................................................................50
11.1.2.1
Definitions and Derivations ......................................................................50
11.1.3
Protocol Deviations...................................................................................50
11.1.4
Demographics...........................................................................................50
11.1.5
Baseline Characteristics ............................................................................50
11.1.6
Disease Characteristics .............................................................................50
11.1.7
Medical History and Concomitant Disease................................................50
11.1.8
Prior and Concomitant Medications ..........................................................50
11.1.9
Dose-Limiting Toxicity(DLT) ..................................................................51
11.1.9.1
Definitions and Derivations ......................................................................51
11.1.9.2
Presentation ..............................................................................................51
11.2
Endpoint Analyses....................................................................................52
11.4
Pharmacodynamic Endpoint(s) .................................................................52
11.5
Pharmacokinetics......................................................................................52
11.5.1
Definitions and Derivations ......................................................................52
11.5.2
Presentation ..............................................................................................54
11.6
Immunogenicity........................................................................................54
11.7
Safety Analyses ........................................................................................54
11.7.1
Exposure...................................................................................................54
11.7.2
Adverse Events.........................................................................................54
11.7.3
Clinical Laboratory...................................................................................54
11.7.4
Vital Signs................................................................................................54
11.7.5
Electrocardiogram.....................................................................................54
11.7.6
Other Safety Assessments.........................................................................54
12
INTERIM ANALYSIS – MODULE 1......................................................55
12.1
Dose Escalation Committee ......................................................................55
12.2
Interim Analysis .......................................................................................55
13
REFERENCES.........................................................................................56
14
APPENDIX ..............................................................................................57


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
6 of 65
LIST OF ABBREVIATIONS
Abbreviation or 
Specialized 
Term
Definition
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AESI
Adverse event of special interest
Bcl-2
B-cell lymphoma 2
Bcl-xL
B-cell lymphoma-extra large
BMI
Body mass index
B-NHL
B-cell non-Hodgkin lymphoma
CI
confidence interval
eCRF
electronic case report form
CSP
Clinical Study Protocol
CSR
Clinical Study Report
COVID-19
Coronavirus disease 2019
CR
Complete response
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DCO
Data cut-off
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
Gmean
Geometric mean
ICF
Informed consent form
IP
Investigational Product
IPD
Important Protocol Deviation
ITT
Intent-to-Treat
LVEF
Left ventricular ejection fraction
MCL
Mantle cell lymphoma


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
7 of 65
Abbreviation or 
Specialized 
Term
Definition
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
mTPI-2 
Modified toxicity probability interval
MUGA
Multigated acquisition scan
MZL
Marginal zone lymphoma
NA
Not applicable
NC
Not calculable
NCI
National Cancer Institute
NHL
Non-Hodgkin lymphoma
NQ
Non-quantifiable
NTLs
Non-target lesions
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetics
PR
Partial response
RP2D
Recommended Phase II dose
R/R
Relapsed/refractory
QTcF
QTc corrected by Fridericia’s formula
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SD
Stable disease
SRC
Safety Review Committee
Std Dev
Standard deviation
TEAE
Treatment emergent adverse event
TLs
Target lessions
TLS
Tumour lysis syndrome
TTR
Time to response


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
8 of 65
AMENDMENT HISTORY
CATEGORY
Change refers to:
Date
Description of change
In line with CSP?
Rationale
N/A
Click or tap to 
enter a date.
Initial approved SAP
N/A
N/A


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
9 of 65
1
INTRODUCTION 
This is a modular Phase I/II, open-label, dose escalation and expansion, multicentre study 
that evaluates the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of 
AZD0466 as monotherapy or in combination with other anticancer agents in patients with 
advanced non-Hodgkin lymphoma (NHL). 
This SAP provides a technical elaboration of the statistical analyses for all modules as 
outlined in the clinical study protocol.  The SAP would be amended in future modules 
based on the module-specific protocol amendments to include AZD0466 in combination 
with other anticancer treatments.
This SAP should not be read in isolation but in conjunction with the clinical study protocol 
(CSP) and the case report form (CRF). The analyses described in this SAP are based upon 
the following study documents:

CSP, Version 2.0 (Nov 01, 2021)

Electronic Case Report Form (eCRF), version 1.0 (Jan 26, 2022)
Specifications for tables, figures, and listings are contained in a separate document.






STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
12 of 65
3
CHANGES TO PROTOCOL PLANNED ANALYSES - CORE 
Not Applicable.
4
DATA ANALYSIS CONSIDERATION - CORE 
4.1
Timing of Analyses
For the timing of analyses, refer to the individual modules.
4.2
Analysis Populations
For the definitions of the analysis population refer to the individual modules.
4.3
General Considerations
4.3.1
Data Quality Assurance
All tables, figures and listings to be included in the report will be independently checked 
for consistency, integrity and in accordance with standard Parexel procedures.
4.3.2
General Presentation Considerations
No formal hypothesis testing is planned for this study. 
Unless stated otherwise, each module and cohort will be analysed separately.
The below mentioned general principles will be followed throughout the study: 

Continuous endpoints are summarised by the number of observations, mean, 
standard deviation (Std Dev), median, upper and lower quartiles (as applicable), 
minimum, and maximum.  For data that requires log-transformation, it is more 
appropriate to present geometric mean, coefficient of variation (CV), median, 
minimum and maximum.  Categorical endpoints are summarised by frequency 
counts and percentages for each category.

If data are available for less than 3 patients, no summary statistics other than 
minimum, maximum and number of observations are presented.

Unless otherwise stated, percentages will be calculated out of the analysis set total, 
by dose level/cohort as appropriate.

For continuous data, descriptive summary statistics (mean, median, Std Dev, 
standard error, confidence intervals [CIs]) will be rounded to 1 additional decimal 
place compared to the original data.  Minimum and maximum will be displayed 
with the same accuracy as the original data.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
13 of 65

For categorical data, percentages will be presented to 1 decimal place. 

All CIs presented will be two-sided at the 95% level unless stated otherwise. 

SAS® version 9.4 (as a minimum) will be used for all analyses.
4.3.3
General Study Level Definitions
Baseline is the last non-missing value obtained prior to the first dose/administration of any 
study treatment and any information collected after first dose/administration of study 
treatment is regarded as post-baseline information. If two visits are equally eligible to 
assess patient status at baseline (e.g., screening and baseline assessments both on the same 
date prior to first dose/administration with no washout or other treatment in the screening 
period), the average is taken as the baseline value.  For non-numeric laboratory tests (i.e. 
some of the urinalysis parameters) where taking an average is not possible then the best 
value is taken as baseline as this is the most conservative. In the scenario where there are 
two assessments on Day 1 prior to first dose, one with time recorded and the other without 
time recorded, the one with time recorded is selected as baseline. Where safety data are 
summarised over time, study day is calculated in relation to date of first treatment.  For 
assessments on the day of first dose where time is not captured, a nominal pre-dose 
indicator, if available, serves as sufficient evidence that the assessment occurred prior to 
first dose. Assessments on the day of the first dose where neither time nor a nominal pre-
dose indicator are captured is considered prior to the first dose if such procedures are 
required by the protocol to be conducted before the first dose. If no value exists before the 
first dose/administration, then the baseline value is treated as missing. 
Change from baseline will be calculated as the post-dose value minus the baseline value as: 
post-baseline value - baseline value
Percent change from baseline will be calculated as: 
post-baseline value - baseline value
baseline value
× 100
Study day 1 is defined as the date of first dose of study treatment (Cycle 1 Day 1). For 
visits (or events) prior to first dose, study day is defined as (date of visit [event] – date of 
first dose of study treatment). For visits (or events) that occur on or after first dose of study 
treatment, study day is defined as (date of visit [event] – date of first dose of study 
treatment + 1). 
For listings (such as for adverse events [AEs]) that include the derivation of  “days since 
last dose” is defined as (event date – date of last dose) where “date of last dose” is defined 
as date of the most recent dosing immediately preceding the event occurrence. Thus, events 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
14 of 65
on the same day as the last dose will be described as occurring zero days from last dose of 
study treatment.
4.3.4
Visit Window
Visit windows will be defined for any presentations that summarize values by visit. The 
following conventions will apply: 

Visit windows will be exhaustive so that data recorded at any timepoint has the 
potential to be summarized. Inclusion within the visit window will be based on the 
actual date and not the intended date of the visit. 

The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls halfway between the 2 visits (the lower limit of the first 
post-baseline visit will be Day 2). If an even number of days exists between 2 
consecutive visits, then the upper limit will be taken as the midpoint value minus 1 day. 
-
Examples applicable to each module will be defined separately for that module.

Visit windowing will be conducted up to and including the end of treatment visit. That 
is, the end of treatment visit will be reassigned a scheduled visit based on the study day
the end of treatment visit occurred at.

If there are more than one value per patient within a time window then the closest value 
to the scheduled visit date are summarised, or the earlier, in the event the values are 
equidistant from the nominal visit date. The listings highlight the value for the patient 
that contributed to the summary table, wherever feasible. Note: in summaries of 
extreme values, all post baseline values collected are used including those collected at 
unscheduled visits regardless of whether or not the value is closest to the scheduled visit 
date.

For summaries at a patient level, all values are included, regardless of whether they 
appear in a corresponding visit based summary, when deriving a patient level statistic 
such as a maximum.

Visit windowing will be done separately for each assessment based on the schedule of 
events specific to that assessment.

Should Study Day be missing (due to partial or missing dates), then visit will be 
assigned to the nominal visit at which that assessment was recorded, and no windowing 
will be performed.

For summaries showing the maximum or minimum values, the maximum/minimum 
values recorded while on study treatment will be used (regardless of where it falls in an 
interval).


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
15 of 65

Listings should display all values contributing to a timepoint for a patient.

If multiple measurements are taken on the same day, a measurement due to 
inappropriate procedures or any other issues with the first measurement, the 
reassessment measurement on that day will take preference for analysis, should the 
values for that day be in the analysis after visit windowing rules have been applied.
4.3.5
Handling of Unscheduled Visits 
All unscheduled visit data have the potential to be included in the summaries, based on the 
assignment of visit using visit windowing as described in Section 4.3.4. Unscheduled visits 
will be considered for summaries showing the maximum or minimum values recorded 
while on study treatment.
4.3.6
Multiplicity/Multiple Comparisons
Not Applicable.
4.3.7
Handling of Protocol Deviations in Study Analysis
Important protocol deviations are defined as those deviations from the protocol likely to 
have an impact on the perceived efficacy and/or safety of study treatment. 
The following general deviation categories will be defined. These deviations will be 
reviewed and assessed on a case-by-case basis by AstraZeneca to determine importance. 
Deviations considered to be important will be listed and discussed in the clinical study 
report (CSR) as appropriate. All decisions on importance will be made ahead of database 
lock and will be documented prior to the analysis being performed.

Patients who deviate from entry criteria per CSP (Deviation 1)

No baseline Lugano assessments on or before the date of first dose (Deviation 2)

Received prohibited concomitant medications or therapies (Deviation 3)

Patients deviating from prescribed dosing regimen (Deviation 4)

Missed visits, assessments, or treatments that, in the opinion of the investigator, 
were due to Corona virus disease 2019 (COVID-19) global pandemic, and where 
there was a significant effect on either completeness, accuracy and/or reliability of 
the patient’s data, or the patient’s rights, safety or wellbeing (Deviation 5)

Deviation from Good Clinical Practice as determined by medical review (Deviation 
6) 
None of the deviations should lead to subjects being excluded from any analysis 
populations described in the SAP, unless otherwise specified. However, if a deviation is 
serious enough to have a potential impact on the primary analysis, sensitivity analyses may 
be performed.  The need for such a sensitivity analysis will be determined following review 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
16 of 65
of the protocol deviations ahead of database lock and will be documented prior to the 
analysis being conducted.  
A list of all protocol deviations will be reviewed and decisions regarding how to handle 
these deviations in the analyses will be documented by the study team physician, clinical 
pharmacology scientist and statistician prior to database lock.
4.3.8
Missing Dates
Generally, the imputation of dates is used to decide if an observation is treatment emergent 
for adverse events or concomitant medications. The imputed dates should not be used to 
calculate durations, where the results would be less accurate.
The following are the guidelines used when partial dates are detected in the study:

For missing diagnostic dates (e.g., disease diagnosis), if the day and/or month are 
missing use 01 and/or Jan. If year is missing, put the complete date to missing

For missing AE or concomitant medication start dates the following will be 
applied: 
a.
Missing day: Impute the 1st day of the month unless month is the same as 
month of first dose of study treatment then impute first dose date.
b. Missing day and month: Impute 1st January unless year is the same as first 
dose date then impute first dose date. 
c.
Completely missing: Impute first dose date unless the end date suggests it 
could have started prior to this in which case impute the 1st January of the 
same year as the end date. 
d. Imputed start date should be no later than the end date.

For missing AE or medication end dates, the following will be applied: 
a.
Missing day - impute the last day of the month unless both the month and the 
year are the same as the last dose date or the primary analysis data cut-off date 
then impute the last dose date or the primary analysis data cut-off date. 
b. Missing day and month - impute 31st December unless the year is the same as 
the last dose date or the primary analysis data cut-off date then impute the last 
dose date or the primary analysis data cut-off date. 
c.
Completely Missing – need to look at whether the AE/medication is still 
ongoing before imputing a date and also when it started in relation to study 
drug. If the ongoing flag is missing then assume that AE is still present / 
medication is still being taken (i.e. do not impute a date). If the AE/medication 
has stopped and start date is prior to first dose date then impute first dose date. 
Or if it started on or after first dose date then impute a date that is after the last 
dose of study drug date.

Flags will be retained in the datasets indicating where any programmatic 
imputation has been applied, and in such cases, any durations would not be 
calculated.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
17 of 65

If a patient is known to have died where only a partial death date is available then 
the date of death is imputed as the latest of the last date known to be alive +1 from 
the database and the death date using the available information provided and 
applying the following:-
−
For Missing day only – using the 1st of the month. 
−
For Missing day and Month – using the 1st of January.
4.3.9
Sample Size
Refer to the individual modules for details of sample sizes.
5
STATISTICAL ANALYSIS - CORE 
This section provides information on definitions, derivation and analysis/data presentation 
per domain.
The analyses in this section focus on items that are applicable to all modules and the 
module specific analyses are described separately within the individual module sections.
5.1
Study Population
The domain study population covers patient disposition, analysis sets, protocol deviations, 
demographics, baseline characteristics medical history, prior and concomitant medication 
and study drug compliance. 
5.1.1
Patient Disposition and Completion Status
5.1.1.1
Definitions and Derivations
A clear account of the disposition of all patients who enter the study will be provided.  
Study patient (i.e., a patient is “enrolled”) is defined as having a signed informed consent 
available. 
The end of study and end of module is defined in protocol Section 4.4
5.1.1.2
Presentation
Patient disposition including screen failures and reason for screen failure will be 
summarised and listed based on all patients enrolled/screened (i.e. informed consent 
received) by dose level/cohort or all patients combined as defined by the current relevant 
tables, figures, listings (TFL) standards. The number and percentage of patients for the 
following are summarised:

Patients screened

Patients assigned to treatment 

Patients who received study treatment and patients who did not receive treatment 

Patients who discontinued treatment


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
18 of 65

Patients ongoing in the study at data cut-off (DCO)

Patients ongoing treatment at DCO

Patients who terminated study.
In addition, the number and percentage of patients who discontinued treatment and who 
discontinued the study, including a breakdown of the reason for discontinuation will be 
presented for all patients. 
Discontinuation of treatment and/or withdrawal from study due to COVID-19 will be 
presented separately.
The number of patients recruited in each country will be presented. 
The number and percentage of patients with confirmed or suspected COVID-19 infection 
will be presented separately, including details on COVID-19 related interruptions 
impacting on visits and investigational product administration. Listings of patients affected 
by the COVID-19 pandemic will be presented detailing any affect and impact on the study. 
Issues reported in the Clinical Trial Management System will be considered for presented 
in listings as well.
5.1.2
Analysis Sets
5.1.2.1
Definitions and Derivations
For the definitions of the analysis sets refer to the individual modules.
5.1.2.2
Presentation
The analysis sets will be summarised by dose level/cohort and for all patients combined. 
For the safety analyses, participants will be reported by the actual treatment(s) received and 
grouped by their assigned target dose level of AZD0466.
Any exclusions from analysis sets will be listed together with the reasons.
5.1.3
Protocol Deviations
5.1.3.1
Definitions and Derivations
Refer to Section 4.3.7
5.1.3.2
Presentation
The incidence of important protocol deviations (IPDs) will be summarised for the ITT 
analysis set by deviation categories. The number and percentage of patients in the following 
categories will be summarised:

Number of patients with at least 1 IPD 

Number of patients with at least 1 pandemic related IPD

Number of patients with at least 1 IPD, excluding pandemic related IPDs.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
19 of 65
A listing is provided with the IPD details. 
5.1.4
Demographics
5.1.4.1
Definitions and Derivations
Age is grouped accordingly in the following categories: <50, ≥ 50 - < 65, ≥ 65 - < 75 and ≥ 
75 years. Each race category counts patients who selected only that category. 
5.1.4.2
Presentation
Demographic will be summarised and listed for all patients in the safety analysis set (SAF) 
by dose level/cohort and for all particpants combined as defined by the current relevant 
TFL standards. The following will be summarised: age, age group, sex, race, and ethnicity. 
Demographics will further be summarized separately for all patients who had confirmed or 
suspected COVID-19 infection. If less than 5 patients have confirmed or suspected 
COVID-19 infection, this will be presented in a listing rather than being summarised.
5.1.5
Baseline Characteristics
5.1.5.1
Definitions and Derivations
Body mass index (BMI) will be derived as: BMI (
	

) = 
 ()
[ ()]
5.1.5.2
Presentation
Patient characteristics at baseline (height, weight and BMI) will be summarized for all 
patients in the SAF. Baseline characteristics are listed and summarised for the FAS by dose 
level/cohort and for all patients combined as defined by the current relevant TFL standards. 
The following are summarised: height, weight and BMI.
Patient characteristics will further be summarised separately for all patients who had 
confirmed or suspected COVID-19 infection.  If less than 5 patients have confirmed or 
suspected COVID-19 infection, this will be presented in a listing rather than being 
summarised.
5.1.6
Disease Characteristics
5.1.6.1
Presentation
Disease characteristics at baseline will be summarised and listed for all patients in the SAF 
by dose level/cohort and for all patients combined as defined by the current relevant TFL 
standards. 
Summaries will be produced that present: 

NHL type

B-symptoms

Ann Arbor Staging 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
20 of 65
!
Brain involvement 
!
Spleen involvement 
!
Bone marrow involvement
!
Liver involvement 
!
Gastrointestinal involvement
!
Extranodal involvement 
!
Bulky nodal disease
!
FLIPI and FLIPI-2 score 
!
International Prognosis Index score 
!
Simplified MIPI 
!
Overexpresion of cyclin D1 
!
Chromosome translocation t(11;14)(q13;q32) 
!
EBV specification
!
TP53 mutation
!
ALK gene mutation positive
!
MYC rearrangement by FISH 
!
MYC overexpression by immunohistochemistry (IHC)
!
 rearrangement by FISH
!
 overexpression by IHC
!
 overexpresion by IHC 
!
 overexpresion by FISH 
In addition, summaries will be produced that present summary statistics on patients’ target 
lesions (TLs) and non-target lesions (NTLs), sum of target lesions, number of metastatic 
sites, other.
5.1.7
Medical History and Concomitant Disease
5.1.7.1
Definitions and Derivations
Medical history and surgical history will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA).
5.1.7.2
Presentation
Medical history, surgical history and concomitant disease will be listed and summarised for 
the SAF by dose level/cohort and for all patients combined as defined by the current TFL 
standards.
A separate summary will be presented for patients who had confirmed or suspected 
COVID-19 infection.  If less than 5 patients have confirmed or suspected COVID-19 
infection, this will be presented in a listing rather than being summarised.
CCI
CCI
CCI
CCI


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
21 of 65
Previous Disease-related Treatment Modalities
Summaries of the number and percentage of patients who have had previous disease-
related treatments will be presented for each type of modality (immunotherapy, 
cytotoxic chemotherapy, platinum chemotherapy, biologic therapy, experimental 
therapy, autologous haematopoietic stem cell transplantation, antibody-drug 
conjugate therapy, allogeneic haematopoietic stem cell transplantation, CAR-T cell 
therapy and other). 
Summaries for the number and percentage of patients who had a certain number of 
prior regimens and the best response on most recent regimen will be produced.
All summaries on previous disease related treatment modalities will be presented for 
the SAF by dose level/cohort and for all patients combined.
Prior Anticancer Treatment
The number and percentage of patients who have had prior anticancer treatments will 
be summarised for the SAF by dose level/cohort and for all patients combined.
5.1.8
Prior and Concomitant Medications
5.1.8.1
Definitions and Derivations
For the purpose of inclusion in prior and/or concomitant medication or therapy summaries, 
incomplete medication or radiotherapy start and stop dates will be imputed as detailed in 
section 4.3.8.
Prior medications, concomitant and post-treatment medications are defined based on 
imputed start and stop dates as follows:

Prior medications are those taken prior to study treatment with a stop date prior to the 
first dose of study treatment.

Concomitant medications are those with a stop date on or after the first dose date of 
study treatment, and must have started prior to or during treatment so there is at least 
one day in common with the study treatment.

Post-treatment medications are those with a start date after the last dose date of study 
treatment.
Disallowed medications will be identified through medical review prior to any analysis of 
concomitant medications.
5.1.8.2
Presentation
The number and percentage of patients who took prior and concomitant medications will be 
summarised by Anatomical Therapeutic Chemical (ATC) classification codes and the 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
22 of 65
generic term coded by World health organization (WHO) – Drug dictionary for the SAF by 
dose level/cohort and for all patients combined. 
Summary of disallowed concomitant medications will be produced. All prior, concomitant 
and post study treatment medication data will be listed.
Missing coding terms will be listed and summarised as “Not coded”.
5.2
Endpoint Analyses
This section covers details related to the endpoint analyses such as primary, secondary, 
other endpoints including sensitivity and supportive analyses. See Table 1 for details.
Efficacy analyses, except for OS, will be based on investigator assessments based on 
Lugano criteria for malignant lymphoma (Cheson et al 2014)
All efficacy results will also be listed.
All efficacy analyses will be presented by dose level/cohort.
5.2.1
Primary Endpoint – Objective Response Rate
Part B 
The primary efficacy endpoint is the objective response rate (ORR) based on the Lugano 
classification for Non-Hodgkin Lymphoma (NHL) (Cheson et al 2014).
5.2.1.1
Definition and Derivations
The Objective Response Rate (ORR) is defined as the proportion of patients who achieve 
either a partial response (PR) or complete response (CR) as determined by the investigator 
at local site per Lugano criteria prior to any evidence of progression and will be based on 
the evaluable for response analysis set. A response does not need to be confirmed to be 
included in the calculation of ORR.
Data obtained from first dose up until progression, or the last evaluable assessment in the 
absence of progression, will be included in the assessment of ORR, regardless of whether 
the patient withdraws from therapy. Patients who discontinue treatment without a response 
or progression, receive a subsequent anticancer therapy and then respond will not be 
included as responders in the ORR (i.e., the visit contributing to a response must be prior to 
subsequent therapy for the patient to be considered as a responder).
The ORR will be based on the investigator assessment using all scans, regardless of 
whether the scan was scheduled or not.
Best objective response (BoR)


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
23 of 65
If data permits, this endpoint will also be considered for Part A as exploratory. 
Best objective response is calculated based on overall visit responses from Lugano 
assessments by the investigator recorded in the eCRF. It is the best response a patient has 
had following start of treatment, but prior to starting any subsequent cancer therapy and up 
to and including Lugano progression or the latest evaluable assessment in the absence of 
Lugano progression. Categories of BoR will be based on Lugano criteria using the 
following response criteria (CR, PR, Stable disease [SD], Progressive disease (PD), and 
Not evaluable [NE]).
5.2.1.2
Primary Analysis of Primary Endpoint: ORR
Summaries will be produced that present the number and percentage of patients with a 
tumour response (CR/PR) based on the evaluable for response analysis set. ORR will be 
calculated and a binomial exact two-sided confidence interval at 80% and 95% using the 
Clopper-Pearson method will be presented for patients in the evaluable for response 
analysis set. Patients that have missing overall response assessments at all visits are 
considered as non-responders, and are therefore counted in the denominator of ORR.
BoR will be summarised by number of patients and percentage for each category (CR, PR, 
SD, PD, and NE). No formal statistical analyses are planned for BoR.
5.2.1.3
Sensitivity Analysis of ORR Endpoint
A sensitivity analysis will be performed on the ORR endpoint as in section 5.2.1.2 but with 
the intent-to-treat analysis set.
5.2.2
Secondary Endpoint: Complete Response
Part B 
The Complete Response is a secondary endpoint.
5.2.2.1
Definition and Derivations
CR rate is defined as the proportion of patients who achieve CR, according to the response 
criteria for malignant lymphoma reported by the investigator.
5.2.2.2
Primary Analysis of Secondary Endpoint: CR
The CR rate will be calculated and binomial exact two-sided confidence intervals at 80% 
and 95% will be presented for patients in the evaluable for response analysis set.
5.2.3
Secondary Endpoint: Duration of Response 
Part B 
The Duration of Response (DoR) is a secondary endpoint.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
24 of 65
5.2.3.1
Definition
DoR is defined as the time from the date of first documented objective response (CR or PR) 
until date of first documented disease progression per Lugano classification as assessed by 
investigator at local site or death (by any cause in the absence of disease progression).
5.2.3.2
Derivations
DoR (months) = (date of PFS event [progression/death] or censoring – date of first 
objective response + 1) / (365.25/12).
The end of response should coincide with the date of progression or death from any cause 
used for the PFS endpoint.  The time of the initial response is defined as the latest of the 
dates contributing towards the first visit response of CR or PR. If a patient does not 
progress following a response, then their DoR is censored on the PFS censoring date. Only 
patients who have achieved objective response are evaluated for DoR.
5.2.3.3
Primary Analysis of Secondary Endpoint: DoR
Only patients who achieved objective response (CR or PR) will be included in the 
summaries of DoR. Kaplan-Meier plots of DoR will be presented. The median DoR and 
two-sided 95% CI will be estimated using the Kaplan-Meier method. In addition, the 
proportion of patients still responding at 3, 6, and 12 months after initial response will also 
be presented.  This will be based on patients in the evaluable for response analysis set.
Swimmer plots by patient (including non-responders) that clearly show the profile of each 
patient will be produced.
5.2.4
Secondary Endpoint: Time to Objective Response
Part B 
The Time to objective Response (TTR) is a secondary efficacy endpoint.
5.2.4.1
Definition 
TTR is defined as the time from first dose until the first documentation objective response. 
5.2.4.2
Derivations
TTR (months) = (date of first objective response – date of first dose + 1) / (365.25/12).
Only patients who have achieved objective response (CR or PR) are evaluated for TTR.
5.2.4.3
Primary Analysis of Secondary Endpoint: TTR
The median TTR and two-sided 95% CI is assessed using the Kaplan-Meier method 
(without censoring because all patients have events). The number of patients with response 
at different disease assessment timepoints may be provided. This is based patients in the 
evaluable for response analysis set.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
25 of 65
5.2.5
Secondary Endpoint: Progression-free Survival (PFS)
Part B 
The Progression Free Survival (PFS) is a secondary endpoint.
5.2.5.1
Definition 
PFS is defined as the time from first dose until the date of first documented disease 
progression, per Lugano classification as assessed by the investigator at local site, or death 
(by any cause in the absence of disease progression), regardless of whether the patient 
withdraws from therapy or receives another anticancer prior to Lugano progression.
5.2.5.2
Derivations
PFS (months) = (date of PFS event [progression/death] or censoring – date of first dose + 1) 
/ (365.25/12).
Patients who have not progressed or died at the time of analysis, or have unknown status, 
are censored at the time of the latest date of assessment from their last evaluable disease 
assessment.  However, if the patient progresses or dies immediately after two or more 
consecutive missed visits, the patient is censored at the time of the latest evaluable disease 
assessment prior to the two missed visits. Note: a NE visit is not considered as a missed 
visit. 
Given the schedule visit assessment scheme (i.e., eight-weekly for the first 24 weeks then 
twelve-weekly thereafter) the definition of 2 missed visits will change. 
If the previous assessment is less than study day 113 (i.e., week 16) then 2 missing visits 
will equate to 18 weeks since the previous assessment, allowing for early and late visits 
(i.e., 2 x 8 weeks + 1 week for an early assessment + 1 week for a late assessment= 18
weeks). 
If the 2 missed visits occur over the period when the scheduled frequency of assessment 
changes from eight-weekly to twelve-weekly this will equate to 22 weeks (i.e., take the 
average of 8 and 12 weeks which gives 10 weeks and then apply the same rationale, hence 
2 x 10 weeks + 1 week for early assessment + 1 week for late assessment =22 weeks). The 
time period for the previous assessment is from study days 113 to 168 (i.e., week 16 to 
week 24).
From week 24 onwards (when the scheduling changes to 12-weekly assessments), two 
missing visits equates to 26 weeks (i.e. 2 x 12 weeks + 1 week for an early assessment + 1 
week for a late assessment = 26 weeks). 
If the patient has no evaluable disease assessments post-baseline or does not have baseline 
tumour assessment data, they will be censored at Day 1 unless they die within two visits of 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
26 of 65
baseline (16 weeks plus 1 week allowing for a late assessment within the visit window) 
when the death date qualifies as a PFS event.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
27 of 65
A summary of censoring rules and the date of PD/death or censoring are given in Table 2  
Summary of Censoring Rules for PFS. Note that censoring overrides event in certain 
specified cases.
Table 2  Summary of Censoring Rules for PFS
Situation
Date of PD/Death or Censoring
PFS Outcome
Documented Progressive Disease (PD) or death in 
the absence of progression
Date of earliest documentation of PD 
or date of death in the absence of 
progression
Event
Either no tumour assessment at baseline or no 
evaluable assessments post-baseline AND death 
prior to second scheduled post-baseline disease 
assessment  
Date of death
Event 
Either no tumour assessment at baseline or no 
evaluable assessments post-baseline AND no 
death prior to second scheduled post-baseline 
disease assessment
Date of first dose (Day 1)  
Censored
PD or death (in the absence of progression) 
immediately after ≥ 2 consecutive missed disease 
assessments as per the protocol specified 
assessment schedule
Last evaluable progression-free 
disease assessment prior to missed 
assessments
Censored
On-going with neither PD nor death at the time of 
analysis or lost to follow-up or withdrawn consent
Date of last evaluable disease 
assessment
Censored
Abbreviations: PD = progressive disease; PFS = progression-free survival
The PFS time is always derived based on scan/assessment dates not visit dates.
Disease assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules are applied:

The date of progression is determined based on the earliest of the dates of 
the component that triggered the progression.

When censoring a patient for PFS the patient is censored at the latest of the 
dates contributing to a particular overall visit assessment. 
Note: for TLs only the latest scan date is recorded out of all scans performed at that 
assessment for the TLs and similarly for NTLs only the latest scan date is recorded out of 
all scans performed at that assessment for the NTLs.
Duration of follow-up for PFS is defined as follows:
Duration of follow-up for PFS (months) = (date of PFS event (progression/death) or 
censoring – date of first dose + 1) / (365.25/12).


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
28 of 65
5.2.5.3
Primary Analysis of Secondary Endpoint: PFS
The analysis of PFS is based on the ITT analysis set. The number and percentage of 
patients experiencing a PFS event (broken down by type of event/censoring) and Kaplan-
Meier plots of PFS will be presented. The median PFS and its two-sided 95% CI will be 
estimated using the Kaplan-Meier method (if patient numbers allow).
The treatment status at progression of patients at the time of analysis will be summarised.  
This includes the number (%) of patients who were on treatment at the time of progression, 
the number (%) of patients who discontinued study treatment prior to progression, the 
number (%) of patients who have not progressed and were on treatment or discontinued 
treatment.
A summary of the ‘potential’ duration of follow-up for PFS is included using median 
(range). This is presented for censored patients (including all types of PFS censoring).
The proportion of patients alive and progression free at every 3 months (3, 6, 9, 12, etc.) 
and associated two-sided 95% CI will be estimated using the Kaplan-Meier method. 
5.2.5.4
Sensitivity Analysis of PFS Endpoint
A sensitivity analysis will be performed censoring PFS at the date of the last 
progression-free disease assessment prior to initiation of subsequent anticancer treatment.
Separately, a sensitivity analysis will also be conducted to assess the impact of COVID-19 
related deaths on PFS.  That is, patients who had a PFS event due to death where the 
primary or secondary cause of death was COVID-19 infection or COVID-19 infection was 
reported as a fatal AE, will be censored on the last available tumour assessment prior to 
COVID-19 infection related death.
5.2.6
Secondary Endpoint: Overall Survival
The Overall Survival (OS) is a secondary efficacy endpoint.
Part B.
If data permits, this endpoint will also be considered for Part A as exploratory. 
5.2.6.1
Definition
Overall survival is defined as the time from the date of first dose until death due to any 
cause regardless of whether the patient withdraws from study therapy or receives another 
anticancer therapy.
5.2.6.2
Derivations
OS (months) = (date of death or censoring – date of first dose + 1) / (365.25/12).


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
29 of 65
Any patient not known to have died at the time of analysis will be censored based on the 
last recorded date on which the patient was known to be alive. Patients known to be alive or 
dead after the data cut-off for analysis will be censored at the DCO.  Patients lost to follow-
up will be censored at the date the patient is last know have been alive.
Note: Survival calls will be made in the week following the date of DCO for the analysis, 
and if patients are confirmed to be alive or if the death date is post the DCO date these 
patients will be censored at the date of DCO.  The status of ongoing, withdrawn (from the 
study) and “lost to follow-up” patients at the time of the final OS analysis should be 
obtained by the site personnel by checking the patient’s notes, hospital records, contacting 
the patient’s general practitioner and checking publicly-available death registries. In the 
event that the patient has actively withdrawn consent to the processing of their personal 
data, the vital status of the patient can be obtained by site personnel from publicly available 
resources where it is possible to do so under applicable local laws.
Note: For any OS analysis performed prior to the final OS analysis, in the absence of 
survival calls being made, it may be necessary to use all relevant CRF fields to determine 
the last recorded date on which the patient was known to be alive for those patients still on 
treatment (since the SURVIVE module is only completed for patients off treatment if a 
survival sweep is not performed). The last date for each individual patient is defined as the 
latest among the following dates recorded on the CRFs:
• AE start, stop and change in severity dates
• Admission and discharge dates of hospitalization
• Study treatment date
• End of treatment date
• Concomitant medication start and stop dates
• Laboratory test dates
• Date of vital signs
• Disease assessment dates on CRF
• Start and stop dates of alternative anticancer treatment
• Date last known alive on survival status CRF
• End of study date
Duration of follow-up for OS is defined as follows:
Duration of follow-up for OS (months) = (date of death or censoring (date last known to be 
alive) – date of first dose + 1) / (365.25/12).


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
30 of 65
5.2.6.3
Handling of Dropouts and Missing Data
If a patient is known to have died where only a partial death date is available, then the date 
of death is imputed as the latest of the last date known to be alive +1 from the database and 
the death date using the available information provided: 

For Missing day only – using the 1st of the month. 

For Missing day and Month – using the 1st of January.
If there is evidence of death but the date is entirely missing, it is treated as missing, i.e., 
censored at the last known alive date.
5.2.6.4
Primary Analysis of Secondary Endpoint: OS
The analysis of OS is based on the ITT analysis set. The number and percentage of patients 
experiencing an OS event and Kaplan-Meier plots of OS will be presented. The median OS 
and two-sided 95% CI will be estimated using the Kaplan-Meier method (if patient 
numbers allow).
Summaries of the number and percentage of patients who have died, those still in survival 
follow-up, those lost to follow-up and those who have withdrawn consent will be provided.
A summary of the ‘potential’ duration of follow-up for OS is included using median 
(range). This is presented separately for censored patients.
The proportion of patients alive at every 3 months (3, 6, 9, 12, etc.) and associated two-
sided 95% CI will be estimated using the Kaplan-Meier method. 
5.2.6.5
Sensitivity Analysis of OS Endpoint
A sensitivity analysis will also be conducted to assess the impact of COVID-19 related 
deaths on OS. That is, patients who had a OS event due to death where the primary or 
secondary cause of death was COVID-19 infection or COVID-19 infection was reported as 
a fatal AE, will be censored on the date of their COVID-19 infection related death.
5.3
Pharmacodynamic Endpoint(s)
Refer to the individual modules.  
5.4
Pharmacokinetics
For the definitions of the pharmacokinetic variables refer to the individual modules.
AZD0466 exposure is evaluated indirectly by AZD4320 concentration measurement. The 
term ‘total’ AZD4320 is defined as the sum of dendrimer-conjugated AZD4320 and 
released AZD4320. ‘Released’ AZD4320 in the plasma is the sum of protein bound and 
unbound AZD4320, which is not dendrimer-conjugated.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
31 of 65
5.4.1
Pharmacokinetic Concentrations
Plasma concentrations of total and released AZD4320 and its metabolites (if available and 
appropriate) will be listed by actual and relative (to dose administration) sampling time.  
The following summary statistics will be presented for the concentrations at each time point 
separately by dose level and dose level/cohort: 

n below LLOQ (only for concentrations)

Geometric Mean (gmean, calculated as exp [μ], where μ is the mean of the data on a 
logarithmic scale)

Geometric CV% (gCV, calculated as 100 √ [exp(s2)-1], where s is the standard 
deviation of the data on a log scale)

Gmean + gSD (gSD calculated as exp[μ±s])

Gmean - gSD

Arithmetic Mean

Arithmetic SD (SD)

Minimum

Median

Maximum

Number of observations 
In listings, concentrations below the lower limit of quantification (LLOQ) will be presented 
as BLQ.  In listings and tables where the terms BLQ or LLOQ are included, the LLOQ 
(numerical value) will be included in a footnote. 
For the calculation of statistics, concentrations that are BLQ will be handled as follows at 
each time point:
If ≤50% of the concentrations are BLQ, all BLQ values will be set to the LLOQ, and all 
descriptive statistics will be calculated.
If >50%, but not all, of the concentrations are BLQ, the geometric mean, geometric CV, 
arithmetic mean, and arithmetic SD will be reported as ‘NC’ (not calculable).  The 
maximum value will be reported from the individual data, and the minimum and 
median will be set as ‘BLQ’.
If all concentrations are BLQ, no descriptive statistics will be calculated.  ‘NA’ (not 
applicable) will be presented for geometric CV, and arithmetic SD, and ‘BLQ’ will be 
presented for geometric mean, arithmetic mean, median, minimum, and maximum.
For PK concentration and parameter data, if there are <3 values available at a time point, 
only the maximum, minimum, and n will be reported; the remaining descriptive statistics 
will be reported as ‘NC’.  Concentrations that are BLQ are considered a value.
Missing samples will be reported as no sample ("NS") and excluded from analysis. 
Source data shall be used in all derived PK concentrations without prior rounding 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
32 of 65
The following figures, in black and white, will be generated for total and released 
AZD4320, and its metabolites (if available and appropriate):

Patient Profiles, Plasma Concentration Time Data – Linear Scale

Patient Profiles, Plasma Concentration Time Data - Semi-Logarithmic Scale 

Gmean (± gSD), Plasma Concentration Time Data 

Gmean, Plasma Concentration Time Data - Semi-Logarithmic Scale
Individual figures will be plotted using concentration versus actual time, and mean figures 
will be plotted using concentration versus nominal time, by treatment or dose level and 
cycle/PK day, as needed. Scatter plots of PK parameters versus dose, or log-dose, may also 
be considered to assess dose proportionality.
5.4.2
Pharmacokinetic Parameters Calculation and Summary 
The pharmacokinetic (PK) parameters of the concentration data for AZD4320 and its 
metabolites (if applicable) will be derived using non-compartmental methods in Phoenix®
WinNonlin® Version 8.1 or higher as data applicable.  The PK parameters are calculated / 
estimated according to AstraZeneca standards
Derived PK parameters will be summarized by cycle, separately per dose level/cohort.  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) 

gCV (calculated as 100 √ [exp(s2)-1], where s is the standard deviation of the data on 
a log scale) 

Gmean + gSD (gSD calculated as exp[μ±s])

Gmean - gSD

Arithmetic mean calculated using untransformed data 

Standard deviation calculated using untransformed data 

Minimum 

Median

Maximum 

Number of observations 
The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings for PK parameters: 

Individual PK parameters will be presented to four significant digits, with the 
exception of tmax, which will be presented to two decimal places. 

Parameters derived directly from source data (e.g. Cmax,) shall be reported with the 
same precision as the source data (if this is not four significant digits). 

The mean, geometric mean, median and SD values will be reported to four significant 
digits, all other descriptive statistics will be reported to three significant digits except 
for CV% which will be presented to one decimal place. 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
33 of 65

For tmax the minimum and maximum will be presented to two decimals places and all 
other descriptive statistics will be presented to three decimal places. 

Estimates and confidence intervals in the form of percentages will be presented to 
two decimal places. 
5.4.3
Criteria for Handling Concentrations Below the Limit of 
Quantification or Missing Concentrations in Pharmacokinetic 
Analysis
For the non-compartmental analysis (NCA) and individual plot, if a BLQ value occurs 
before the first measurable concentration, it will be treated as zero.  Thereafter, BLQ values 
will be treated as missing for PK analysis, with special situations described below. The 
following rules apply with special situations defined below: 

Where 2 or more consecutive concentrations are BLQ at the end of a profile, the 
profile will be deemed to have terminated and any further quantifiable concentrations 
will be set to missing for the calculation of the PK parameters unless they are 
considered to be a true characteristic of the profile of the drug.

If an entire concentration-time profile is BLQ, the profile will be excluded from the 
PK analysis.

If a pre-dose measurement for the first dose of cycle 1 is missing it will be set to zero 
for a single dose, or to the minimum observed concentration for a repeat dose.
5.4.4
Treatment of Outliers in Pharmacokinetic Analysis
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis.  However, the 
exclusion of data must have strong justification and will be documented in CSR.  
Quantifiable pre-dose concentration values in the first dosing of cycle 1 (i.e., the first ramp-
up dose) will be considered anomalous and set to missing for the PK analysis. 
5.5
Immunogenicity
Refer to the individual modules.  
5.6
Safety Analyses 
The domain safety covers exposure, adverse events, clinical laboratory, vital signs, ECG, 
B-symptoms, and tumour lysis syndrome (TLS). 
Tables will be provided for the SAF, listings are provided for all patients or the SAF 
depending on the availability of data.
All safety analysis will be presented by dose level/cohort. The results from the ramp-up 
period will be presented separately.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
34 of 65
5.6.1
Exposure
5.6.1.1
Definitions and Derivations

Total duration of exposure is defined by the last date of actual dosing (i.e., a dose > 0 
mg/L was given) in the last cycle plus 28 days (28 is by default, the number of days 
in a cycle or until the next scheduled dose, there 7 days during the intrapatient ramp-
up and 21 days thereafter) minus the date of first treatment study treatment.
-
For patients who die whilst on study treatment or if a DCO occurs, duration 
of exposure (months/weeks) is defined as date of death/DCO (whichever 
occurs first) minus the date of first treatment plus 1 day.

Actual treatment duration = total treatment duration, excluding dose interruptions not 
in accordance with the protocol, and any planned no dose periods.

Dose intensity of study treatment is addressed by considering relative dose intensity 
(RDI), where RDI is the percentage of the actual dose delivered relative to the 
intended dose through to treatment discontinuation. More specifically, RDI is defined 
as follows:
-
RDI = 100% × d/D, where d is the actual cumulative dose delivered up to the 
actual last day of dosing and D is the intended cumulative dose up to the actual 
last day of dosing.  D is the total dose that would be delivered, if there were 
no modification to dose or schedule.

The duration of an interruption will be calculated as [date/time treatment resumed –
date/time treatment stopped].  Overall duration of interruption will be calculated as 
the sum of all individual interruptions during the study.
Duration of dose delays will be derived for doses indicated as being delayed on the eCRF.  
For each individual dose, the duration for dose delay is the number of days the dose was 
received outside of the original planned dosing schedule. Overall duration of dose delays 
will be calculated as the sum of all individual dose delays during the study.
5.6.1.2
Presentation
The total and actual duration of exposure to study treatment in months will be summarised 
by descriptive statistics and by frequency. Dose intensity will be summarised by descriptive 
statistics. Exposure to investigational product (IP)(s) i.e. total amount of study drug received 
will be listed for all patients. Exposure swimmer plot(s) will be produced, with a line 
presented for each patient to display relevant exposure and disposition details. 
Dosing deviations for study treatment (s) will be summarized with reasons for deviations for 
the following categories: reductions and interruptions. Dosing delays will be derived based 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
35 of 65
on the scheduled dosing dates using the previous dose given as reference. The number of 
patients with dosing delays and total dose delays will be summarised.
The number of cycles of dose received will also be summarised.
5.6.2
Adverse Events
5.6.2.1
Definitions and Derivations
The latest or current version of MedDRA will be used to code the adverse events (AEs). 
AEs will be graded according to the National Cancer institute Common Terminology 
Criteria for AEs (using the CTCAE version 5.0).
AEs are defined as treatment emergent if they onset or worsen (by investigator report of a 
change in intensity/severity), during the treatment emergent phase defined below. 
Worsening is determined by comparison with the pre-treatment severity of the AE recorded 
closest to the start of dosing.
When assigning AEs to the relevant phase of the study the following rules apply and any 
deviations must be agreed by the study team:

Pre-treatment phase – All AEs with a start date after signing the informed consent 
form (ICF), prior to the first administration of IP that do not subsequently go on to 
worsen during the treatment emergent phase.

Treatment emergent phase – All AEs starting or worsening (severity) following the 
first administration of IP for the duration of the treatment period, up to and 
including 30 days after the last dose of the study treatment as per the study safety 
follow-up period but prior to subsequent cancer therapy. AEs with missing start 
time which occur on the same day as first IP administration will be reported as 
treatment emergent. Note that the treatment emergent phase includes the on 
treatment and safety follow-up periods.

Off-treatment phase – All AEs starting more than 30 days after last dose of study 
treatment or once subsequent cancer therapy is started, whichever is earlier.
Serious Adverse Events (SAEs)
A serious adverse event (SAE) is an AE 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. 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
36 of 65

Is a congenital anomaly or birth defect in offspring of the patient

Is an important medical event that may jeopardise the patient 
AEs of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of the IP and may require close monitoring and rapid communication by 
the investigator to the sponsor.
The following events will be considered to be AESIs:

Tumour lysis syndrome

Hepatoxicity, including potential Hy’s Law, Drug-induced liver injury, Bilirubin 
increases with transaminase (ALT or AST, or both ALT and AST) increase

QRS amplitude shortening
Other categories may be added, or existing terms may be modified as necessary. An 
AstraZeneca medically qualified expert after consultation with the Global Patient Safety 
Physician has reviewed the AEs of interest and identified which higher-level terms and 
which preferred terms contribute to each AESI. Further reviews may take place prior to 
database lock (DBL) to ensure any further terms not already included are captured within 
the categories. 
Other significant adverse events (OAE)
During the evaluation of the AE data, an AstraZeneca medically qualified expert reviews 
the list of AEs that were not reported as SAEs and AEs leading to discontinuation of study 
treatment. Based on the expert’s judgement, AE of particular clinical importance may, after 
consultation with the Global Safety Physician, be considered other significant adverse 
events (OAEs) and reported as such in the Clinical Study Report. A similar review of 
laboratory values, vital signs, ECGs, and other safety assessments will be performed for 
identification of other significant adverse events. This review takes place prior to database 
lock, and any AEs identified will be fully documented in meeting minutes. Further review 
following database lock may result in ad-hoc OAEs being identified, in this case, the other 
OAEs and resulting summaries will be fully documented in the CSR.
Examples of these are marked haematological and other laboratory abnormalities, and 
certain events that lead to treatment (other than those already classified as serious), dose 
reduction or significant additional treatment.
5.6.2.2
Presentation
All AEs reported in the treatment emergent phase will be summarised and listed. 
Pre-treatment AEs and off-treatment AEs will be listed.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
37 of 65
Treatment emergent adverse events (TEAEs) will be counted once for each patient for 
calculating percentages of patients experiencing TEAE. In addition, if the same TEAE 
occurs multiple times within a particular patient, the highest severity and level of 
relationship observed will be reported. For tables by MedDRA system organ class (SOC) 
and MedDRA preferred term (PT), patients with multiple TEAEs will be counted once for 
each SOC/PT.
An overall summary table of the number of patients experiencing each category of adverse 
events will be produced. The number of patients experiencing TEAEs by MedDRA SOC 
and PT will be summarised and the type of incidence, severity, and relationship to IP will 
be summarised. Further splits by CTCAE grade, causal relationship to IP and adverse 
events with Grade 3-4 will also be also summarised.
Separate tables present adverse events leading to discontinuation, serious adverse events, 
IP-related adverse events, and other significant adverse events.
Details of any deaths will be summarised and listed for all patients. AEs leading to death 
will also summarised.
The following summaries for the number and percentage of patients with AEs will be 
created by dose level/cohort and overall as appropriate: 

All AEs in any category

AEs by SOC and PT 

AEs by SOC, PT and maximum reported CTCAE grade 

AEs above 5% of patients by PT (percentage for the threshold may be adapted as 
appropriate) 

AEs assessed by investigator as possibly related to study treatment by SOC and PT  

AEs leading to hospitalisation, by SOC and PT 

AEs by PT and maximum reported intensity

AEs by PT and relationship to study treatment

AEs leading to discontinuation of study treatment by SOC and PT 

AEs leading to discontinuation of study treatment assessed by investigator as 
possibly related to study treatment by SOC and PT

AEs assessed by investigator as possibly related to study treatment by SOC, PT and 
maximum reported CTCAE grade.

AEs of CTCAE grade 3 or higher assessed by investigator as possibly related to 
study treatment by SOC and PT

AEs leading to study treatment dose reduction by SOC and PT Note: For patients 
who have a dose modification, all AEs (due to drug or otherwise) will be assigned 
to the initial dose group.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
38 of 65

AEs leading to study treatment interruption (infusion interruption or missed dose) 
by SOC and PT

Non-serious AEs occurring in greater than 5% of patients

SAEs by SOC and PT
SAEs
SAEs will be summarised as described above for the TEAEs. 
AEs of special interest
Grouped summary tables of certain MedDRA preferred terms will be produced and may 
also show the individual preferred terms which constitute each AESI grouping. Groupings 
will be based on preferred terms provided by the medical team prior to DBL, and a listing 
of the preferred terms in each grouping will be provided.
Summaries of the above-mentioned grouped AE categories include number and percentage 
(%) of patients who have:

At least one AESI presented by event outcome

At least one AESI causally related to IP

At least one AESI leading to discontinuation of study treatment.
A summary of total duration (days) of AESI will be provided for events which have an end 
date, and this may be supported by summaries of ongoing AESIs at death and, separately, at 
data cut-off.
5.6.3
Death
5.6.3.1
Presentations
A summary of deaths will be provided with the number and percentage of patients 
categorised as:

Related to disease under investigation only

AE outcome = death only

Both related to disease under investigation and with AE outcome = death

AE with outcome = death > 30 days after last study treatment

Other deaths
A corresponding listing will also be produced.
5.6.4
Clinical Laboratory, Blood Sample
5.6.4.1
Definitions and Derivations
Laboratory tests will be grouped according to chemistry and haematology




STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
40 of 65
defined. Maximum post-baseline CTC will be also calculated. Absolute values will be 
compared to the local laboratory reference range and classified as low (below range), 
normal (within range or on limits of range) and high (above range). All values classified as 
high or low will be flagged on the listings.
Liver Function Parameters
Patients with elevated post-baseline alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) or Total Bilirubin that fall into these categories will be identified. 
The number and percentages of these patients will be tabulated for the following parameters 
in Table 4. 
Table 4     Liver Function Parameters
Liver Function Parameters
Category
ALT
•
≥3 × – ≤5 × ULN 
•
>5 × – ≤8 × ULN
•
>8 × – ≤10 × ULN
•
>10 × – ≤20 × ULN   
•
>20 × ULN
AST
•
≥3 × – ≤5 × ULN 
•
>5 × – ≤8 × ULN
•
>8 × – ≤10 × ULN,
•
>10 × – ≤20 × ULN   
•
>20 × ULN
Total bilirubin
•
≥2 × – ≤3 × ULN
•
>3 ×  – ≤5 × ULN
•
>5 × ULN 
ALT or AST
•
≥3 × – ≤5 × ULN
•
>5 × – ≤8 × ULN
•
>8 × – ≤10 × ULN,
•
>10 × – ≤20 × ULN   
•
>20 × ULN
Potential Hy’s law
•
(AST ≥ 3 × ULN or ALT ≥ 3 × ULN) and (Total 
Bilirubin ≥ 2×ULN)a 
ULN:  upper limit of normal range.
It includes all patients who have ALT or AST≥3xULN and total bilirubin (BILI) ≥2xULN, and in which 
the elevation in transaminases precede or coincide with (that is, on the same day as) the elevation in BILI.
5.6.4.2
Presentations
For all continuous laboratory assessments the absolute values and change in each parameter 
from baseline to each post-baseline visit will be summarised using descriptive statistics at 
each time point by dose level/cohort as appropriate. Graphical presentations using box plots 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
41 of 65
of absolute values and change from baseline values for haematology and clinical chemistry 
parameters will also be shown.
Laboratory abnormalities occurring from the start of IP administration to the last 
assessment on study will be presented. Worst toxicity grade, rates of grade 3-4 toxicity, and 
grade shifts of 2 or more from baseline to the maximum grade will be presented. 
Summaries indicating hyper- and hypo- directionality of change will be produced, where 
appropriate. Laboratory parameters that cannot be graded via NCI Common Terminology 
Criteria for Adverse Events (CTCAE) will be summarised with frequencies of post-baseline 
laboratory values categorized as low (L), normal (N), or high (H) using laboratory normal 
ranges compared to baseline.
Listings will be provided for all laboratory results. Laboratory parameters will be assessed 
at baseline as well as throughout the study.
Also, a separate table for the changes in platelets and neutrophils will be summarised over 
time per dose level/cohort, as appropriate.
Liver Function Parameters
Number and percentage of particpants with elevated post-baseline ALT, AST, or Total 
Bilirubin will be tabulated. Individual patient data where elevated ALT or AST plus total 
bilirubin fall into the “Potential Hy’s law” will be summarised and/or listed.
Following Safety Review Committee (SRC) review of emerging data additional laboratory 
safety assessment sample times may be added or removed if indicated by the emerging 
data. For presentation of the results this analysis plan will follow the initial time schedule 
for these parameters.
5.6.5
Clinical Laboratory, Urinalysis
5.6.5.1
Definitions and Derivations
Laboratory urinalysis variables that will be measured are detailed in Table 3. Laboratory 
parameters will be assessed at baseline as well as throughout the study. 
Change from baseline in urinalysis endpoints will be calculated for each post-done visit. 
CTC grade will be calculated at each visit for tests with CTC grading defined. Maximum 
post-baseline CTC will also be calculated. Absolute values will be compared to the local 
laboratory reference and classified as low (below range), normal (within range or on limits 
of range) and high (above range). All values classified as high or low will be flagged on the 
listings.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
42 of 65
5.6.5.2
Presentations
Laboratory abnormalities occurring from the start of IP administration to the last 
assessment on study will be presented. Worst toxicity grade, rates of grade 3-4 toxicity, and 
grade shifts of 2 or more from baseline to the maximum grade will be presented. 
Summaries indicating hyper- and hypo- directionality of change will be produced, where 
appropriate. Laboratory parameters that cannot be graded via NCI CTCAE will be 
summarised with frequencies of post-baseline laboratory values categorized as low (L), 
normal (N), or high (H) using laboratory normal ranges compared to baseline.
Listings will be provided for all laboratory results including urinalysis.
5.6.6
Vital Signs
5.6.6.1
Definitions and Derivations
Body temperature, blood pressure, pulse rate, oxygen saturation and body weight will be 
assessed.
5.6.6.2
Presentations
Vital signs will be assessed at baseline and throughout the study. Vital signs may be 
summarised by study visit which may include descriptive statistics for the value of the 
parameters and the changes from baseline. 
Absolute values and change from baseline for vital signs data at each timepoint will be 
presented using box plots. 
5.6.7
B symptoms
5.6.7.1
Presentations
Information on B symptoms (unintentional weight loss of 10% or more within the previous 
6 months, Disease related intermittent fevers >38 C for ≥ 2 weeks without other evidence of 
infection, Drenching Sweats Especially at Night for > 1 month without evidence of 
infection, Worsening of B-symptoms compared to baseline, Worsening of B-symptoms 
compared to prior visit, commnets) will be listed for all patients and visits.
5.6.8
Tumour lysis syndrome
5.6.8.1
Definitions and Derivations
Tumour lysis syndrome (TLS) is an important identified risk for AZD0466. TLS 
prophylaxis is mandatory for all patients starting 3 days before the first dose of AZD0466, 
which should be followed in addition to institutional guidelines.
5.6.8.2
Presentations
Listing of TLS Monitoring including potassium, calcium, phosphate, uric acid, cardiac 
arrhythmia, seizure, grade and creatinine abnormality will be presented.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
43 of 65
A TLS-key patient table should be provided. The listing should include: Highest CTCAE 
grade for TLS event, presence of laboratory TLS (present/non-present), highest Cairo 
Bishop (Cairo and Bishop 2004) grading for clinical TLS event (if criteria clinical TLS are 
met).
5.6.9
Electrocardiogram
5.6.9.1
Definitions and Derivations
Electrocardiogram (ECG) parameters (triplicate recordings) will be assessed at baseline as 
well as throughout the study. The average of the triplicate measures taken will be used in all 
calculations. ECG parameters include PR, RR, QRS, QT, QTcB, and QTcF. The QTcF is 
considered as the primary correction method to assess patient cardiac safety. 
From these resting 12-lead ECGs values of the QT and RR intervals and the QT interval 
corrected for heart rate using Fridericia’s correction (QTcF) will be derived using the 
following formula:
QTcF = 
√


where RR is in seconds 
The values of QTcF (milliseconds) will be re-derived from the values of RR and QT during 
the creation of the reporting database.
The notable ECG interval values while on treatment are:

Maximum QTcF, QTcB and QTc intervals 450 milliseconds, > 480 milliseconds, and 
> 500 milliseconds. 

Maximum changes from baseline in QTcF and QTcB 30, >60, and 90 milliseconds. 
5.6.9.2
Presentations
ECG parameters will be summarised using descriptive statistics by visit and change from 
baseline in ECG endpoints will be calculated for each post-dose visit. Absolute values and 
change from baseline for ECG data at each timepoint will be presented using boxplots.
The number and percentage of patients having notable ECG interval values on treatment 
will be summarised.
5.6.10
Echocardiogram (ECHO)
5.6.10.1
Definitions and Derivations
In addition to screening, an ECHO should be done within 14 days after an abnormal ECG 
finding (T wave inversion/flattening, significant QRS amplitude changes or symptomatic 
patient, etc) or as soon as possible when clinically indicated. If an ECHO cannot be taken, a 
multi-gated acquisition (MUGA) scan to assess left ventricular ejection fraction (LVEF) 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
44 of 65
will be done. In case of any T wave abnormality, the ECHO (or MUGA) should be repeated 
at the 30-day follow-up visit to address the question of recovery, during the off-treatment 
period.
5.6.10.2
Presentations
Absolute value, change from baseline and percentage change from baseline will be 
presented for LVEF.
5.6.11
Other Safety Assessments
Refer to the individual modules.
6
INTERIM ANALYSIS - CORE
Refer to the individual modules.
7
STUDY OBJECTIVES – MODULE 1
The objectives and endpoints for the module 1 are provided below.
Refer to Section 2.1.  Exploratory endpoints related to the pharmacodynamics, biomarkers 
and DNA may be reported outside of the CSR and will not be described further within this 
SAP.




STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
46 of 65
8.2
Overall Design
Module 1 will evaluate the safety, tolerability, PK, and preliminary efficacy of AZD0466 as 
monotherapy. Module 1 comprises 2 parts: AZD0466 monotherapy dose escalation in 
patients with advanced B-NHL (Part A) followed by 3 independent dose expansion cohorts 
of patients with defined lymphoid malignancies (Part B). The Module 1 schema is 
illustrated in Figure 1.

Part A: Phase 1 dose setting to assess the safety and tolerability and determine dose(s) 
and schedule(s) to be evaluated in Part B. 

Part B: Phase 1b/2a dose expansion to assess the preliminary efficacy of AZD0466 in 
3 select patient populations: Relapsed/refractory Mantle cell lymphoma (R/R MCL) 
(Cohort B1) , Relapsed/refractory follicular lymphoma (R/R FL) or 
Relapsed/refractory Marginal zone lymphoma (RR MZL) (Cohort B2), and 
Relapsed/refractory diffuse large B-cell lymphoma (RR DLBCL) (Cohort B3).
An SRC will be responsible for making recommendations for dose escalation or dose 
de-escalation decisions after each dose level. The SRC will also assess all evaluable 
patients to establish the Recommended Phase II dose (RP2D) and determine if the study 
should progress to Part B. Refer to Appendix A 5 A5 of the CSP for details on the SRC. 
Further details on the decision rules for dose escalation are described with in the SRC 
charter. 
Treatment will be administered in the outpatient setting with close monitoring. All patients 
will be treated until disease progression or unacceptable toxicity or withdrawal of consent. 
All patients should be followed for survival every 3 months after the last clinic visit until 
withdrawal of consent or end of study for the purpose of assessing survival status (see 
Section 7.1 of CSP). Patients who achieve a CR will be followed for relapse of disease until 
death.
9
CHANGES TO PLANNED PROTOCOL ANALYSES –
MODULE 1 
Not Applicable.
10
DATA ANALYSIS CONSIDERATION – MODULE 1 
10.1
Timing of Analyses
The details of the analyses planned during the conduct of this study is outlined in Table 5. 


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
47 of 65
Table 5 Summary of analyses During Study Conduct
Analysis
Trigger
Analysis Part A: Dose Escalation
When the MTD has been determined and 
the last patient to be recruited has had the 
opportunity to complete 2 cycles of 
treatment or has discontinued or withdrawn 
from treatment.
Interim Analysis Part B: cohort B1 
Interim analysis will be performed when 
 
.
Interim Analysis Part B: cohort B2
Interim analysis will be performed when 
 
.
Final Analysis Expansion Cohorts (B1, B2 
and B3)
Final analysis will be performed when 
either the last patient from all expansion 
cohorts has had the opportunity to 
 
 
.
10.2
Analysis Populations
The analysis populations for Module 1 Part A and Part B are summarised in Table 6.
Table 6 Module 1 Part A and Part B Analysis Populations 
Analysis population
/Analysis set
Description
Endpoint/Output
Enrolled/Screened 
All patients who sign the ICF
Disposition
Safety 
All patients who received at 
least 1 dose of AZD0466.
For safety analyses, participants 
will be reported by the actual 
treatment(s) received and 
grouped by their assigned target 
dose level of AZD0466
Demography
Baseline 
Exposure
Safety 
Performance status
PK concentrations and 
parameters listings
Intent-to-treat 
All patients who received at 
least 1 dose of AZD0466
OS
PFS
ORR
Evaluable for Response
All patients, with measurable 
disease at baseline, who have 
ORR
DoR
CCI
CCI
CCI


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
48 of 65
received at least 2 doses of 
AZD0466 at the target dose 
level in Cycle 1
CR rate
TTR
DLT Evaluable 
Patients enrolled in dose 
escalation who have received at 
least 2 doses of AZD0466 at the 
target dose level (67% of target 
doses from Day 8 to Day 22 in 
Cycle 1) and have completed the 
safety follow-up through the 
DLT evaluation period or have 
experienced a DLT
DLT
Pharmacokinetics 
Dosed patients with reportable 
plasma concentrations and no 
important AEs or protocol 
deviations that may impact PK
Plasma concentrations
and derived PK 
parameters 
DLT = dose-limiting toxicity; PK = pharmacokinetics; ICF = informed consent form; PFS = progression free 
survival; TTR=Time to response, OS = overall survival; DoR = duration of response; ORR = overall response 
rate; CR = complete response.
10.3
General Considerations
Refer to Section 4.3 of this SAP.
10.3.1
Visit Window
Refer to Section 4.3.4 of this SAP.
An example of visit windows for physical examination data up to Cycle 3 Day 1 for 
Module 1 are given below:

Cycle 1 Day 8 (Study Day 8): 2-11

Cycle 1 Day 15 (Study Day 15): 12-18

Cycle 1 Day 22 (Study Day 22): 19-25

Cycle 2 Day 1 (Study Day 29): 26-32

Cycle 2 Day 8 (Study Day 36): 33-39

Cycle 2 Day 15 (Study Day 43): 40-46

Cycle 2 Day 22 (Study Day 50): 47-53

Cycle 3 Day 1 (Study Day 57): 54-60
10.3.2
Handling of Unscheduled Visits 
Refer to Section 4.3.4. 
10.3.3
Multiplicity/Multiple Comparisons
Not Applicable.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
49 of 65
10.3.4
Handling of Protocol Deviations in Study Analysis
Refer to Section 4.3.7.
10.3.5
Sample Size
10.3.5.1
Modified toxicity probability interval-2 (mTPI-2)
The mTPI-2 employs a simple beta-binomial Bayesian model. The posterior density of the 
toxicity probability is divided into multiple intervals with equal length. These intervals are 
categorized as underdosing (below), proper dosing (equivalent), and overdosing (above) in 
terms of target toxicity. The underdosing interval corresponds to a dose escalation, 
overdosing corresponds to a dose de-escalation, and proper dosing corresponds to staying at 
the current dose. 
For specific dose escalation rules, refer to Section 10.6.6.1 of CSP and Section 10.3.5.2 of 
SAP. 
10.3.5.2
Dose Escalation
Module 1 Part A (Dose Escalation): The primary objective of Part A is to identify the 
maximum tolerated dose (MTD) of AZD0466 monotherapy. 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/expansion/ de-escalation decision can 
be made (unless unacceptable toxicity is encountered prior to enrolment of  patients), 
while the maximum number of patients to be enrolled in any given dose cohort will be 
capped at patients. Dose escalation (or de-escalation) will be determined by mTPI-2 with 
a target DLT rate of 
% and an equivalence interval of (
%, 
%). A dose level will be 
considered non-tolerated with no additional patients enrolled at that dose level, if it has an 
estimated 95% or more probability (P) of exceeding the target DLT rate of 
 
 with at least  patients treated at that dose level. Five doses (DL-1, 
DL1 to DL4, start at DL1), 
total patients, with a maximum of  being DLT evaluable at 
each dose level. The structure of the dose escalation part is shown in Figure 1. 
10.3.5.3
Dose Expansion
Module 1 Part B (Dose Expansion)
Separate expansion cohorts will enrol 3 distinct populations of patients with B-cell non-
Hodgkin's lymphoma: patients diagnosed with R/R MCL will be enrolled in Cohort B1, 
R/R FL or R/R MZL patients in Cohort B2, and R/R DLBCL patients in Cohort B3. 
Cohorts B1 and B2 will recruit up to
 patients, and Cohort B3 will recruit approximately 
 patients. These sample sizes have been determined to ensure confidence intervals 
constructed around the complete ORR, as calculated after all patients have had the 
opportunity to complete 2 treatment cycles, will provide sufficient information to enable 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
50 of 65
decisions to be made around the likely success of future studies in these patient 
populations, using methodology described in Frewer et al 2016 (Frewer et al 2016).
 
 
 
 
 
Refer to Section 10.9.2 of the CSP for details of the target values for cohorts B1, B2 and 
B3.
11
STATISTICAL ANALYSIS – MODULE 1 
This section provides information on definitions, derivation and analysis/data presentation 
per domain.
11.1
Study Population
11.1.1
Patient Disposition and Completion Status
Refer to Section 5.1.1 of this SAP.
11.1.2
Analysis Sets
11.1.2.1
Definitions and Derivations
Refer to Table 6 of Section 10.2 of this SAP.
11.1.3
Protocol Deviations
Refer to Section 5.1.3 of this SAP.
11.1.4
Demographics
Refer to Section 5.1.4 of this SAP.
11.1.5
Baseline Characteristics
Refer to Section 5.1.5 of this SAP.
11.1.6
Disease Characteristics
Refer to Section 5.1.6 of this SAP.
11.1.7
Medical History and Concomitant Disease
Refer to Section 5.1.7 of this SAP.
11.1.8
Prior and Concomitant Medications
Refer to Section 5.1.8 of this SAP.
CCI


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
51 of 65
11.1.9
Dose-Limiting Toxicity(DLT)
11.1.9.1
Definitions and Derivations
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. For more details including maximum tolerated dose, refer to Section 
10.6.6 of the CSP.
Any event that meets the DLT criteria in the opinion of the Investigator should be reported 
to the study physician within 24 hours of knowledge of the event. Events will be assessed 
for DLT criteria according to the NCI CTCAE v5.0 except for TLS, which will be assessed 
for DLT criteria using the Howard et al 2011 modification of Cairo-Bishop 2004 criteria 
(Cairo and Bishop 2004).
Any patient who is not evaluable for DLT assessment will be replaced, with the exception 
of a patient who experiences a DLT; these patients will not be replaced. Additional patients 
enrolled at a previously cleared dose level to provide supplemental safety, efficacy, PK, and 
pharmacodynamics data will not be replaced or evaluated for DLT in support of dose 
escalation decisions. However, these additional patients will be included in the 
determination of the MTD/RP2D upon completion of the dose escalation part.
A DLT evaluable patient is defined as a patient enrolled in Module 1 Part A (dose 
escalation), who has received at least 2 doses of AZD0466 at the target dose level (67% of 
Cycle 1 after ramp-up) and has completed safety follow-up through the DLT evaluation
period, or has experienced a DLT.
During Part A of Module 1, AZD0466 monotherapy dose escalation, AstraZeneca 
pharmacovigilance process and the SRC will evaluate toxicities study-wide (including 
evaluation of previous doses). During Part B of Module 1, AZD0466 monotherapy dose 
expansion, a safety analysis will be performed at the time of the first interim analysis in 
each cohort (Cohort B1 at 
patients, Cohort B2 at 
 patients) and Cohort B3 at 
 
patients,  pooling safety data from all available patients. The study recruitment may be 
paused, pending investigation by the Sponsor and in discussion with SRC, if 
% of 
patients experience safety events that meet the DLT criteria, see Section 10.6.6.3 of CSP 
(including AEs of special interest [Section 8.3.6]), the SRC, will decide to stop the study, 
modify the study, or continue the study, based on the overall risk benefit of the agent. 
Throughout the expansions, the AZ safety team and the SRC, will regularly review 
cumulative safety data including, but not limited to, toxicities that meet the DLT criteria.
11.1.9.2
Presentation
The number of Part A dose-setting patients evaluable for determination of DLTs during 
Cycle 1 and the number of patients with any DLT (and their categorization) will be 
summarised by dose level and based on the DLT evaluable analysis set. The MTD will be 
CCI
CCI
CCI
CCI


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
52 of 65
selected from all tried dose levels that have not been previously declared to be unsafe with 
a DU decision according to the mTPI-2 algorithm (see CSP Table 15). With this constraint, 
the MTD will be determined as the dose level with the DLT estimate closest to the target 
toxicity level of 
%. The MTD will be determined by isotonic regression analysis applied 
to Cycle 1 DLT rates observed during dose exploration using the mTPI-2 method (Ji et al 
2010). 
In the case of dose levels with estimated toxicity of equal distance (tied dose levels) from 
the target toxicity of 
%, the following approach is used: among all tied dose levels the 
highest dose level with target toxicity 
% will be selected, unless all tied dose levels 
have estimated toxicity
%, in which case the lowest dose level will be selected. Part B 
patients in Cycle 1 meeting the same criteria for DLT evaluability that were used for Part A 
dose setting, and the number/percentage of those patients with any safety events that meet 
the DLT criteria (and their categorization) , will be summarised for Part B RP2D-treated 
patients. 
The number and percentage will be reported for pooled RP2D-treated Part A and Part B 
patients that experienced at least one safety event that meet the DLT criteria after receiving 
any amount of study treatment from Cycle 2 onwards. The numbers and types of toxicities 
that meet the DLT criteria  and the cycles (weeks) in which they were observed will also be 
summarised.
11.2
Endpoint Analyses
Refer to Section 5.2 of this SAP.
11.4
Pharmacodynamic Endpoint(s) 
The pharmacodynamic effects of AZD0466 will be assessed by evaluation of laboratory 
parameters which will be reported within the safety section of the CSR. Further exploration 
of potential biological activity by the assessment of pharmacodynamics and exploratory 
biomarkers will be reported outside the main CSR.  
11.5
Pharmacokinetics
This section covers details related to pharmacokinetics endpoints and analyses.
11.5.1
Definitions and Derivations
Plasma PK Parameters
PK analysis will be, where data allow, carried out using actual elapsed times determined 
from the PK sampling and dosing times recorded in the database. If actual elapsed times are 
missing, nominal times may be used at the discretion of the PK scientist with approval from 
the AZ Clinical Pharmacology Scientist. Nominal sampling times may be used for any 
agreed interim PK parameter calculations.
CCI
CCI
CCI
CCI


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
53 of 65
Where data allow, the following PK parameters for total and released AZD4320 will be 
derived from plasma 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
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.
The time period used for the estimation of apparent terminal elimination half-lives, where 
possible, should be over at least two half-lives.  For t1/2 estimates where λz was calculated 
over a time period less than twice their resultant half-life, the reliability of t1/2 and any PK 
parameters derived from λz will be discussed in CSR.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
54 of 65
11.5.2
Presentation
For the definitions of handling, calculation and presentation of pharmacokinetic
concentrations and parameters refer to Section 5.4.
11.6
Immunogenicity
Not applicable.
11.7
Safety Analyses 
The domain safety covers exposure, adverse events, clinical laboratory, vital signs, and 
ECG.
Tables are provided for the SAF, listings are provided for All patients or the SAF 
depending on the availability of data.
11.7.1
Exposure
Refer to Section 5.6.1 of this SAP.
11.7.2
Adverse Events
Refer to Section 5.6.2 of this SAP.
11.7.3
Clinical Laboratory
Refer to Section 5.6.4 of this SAP.
11.7.4
Vital Signs
Refer to Section 5.6.6 of this SAP.
11.7.5
Electrocardiogram
Refer to Section 5.6.9 of this SAP.
11.7.6
Other Safety Assessments
Refer to Section 5.6.11 of this SAP.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
55 of 65
12
INTERIM ANALYSIS – MODULE 1 
12.1
Dose Escalation Committee
This study will utilise an SRC, as described below:
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. 
More details are found in Appendix A5 of the CSP.
12.2
Interim Analysis
For details, see Section 10.1 of this SAP for planned analyses and the DLT criteria in 
Section 10.6.6.3 of the CSP.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
56 of 65
13
REFERENCES 
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. 
Br J Haematol. 2004;127(1):3-11.
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.
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.
Frewer P, Mitchell P, Watkins C, Matcham J. Decision-making in early clinical drug 
development. Pharm Stat. 2016;15(3):255-63.
Guo W, Wang SJ, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design 
addressing Ockham’s razor:  mTPI-2. Contemporary Clinical Trials 2017; 58:23-33.
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-
finding trials. Clin Trials. 2010;7(6):653-63.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
57 of 65
14
APPENDIX 
The schedule of activities for Module 1 Part A and Part B is presented in Table 7 for 
screening and Cycle 1 and in Table 8 for Cycle 2 and beyond and follow-up.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
58 of 65
Table 7
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








STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
62 of 65
X
8.7
                                               
f  If for any reason the sample is not drawn at Cycle 1 Day 1, it may be taken at any visit until the last study visit.
ACTH = adrenocorticotropic hormone; BNP = brain natriuretic peptide; 
; CMV = cytomegalovirus; 
CR = complete response; CSP = clinical study protocol; CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; ECG = electrocardiogram; 
ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; FL = follicular lymphoma; HBV = hepatitis B virus; HCV = hepatitis C virus; 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; 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


STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
63 of 65
Table 8
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




STATISTICAL ANALYSIS PLAN
AstraZeneca
D8242C00001 – ed. 1.0
15-Jun-2022
CONFIDENTIAL AND PROPRIETARY
65 of 65
Blood samples for plasma PK
Xc
C3D1 c, C5D1 c 
10.8.5.1
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
                                               
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; 
; 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
CCI


6,*1$785(3$*(
7KLVLVDUHSUHVHQWDWLRQRIDQHOHFWURQLFUHFRUGWKDWZDVVLJQHG
HOHFWURQLFDOO\DQGWKLVSDJHLVWKHPDQLIHVWDWLRQRIWKHHOHFWURQLFVLJQDWXUH
'RFXPHQW1DPHGFVDSHG
'RFXPHQW7LWOH
6WDWLVWLFDO$QDO\VLV3ODQ(GLWLRQ
'RFXPHQW,'
'RF,'
9HUVLRQ/DEHO
&855(17/$7(67$33529('
6HUYHU'DWH
GG000\\\\++PPµ87&¶=
6LJQHGE\
0HDQLQJRI6LJQDWXUH
-XQ87&
$XWKRU$SSURYDO
-XQ87&
&RQWHQW$SSURYDO
1RWHV'RFXPHQWGHWDLOVDVVWRUHGLQ$1*(/DQ$VWUD=HQHFDGRFXPHQWPDQDJHPHQWV\VWHP
PPD
PPD