Clinical trial NCT04865419
Conditions: Haematological Malignancies
Keywords: Pharmacokinetics AZD0466 Voriconazole Drug-drug interaction
Sponsor: AstraZeneca
Start date: 2021-06-11; Completion date: 2023-08-08
Enrollment: 46 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to the evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of AZD0466 as monotherapy in partciapants with advanced haematological malignancies and also to assess drug-drug interaction (DDI) potential between AZD0466 and the azole antifungal voriconazole.

Detailed description:
The study consists of 2 individual modules as: Module 1 (AZD0466 monotherapy), and Module 2 (DDI study of AZD0466 with voriconazole).

Eligible participants will be assigned to study treatments across Modules 1 and 2.

1. Module 1: AZD0466 monotherapy will include 2 parts- Part A dose escalation cohorts and Part B dose expansion cohorts. Initiation of Part B will depend on the evaluation of safety, tolerability, and PK in Part A.
2. Module 2: AZD0466 and voriconazole DDI study.

All participants will receive AZD0466, and administration will continue until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study treatment.

Arms: arm 1: Participants will receive intravenous infusion of AZD0466 monotherapy once weekly during Cycle 1 (35 days), Cycle 2 (28 days) and Cycle 3 (28 days) and also beyond Cycle 3 until progressive disease, unacceptable toxicity, or withdrawal of consent. arm 2: Participants may receive IV infusion of AZD0466 in combination with or without voriconazole during Cycle 1 (21 days), and Cycle 2 (28 days) and Cycle 3 (28 days) and also beyond Cycle 3 until progressive disease, unacceptable toxicity, or withdrawal of consent.
Interventions: intervention 1: AZD0466 intervention 2: Voriconazole
Intervention descriptions: intervention 1: AZD0466 powder for concentrate for solution for infusion will be administered by IV infusion. intervention 2: Voriconazole film-coated tablet will be administered orally.

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol 
Study Intervention
AZD0466
Study Code
D8241C00001
Version
4.0
Date
29 September 2022
A Modular Phase I/II, Open-Label, Multi-Centre Study to Assess 
the Safety, Tolerability, Pharmacokinetics and Preliminary 
Efficacy of AZD0466 Monotherapy or in Combination in Patients 
with Advanced Haematological Malignancies
Sponsor Name: AstraZeneca AB
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden.
Regulatory Agency Identifier Number(s)
IND number: 142050
European Clinical Trials Database (EudraCT) number: 2020-005106-25
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: D8241C00001
Amendment Number: 3
Study Treatment: AZD0466
Study Phase: Phase I/II


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Short Title: A Phase I/II study of AZD0466 monotherapy or in combination in patients with 
advanced haematological malignancies
Acronym: NIMBLE


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 3
29 Sep 2022
Amendment 2
29 Mar 2022
Amendment 1
14 Jul 2021
Original Protocol
16 Dec 2020
Amendment 3 (29 September 2022)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the council of the European Union.
Overall Rationale for the Amendment:
The global protocol was amended to: add a new dose escalation level to Part A of Module 1;
to increase the number of patients permitted to be enrolled in Module 1 Part A; to increase the 
maximum feasible dose; to include response evaluation criteria for acute myeloid leukaemia 
(AML) for clinical trials; to include myelodysplastic syndrome (MDS) response evaluation 
criteria for neutrophil and platelet haematological improvement; and to address identified 
inconsistencies errors, typos, and to provide further clarification where needed. A summary of 
changes and the rationale for each change are tabulated below.
Section # and 
Name
Description of Changes
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis; 
11.1.3.2 Part A 
Dose Escalation 
Scheme; 11.1.3.3 
Dose Escalation, 
De-escalation, and 
Stopping Decision 
Rules; 11.7.2.1 
AZD0466 
Monotherapy 
Escalation – Part A
Increase in the number of 
patients allowed to be enrolled 
in Module 1 Part A from 40 to 
48, hence increasing the 
number of DLT-evaluable 
patients from 30 to 36, the 
number of patients in 
Module 1 Part A from 58 to 
66, in Module 1 from 146 to 
154, and the total number of 
patients in the study from 
approximately 160 to 168.
A new higher dose level of 
AZD0466 (DL6) was added to the 
study design for Module 1 Part A. 
Consequently, the total number of 
patients in Module 1 Part A was 
increased based on the baseline 
assumption numbers needed per 
cohort plus a 25% fallout rate from 
disease progression.
Substantial
1.1 Synopsis; 
11.1.3.2 Part A 
Dose Escalation 
Scheme; 11.1.3.3 
Dose Escalation, 
Amended language to read 
“approximately 36 
DLT-evaluable patients”.
For consistency throughout the 
CSP.
Non-substantial


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De-escalation, and 
Stopping Decision 
Rules; 11.7.2.1 
AZD0466 
Monotherapy 
Escalation – Part A
1.2 Schema, 
Figure 1; 11.1.3 
Rationale for 
Module 1, Figure 3
Updated to provide illustrative 
doses for DL4 and DL5 (in 
Figure 3), not exceeding a 
2-fold increase of a dose 
declared tolerable by the SRC.
In line with FDA guidance on dose 
escalation for AZD0466 from study 
D8240C00003, the protocol for 
study D8241C00001 allowed up to 
a 2-fold dose increase at the 
discretion of the SRC. Based on 
emerging safety data for doses up 
to 1200 mg, this 2-fold increase 
was applied for dose escalation 
between DL1 to DL4 by the SRC. 
For dose escalation, illustrative 
doses are displayed that would not 
exceed a 2-fold increase of a dose 
declared tolerable by the SRC, or 
the maximum feasible dose as 
specified in Section 11.4.7.5.
Non-substantial
1.2 Schema, 
Figure 1; 11.1.3 
Rationale for 
Module 1, Figure 3
Updated to reflect the addition 
of DL6, and to provide 
illustrative DL6 doses (in 
Figure 3).
A more gradual 50% increase is 
planned between DL4, DL5 and 
DL6. Dose level 6 will be 
determined by emerging safety data
but is predicted to be a target dose 
of 5400 mg, though not exceeding 
6000 mg, which is the maximum 
feasible dose as specified in Section 
11.4.7.5. The purpose of including 
DL6 is to provide the option to 
explore a higher dose, given the 
predicted efficacious dose range of 
600 to 6000 mg, based on 
pre-clinical studies, hereby 
balancing potential patient benefit 
against risk of possible toxicities.
Substantial
1.2 Schema, 
Figure 1; 11.1.3 
Rationale for 
Module 1, Figure 3; 
11.1.3.4 Dose 
Expansion Design; 
11.3.1 Inclusion 
Wording added and/or 
amended to clarify that 
patients included in Cohort B3 
are ineligible for inclusion in 
Cohorts B1 and B2.
For clarity.
Non-substantial


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Criteria
1.2 Schema, Figure 
1; 11.1.3 Rationale 
for Module 1, 
Figure 3; 12.1.5 
Module 2 Study 
Design, Figure 4, 
Table 22; 12.4.1 
Study Treatment(s) 
– AZD0466 and 
Voriconazole
Wording relating to the D15 
dose in Period 3 of Module 2 
has been amended to indicate 
that the dose of AZD0466 
administered on D15 with 
voriconazole should be the 
same dose as the D1 dose, 
rather than ¼ of the target 
dose.
In order to assess the DDI (ie, 
change in AZD4320 exposures in 
the presence [D15] or absence [D1] 
of voriconazole), the D1 and D15 
doses have to be the same. For the 
dose levels where there is a 
doubling of dose from D1 to D4 to 
D8, a quarter of the target dose at 
D15 is the same as D1. However, if 
the dose level at target (D8) is less 
than 4-fold higher than D1 (eg, 
DL5 and DL6) then the doses at D1 
(first ramp up dose, in the absence 
of voriconazole) and D15 (quarter 
of the target dose, in the presence 
of voriconazole) will be different 
and therefore not allow DDI 
assessment (ie, not be able to 
differentiate the increase in 
AZD4320 exposures due to 
voriconazole versus increase in 
dose). Additionally, administering a 
dose greater than a quarter of the 
target dose on D15 may not allow 
for an adequate safety margin (of at 
least 4-fold, based on the 
anticipated magnitude of DDI with 
voriconazole) for co-administering 
AZD0466 with voriconazole, 
especially for DL6.
Non-substantial
2.1.2 Rationale for 
AZD0466 in 
treatment of 
haematological 
malignancies; 2.2 
Benefit-Risk 
Assessment; 
11.1.3.1 
Justification for 
Starting Dose
Amended language relating to 
study D8240C00003 to reflect 
the fact that this study is no 
longer ongoing but has now 
closed.
To reflect the closure of study 
D8240C00003.
Non-substantial
2.3 Study 
Rationale; 5.1 Core 
Inclusion Criteria;
9.6 Efficacy;
11.1.3.2 Part A 
“High-risk MDS” amended to 
“intermediate or higher risk 
MDS”.
Language amended to define more 
accurately the prognostic risk 
categories of patients eligible for 
enrolment. 
Non-substantial


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Dose Escalation 
Scheme; 11.2.3 
Exploratory 
Objectives, Table 
14; Appendix O 1 
Prognostic Scoring 
System for MDS: 
The International 
Prognostic Scoring 
System – Revised 
(IPSS-R)
5.1 Core Inclusion 
Criteria
Inclusion Criterion 9 amended 
to “White blood cell count 
must be < 10 x 109/L prior to 
the first dose in Cycle 1, 
Day 1. Treatment with 
hydroxyurea (AML) or high-
dose steroids (ALL and 
leukaemia of ambiguous 
lineage) during screening and 
Cycle 1 to control white blood 
cell count is permitted.”. 
No change has been made to 
Inclusion Criterion 9. Text relating 
to permissible hydroxyurea and 
steroid usage has been updated for 
consistency throughout the 
protocol. 
Non-substantial
6.6 Dose 
Modification and 
Toxicity 
Management, 
Table 4
Table 4 (Dose Reduction 
Modifications) updated.
To include all dosing options for 
dose modifications, based on 
proposed dose levels.
Non-substantial
6.6 Dose 
Modification and 
Toxicity 
Management, 
Table 4
Dose level 2 added to Table 4 
and subsequent dose level 
numbering corrected.
To correct unintentional omission 
of dose level 2 from previous 
protocol version.
Non-substantial
8.7 Optional 
Genomics Initiative 
Sample; Appendix 
D 2 Genetic 
Research Plan and 
Procedures
Wording amended to reflect 
that the ICF for the optional 
genetic component of the 
study may form part of the 
main study ICF or be provided 
as an addendum to the main 
study ICF. 
To reflect a change in process at 
some investigational sites.
Non-substantial
11.1.3.3 Dose 
Escalation, 
De-escalation, and 
Stopping Decision 
Table updated to 
accommodate 6 dose levels.
Operating characteristics are based 
on the number of cohorts, therefore 
a re-run was required to allow the 
addition of DL6.
Substantial


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Rules, Table 11
11.4.7.5 Definition 
of Maximum 
Feasible Dose
Increase in the maximum dose 
permitted based on CMC 
quality specifications from 
3600 mg to 6000 mg.
To align with the predicted 
efficacious dose range of 
600-6000 mg per week and with 
emerging safety profile, CMC 
updated quality specifications 
accordingly.
Substantial
11.5.1 Schedule of 
Activities, Table 16 
Timepoints for CT/MRI/PET 
scans (only if extramedullary 
disease) amended to align with 
Section 8.1.1.
Correction.
Non-substantial
11.5.1 Schedule of 
Activities, Table 16 
and Table 17
Timepoints for plasma 
samples
 
 
corrected to align with section 
11.6.3.1.3.
Correction.
Non-substantial
11.5.1 Schedule of 
Activities, Table 16; 
11.6.2.9.12 
Overnight Stays for 
TLS Monitoring; 
12.6.2.9.12 
Overnight Stays for 
TLS Monitoring
Wording amended to 
“Overnight stays are 
recommended on …, but 
patients may be discharged 
prior to 36 hours post-dose, as 
per investigator discretion, if 
their TLS laboratory values 
are appropriate, and if the 
patient is able to return for a 
follow-up clinic visit to 
complete required safety and 
laboratory assessments within 
the specified time windows.”
For clarity and consistency.
Non-substantial
11.5.1 Schedule of 
Activities, Table 16; 
11.6.2.9.12 
Overnight Stays for 
TLS Monitoring; 
12.5.1 Schedule of 
Activities, Table 25 
and 26; 12.6.2.9.12 
Overnight Stays for 
TLS Monitoring
Wording in relation to TLS 
monitoring amended to: “At 
least twice in the first 24 hours 
after each administration of 
AZD0466, and as clinically 
indicated.”
For clarity and consistency.
Non-substantial
12.1.5 Module 2 
Study Design; 
12.4.1 Study 
Treatments(s) –
Text amended and new 
Table 22 (Module 2 AZD0466 
Dose Guidance) added.
To provide clarity on target doses 
and permissible change to a higher 
target dose based on SRC-declared 
Substantial
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AZD0466 and 
Voriconazole
tolerated dose in Module 1 Part A.
12.5.1 Schedule of 
Activities, Table 25
Footnotes e to i corrected to 
match with the correct 
reference within the table.
Correction.
Non-substantial
12.5.1 Schedule of 
Activities, Table 25
Reference to Section 12.1.5 
(Module 2 Study Design)
added in relation to AZD0466 
administration.
For clarity.
Non-substantial
Appendix F 1.1
Prophylaxis for 
TLS
Additional guidance added in 
relation to use of Rasburicase 
as prophylaxis.
Rasburicase is contraindicated for 
patients with G6PD deficiency. A 
recommendation to assess G6PD 
status was added for site support.
Non-substantial
Appendix F 1.1
Prophylaxis for 
TLS, Table 32; 
F 1.2 AZD0466 
Dose Modifications 
for TLS, Table 33
Correction to references in 
table footnotes.
Correction.
Non-substantial
Appendix F 4 
References
Howard et al 2011 added as a 
new reference.
Source information for prophylaxis 
for TLS and dose modifications for 
TLS.
Non-substantial
Appendix J 
Response 
Evaluation Criteria 
for Acute Myeloid 
Leukaemia
Addition of response criteria 
for clinical trials.
For information.
Non-substantial
Appendix K 1 
References
Advani et al 2022 added as a 
new reference.
To support investigators in 
response assessment of ALL.
Non-substantial
Appendix O 1 
Prognostic Scoring 
System for 
High-Risk MDS: 
The International 
Prognostic Scoring 
System – Revised 
(IPSS-R)
IPSS-R score of “bad” and 
very bad” amended to “poor” 
and “very poor” for the 
prognostic variable of 
cytogenetics.
Prognostic factor score value 
4.5 amended to 4.0.
Bone Marrow blast % -
Correction to align with prognostic 
variables in “Revised international 
prognostic scoring system for 
myelodysplastic syndromes” in 
Greenberg et al 2012.
Non-substantial


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“> 10%” deleted from variable 
4.
Appendix P 2 
Haematological 
Improvement (IWG 
2018)
Response evaluation criteria 
for haematological 
improvement with respect to 
platelets and neutrophils added 
to table.
Updated in line with proposals for 
revised IWG 2018 haematological 
response criteria in patients with 
MDS included in clinical trials
Non-substantial
ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; CMC, Chemistry Manufacturing and 
Controls; D, day; DDI, drug-drug interaction; DL, dose level; FDA, Federal Food and Drug Administration; 
G6PD, Glucose-6-Phosphate-Dehydrogenase; ICF, informed consent form; IPSS-R, Revised International 
Prognostic Scoring System; IWG, International Working Group; MDS, myelodysplastic syndrome; SRC, Safety 
Review Committee; TLS, tumour lysis syndrome


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 3
TABLE OF CONTENTS.................................................................................................... 10
1
PROTOCOL SUMMARY................................................................................ 19
1.1
Synopsis ........................................................................................................... 19
1.2
Schema............................................................................................................. 22
2
INTRODUCTION - CORE............................................................................... 23
2.1
Background ...................................................................................................... 23
2.1.1
Apoptosis and Cancer ....................................................................................... 23
2.1.2
Rationale for AZD0466 in treatment of haematological malignancies ............... 24
2.2
Benefit-Risk Assessment .................................................................................. 24
2.3
Study Rationale ................................................................................................ 25
3
OBJECTIVES AND ENDPOINTS - CORE ..................................................... 25
4
STUDY DESIGN - CORE................................................................................ 27
4.1
Overall Design.................................................................................................. 27
4.2
Rationale for Study Design ............................................................................... 28
4.2.1
Regulatory Amendments for Additional Modules ............................................. 28
4.3
Justification for Dose........................................................................................ 28
4.4
End of Study Definition.................................................................................... 28
4.5
Criteria for Stopping or Pausing Study Recruitment.......................................... 29
5
STUDY POPULATION - CORE...................................................................... 30
5.1
Core Inclusion Criteria...................................................................................... 30
5.2
Core Exclusion Criteria..................................................................................... 32
5.3
Lifestyle Considerations ................................................................................... 36
5.3.1
Meals and Dietary Restrictions ......................................................................... 37
5.3.2
Caffeine, Alcohol, and Tobacco........................................................................ 37
5.4
Screen Failures ................................................................................................. 37
6
STUDY INTERVENTION - CORE.................................................................. 38
6.1
Study Treatment(s) Administered ..................................................................... 38
6.2
Preparation/Handling/Storage/Accountability ................................................... 38
6.2.1
AZD0466 Preparation and Administration........................................................ 38
6.2.2
Storage ............................................................................................................. 39
6.2.3
Accountability .................................................................................................. 39
6.3
Measures to Minimise Bias............................................................................... 39
6.3.1
Methods for Assigning Treatment Groups......................................................... 39
6.4
Study Treatment Compliance............................................................................ 40
6.4.1
Treatment Compliance for AZD0466................................................................ 40
6.5
Concomitant Therapy........................................................................................ 40


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6.5.1
Permitted Concomitant Medications and Treatments......................................... 40
6.5.2
Prohibited Concomitant Medications and Treatments........................................ 42
6.6
Dose Modification and Toxicity Management................................................... 43
6.6.1
Dose Modifications Based on Haematological Parameters ................................ 45
6.6.2
Retreatment Criteria.......................................................................................... 46
6.6.3
Dose Modifications for Non-haematological Toxicities..................................... 48
6.6.4
Dose Modifications for Hepatotoxicity ............................................................. 49
6.6.5
Cardiac findings................................................................................................ 51
6.6.6
Infusion-site reactions....................................................................................... 52
6.7
Dose-limiting Toxicity...................................................................................... 52
6.7.1
Definition of Maximum Tolerated Dose............................................................ 52
6.7.2
Definition of Recommended Phase II Dose....................................................... 52
6.7.3
Definition of Maximum Feasible Dose.............................................................. 52
6.7.4
Safety Review Committee................................................................................. 52
6.8
Treatment After the End of Study ..................................................................... 52
7
DISCONTINUATION OF STUDY TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL - CORE ............................................ 53
7.1
Discontinuation of Study Treatment.................................................................. 53
7.1.1
Procedures for Discontinuation of Study Treatment .......................................... 54
7.1.2
Procedures for Handling Patients who are Incorrectly Initiated on Study 
Treatment ......................................................................................................... 54
7.2
Patient Withdrawal from the Study ................................................................... 55
7.2.1
Procedures for Withdrawal from Study............................................................. 55
7.3
Lost to Follow-up ............................................................................................. 55
8
STUDY ASSESSMENTS AND PROCEDURES - CORE................................ 56
8.1
Efficacy Assessments........................................................................................ 58
8.1.1
Disease Assessment in Patients With Known or Suspected Extramedullary 
Disease ............................................................................................................. 58
8.2
Safety Assessments........................................................................................... 59
8.3
Adverse Events and Serious Adverse Events..................................................... 59
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 59
8.3.2
Follow-up of AEs and SAEs ............................................................................. 59
8.3.3
Causality Collection.......................................................................................... 60
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 61
8.3.5
Adverse Events Based on Examinations and Tests............................................ 61
8.3.6
Hy’s Law.......................................................................................................... 61
8.3.7
Disease Progression.......................................................................................... 62
8.3.8
Disease Under Study......................................................................................... 62
8.3.9
New Cancers..................................................................................................... 62
8.3.10
Deaths .............................................................................................................. 62
8.3.11
Reporting of Serious Adverse Events................................................................ 63
8.3.12
Adverse Events of Special Interest.................................................................... 64
8.3.13
Pregnancy......................................................................................................... 64
8.3.13.1
Maternal Exposure............................................................................................ 64


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8.3.13.2
Paternal Exposure............................................................................................. 65
8.3.14
Medication Error............................................................................................... 65
8.4
Overdose .......................................................................................................... 66
8.5
Human Biological Samples............................................................................... 66
8.5.1
Pharmacokinetics.............................................................................................. 67
8.5.1.1
Collection of Pharmacokinetic Samples ............................................................ 67
8.5.1.2
Determination of Drug Concentration ............................................................... 67
8.5.2
Pharmacodynamics........................................................................................... 67
8.6
Human Biological Sample Biomarkers ............................................................. 68
8.6.1
Collection of Mandatory Samples for Biomarker Analysis................................ 68
8.6.1.1
8.6.2
Other Study Related Biomarker Research ......................................................... 68
8.7
Optional Genomics Initiative Sample................................................................ 68
8.8
Medical Resource Utilisation and Health Economics ........................................ 68
9
STATISTICAL CONSIDERATIONS - CORE................................................. 69
9.1
Statistical Hypotheses....................................................................................... 69
9.2
Sample Size Determination............................................................................... 69
9.3
Populations for Analysis ................................................................................... 69
9.4
Statistical Analyses........................................................................................... 69
9.5
General Considerations..................................................................................... 69
9.6
Efficacy ............................................................................................................ 70
9.7
Safety ............................................................................................................... 70
9.7.1
Adverse Events................................................................................................. 70
9.7.2
Other safety parameters .................................................................................... 71
9.8
Other Analyses ................................................................................................. 71
9.9
Interim Analyses............................................................................................... 71
10
REFERENCES - CORE.................................................................................... 71
11
MODULE 1: AZD0466 MONOTHERAPY DOSE ESCALATION (PART A) 
AND DOSE EXPANSION (PART B) IN PATIENTS WITH ADVANCED 
HAEMATOLOGICAL MALIGNANCIES....................................................... 73
11.1
BACKGROUND - MODULE 1 ....................................................................... 73
11.1.1
Study Treatment ............................................................................................... 73
11.1.2
Nonclinical Information and Correlative Studies............................................... 73
11.1.3
Rationale for Module 1 ..................................................................................... 73
11.1.3.1
Justification for Starting Dose........................................................................... 74
11.1.3.2
Part A Dose Escalation Scheme ........................................................................ 75
11.1.3.3
Dose Escalation, De-escalation, and Stopping Decision Rules........................... 75
11.1.3.4
Dose Expansion Design .................................................................................... 77
11.1.4
Benefit-risk Assessment for Module 1 .............................................................. 77
11.2
OBJECTIVES AND ENDPOINTS - MODULE 1 ............................................ 78
11.2.1
Primary Objectives ........................................................................................... 78
11.2.2
Secondary Objectives........................................................................................ 78
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11.2.3
Exploratory Objectives ..................................................................................... 80
11.3
STUDY POPULATION - MODULE 1............................................................. 80
11.3.1
Inclusion Criteria .............................................................................................. 81
11.3.2
Exclusion Criteria ............................................................................................. 82
11.3.3
Lifestyle Considerations ................................................................................... 82
11.3.4
Concomitant Medications ................................................................................. 82
11.3.5
Screen Failures ................................................................................................. 82
11.4
STUDY TREATMENT - MODULE 1.............................................................. 82
11.4.1
Study Treatment – AZD0466............................................................................ 83
11.4.2
Preparation, Handling, Storage, and Accountability of Study Treatment ........... 84
11.4.3
Measures to Minimise Bias............................................................................... 84
11.4.4
Study Treatment Compliance............................................................................ 84
11.4.5
Concomitant Therapy........................................................................................ 84
11.4.6
Dose Modification ............................................................................................ 84
11.4.7
Dose-limiting Toxicity...................................................................................... 84
11.4.7.1
Definition of DLT-evaluable Patients................................................................ 84
11.4.7.2
Dose-limiting Toxicity...................................................................................... 85
11.4.7.3
Definition of Maximum Tolerated Dose............................................................ 86
11.4.7.4
Definition of Recommended Phase II Dose....................................................... 86
11.4.7.5
Definition of Maximum Feasible Dose.............................................................. 86
11.4.7.6
Safety Review Committee................................................................................. 87
11.4.7.7
Expansion Cohorts (Part B) - Module 1 ............................................................ 87
11.4.7.8
Discontinuation of AZD0466 and Patient Withdrawal from Study .................... 87
11.4.8
Intervention After the End of the Study............................................................. 87
11.5
STUDY PLAN AND TIMING OF PROCEDURES – MODULE 1.................. 87
11.5.1
Schedule of Activities....................................................................................... 87
11.6
STUDY ASSESSMENTS AND PROCEDURES - MODULE 1....................... 98
11.6.1
Efficacy Assessments........................................................................................ 98
11.6.1.1
Peripheral Blood............................................................................................... 98
11.6.1.2
Extramedullary Disease .................................................................................... 98
11.6.1.3
Bone Marrow.................................................................................................... 98
11.6.1.4
Minimal/Measurable Residual Disease (Part B Only)........................................ 98
11.6.1.5
Survival Follow-up ........................................................................................... 99
11.6.2
Safety Assessments........................................................................................... 99
11.6.2.1
Physical Examination........................................................................................ 99
11.6.2.2
Medical History.............................................................................................. 100
11.6.2.3
Height and Body Weight................................................................................. 100
11.6.2.4
Chest X-ray .................................................................................................... 100
11.6.2.5
Vital Signs...................................................................................................... 100
11.6.2.6
Electrocardiograms......................................................................................... 101
11.6.2.7
Cardiac MUGA/MRI/ECHO........................................................................... 103
11.6.2.8
Performance Status......................................................................................... 104
11.6.2.9
Clinical Safety Laboratory Assessments.......................................................... 104
11.6.2.10
Adverse Events and Serious Adverse Events................................................... 110
11.6.3
Human Biological Samples............................................................................. 110
11.6.3.1
Pharmacokinetics............................................................................................ 110


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11.6.3.2
Pharmacodynamics......................................................................................... 113
11.6.4
Human Biological Sample Biomarkers ........................................................... 116
11.6.4.1
Collection of Mandatory Samples for Biomarker Analysis.............................. 116
11.6.4.2
Collection of Optional Biomarker Samples ..................................................... 119
11.6.5
Other Study Related Biomarker Research ....................................................... 119
11.6.5.1
Mandatory Control Saliva Sample .................................................................. 119
11.6.6
Optional Genomics Initiative Sample.............................................................. 120
11.7
STATISTICAL CONSIDERATIONS - MODULE 1...................................... 120
11.7.1
Statistical Hypotheses..................................................................................... 120
11.7.2
Sample Size Determination............................................................................. 120
11.7.2.1
AZD0466 Monotherapy Escalation - Part A.................................................... 120
11.7.2.2
Part B Monotherapy Dose Expansion.............................................................. 120
11.7.3
Populations for Analyses ................................................................................ 121
11.7.4
Statistical Analyses......................................................................................... 122
11.7.5
General Considerations................................................................................... 122
11.7.6
Efficacy .......................................................................................................... 123
11.7.7
Safety ............................................................................................................. 124
11.7.8
Other Analyses ............................................................................................... 124
11.7.8.1
Pharmacokinetics............................................................................................ 124
11.7.9
Interim Analyses............................................................................................. 127
11.7.10
Data Monitoring Committee ........................................................................... 127
11.8
REFERENCES - MODULE 1 ........................................................................ 129
12
MODULE 2: INVESTIGATION OF DRUG-DRUG INTERACTION 
BETWEEN AZD0466 AND VORICONAZOLE IN PATIENTS WITH 
ADVANCED HAEMATOLOGICAL MALIGNANCIES .............................. 130
12.1
BACKGROUND - MODULE 2 ..................................................................... 130
12.1.1
Study Treatment ............................................................................................. 130
12.1.1.1
Non-investigational Product –Voriconazole .................................................... 130
12.1.2
Nonclinical Information and Correlative Studies............................................. 130
12.1.3
Rationale for Module 2 ................................................................................... 130
12.1.4
Justification for Module 2 Dose ...................................................................... 131
12.1.5
Module 2 Study Design................................................................................... 131
12.1.6
Benefit-risk Assessment.................................................................................. 133
12.2
OBJECTIVES AND ENDPOINTS - MODULE 2 .......................................... 134
12.2.1
Primary Objectives ......................................................................................... 134
12.2.2
Secondary Objectives...................................................................................... 134
12.2.3
Exploratory Objectives ................................................................................... 134
12.3
STUDY POPULATION - MODULE 2........................................................... 134
12.3.1
Inclusion Criteria ............................................................................................ 134
12.3.2
Exclusion Criteria ........................................................................................... 135
12.3.3
Lifestyle Considerations ................................................................................. 135
12.3.4
Concomitant Medications ............................................................................... 135
12.3.5
Screen Failures ............................................................................................... 135
12.4
Study Treatment - Module 2 ........................................................................... 135
12.4.1
Study Treatment(s) – AZD0466 and Voriconazole.......................................... 135


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12.4.2
Preparation, Handling, Storage, and Accountability of Study Treatment ......... 137
12.4.3
Measures to Minimise Bias............................................................................. 137
12.4.4
Study Treatment Compliance.......................................................................... 137
12.4.5
Intervention After the End of the Study........................................................... 137
12.5
STUDY PLAN AND TIMING OF PROCEDURES – MODULE 2................ 138
12.5.1
Schedule of Activities..................................................................................... 138
12.6
STUDY ASSESSMENTS AND PROCEDURES - MODULE 2..................... 148
12.6.1
Efficacy Assessments...................................................................................... 148
12.6.1.1
Peripheral Blood............................................................................................. 148
12.6.1.2
Extramedullary Disease .................................................................................. 148
12.6.1.3
Bone Marrow.................................................................................................. 148
12.6.1.4
Survival Follow-up ......................................................................................... 148
12.6.2
Safety Assessments......................................................................................... 149
12.6.2.1
Physical Examination...................................................................................... 149
12.6.2.2
Medical history............................................................................................... 149
12.6.2.3
Height and Body Weight................................................................................. 149
12.6.2.4
Chest X-ray .................................................................................................... 149
12.6.2.5
Vital Signs...................................................................................................... 150
12.6.2.6
Electrocardiograms......................................................................................... 151
12.6.2.7
Cardiac MUGA/MRI/ECHO........................................................................... 153
12.6.2.8
Performance Status......................................................................................... 153
12.6.2.9
Clinical Safety Laboratory Assessments.......................................................... 153
12.6.2.10
Adverse Events and Serious Adverse Events................................................... 158
12.6.3
Human Biological Samples............................................................................. 159
12.6.3.1
Pharmacokinetics............................................................................................ 159
12.6.3.2
Pharmacodynamics......................................................................................... 160
12.6.4
Human Biological Sample Biomarkers ........................................................... 163
12.6.4.1
Collection of Mandatory Samples for Biomarker Analysis.............................. 163
12.7
Statistical Considerations – Module 2 ............................................................. 164
12.7.1
Statistical Hypotheses..................................................................................... 164
12.7.2
Sample Size Determination............................................................................. 164
12.7.3
Populations for Analysis ................................................................................. 165
12.7.4
Statistical Analyses......................................................................................... 165
12.7.5
General Considerations................................................................................... 165
12.7.6
Efficacy .......................................................................................................... 165
12.7.7
Safety ............................................................................................................. 165
12.7.8
Other Analyses ............................................................................................... 165
12.7.8.1
Pharmacokinetics............................................................................................ 165
12.7.9
Interim Analyses............................................................................................. 168
12.8
References - Module 2.................................................................................... 168
13
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 168


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LIST OF FIGURES
Figure 1
Study Schema.......................................................................................... 22
Figure 2
Modular Protocol Design......................................................................... 27
Figure 3
Schema for Module 1............................................................................... 74
Figure 4
Schema for Cycle 1 of Module 2............................................................ 132
LIST OF TABLES
Table 1
Objectives and Endpoints......................................................................... 20
Table 2
Objectives and Endpoints......................................................................... 26
Table 3 
Organ Function Parameters...................................................................... 31
Table 4
Dose Reduction Modifications................................................................. 44
Table 5
Recommended Dose Modifications for Haematological Toxicities .......... 45
Table 6
Treatment Criteria Based on Bone Marrow, ANC and Transfusion 
Independent Platelet Count in the Absence of Peripheral Blasts............... 47
Table 7
Dose Modifications for Non-haematological Toxicities............................ 48
Table 8
Dose Modification for Hepatotoxicity...................................................... 50
Table 9
Summary of Disease Characteristics for Patients Enrolled in Module 1 
Part B Dose Expansion Cohorts............................................................... 73
Table 10
Decision Rules Based on mTPI-2 for Dose Escalation ............................. 76
Table 11
Operating Characteristics for Selecting Maximum Tolerated Dose........... 76
Table 12
Primary Objectives - Module 1 - Part A................................................... 78
Table 13
Secondary Objectives - Module 1 ............................................................ 78
Table 14
Exploratory Objectives - Module 1 .......................................................... 80
Table 15
Study Treatment for Module 1 ................................................................. 83
Table 16 
Module 1 - Schedule of Activities for Screening and Cycle 1 (Parts A 
and B)...................................................................................................... 88
Table 17
Module 1 - Schedule of Activities for Treatment Cycle 2 and Beyond 
and Follow-up Periods (Part A and B)...................................................... 93
Table 18
Safety ECG Timepoints and Holter ECG extractions (Module 1)........... 102
Table 19
Clinical Chemistry................................................................................. 106
Table 20
Haematology Assessments..................................................................... 107
Table 21
Populations for Analysis ........................................................................ 122
Table 22
Module 2 AZD0466 Dose Guidance ...................................................... 133


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Table 23 
Secondary Objective – Module 2 ........................................................... 134
Table 24
Study Treatment for Module 2 ............................................................... 136
Table 25
Module 2 - Schedule of Activities for Screening and Cycle 1................. 139
Table 26
Module 2 - Schedule of Activities for Cycle 2 and beyond..................... 142
Table 27
PK Timepoints and Corresponding Safety ECG Timepoints (Module 2) 152
Table 28
Clinical Chemistry................................................................................. 155
Table 29
Haematology Assessments..................................................................... 156
Table 30
Populations for Analysis ........................................................................ 165
Table 31 
Risk Assessment for Tumour Lysis Syndrome ....................................... 193
Table 32 
Recommended Prophylaxis for Tumour Lysis Syndrome....................... 195
Table 33
AZD0466 Dose Modifications for TLS.................................................. 196
Table 34 
Recommended Management of Electrolyte Abnormalities in TLS ......... 197
Table 35
Criteria for Laboratory and Clinical Tumour Lysis Syndrome................ 201
Table 36
Grading of Tumour Lysis Syndrome...................................................... 202
Table 37
Drugs with a known risk of Torsades de Pointes .................................... 203
Table 38
Highly Effective Methods of Contraception........................................... 206
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 169
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 176
Appendix C
Handling of Human Biological Samples ................................................ 181
Appendix D
Optional Genomics Initiative Sample..................................................... 183
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 186
Appendix F
Management of Specific Adverse Events............................................... 193
Appendix G
Classification of Tumour Lysis Syndrome ............................................. 201
Appendix H
Drugs That Prolong QT Interval and/or Induce Torsades De Pointes...... 203
Appendix I
Contraception Guidance......................................................................... 205
Appendix J
Response Evaluation Criteria for Acute Myeloid Leukaemia ................. 207
Appendix K
Response Assessment for Acute Lymphoblastic Leukaemia................... 209
Appendix L
Eastern Cooperative Oncology Group Performance Status Scoring........ 212
Appendix M
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 213


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Appendix N
New York Heart Association Functional Classification.......................... 214
Appendix O
Prognostic Scoring for Myelodysplastic Syndrome ................................ 215
Appendix P
Response Criteria for Myelodysplastic Syndrome.................................. 216
Appendix Q
Abbreviations ........................................................................................ 220
Appendix R
Protocol Amendment History................................................................. 224


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title:
A Modular Phase I/II, Open-Label, Multi-Centre Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Preliminary Efficacy of AZD0466 Monotherapy or in Combination in 
Patients with Advanced Haematological Malignancies.
Short Title: 
A Phase I/II Study of AZD0466 Monotherapy or in Combination in Patients with Advanced 
Haematological Malignancies
Rationale:
Proteins of the B-cell lymphoma 2 (Bcl-2) family regulate the intrinsic apoptosis pathway. 
Under normal conditions, apoptosis is prevented by pro-survival proteins (including Bcl-2 and 
B-cell lymphoma-extra large [Bcl-xL]) binding to and inhibiting the pro-apoptotic proteins 
(Bak and Bax). Overexpression of pro-survival Bcl-2 family proteins Bcl-2 and Bcl-xL has 
been associated with tumour initiation, progression, and resistance to a variety of current 
therapies (Czabotar et al 2014 and Delbridge and Strasser 2015).
AZD0466 is a drug-dendrimer conjugate that consists of an active moiety (AZD4320, a dual 
Bcl-2/Bcl-xL-specific inhibitor) covalently conjugated to a pegylated poly-L-lysine 
dendrimer, which gradually releases the active moiety by hydrolysis. AZD0466 exhibits 
potent Bcl-2/Bcl-xL-selective inhibition and has pharmacokinetic properties that minimise the 
potential for maximum concentration (Cmax)-dependent Bcl-xL-mediated adverse events 
(AEs).
AZD0466 has shown activity across a range of nonclinical models of haematological 
malignancy. This study is modular in design: the core protocol contains study information 
applicable to all patients in the study; Module 1 will evaluate the safety, tolerability, 
pharmacokinetics (PK), and efficacy of AZD0466 as monotherapy; Module 2 is a drug-drug 
interaction (DDI) study that will investigate the safety and establish the sensitivity of 
AZD0466 to strong inhibitors of cytochrome P450 3A (CYP3A) isoforms. Further modules 
may be added via protocol amendments to investigate AZD0466 in combination with other 
anticancer treatments. These additional modules will describe the rationale for each 
combination treatment arm, along with study information and assessments specific to the 
combination. Up to 4 additional modules may be added, where permissible by local 
regulations.
Objectives and Endpoints
The objectives and endpoints that are common to all study modules are listed below (Table 1). 




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basis.
Disclosure Statement: This is a non-randomised, open-label, sequential, dose-escalation, and 
expansion study. 
Number of Patients:
Approximately 168 patients will be assigned to study treatments across Modules 1 and 2. 
Additional patients may be recruited in response to emerging data that indicates a benefit to 
investigating alternative treatment regimens, combination agents, or indications through a 
protocol amendment.
!
Module 1: AZD0466 monotherapy (n = 154 patients)
Part A dose escalation cohorts:
∀
In total, approximately 66 patients will be included in the dose escalation part. Up to 
48 patients will be enrolled to yield approximately 36 dose-limiting toxicity 
(DLT)-evaluable patients. Cohorts may be expanded at the discretion of the SRC, by 
up to a maximum of 18 additional patients across all cohorts, for further evaluation of 
PK, pharmacodynamics (PD), safety, or biological efficacy.
Initiation of Part B will depend on the evaluation of safety, tolerability, and PK in Part A. 
Part B dose expansion cohorts: 
∀
The dose expansion part of the study will enrol up to 88 patients. The decision for 
opening or closing Part B expansion cohorts and for starting new modules will be at 
the discretion of the sponsor in discussion with the SRC.
!
Module 2: AZD0466 and voriconazole DDI study
∀
Approximately 10 (maximum 14) patients will be assigned to study treatment in 
Module 2. 
Additional patients may be recruited in subsequent modules in response to emerging data that 
indicates a benefit to investigating alternative treatment regimens, combination agents, or 
indications through a protocol amendment, where permissible by local regulations.
Treatment Groups and Duration:
All patients will receive AZD0466, and administration will continue until disease progression, 
initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or 
other reasons to discontinue study treatment. 
Patients in Module 1 will receive AZD0466 monotherapy and patients in Module 2 will 


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receive AZD0466 monotherapy with and without voriconazole. Patients enrolled into 
subsequent modules incorporated via protocol amendments may receive AZD0466 in 
combination with other anticancer treatments. 
Data Monitoring Committee: 
There will be no data monitoring committee (DMC) for this study. 
Safety Review Committee:
Refer to individual modules.
Statistical Methods:
Refer to individual modules for statistical considerations in this study.
1.2
Schema
The study design in summarised in Figure 1.
Figure 1
Study Schema
Dotted paths contingent on emerging data.
ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; D, Day; DL, dose level; IA, interim 
analysis; MPN, myeloproliferative neoplasm; TP53, gene encoding tumour protein p53; TD, target dose.


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2
INTRODUCTION - CORE
This is a modular, Phase I/II study of AZD0466 as monotherapy or in combination with other 
treatments in patients with advanced haematological malignancies. The core protocol contains 
study information applicable to all patients in this study. Further modules may be added via 
protocol amendment describing AZD0466 in combination with other treatments, where 
permissible by local regulations. A substantial protocol amendment with relevant supportive 
rationale will be submitted to the relevant authorities before starting a new module.
2.1
Background 
2.1.1
Apoptosis and Cancer
Apoptosis is a cellular process necessary in the development and maintenance of tissue 
homeostasis. Dysregulation of apoptosis leads to a variety of pathologies, including cancer. 
The importance of apoptosis in regulating tumour growth was first identified in 1972 (
Kerr et al 1972) and evading apoptosis is considered one of the 6 hallmarks of cancer 
(Hanahan and Weinberg 2000).
Intrinsic, mitochondrial-mediated, apoptosis is regulated by members of the Bcl-2 family of 
proteins which can be divided into groups that interact to regulate the apoptotic pathway, as 
follows: 1) multi-domain, pro-survival proteins (eg, Bcl-2, Bcl-xL, Mcl-1, Bcl-2-A1, Bcl-w, 
and Bcl-B), 2) multi-domain pro-apoptotic proteins (eg, Bak and Bax), and 3) BH3-only 
pro-apoptotic proteins (eg, Bim, Noxa, Bad, Bid, and Puma). Under normal conditions, 
apoptosis is prevented by pro-survival proteins (including Bcl-2 and Bcl-xL) binding to and 
inhibiting the pro-apoptotic proteins. During cellular stress, such as deoxyribonucleic acid 
(DNA) damage, the apoptotic pathway is activated via sequestration of pro-survival proteins 
binding to BH3-only pro-apoptotic proteins (Czabotar et al 2014). However, overexpression 
of pro-survival proteins may deregulate this intricate balance, blocking apoptosis even under 
conditions of cell stress. 
Bcl-2 family proteins were first shown to be critical in the regulation of apoptosis in cancer 
with the discovery of Bcl-2, and its identification as an oncogene in a follicular lymphoma cell 
line with a t(14;18) translocation that resulted in Bcl-2 overexpression (Vaux et al 1988). In 
addition, Bcl-2 has been associated with chronic lymphocytic leukaemia (CLL), diffuse large 
B-cell lymphoma (DLBCL), and neuroblastoma, while Bcl-xL overexpression has been 
reported in follicular lymphoma, DLBCL, multiple myeloma, and lung cancer (Adams et al 
2018, Delbridge and Strasser 2015). Furthermore, progenitors of high-risk MDS were 
sensitive to agents that target not only Bcl-2 (Jilg et al 2016, Reidel et al 2018) but also Bcl-xL 
(Jilg et al 2016) The pro-survival Bcl-2 family proteins including Bcl-2 and Bcl-xL have been 
associated with tumour initiation, progression, and resistance to a variety of current anticancer 
therapies (Czabotar et al 2014 and Delbridge and Strasser 2015).


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2.1.2
Rationale for AZD0466 in treatment of haematological malignancies
AZD0466 is a drug-dendrimer conjugate that consists of the active moiety, the dual 
Bcl-2/Bcl-xL-specific inhibitor AZD4320, covalently conjugated to a pegylated poly-L-lysine 
type dendrimer, which gradually releases the active moiety by hydrolysis. AZD0466 was 
developed to mitigate the nonclinical toxicity findings observed with AZD4320. 
Administration of AZD0466 results in lower peak plasma levels of AZD4320 than can be 
readily achieved by direct infusion of AZD4320 at similar exposure concentrations. Thus, 
AZD0466 exhibits potent Bcl-2/Bcl-xL-selective inhibition and has PK properties that 
minimise the potential for Cmax-dependent Bcl-xL-mediated AEs. 
In vitro, AZD0466 induces apoptotic cell death in a variety of tumour cell lines, with 
particularly broad activity in cell lines derived from haematological malignancies. It also 
demonstrates significant dose-dependent in vivo anti-tumour activity as a single agent across a 
range of human tumour xenograft and patient-derived models, including acute lymphoblastic 
leukaemia (ALL), acute myeloid leukaemia (AML), DLBCL, and small cell lung carcinoma. 
Enhanced nonclinical activity has also been observed for AZD0466 in combination with many 
standard-of-care anticancer therapies. 
In nonclinical studies, anticipated on-target effects include rapid onset, transient abnormalities 
of hepatic transaminases, and thrombocytopenia. Based on nonclinical data, reduced QRS 
amplitude may also be observed at clinically predicted dose ranges. A detailed description of 
the chemistry, pharmacology, and nonclinical efficacy and safety of AZD0466 is provided in 
the Investigator’s Brochure (IB). 
AZD0466 has been administered to 9 patients with advanced solid malignancies at doses 
declared tolerable in the first-time-in-human study (D8240C00003). No dose-limiting 
toxicities (DLTs) have been recorded (data on file, AstraZeneca).
A detailed description of the chemistry, pharmacology, and nonclinical efficacy and safety of 
AZD0466 is provided in the IB.
2.2
Benefit-Risk Assessment
AZD0466 has dose-dependent in vivo anti-tumour 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. 
Potential risks of AZD0466 may be anticipated due to its mechanism of action as a dual 
Bcl-2/Bcl-xL-specific inhibitor, published literature on clinical use of Bcl-2 and Bcl-2/Bcl-xL 
inhibitors, and observations from nonclinical studies of AZD0466 (drug-dendrimer conjugate) 


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and AZD4320 (active moiety). Important potential risks of AZD0466 include 
thrombocytopenia, hepatotoxicity, and QRS amplitude decrease. Potential risks of AZD0466 
include tumour lysis syndrome (TLS), hypocellularity of the bone marrow and lymphoid 
tissue (neutropenia, lymphopenia, anaemia), thymus and spleen effects, pancreatic toxicity, 
DDIs, reproductive toxicity, and infusion site reactions. No safety findings emerged from the 
first-time-in-human study (D8240C00003) that would preclude investigation of AZD0466 in 
patients with advanced haematological malignancies. 
The dosing schedule for AZD0466 utilises an intra-patient dose ramp-up schedule to mitigate 
the risk of TLS (Roberts et al 2016). The study protocol incorporates mandatory safety 
monitoring procedures, dose modification guidelines (Section 6.6), and additional guidance 
for management of specific AEs (Appendix F). The study will be performed in accordance 
with ethical principles that have their origin in the Declaration of Helsinki and are consistent 
with International Council for Harmonisation (ICH) Good Clinical Practice (GCP), and 
applicable regulatory requirements.
The available nonclinical and clinical information supports an acceptable benefit-risk 
assessment for investigation of AZD0466 in patients with advanced haematological 
malignancies for which there are limited treatment options.
Additional considerations for the benefit-risk assessment of AZD0466 specific to individual 
modules are described in the respective modules. 
2.3
Study Rationale
This study will investigate AZD0466 in patients with advanced haematological malignancies 
for which there are limited treatment options, including patients with intermediate and higher 
risk MDS. Patients with intermediate and higher risk MDS who are on a clinical continuum 
with AML have equally very poor prognosis and may also receive benefit from AZD0466 
(Estey et al 2022, Greenberg et al 2012, Vardiman et al 2009).
The study is modular in design; the core protocol will contain study information applicable to 
all patients in this study. Module 1 will evaluate the safety, tolerability, PK, and efficacy of 
AZD0466 as monotherapy. Module 2 is a DDI study that will evaluate AZD0466 with 
voriconazole, a strong inhibitor of CYP3A4. The mechanism of action and nonclinical in vivo 
data suggest the potential to combine AZD0466 with a number of other anticancer treatments, 
resulting in enhanced activity. Further modules may be added via protocol amendment, where 
permissible by local regulations, and will include AZD0466 in combination with other 
anticancer treatments.
3
OBJECTIVES AND ENDPOINTS - CORE
The objectives and endpoints that are common to all study modules are shown in Table 2. See 






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This study will characterise the PK profile of AZD0466 following intravenous (IV) 
administration (via PK profiles of the active moiety AZD4320 in plasma). Plasma 
concentrations and derived PK parameters for total and released AZD4320 will be determined 
and specified in each module.
As part of the clinical drug development program for AZD0466, AstraZeneca will investigate 
 
 profiles and their relationship to drug effect. There are many potential benefits of 
this exploratory research, including identification of patients most likely to benefit from 
treatment, those who may not respond to treatment; and those who may experience adverse 
reactions. Ultimately, this research will provide the information and understanding required to 
deliver well tolerated and effective new medicines to patients.
4.2
Rationale for Study Design
The rationale for each module will be described in the respective modules.
4.2.1
Regulatory Amendments for Additional Modules
Additional modules will be provided as regulatory amendments to the protocol together with 
any additional documents (eg, updates to quality and/or nonclinical information, etc.) to the 
clinical trial application as required. Up to 4 additional modules may be added, where 
permissible by local regulations.
4.3
Justification for Dose
Refer to individual modules for details.
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 Schedule of Activities (SoA) for the last patient in the study 
globally.
The End of Module is defined as the date of the last visit of the last patient in a Module or the 
last scheduled procedure shown in the respective SoA for the last patient in that Module.
A patient is considered to have completed the study if he/she has completed all phases of the 
study module including the last visit or the last scheduled procedure shown in the SoA 
including follow-up for overall survival (OS).
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 
CCI
CCI


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allow for completion of the study in the planned timeframe.
The results from each Module will be reported to regulatory authorities in accordance with 
clinical trial regulatory maintenance requirements in each region.
Following attainment of the final analyses for all modules and the overall end of study 
milestone, a final Clinical Study Report (CSR) including individual module reports and an 
assessment of fulfilment of the core clinical trial objectives will be produced for submission to 
Regulatory Authorities by the required timelines (ie, within 1 year of the overall end of the 
study).
4.5
Criteria for Stopping or Pausing 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 after full aetiological work-up. This will also result in a comprehensive review of 
safety.
!
Unexpected and life-threatening events deemed related to study treatment by the Sponsor 
and in discussion with the SRC.
!
Sponsor decision that study patients are placed at undue safety risk (also see Section 4.4).
!
Sponsor decision to discontinue the development of the study treatment in the proposed 
indications.
During Part A of Module 1 and during Module 2, 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 (IA) in each cohort. The study recruitment 
may be paused, pending investigation by the Sponsor and in discussion with SRC, if > 30% of 
patients experience AEs leading to study treatment discontinuation (see Section 11.7.9), the 
SRC may decide to stop the study, modify the study, or continue the study, based on the 
overall risk benefit of the agent. In addition, individual cohort level stopping criteria are 
provided in Section 11.7.2.2. Throughout the expansions, the AstraZeneca safety team and the 
SRC, will regularly review cumulative safety data including, but not limited to, toxicities that 
meet the DLT criteria.


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5
STUDY POPULATION - CORE
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each patient must meet all of the inclusion criteria and none of the exclusion criteria for this 
study at the time of starting study treatment. Under no circumstances can there be exceptions 
to this rule. 
5.1
Core Inclusion Criteria
The inclusion criteria that are applicable to all modules in the study are described in this 
section. Additional module-specific criteria are included in the specific modules. If specific 
module criteria are more stringent than the core inclusion criteria, the module criteria must be 
met. 
Informed Consent
1
Provision of signed and dated written informed consent prior to any study-specific 
procedures, sampling, and analyses. Informed consent is described in Appendix A 3,
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
∀
If a patient declines to participate in optional exploratory research and/or genetic 
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.
Age
2
Patient must be aged ≥18 years, at the time of signing the informed consent. In some 
countries parental consent may be required in addition to an assent form for patients who 
are18 years of age.
Patient and Disease Characteristics
3
Diagnosis of AML, ALL, or intermediate or higher risk myelodysplastic syndrome 
(MDS; Part A only), which is histologically proven based on criteria established by the 
World Health Organization (WHO) as documented by medical records. 
4
Patients must have received at least one prior line of therapy, and an established standard 
of care with proven benefit, and for which the patient is eligible, must not be available at 
the time of enrolment.
5
For AML or ALL patients, documented active disease requiring treatment that is relapsed 
or refractory defined as:
∀
Recurrence/relapse of disease after response to prior line(s) of therapy 
∀
Progressive disease (refractory) on/after completion of the treatment regimen 
preceding entry into the study 


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6
For intermediate and higher risk MDS, documented active disease is defined as:
∀
Patients with > 10% blasts, and/or
∀
MDS with intermediate, high, or very high risk (risk score > 3) per the Revised 
International Prognosis Scoring System (IPSS-R) (Appendix O).
7
Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Performance 
status must not have deteriorated by ≥2 levels within 2 weeks after providing informed 
consent.
8
Predicted life expectancy ≥8 weeks.
9
White blood cell count must be < 10 x 109/L prior to the first dose in Cycle 1, Day 1. 
Treatment with hydroxyurea (AML) or high-dose steroids (ALL and leukaemia of 
ambiguous lineage) during screening and Cycle 1 to control white blood cell count is 
permitted. Both medications can be started or stopped at any point during this period. 
10 Adequate organ function at screening defined in Table 3: 
Table 3
Organ Function Parameters
Category
Parameter
Value
Hepatic
Total bilirubin
≤1.5 × ULN
≤3 × ULN 
in presence of 
Gilbert’s syndrome
AST and ALT
≤ 2.5 × ULN
Coagulation
INR
< 1.5 × ULN
Pancreatic
Lipase
≤ 1.5 × ULN
Amylase
≤ 1.5 × ULN and absence 
of clinical pancreatitis
Renal*
Serum creatinine 
≤ 1.5 × ULN
CrCl by Cockcroft and Gault method: 
CrCl (mL/min) = (140 - age [years]) × weight (kg) × (F) a
(72 × serum creatinine mg/dL)
awhere F = 0.85 for females and F = 1 for males
≥ 50 mL/min
*For patients with below ideal body weight, the 24-hour urine test may be used: ideal body weight (kg) = 
constant + 0.91 (height [cm] - 152.4); constant is 50 for men and 45.5 for women.
ALT, alanine transaminase; AST, aspartate transaminase; CrCl, creatinine clearance; INR, international 
normalised ratio; ULN, upper limit normal.
11 Adequate cardiac function as demonstrated by left ventricular ejection fraction (LVEF) 
> 50% on screening cardiac multigated acquisition (MUGA), magnetic resonance 
imaging (MRI), or echocardiogram (ECHO).


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12 Willing and able to participate in all required study evaluations and procedures including 
receiving IV administration of study treatment and admission to the hospital, when 
required, for administration of study treatment and monitoring. 
13 All patients must consent to and undergo both pretreatment and on-treatment fresh bone 
marrow aspirates and biopsies
14 For inclusion in the 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.
Reproduction
Women of childbearing potential must be willing to use highly effective contraceptive 
measures (see Section 5.3), should not be breastfeeding and must have a negative pregnancy 
test (serum) prior to start of dosing, or must have evidence of non-childbearing potential by 
fulfilling one of the following criteria at screening:
15 Women under 50 years of age would be considered postmenopausal if they have been 
amenorrhoeic for the last 12 months following the cessation of exogenous hormonal 
treatments and have serum follicle-stimulating hormone and luteinising hormone levels in 
the postmenopausal range for the institution.
16 Women with documentation of irreversible surgical sterilisation by hysterectomy, 
bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
Men should be willing to use barrier contraception (ie, condoms) and refrain from sperm 
donation during and after the conduct of the trial (see Section 5.3). If not done previously, 
storage of sperm before receiving AZD0466 will be advised to male patients with a desire to 
have children.
5.2
Core Exclusion Criteria 
The exclusion criteria that are applicable to all modules in the study are described in this 
section. Please refer to the individual modules for additional module-specific exclusion 
criteria. 


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Patients must not enter the study if any of the following criteria are fulfilled:
Medical Conditions
1
Unresolved toxicity from prior anticancer therapy of Common Terminology Criteria for 
Adverse Events (CTCAE) Grade ≥2. Patients with Grade 2 neuropathy or Grade 2 
alopecia are eligible. 
2
Active idiopathic thrombocytopenic purpura.
3
Haemopoietic stem cell transplant < 100 days prior to the first dose of study treatment.
4
Immunosuppression for graft versus host disease (GVHD) or GVHD prophylaxis within 
4 weeks prior to the first dose of study treatment. The following are permitted:
(a) topical steroids for GVHD may continue indefinitely
(b) systemic steroids for GVHD up to 2 weeks prior to the first dose of study treatment
(c) Treatment with high-dose steroids (ALL and leukaemia of ambiguous lineage) for 
white blood cell count control is permitted during screening, and in Cycle 1 up to 
4 days (maximum dexamethasone IV 40 mg/day or equivalent). It can be started or 
stopped at any point during this period.
5
Active central nervous system (CNS) leukaemia/leptomeningeal disease/spinal cord 
compression. Patients who have a history of CNS leukaemia must be free of CNS 
leukaemia for > 30 days prior to the first dose of study treatment, and the most recent 
2 lumbar punctures must be negative for leukaemic cells, to be eligible.
6
Known history of infection with human immunodeficiency virus (HIV).
7
Known serologic status reflecting active hepatitis B or C infection.
(a) Patients who are anti-HBc antibody positive and who are surface antigen negative 
will need to have a negative polymerase chain reaction (PCR) result before 
enrolment. Those who are hepatitis B surface antigen positive or hepatitis B PCR 
positive will be excluded.
(b) 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 uncontrolled infection with cytomegalovirus (CMV).
9
Patients should be tested for COVID-19 and those with active infection detected either 
using 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])


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∀
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:
∀
Patients with history of myocarditis within one year of study entry, or heart failure 
New York Heart Association Functional Classification Class 3 or 4 (Appendix N).
∀
Mean resting corrected QT interval (QTcF) ≥470 msec obtained from 
3 electrocardiograms (ECGs), in the absence of a cardiac pacemaker.
∀
Abnormalities in rhythm, conduction or morphology of resting ECG that pose an 
unacceptable risk to the subject in the opinion of the enrolling physician.
∀
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.
12 History of another life-threatening malignancy ≤2 years prior to first dose of study 
treatment. The following are permitted:
∀
Myelodysplastic syndrome or myeloproliferative neoplasm (including chronic 
myelomonocytic leukaemia [CMML]).
∀
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 treatment:
∀
coronary artery bypass graft
∀
angioplasty
∀
vascular stent
∀
myocardial infarction
∀
angina pectoris
∀
haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other 
CNS bleeding.


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Prior/Concomitant Therapy
14 Treatment with any of the following:
∀
Radiotherapy less than 3 weeks prior to the first dose of study treatment.
∀
Anticancer agents within ≤14 days or 5 half-lives (whichever is shorter) prior to the 
first dose of study treatment. Some anticancer agents may be strong CYP3A inducers 
or inhibitors, and should be withheld accordingly (Section 6.5.2).
∀
Treatment with high-dose steroids (ALL and leukaemia of ambiguous lineage) for 
white blood cell count control is permitted during screening, and in Cycle 1 up to 
4 days (maximum dexamethasone IV 40 mg/day or equivalent). It can be started or 
stopped at any point during this period. 
∀
Patients can continue to receive hydroxyurea (AML) until the start of Cycle 2 for 
white blood cell count control. It can be started or stopped at any point during this 
period.
∀
Patients who relapse while on maintenance-type ALL therapy or are receiving 
maintenance therapy for disease stabilisation should have therapy discontinued at 
least 7 days prior to first dose of study treatment.
∀
Immunotherapies and cellular therapies such as chimeric antigen receptor T cell 
therapy (CAR-T) within 4 weeks prior to the first dose of study treatment. 
∀
Investigational drugs within ≤14 days or 5 half-lives (whichever is shorter) prior to 
the first dose of study treatment.
∀
Major surgery (excluding placement of vascular access) ≤21 days, or minor surgical 
procedures ≤7 days, prior to the first dose of study treatment. No waiting is required 
following implantable port or catheter placement.
∀
Prescription or non-prescription drugs or other products known to be sensitive 
substrates of BCRP, OCT2, OAT3, OATP1B1, OATP1B3, CYP2B6, CYP2C8, 
CYP2C9, or CYP2D6 (Section 6.5.2), which cannot be discontinued within 
5 half-lives prior to the first dose of study treatment and withheld throughout the 
study until 14 days after the last dose of AZD0466. 
∀
Reversible CYP3A inhibitors (Section 6.5.2), which cannot be discontinued within 
14 days or 5 half-lives, whichever is shorter, prior to the first dose of study treatment 
and withheld throughout the study until 14 days after the last dose of AZD0466.
∀
Moderate or strong mechanism-based inhibitors or inducers of CYP3A4 which 
cannot be discontinued within 14 days prior to the first dose of study treatment, and 
withheld until 14 days after the last dose of AZD0466 (see Section 6.5.2 for a list of 
medications).
∀
Concurrent anti-coagulation therapy, including aspirin and heparin, which cannot be 
stopped. Heparin for vascular line management is allowed. 


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∀
Medications with known risk of Torsades de Pointes (TdP; see Appendix H), which 
cannot be discontinued within 5 half-lives of the first dose of study treatment and 
withheld until 14 days after the last dose of AZD0466. Some of the medications 
listed as a possible risk of TdP may be allowed at the Investigator’s discretion after 
approval by the Medical Monitor 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.
Prior/Concurrent Clinical Study Experience
15 History of hypersensitivity to polyethylene glycol (PEG), PEGylated products or drugs 
with a similar chemical structure or class to AZD0466 or other BH3 mimetic.
Other exclusions
16 Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol.
17 Judgement by the Investigator or Medical Monitor that the patient should not participate 
in the study if the patient is unlikely to comply with study procedures, restrictions and 
requirements.
18 Lactating, breastfeeding, or positive pregnancy test for women of childbearing potential.
19 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
20 Persons who, due to an official directive or court order, have been accommodated in an 
institution, must be excluded from participation.
21 Persons who are dependents of the Sponsor, Investigator, or the study site are also to be 
excluded from participation.
5.3
Lifestyle Considerations
Refer to the individual modules for any possible lifestyle restrictions in addition to those listed 
below. 
Restrictions
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after:
Female patients
1
Women of childbearing potential should use highly effective contraception from the time 
of screening until 6 months after discontinuing study treatment. Acceptable methods of 
contraception include abstinence, tubal ligation, tricycle combined oral or transdermal 
contraceptives, copper-banded intrauterine devices or vasectomised partner. It is not 
known whether AZD0466 has the capacity to induce hepatic enzymes in humans so 


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hormonal contraceptives should be combined with a barrier method of contraception. 
Refer to Appendix I for effective methods of contraception.
2
Female subjects must not breastfeed and must not donate or retrieve ova for their own use 
from screening to approximately 6 months after the last dose of study treatment.
Male patients
3
Male patients should be asked to avoid unprotected sex with women of childbearing 
potential from the time of screening until 6 months after the last dose of study treatment. 
Where there are effects on spermatogenesis, patients should avoid procreation and 
donating sperm for 6 months after the last dose of study treatment. If male patients wish 
to father children, they should be advised to arrange for freezing of sperm samples prior 
to the start of study treatment.
4
Male patients should use a condom during the trial, and for 35 days after the last dose of 
AZD0466, with all sexual partners to avoid potential exposure to drug from the semen. 
Refer to Appendix I for effective methods of contraception.
5.3.1
Meals and Dietary Restrictions
Patients should refrain from consumption of Seville oranges, grapefruit or grapefruit juice, 
pomelos, exotic citrus fruits, or grapefruit hybrids, from 14 days before the first dose of study 
treatment until 14 days after the last dose of study treatment. 
5.3.2
Caffeine, Alcohol, and Tobacco
Patients should refrain from consumption of red wine. 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 assigned to study treatment. 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 (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and all AEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
re-screened up to 2 times. Re-screened patients should be assigned the same patient number as 
for the initial screening. However, re-screening should be documented so that its effect on 
study results, if any, can be assessed. Unused samples will be destroyed.
The reason for study withdrawal for all patients who are screen failures should be recorded in 
the electronic case report form (eCRF).


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6
STUDY INTERVENTION - CORE
6.1
Study Treatment(s) Administered
Study treatment is defined as any investigational intervention, marketed product or placebo 
intended to be administered to or medical devices utilised by a study patient according to the 
study protocol.
All patients will receive treatment with the investigational product AZD0466. The AZD0466 
drug product is provided with a custom solvent. The custom solvent is supplied to reconstitute 
AZD0466 drug product and subsequently dilute to lower concentrations, if needed, for clinical 
dosing.
Dosing details for AZD0466 administered as monotherapy, or in combination with other 
treatments used in patients with advanced haematological malignancies, is included in the 
specific module and associated handling instructions; combination treatments may be included 
in additional modules (where permissible by local regulations) and alternate frequencies and 
schedules may be instigated in response to emerging safety, tolerability, or PK data introduced 
through protocol amendment.
Patients should be encouraged to maintain adequate oral hydration during treatment with 
AZD0466, as prophylaxis for TLS, as described in Appendix F.
6.2
Preparation/Handling/Storage/Accountability
Only patients enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment. All study treatment must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the Investigator and authorised site staff.
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 take place under aseptic handling conditions. 
Preparation and dosing of AZD0466 should not take place 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).
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 


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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 treatment shipments received and any discrepancies are 
reported and resolved before use of the study treatment(s).
All study treatments should be kept in a secure place under appropriate storage conditions. For 
specific storage conditions refer to the product label.
6.2.3
Accountability
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment 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 
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 treatment is 
provided in the Pharmacy Manual. 
6.3
Measures to Minimise Bias
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 other patients.
6.3.1
Methods for Assigning Treatment Groups
The actual treatment given to patients will be determined by the opened module/cohorts with 
the priority always to an open dose-escalation cohort. As not all modules/cohorts will be open 
at a given time, patients can only be allocated to open modules/cohorts. If only one 
module/cohort is open, treatment assignment can still occur.
When the study treatment is provided centrally by AstraZeneca, the Interactive Response 
Technology (IRT) will provide the kit identification number to be allocated to the patient at 


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the treatment allocation visit and subsequent treatment visits.
6.4
Study Treatment Compliance
The administration of all study treatments should be recorded in the appropriate sections of 
the eCRF. Any changes from the dosing schedule, dose reductions and dose discontinuations 
should be recorded in the eCRF. The reason should also be documented.
The study treatment Storage Manager is responsible for managing the study treatments from 
receipt by the study site until the destruction of unused study treatments. 
Use of doses in excess of that specified in the protocol is considered to be an overdose.
Overdose and 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. The dose of study treatment and 
patient identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study treatment. 
The Investigator or pharmacist must retain records of all study treatments administered at the 
site. The Medical Monitor will check these records to confirm compliance with the protocol 
administration schedule.
6.5
Concomitant Therapy
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrolment or receives 
during the study must be recorded along with: 
!
Reason for use 
!
Dates of administration including start and end dates 
!
Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Permitted Concomitant Medications and Treatments 
!
Anti-emetics are permitted for the treatment of nausea and vomiting and may be 
administered prophylactically for recurrent events. Routine pre-medication with 
anti-emetics for all patients is not advised. 


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!
Hydroxyurea (AML) is permitted to control white blood cell count < 10 x 109/L during 
screening until the start of Cycle 2. It can be started or stopped at any point during this 
period. With the exception of hydroxyurea, no other direct anti-leukaemia therapy is 
permitted once study treatment has begun. Detailed documentation of dose and frequency 
must be recorded in the eCRFs and medication diary.
!
High-dose steroids (ALL and leukaemia of ambiguous lineage) is permitted to control 
white blood cell count < 10 x 109/L during screening and Cycle 1 up to 4 days (maximum 
dexamethasone IV 40 mg/day or equivalent). It can be started or stopped at any point 
during this period. Detailed documentation of dose and frequency must be recorded in the 
eCRFs and medication diary.
!
Low dose prednisone (10 mg or less) or equivalent dose of alternative steroid 
!
Intrathecal CNS prophylaxis may be continued.
!
Supportive care, blood transfusions, and other medications that are considered necessary 
for the patient’s wellbeing may be given at the discretion of the Investigator.
!
Patients already receiving erythropoietin at the time of screening for the study may 
continue to receive it, provided they have been receiving it for > 1 month at the time 
study treatment is started. Prophylactic erythropoietin should not be started before 
Cycle 2.
!
Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage 
colony-stimulating factor (GM-CSF) may be considered for prolonged neutropenia 
(> 7 days) and < 5% blast in bone marrow following discussion with the Medical Monitor 
(Appendix F). However, long-acting pegylated G-CSF (pegfilgrastim) or darbepoetin is 
not permitted. 
!
Patients may receive treatment with receptor activator of nuclear factor kappa-B ligand 
(RANKL) inhibitors and/or bisphosphonates for the treatment of osteopenia, as 
recommended according to practice guidelines.
!
Allopurinol is mandatory prophylaxis for TLS, with dosing and schedule as per 
institutional guidelines. Rasburicase should be considered based on Appendix F and 
institutional guidelines. 
!
Diuretics should be used with care; prophylactic use should be considered only if patients 
have signs of volume overload.
!
Patients with an implanted pacemaker at study entry are eligible at the Investigator’s 
discretion. 
!
Acetaminophen (paracetamol) is 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, including Coronavirus disease 
2019 (COVID-19) vaccines, following a benefit/risk evaluation for the individual patient 


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and in accordance with local rules and regulations, and the local vaccination guideline. 
COVID-19 vaccines should be administered at least 7 days prior to the first dose of 
AZD0466, where possible. Use of live attenuated vaccines (eg, Influenza vaccine 
delivered as nasal spray) is prohibited. 
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 suggests 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 
treatment. Note: Hydroxyurea and high-dose steroids are not permitted during Cycle 2 or 
subsequent cycles to control white blood cell count in patients. Radiation therapy for 
palliative care to focal sites is allowed. 
!
Due to potential DDIs, the following medications should not be administered while the 
patient is receiving AZD0466, and in the 14 days after the completion of study treatment. 
In addition, each type of the following medications should not be given within the 
specified time prior to starting AZD0466 treatment:
!
14 days for the following medications:
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.
Note: This list is not comprehensive and other medications that fit into a similar category should also follow this 
guideline. 


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!
5 half-lives or 14 days, whichever is shorter, 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 BCRP
rosuvastatin and sulfasalazine.
*Voriconazole may be administered as study treatment as described in the schedule of assessments during the 
drug-drug interaction part of Module 2.
Note: This list is not comprehensive and other medications that fit into a similar category should also follow this 
guideline. 
6.6
Dose Modification and Toxicity Management 
AZD0466 may be withheld and the dose reduced due to haematological or 
non-haematological toxicities. In general, no AZD0466 dose modification is required if a 
patient experiences a Grade 1 or Grade 2 AE. However, AZD0466 should be modified or 
discontinued when the AEs described in this section are observed whether during ramp-up or 
once target dose is reached. Modifications based on cardiac AEs are described in Section 
6.6.5.
Acceptable dose modifications shown in Table 4 are applicable during ramp-up and once 
target dose is reached. A maximum of 3 dose modifications are acceptable, except for CTCAE 
Grade 3 or 4 haemorrhage and any intracranial haemorrhage or haematoma, of which only one 
event is allowed. Also see Table 5, Table 6, Table 7, and Table 8.


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Table 4
Dose Reduction Modifications
Cohort level
AZD0466 dose
Dose reductions
1 lower dose
2 lower doses
3 lower doses
DL-1
37.5 mg
--
--
--
75 mg
37.5 mg
--
--
150 mg
75 mg
37.5 mg
--
DL1
75 mg
37.5 mg
--
--
150 mg
75 mg
37.5 mg
--
300 mg
150 mg
75 mg
37.5 mg
DL2
150 mg
75 mg
37.5 mg
--
300 mg
150 mg
75 mg
37.5 mg
600mg 
300 mg
150 mg
75 mg
DL3
300 mg 
150 mg
75 mg
37.5 mg
600 mg
300 mg
150 mg
75 mg
1200 mg
600 mg
300 mg
150 mg
DL4
600 mg
300 mg
150 mg
75 mg
1200 mg
600 mg
300 mg
150 mg 
2400 mg
1200 mg
600 mg
300 mg
DL5 a
1200 mg 
600 mg
300 mg
150 mg
2400 mg
1200 mg
600 mg
300 mg
3600 mg 
2400 mg
1200 mg
600 mg
DL6 a
2400 mg
1200 mg
600 mg
300 mg
3600 mg
2400 mg
1200 mg
600 mg
5400 mg
3600 mg
2400 mg
1200 mg
DL6 –
alternative 
ramp-up b
1400 mg
600 mg
300 mg
150 mg
2800 mg
1200 mg
600 mg
300 mg
5400 mg
3600 mg
2400 mg
1200 mg
a
AZD0466 doses shown are illustrative. Actual doses will not exceed a 2-fold increase of a dose declared 
tolerable by the SRC, or the maximum feasible dose as specified in Section 11.4.7.5.
b
SRC to determine ramp-up as well as target dose.
DL, dose level; SRC, Safety Review Committee
While on study, patients diagnosed with COVID-19 and are thought to be receiving clinical 
benefit as deemed by the investigator may continue to receive AZD0466; however, must pause 
treatment if they meet pause or discontinuation criteria for dose modifications based on 
haematological parameters (Section 6.6.1, neutropenia), or CTCAE Grade 2 or higher non-
haematological toxicities (Section 6.6.3), which would include pneumonia or other infectious 
complications.


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6.6.1
Dose Modifications Based on Haematological Parameters
Myelosuppression and cytopenias are expected outcomes of leukaemia treatment, hence the 
aim of these dose modification guidelines is to prevent cumulative bone marrow suppression. 
Dose modifications for haematological changes are not allowed in the first 35 days after 
starting AZD0466 during Cycle 1 but supportive care should be provided as clinically 
indicated. 
If a patient experiences a clinically significant and/or unacceptable haematological toxicity 
(including a DLT) considered by the Investigator to be related to study treatment 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; Figure 3) and supportive therapy (Appendix F) 
administered as required. Recommended dose modifications for haematological toxicities 
associated with AZD0466 observed in patients with haematological malignancies are shown in 
Table 5. 
Table 5
Recommended Dose Modifications for Haematological Toxicities 
Toxicity Grade
Occurrence
Action
Grade 4 neutropenia, with or 
without fever or infection
Occurrence prior to achieving 
remission
Administer prophylactic or treatment 
anti-infectives and growth factor 
support as clinically indicated. In most 
instances, AZD0466 should not be 
interrupted due to neutropenias prior 
to achieving remission; however, 
Investigator judgment may be applied 
to determine the aetiology of 
neutropenias.
Occurrences after achieving 
remission and lasting at least 
7 days
Withhold AZD0466 until infection is 
resolved, and antibiotics no longer 
required (except prophylactic) and 
ANC ≥0.5 × 109/L.a
Dosing should be discussed with 
Medical Monitor.
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
Any
Withhold AZD0466
Maintain platelets at ≥50 × 109/L until 
resolution of bleeding.
Following discussion with Medical 
Monitor, if evidence of clinical 
benefit, may consider re-challenge at 
2 dose levels below current dose. 


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Table 5
Recommended Dose Modifications for Haematological Toxicities 
Toxicity Grade
Occurrence
Action
For any other bleeding events eg, 
petechiae, purpura, bleeding 
gums, epistaxis, etc
Any
Monitor platelets and action as above 
if thrombocytopenia ≥Grade 3
a
Recovery of ANC to ≥0.5 x 109/L only applicable for patients with ANC ≥0.5 x 109/L at 
baseline/screening. For other patients discuss with Medical Monitor.
ANC, absolute neutrophil count.
6.6.2
Retreatment Criteria
Administration of AZD0466 in subsequent cycles will be guided by presence of measurable 
disease and adequate haematopoiesis, as described below.
Criteria for holding administration of AZD0466
The haematological criteria for withholding AZD0466 are as follows (Table 6):
1
Inadequate haematopoiesis as demonstrated by lack of peripheral blood count recovery 
[absolute neutrophil count (ANC) < 0.5 × 109/L, and platelet count < 50 × 109/L] in the 
absence of active bone marrow leukaemia (marrow blasts < 5%). 
∀
Some patients with low blood counts (ANC < 0.5 × 109/L and platelet count < 50 ×
109/L) may have an aplastic or hypoplastic marrow (< 10% cellularity on bone 
marrow core biopsy). In patients with an aplastic or hypoplastic marrow and high 
leukaemic burden (eg, 5% cellularity and 95% leukaemic blasts), or if the 
Investigator determines the hypocellularity is attributable to residual leukaemia and 
not AZD0466, continued administration of AZD0466 may be permitted after 
discussion with the Medical Monitor.
∀
If AZD0466 is withheld due to cytopenias and bone marrow aplasia/hypoplasia 
(< 10% cellularity on core bone marrow core biopsy) in the absence of leukaemia 
(eg, 5% leukaemic blasts), the patient should be closely monitored for blood count 
recovery and a repeat bone marrow assessment should be considered at weekly 
intervals. 
2
Progressive disease (Appendix J and Appendix K): permanently discontinue AZD0466 
in the absence of clinical benefit after discussion with the Medical Monitor.
Criteria for administration/continuation of AZD0466
The next cycle of AZD0466 can proceed without delay if ANC > 0.5 x 109/L and platelets 
> 50 x 109/L (without platelet or growth factor support). For patients without peripheral blood 
count recovery, the next cycle can start if there is active leukaemia with 5% or higher blasts in 
the bone marrow.


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Table 6
Treatment Criteria Based on Bone Marrow, ANC and Transfusion 
Independent Platelet Count in the Absence of Peripheral Blasts
Event
ANC
(109/L)
Platelets
(109/L)
Bone 
marrow
Action
Cycle 1
> 0.5
> 50
-
•
Evaluate bone marrow disease but continue to 
next cycle irrespective of percentage of blasts 
(unless determined to have rapidly progressive 
disease and taken off study)
< 0.5
< 50
< 5% blast 
and 
cellularity 
< 10%
•
No count recovery at day 35 hold AZD0466 
wait to see if recovery at Day 42.
•
If no recovery, repeat bone marrow at Day 42.
•
Blasts count < 5% and no count recovery this 
is prolonged myelosuppression and a DLT. 
Discontinue AZD0466
•
Blasts count ≥5% and no count recovery, 
either continue to Cycle 2 or discontinue due to 
lack of response after discussion with Medical 
Monitor
< 0.5
< 50
> 5% blast 
•
If significant reduction of leukaemic burden 
and clinical benefit as assessed by the 
Investigator, discuss with the Medical Monitor 
and may continue to Cycle 2. 
•
If lack of clinical response or benefit consider 
discontinuation from study.
Cycle 2 and 
beyond
> 0.5
> 50
< 5% blast 
and normal 
cellularity 
(> 10 %)
<5% blast 
and bone 
marrow 
hypocellular 
(< 10% 
cellularity)
•
Continue to next cycle
•
Hold AZD0466 and monitor for count 
recovery and assess bone marrow weekly. 
Once adequate hemopoiesis met (> 20% 
cellularity) restart AZ0466. Consider restarting 
at one lower dose than the current dose.
> 0.5
> 50
> 5% blast 
•
Continue to next cycle if the patient is deriving 
benefit in the opinion of the Investigator
< 0.5
< 50
Aplastic/
Hypoplastic
(< 10% 
cellularity) 
and < 5% 
blasts
•
Hold and monitor for count recovery and 
assess bone marrow weekly. Once adequate 
hemopoiesis met (> 10% cellularity), restart 
AZ0466. Consider restarting at one lower dose
than the current dose. 
•
If hypocellularity is due to high leukaemic 
burden (95% blast) or if Investigator attributes 
hypocellularity to residual leukaemia, consider 
dosing after discussion with Medical Monitor


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Table 6
Treatment Criteria Based on Bone Marrow, ANC and Transfusion 
Independent Platelet Count in the Absence of Peripheral Blasts
Event
ANC
(109/L)
Platelets
(109/L)
Bone 
marrow
Action
< 0.5
< 50
> 5% blast 
•
Discuss with Medical Monitor consider 
discontinuation due to continued lack of 
response. Further cycles may be considered
ANC, absolute neutrophil count; DLT, dose-limiting toxicity.
Contact the Medical Monitor to discuss action with AZD0466 for any scenario not described 
above.
6.6.3
Dose Modifications for Non-haematological Toxicities
Dose modifications for non-haematological toxicities may occur at any time and the 
management are shown Table 7 toxicities are graded according to CTCAE version 5. Special 
considerations for TLS and specific AEs are included in Appendix F.
Dose modifications for changes in hepatic biochemistry are summarised in Section 6.6.4.
If a patient experiences a clinically significant and/or unacceptable non-haematological 
toxicity (including a DLT), considered by the Investigator to be related to study treatment, and 
not attributable to the disease (or to disease-related processes) under investigation, dosing will 
be withheld or the dose reduced and supportive therapy administered as required. 
Table 7
Dose Modifications for Non-haematological Toxicities
Event
Occurrence
Action with AZD0466
Non-haematological Toxicities (except hepatic and cardiac changes, see Sections 6.6.4 and 6.6.5)
CTCAE Grade 1 
non-haematological toxicities
Any
None
CTCAE Grade 2 
non-haematological toxicities
First occurrence 
None
Second and 
subsequent 
occurrences
•
Withhold AZD0466 until resolution to CTCAE 
Grade ≤1 or baseline. Maximum dose hold 21 days.
•
Restart AZD0466 at same dose level if at target 
dose or dose escalate if at ramp-up.
•
For > 3 occurrences, consider restarting AZD0466 
at one lower dose level if at target or consider to 
discontinue if at ramp-up.


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Table 7
Dose Modifications for Non-haematological Toxicities
Event
Occurrence
Action with AZD0466
CTCAE Grade 3 
non-haematological toxicities 
First occurrence 
•
Withhold AZD0466 until resolution to CTCAE 
Grade ≤1 or baseline. 
•
Supportive therapy should be given as per 
institutional guidelines. 
•
If resolution occurs in ≤ 7 days, restart AZD0466 at 
the same dose level if at target or dose escalate if 
at ramp-up, after discussion with Medical Monitor. 
•
If no resolution in ≤ 7 days, withhold AZD0466 for 
up to a total of 21 days.
•
If resolution occurs in > 7 days but ≤ 21 days, 
restart AZD0466. At one lower dose level if at 
target or consider to discontinue if at ramp-up.
•
Discontinue AZD0466 if no resolution to CTCAE 
Grade ≤ 1 in < 21 days 
Second and 
subsequent 
occurrences
•
Withhold AZD0466 and provide supportive therapy 
as per institutional guidelines.
•
Discontinue if at ramp-up.
•
If at target and resolution occurs in ≤ 7 days: restart 
AZD0466 at one lower dose after discussion with 
Medical Monitor. 
•
If no resolution in ≤ 7 days, withhold AZD0466 for 
up to a total of 21 days. 
•
If resolution to CTCAE ≤ Grade 1 occurs within 21 
days, discuss with Investigator and Medical 
Monitor to further dose reduce by one dose level
from previous dose, and to continue treatment if the 
patient is deriving clinical benefit. 
•
Discontinue AZD0466 if no resolution to CTCAE 
Grade ≤1 in ≤21 days.
CTCAE Grade 4 non-
haematological toxicities
Any
•
Discontinue AZD0466.
CTCAE, Common Terminology Criteria for Adverse Events (Version 5) 
6.6.4
Dose Modifications for Hepatotoxicity
AZD0466 dosing should be modified if a patient with normal or abnormal baseline liver 
function experiences a clinically significant and/or unacceptable change in hepatic 
biochemistry (including a DLT) described in Table 8 that is considered by the Investigator to 
be related to study treatment and not attributable to the disease (or to disease-related 
processes) under investigation. 


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Table 8
Dose Modification for Hepatotoxicity
Event
Occurrence
Action with AZD0466
For patients with normal 
baseline liver function:
ALT and/or AST > 5 × ULN 
and ≤ 8 × ULN without 
concomitant elevation in 
bilirubin, which return to 
baseline within 7 days
OR
For patients with abnormal 
baseline liver function:
ALT and/or AST > 5 × 
baseline and ≤ 8 × baseline or 
ALT and/or AST >7 × ULN 
and ≤ 10 × ULN, (whichever 
is lower in × ULN), without 
concomitant elevation in 
bilirubin, which return to 
baseline levels within 7 days
First occurrence
•
Withhold AZD0466 until values return to CTCAE 
Grade ≤ 1 or baseline.
•
Restart AZD0466 at same dose level if at target or 
dose escalate if at ramp-up.
Second 
occurrence
•
Withhold AZD0466 until values return to CTCAE 
Grade ≤ 1 or baseline.
•
Restart AZD0466 at one lower dose if at target or 
consider to discontinue if at ramp-up.
Third 
occurrence
•
Withhold AZD0466 until values return to CTCAE 
Grade ≤ 1 or baseline.
•
Discontinue if at ramp-up.
•
If at target dose: Restart AZD0466 at one lower 
dose than the current dose if all values resolve to 
baseline or Grade ≤ 1 within 7 days and there is 
clear evidence of clinical benefit. A Q2W schedule 
may be considered. 
•
Discontinue AZD0466 if the above criteria are not 
met.
For patients with normal 
baseline liver function:
ALT and/or AST > 8 × ULN 
and ≤ 20 × ULN without 
concomitant elevation in 
bilirubin, which return to 
baseline or Grade 1 levels 
within 14 days
OR
For patients with abnormal 
baseline liver function:
ALT and/or AST > 8 × 
baseline and ≤ 20 × baseline or 
ALT and/or AST > 10 × ULN 
and ≤20 × ULN, (whichever 
is lower in x ULN), without 
concomitant elevation in 
bilirubin, which return to 
baseline or Grade 1 levels 
within 14 days 
First occurrence
•
Withhold AZD0466 until values return to CTCAE 
Grade ≤1 or baseline.
•
Consider to discontinue if at ramp-up.
•
If at target dose: Restart AZD0466 at one lower 
dose than the current dose.
Second 
occurrence
•
Withhold AZD0466 until values return to CTCAE 
Grade ≤1 or baseline.
•
Discontinue if at ramp-up and not previously 
stopped.
•
If at target dose: Restart AZD0466 at one lower 
dose than the current dose and consider Q2W 
dosing schedule.
Third 
occurrence
•
Withhold AZD0466 until values return to CTCAE 
Grade ≤1 or baseline.
•
Restart AZD0466 at 2 lower dose levels than 
current dose and resume on a Q2W schedule, if all 
values resolve to baseline or CTCAE Grade ≤ 1 
within 14 days and there is clear evidence of 
clinical benefit.
•
Discontinue AZD0466 if the above criteria are not 
met.


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Table 8
Dose Modification for Hepatotoxicity
Event
Occurrence
Action with AZD0466
For patients with normal 
baseline liver function:
ALT and/or AST ≥ 3 × ULN 
with concomitant elevation in 
bilirubin ≥ 2 × ULN 
OR
For patients with abnormal 
baseline liver function:
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 14 days
6.6.5
Cardiac findings
AZD0466 should be withheld if any of the following occur at any time during study treatment: 
!
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 if 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 treatment, if considered by the Investigator to be related to study 
treatment.
Patients should be monitored closely including continuous ECG monitoring as clinically 
indicated (including for QTcF prolongations > 500 milliseconds) and until such a time as 
deemed safe to discontinue monitoring by medical review, with cardiologist input considered 
in the instance of abnormal ECG findings. AZD0466 may be restarted after resolution of 


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cardiac findings to the patient’s baseline at the discretion of the Investigator and after 
discussion with the Medical Monitor.
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.
6.7
Dose-limiting Toxicity
Refer to Module 1 (Section 11.4.7).
6.7.1
Definition of Maximum Tolerated Dose
Maximum tolerated dose will be determined using the modified toxicity probability interval 
(mTPI-2) approach as described in Module 1 (Section 11.4.7.3)
6.7.2
Definition of Recommended Phase II Dose
Refer to Module 1 (Section 11.4.7.4).
6.7.3
Definition of Maximum Feasible Dose
Refer to Module 1 (Section 11.4.7.5).
6.7.4
Safety Review Committee
Refer to Appendix A 5.
6.8
Treatment After the End of Study
Patients are permitted to receive further therapy or may continue to receive study treatment 
following the end of the study if, in the opinion of the Investigator, they are continuing to 
receive benefit from treatment. After discontinuation of study treatment, the Investigator will 
be at liberty to define further the most appropriate anticancer treatment.
Subsequent anticancer treatment is expected to be initiated following the cancer recurrence or 
development of a new cancer. Information on subsequent anticancer therapies should be 
recorded on the clinical database.


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7
DISCONTINUATION OF STUDY TREATMENT AND 
PATIENT DISCONTINUATION/WITHDRAWAL - CORE
7.1
Discontinuation of Study Treatment
Patients who permanently discontinue study treatment will continue to have follow-up 
assessments per the SoA. Patients will be permanently discontinued from study treatment if 
the following criteria are met:
!
Patient decision. The patient is at any time free to discontinue study treatment, without 
prejudice to further treatment. A patient who discontinues study treatment is normally 
expected to continue to participate in the study (eg, for safety and survival follow-up) 
unless they specifically withdraw their consent to all further participation in any study 
procedures and assessments.
!
Investigator decision
!
Occurrence of any AE that, in the opinion of the Investigator or AstraZeneca 
contraindicates further dosing
!
Pregnancy or intent to become pregnant 
!
Patients incorrectly initiated on study treatment (Section 7.1.2) 
!
Severe noncompliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from study treatment (eg, refusal to adhere to 
scheduled visits)
!
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled
in the study
!
Decision to modify the development plan of the drug
!
Initiation of alternative anticancer therapy including another investigational agent
!
Confirmed disease progression (Appendix J and Appendix K)
!
Death
All patients who are discontinued from study treatment should complete protocol-specified 
procedures for discontinuation of study treatment and follow-up procedures. Discontinued 
patients will be followed for survival, either through direct contacts or by collecting public 
records (eg, death certificates) as allowed by local laws. 
The end of treatment (EoT) visit should be performed as soon as the patient is permanently 
discontinued from study treatment. The reason for discontinuation should be documented in 
the source document and the appropriate section of the eCRF.
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without prejudice to further treatment and independent of any decision concerning 
participation in other aspects of the main study. Procedures for withdrawal from the 
exploratory research are outlined in Appendix C 2.
7.1.1
Procedures for Discontinuation of Study Treatment
Discontinuation of study treatment does not affect the patient’s participation in the study. A 
patient who decides to discontinue the study treatment will always be asked about the 
reason(s) for discontinuation and the presence of any AE. The patient should continue 
attending subsequent study visits, and data collection should continue according to the study 
protocol. If the patient does not agree to continue to attend study visits in person, where 
possible, a modified follow-up must be arranged to ensure the collection of endpoints and 
safety information. The approach taken should be recorded in the medical records. A patient 
that agrees to modified follow-up is not considered to have withdrawn consent or to have 
withdrawn from the study.
Patients who are permanently discontinued from further receipt of study treatment, regardless 
of the reason, will be identified as having permanently discontinued treatment, followed by 
entry into follow-up. Patients who have permanently discontinued from further receipt of 
study treatment will need to be recorded in the IRT.
All patients will be followed for survival until the end of the study. Survival information may 
be obtained via telephone contact with the patient, patient’s family, or by contact with the 
patient’s current physician. Patients who decline to return to the site for evaluations should be 
contacted by telephone, following the timing and procedures indicated in the SoA, as an 
alternative.
7.1.2
Procedures for Handling Patients who are Incorrectly Initiated on 
Study Treatment 
Patients who do not meet the inclusion/exclusion criteria should not, under any circumstances, 
receive study treatment. There can be no exceptions to this rule. 
Where patients that do not meet the inclusion/exclusion criteria are incorrectly started on 
treatment, or where patients subsequently fail to meet the study criteria post initiation, the 
Investigator should inform the AstraZeneca Medical Monitor immediately. 
Any patient who is found to have failed to meet the selection criteria, but has started 
treatment, will be removed from the study following completion of safety follow-up activities. 
Every effort should be made to ensure ineligible patients complete all safety follow-up 
activities. The Medical Monitor is to ensure all such contacts are appropriately documented.


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7.2
Patient Withdrawal from the Study
A patient may withdraw from the study at any time at his/her own request. A patient who 
considers withdrawing from the study must be informed by the Investigator about modified 
follow-up options (eg, telephone contact, a contact with a relative or treating physician, or 
information from medical records). Patients may be withdrawn at any time at the discretion of 
the Investigator for safety, behavioural, compliance, or administrative reasons; this is expected 
to be uncommon.
If the patient is on study treatment, this will be discontinued and the patient will be withdrawn 
from the study at this time. An EoT visit should be conducted at the time of withdrawal from 
the study, if it has not already been performed.
If the patient withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a patient 
withdraws from the study, it should be confirmed if he/she still agrees for existing samples to 
be used in line with the original consent. If he/she requests withdrawal of consent for use of 
samples, destruction of any samples taken and not tested should be carried out in line with 
what was stated in the informed consent and local regulation. The Investigator must document 
the decision on use of existing samples in the site study records and inform the Global Study 
Team.
Patients that are withdrawn from the study but are evaluable per the definition of 
DLT-evaluable (Section 11.7.3) will not be replaced. Patients who do not experience a DLT 
(Section 11.4.7) can be replaced if the patient withdraws before the end of the DLT window. 
Any patient that is withdrawn and is not evaluable will be replaced to ensure a minimum 
number of evaluable patients.
7.2.1
Procedures for Withdrawal from Study
Patients who withdraw from the study will always be asked about the reason(s) and the 
presence of any AEs. If possible, they will be seen by an Investigator and undergo the 
assessments and procedures scheduled for the post-study assessment. AEs should be followed 
up and study treatment should be returned by the patient.
7.3
Lost to Follow-up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.


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The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:
!
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
study.
!
Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record.
!
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 treatment. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented and the 
patient will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
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 Medical Monitor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment. Adherence to the study requirements, including those specified in the SoA for each 
module, is essential and required for study conduct. 
The maximum amount of blood collected from each patient during the first 28 days of 
treatment for research assessments is not anticipated to exceed 275 mL.
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 take place for up to 28 days from the 
date of enrolment. Every effort should be made to minimise the time between treatment 


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assignment and dosing, preferably to within 14 days. Patients who fail to meet the eligibility 
criteria will be recorded as a “screen failure”. Individuals who do not meet the criteria for 
participation in this study (screen failure) may be re-screened up to 2 times. Each potential 
patient is assigned a unique patient number. If a patient withdraws from the study, then 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 electronic data capture (EDC) system.
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 
appropriate time frame relative to the first dose of study treatment, as defined in the SoA.
Demographic data and other characteristics will be recorded and will include gender, race, and 
ethnicity according to local regulations. A standard medical history, medication history, and 
surgical history will be obtained during review of the selection criteria. This will include the 
date of initial diagnosis of the disease under study, disease assessment within 28 days prior to 
the first dose of AZD0466, prognostic indices/disease profiling (if available from local 
laboratory results) for each disease indication, and all prior anticancer treatments (including 
responses and duration of response) for the disease under study.
Disease assessments and other clinical data obtained as standard of care (SoC) prior to consent 
may be used for the study, provided the assessments fall within the protocol-specified period 
prior to the first dose of study treatment.
Follow-up Period
The EoT assessment will be performed at the time study treatment is permanently 
discontinued. In addition, patients should be followed up for 28 days after the last dose of 
study treatment for any new AEs, follow-up of existing AEs and other study assessments. 
Patients should also be asked about concomitant medications at this follow-up. Patients will 
continue to be followed until disease progression or withdrawal of consent. All patients should 
be followed monthly for survival after the last clinic visit until withdrawal of consent or end 
of study for the purpose of assessing survival status (see Section 7.1). Patients who achieve a 
complete remission (CR) or CR with incomplete haematological recovery (CRi) should be 
followed for relapse of disease until death. 


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8.1
Efficacy Assessments 
Disease assessments will be based on bone marrow biopsy and aspirate in conjunction with 
assessment of peripheral blood samples. Assessments will be performed according to the 
individual module SoA. Unscheduled disease assessments may be performed if clinically 
indicated.
8.1.1
Disease Assessment in Patients With Known or Suspected 
Extramedullary Disease
Baseline disease assessments for patients with known or suspected extramedullary disease will 
be conducted using radiological imaging (computerised tomography [CT] with contrast 
preferred or magnetic resonance image [MRI], or if applicable, also positron emission 
tomography [PET] CT scan) of the neck, chest, abdomen, and pelvis performed within 
28 days before the first dose of study treatment. Scans will be repeated at times of disease 
assessment as described in the individual module SoA (ie, after Cycle 1 and 2 and 
subsequently as per modules) until resolution of extramedullary disease.
Extramedullary disease is classified as follows:
!
Measurable extramedullary disease: lesions that can be accurately measured in 
2 dimensions by CT or MRI.
!
Non-measurable extramedullary disease: all other lesions (including unidimensional 
lesions, lesions too small to be considered measurable), pleural or pericardial effusion, 
ascites, bone disease, leptomeningeal disease, lymphangitis, pulmonitis, abdominal 
masses not confirmed or followed by imaging techniques, or disease documented by 
indirect evidence only (eg, laboratory values).
Up to 6 measurable extramedullary disease lesions that are clearly measurable in 
2 perpendicular dimensions will be followed as target lesions for each patient (target lesions 
must be > 1.0 cm in the longest diameter). The selected sites of measurable disease should be 
representative of the patient’s disease. In addition, selection of target lesions should be from 
disparate regions of the body when these areas are significantly involved. If additional 
non-measurable extramedullary disease lesions are present, they may be recorded as non-
target lesions and followed throughout the study. For patients with hepatosplenomegaly at 
baseline, the cranio-caudal measurement of the spleen and the longest diameter of the liver 
will be assessed at screening and all subsequent response evaluations. 
An MRI 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. 


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8.2
Safety Assessments
Refer to each module for details.
8.3
Adverse Events and Serious Adverse Events
The Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section.
The definitions of an AE or serious adverse event (SAE) can be found in Appendix B. Adverse 
events will be reported to the Investigator by the patient (or, when appropriate, by a caregiver, 
surrogate, or the patient's legally authorised representative). The Investigator and any 
designees are responsible for detecting, documenting, and recording events that meet the 
definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
AEs and SAEs will be collected from time of signature of the informed consent form 
throughout the treatment period and including the follow-up period (28 days after the last dose 
of the study treatment). If an event that starts after the defined safety follow-up period noted 
above is considered to be due to a late-onset toxicity to study treatment, it should be reported 
as an AE or SAE as applicable.
All SAEs will be recorded and reported to AstraZeneca or its designee within 24 hours. The 
Investigator will submit any updated SAE data to AstraZeneca within 24 hours of it being 
available.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
If the Investigator becomes aware of an SAE with a suspected causal relationship to study 
treatment that occurs after the end of the clinical study in a patient treated by him or her, the 
Investigator shall, without undue delay, report the SAE to the sponsor.
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-serious AEs 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 treatment), 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.


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Adverse event variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
CTCAE grade
!
Whether the AE is serious or not
!
Investigator causality rating against study treatment (yes or no)
!
Action taken with regard to study treatment
!
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
The grading scales found in the revised National Cancer Institute (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 Cancer Therapy Evaluation Program (CTEP) website 
(http://ctep.cancer.gov).
8.3.3 Causality Collection
The Investigator should assess causal relationship between each study treatment (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 treatment?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 


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relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol (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 treatment, 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 treatment, eg, dose modification).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.3.6 Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation 


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and occurrences of aspartate aminotransferase/transaminase (AST) or alanine 
aminotransferase/transaminase (ALT) ≥ 3 × upper limit of normal (ULN) together with total 
bilirubin (TBL) ≥ 2 × ULN may need to be reported as SAEs. Please refer to Appendix E for 
further instruction on cases of increases in liver biochemistry and evaluation of Hy’s Law.
8.3.7 Disease Progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the study treatment is being 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 > 5% leukaemic blasts in the bone marrow, appearance or increase of leukaemic blasts in 
peripheral blood, or development of extramedullary disease should be considered as disease 
progression and not an AE. Events, which are unequivocally due to disease progression, 
should not be reported as an AE during the study.
8.3.8 Disease Under Study 
Symptoms of disease under study (DUS) are those which might be expected to occur as a 
direct result of the advanced haematological malignancy. Events which are unequivocally due 
to DUS should not be reported as an AE during the study unless they meet SAE criteria or 
lead to discontinuation of the study treatment.
8.3.9
New Cancers
The development of a new cancer should be regarded as an SAE and will generally meet at 
least the serious criteria of important medical event if no other criteria applies. New cancers 
are those that are not the primary reason for the administration of the study treatment and have 
been identified after the patient’s inclusion in this study.
8.3.10
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 treatment, should be reported as follows:
!
Death, which is unequivocally due to disease progression, should be communicated to the 
Medical Monitor at the next monitoring visit and should be documented in the CRF 
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 Medical Monitor as a Grade 5 SAE within 
24 hours. It should also be documented in the CRF module. The SAE report should 
contain a comment regarding the co-involvement of progression of disease, if appropriate, 
and should assign a single primary cause of death together with any contributory causes.
!
Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the CRF module. A postmortem may be helpful in the assessment of the 


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cause of death, and if performed, a copy of the postmortem results (with translation of 
essential details into English) should be reported in an expedited fashion to the sponsor 
representative within the usual timeframes. 
!
Deaths occurring after the protocol-defined safety follow-up period after the 
administration of the last dose of study treatment should be documented in the Statement 
of Death page. If the death occurred as a result of an event that started post the defined 
safety follow-up period and the event is considered to be due to a late-onset toxicity to 
study treatment, then it should also be reported as an SAE.
8.3.11
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
treatment or to study procedures. All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, Investigators or other site personnel will inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
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 how to proceed.
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, see Appendix B of the CSP.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 


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drug. 
Where hospitalisation for longer than the mandated 24 hours is required it should be noted that 
if this is due to occurrence of an AE then the event must be reported as an SAE, per definition. 
However, if it is purely for the purposes of extended observation then this does not qualify as 
an SAE and does not need to be reported.
8.3.12
Adverse Events of Special Interest
An adverse event of special interest (AESI) is an AE, serious or non-serious, that is of 
scientific and medical interest specific to the understanding of the study treatment and may 
require closer monitoring, with collecting of additional information by the Investigator and 
reporting these to the sponsor. The rapid reporting of AESIs by the Investigator allows 
ongoing surveillance of these events in order to further characterise and understand them in 
relation to the use of the study treatment. All AESIs should be recorded in the eCRF as soon as 
possible, preferably within 24 hours. All AESIs that are also serious (ie, are SAEs) should be 
reported to AstraZeneca Patient Safety within 24 hours, as per safety reporting requirements.
In this study, the following are considered to be AESIs:
!
Tumour lysis syndrome (Appendix G)
!
Hepatotoxicity, including potential Hy’s Law, drug-induced liver injury (DILI), and 
bilirubin increase with transaminase (ALT or AST or both ALT and AST) increase
!
QRS amplitude decrease 
8.3.13
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca within 
24 hours except for pregnancy that is discovered before the study patient has received any 
study treatment.
8.3.13.1
Maternal Exposure
If a patient becomes pregnant during the course of the study, study treatment should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
patient was discontinued from the study.


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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 8.3.11) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
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.
8.3.13.2
Paternal Exposure 
The outcome of any conception occurring from the date of the first dose until 6 months after 
the last dose of study treatment 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 abnormality), occurring from the date of the first dose and for 35 days after the 
last dose of AZD0466 -plus 6 months - should, if possible, be followed up and documented in 
the Pregnancy Report Form. Consent from the partner must be obtained before the Pregnancy 
Report Form is completed.
If a pregnancy occurs in a 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 protocol.
8.3.14
Medication Error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 


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Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.11) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Appendix B 4.
8.4
Overdose
For this study, any dose of AZD0466 greater than the highest dose intended for the individual 
patient at that timepoint in the protocol will be considered an overdose. For example, during 
ramp-up, doses exceeding the specified dose at that timepoint will also be classified as an 
overdose, even if the dose administered is less than the target dose for that patient. 
Investigators should be advised that any patient who receives a higher dose of AZD0466 than 
that intended should be monitored closely, managed with appropriate supportive care and 
followed up expectantly. There are no data available on overdose with AZD0466 and there is 
no known antidote.
Overdose should be recorded as follows:
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose on an AstraZeneca study treatment occurs in the course of the study, the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for overdoses associated with an SAE (see Section 8.3.11) and within 
30 days for all other overdoses. 
Refer to the individual modules for overdose information on module-specific study 
treatments.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
-specific Laboratory Manual. Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality. For further details on Handling of Human 
Biological Samples, see Appendix C.


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Samples will be stored for a maximum of 15 years from the date of the last patient visit in line 
with consent and local requirements, after which they will be destroyed/repatriated. 
PK samples will be disposed of after the Bioanalytical Report finalisation or 6 months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless consented for future 
analyses. 
PK samples may be disposed of or anonymised by pooling. Additional analyses may be 
conducted on the anonymised, pooled PK samples to further evaluate and validate the 
analytical method. Any results from such analyses may be reported separately from the CSR. 
8.5.1
Pharmacokinetics
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. 
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 CSR but 
separately in a Bioanalytical Report.
8.5.1.1
Collection of Pharmacokinetic Samples
Refer to each individual module for details of collection schedule and procedures for PK 
sample collection.
8.5.1.2
Determination of Drug Concentration
Refer to each individual module for details of determination of drug concentration.
8.5.2
Pharmacodynamics
Refer to each module for details of collection schedule and procedures for PD samples 
collection. 


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8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
Refer to individual modules for details on module-specific mandatory samples for biomarker 
analysis.
8.6.1.1
 
 
 
 
 
8.6.2
Other Study Related Biomarker Research
Refer to individual modules for details. 
8.7
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in the individual module SoA and is subject to agreement in the ICF/ICF addendum.
 
 
 
See Appendix D for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found either in 
the appendices or in the Laboratory Manual. 
For storage and destruction of genetic samples, see Appendix D. See Appendix C for labelling, 
chain of custody, shipment, handling and withdrawal of consent for donated biological 
samples.
8.8
Medical Resource Utilisation and Health Economics
Health Economics/Medical Resource Utilisation and Health Economics parameters are not 
evaluated in this study.
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9
STATISTICAL CONSIDERATIONS - CORE
9.1
Statistical Hypotheses 
No formal statistical hypothesis testing is planned.
9.2
Sample Size Determination
Please refer to individual study modules for details of sample sizes.
9.3
Populations for Analysis
Please refer to individual study modules for details of populations for analysis.
9.4
Statistical Analyses
The statistical analysis plan (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.
9.5
General Considerations
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 data will be summarised on the safety 
population set. Exposure data will be summarised on the safety population set. The efficacy 
endpoints for response will be summarised on the appropriate evaluable for response 
population set. The efficacy endpoints for OS will be summarised on the intent-to-treat (ITT) 
population set (Section 11.7.3). Safety data will be summarised on the safety population set 
(Section 11.7.3).
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 treatment will be listed including the study day of treatment 
discontinuation and will be summarised by dose group if appropriate.
Exposure
Exposure to study treatment ie, total amount of study drug 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 


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number of observations.
9.6
Efficacy
Clinical responses (including CR and CRi will be listed and summarised by dose group and by 
appropriate response category for AML, ALL, and intermediate and higher risk MDS. Clinical 
responses for AML, ALL, and intermediate and higher risk MDS will be derived by applying 
the criteria as described in Appendix K, Appendix J, and Appendix P. In addition, bone 
marrow and 
 and changes from baseline scaled ratio 
will be summarised appropriately.
9.7
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. 
All patients receiving a particular dose level within each part of the study will be grouped 
together for summary and analysis and defined as a dose group.
9.7.1
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.
Data from all cycles of initial treatment will be combined in the presentation of safety data. 
AEs will be listed individually by patient and dose group. For patients who have a dose 
modification, all AEs (due to drug or otherwise) will be assigned to the initial dose group. The 
number of patients experiencing each AE will be summarised by the Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class, MedDRA preferred term and CTCAE 
grade. The number and percentage of patients with AEs in different categories (eg, causally 
related, CTCAE grade ≥ 3, etc) will be summarised by dose group, and events in each 
category will be further summarised by MedDRA system organ class and preferred term, by 
dose group. SAEs will be summarised separately if a sufficient number occur.
Any AE occurring before the first dose of study treatment (ie, before study Day 1) will be 
included in the data listings but will not be included in the summary tables of AEs.
Any AE occurring within the defined 28 day follow-up period after discontinuation of study 
treatment will be included in the AE summaries. Any AEs in this period that occur after a 
patient has received further therapy for cancer (following discontinuation of study treatment) 
will be flagged in the data listings. AEs occurring after the 28 day follow-up period after 
discontinuation of study treatment will be listed separately, but not included in the summaries.
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9.7.2
Other safety parameters
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. 
9.8
Other Analyses
Please see individual modules for details.
9.9
Interim Analyses 
Please see individual modules for details.
10
REFERENCES - CORE
Adams et al 2018
Adams CM, Clark-Garvey S, Porcu P, Eischen CM. Targeting the Bcl-2 Family in B Cell 
Lymphoma. Front Oncol. 2019:8:636.
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.
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.
Delbridge and Strasser 2015
Delbridge ARD and Strasser A. The BCL-2 protein family, BH3-mimetics and cancer therapy. 
Cell Death Differ 2015;22(7):1071-80.
Döhner et al 2017
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and 
management of AML in adults: 2017 ELN recommendations from an international expert 
panel. Blood. 2017;129(4):424-47.


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Estey et al 2022
Estey E, Hasserjian RP, Döhner H. Distinguishing AML from MDS: a fixed blast percentage 
may no longer be optimal. Blood. 2022;139(3):323-32.
Greenberg et al 2012
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised 
international prognostic scoring system for myelodysplastic syndromes. Blood 
2012;120(12):2454-65.
Hanahan and Weinberg 2000
Hanahan D and Weinberg. The hallmarks of cancer. Cell. 2000;100(1):57-70.
Jilg et al 2016
Jilg S, Reidel V., Müller-Thomas C et al. Blockade of BCL-2 proteins efficiently induces 
apoptosis in progenitor cells of high-risk myelodysplastic syndromes 
patients. Leukemia 2016;30, 112–23.
Kerr et al 1972
Kerr JFR, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-
ranging implications in tissue kinetics. Br J Cancer 1972;26(4):239-57.
Reidel et al 2018
Reidel V, Kauschinger J, Hauch RT, et al. Selective inhibition of BCL-2 is a promising target 
in patients with high-risk myelodysplastic syndromes and adverse mutational 
profile. Oncotarget. 2018;9(25):17270-81. 
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.
Vardiman et al 2009
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 
revision of the World Health Organization (WHO) classification of myeloid neoplasms and 
acute leukemia: rationale and important changes. Blood 2009;114(5):937-51.
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 1998;335(6189):440-2.


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11
MODULE 1: AZD0466 MONOTHERAPY DOSE ESCALATION 
(PART A) AND DOSE EXPANSION (PART B) IN PATIENTS 
WITH ADVANCED HAEMATOLOGICAL MALIGNANCIES
11.1
BACKGROUND - MODULE 1
11.1.1
Study Treatment 
Study treatment in Module 1 is the investigational product, AZD0466. Refer to Section 6 and 
Section 11.4; further details are provided in the IB. 
11.1.2
Nonclinical Information and Correlative Studies
Refer to Section 2.1.2; further details are provided in the IB.
11.1.3
Rationale for Module 1
The overall rationale for investigating AZD0466 in patients with advanced haematological 
malignancies is presented in Section 2.3.
As AZD0466 has not been investigated in patients with advanced haematological 
malignancies, Module 1 Part A is a dose escalation assessment of the safety and tolerability of 
AZD0466 to determine the recommended dose and schedule for further evaluation. Module 1 
Part B will further explore the preliminary anticancer efficacy of AZD0466 in 4 cohorts of 
patients with AML or ALL (Table 9). These expansion cohorts have been proposed on the 
basis of preclinical data supporting potentially enhanced efficacy of AZD0466, a dual 
Bcl-2/Bcl-xL inhibitor, compared to compounds that inhibit Bcl-2 alone and in consideration 
of the unmet medical need in each of these populations.
A summary of the advanced haematological malignancies included in the Part B dose 
expansion cohorts is shown in Table 9.
Table 9
Summary of Disease Characteristics for Patients Enrolled in 
Module 1 Part B Dose Expansion Cohorts
Expansion 
cohort
Lineage
Prior history 
myeloproliferative
neoplasm
TP53 mutation
Prior treatment
B1
Acute myeloid leukaemia
Yes
Yes or No
≤ 2 lines
venetoclax permitted
B2
Acute myeloid leukaemia
No
Yes
≤ 3 lines
venetoclax permitted
B3
Acute myeloid leukaemia
No
No
≤ 3 lines; 
to include venetoclax 
B4
Acute lymphoblastic leukaemia
-
-
≤ 3 lines
TP53, gene encoding tumour protein p53.


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Design of Module 1
Module 1 Part A is a Phase I dose escalation evaluation of AZD0466 monotherapy; Module 1 
Part B is a dose expansion evaluating the recommended Phase II dose of AZD0466 
monotherapy in 4 cohorts of patients.
A visual representation of Module 1 is shown in Figure 3.
Figure 3
Schema for Module 1
a
AZD0466 doses shown are illustrative. Actual doses will not exceed a 2-fold increase of a dose declared 
tolerable by the SRC, or the maximum feasible dose as specified in Section 11.4.7.5.
Dotted paths contingent on emerging data.
ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; D, Day; IA, interim analysis; MPN, 
myeloproliferative neoplasm; SRC, Safety Review Committee; TD, target dose; TP53, gene encoding tumour 
protein p53.
11.1.3.1
Justification for Starting Dose
A physiologically based PK model validated across nonclinical species was used to predict 
AZD0466 human PK and, in conjunction with the PK/PD model used, to predict human doses 
and exposures expected to drive tumour regression. The efficacious dose range is predicted to 
be AZD0466 10 to 100 mg/kg per week, or 600–6000 mg per week administered as a one-
hour IV infusion (based on a 60-kg patient). Further information on PK modelling of 
AZD0466 can be found in the IB.
Study D8240C00003 demonstrated that weekly administration of AZD0466 200 mg IV is 
tolerated in patients with advanced solid malignancies (data on file, AstraZeneca). The 
treatment schedule for patients with haematological malignancies included an intra-patient 
dose ramp-up, derived from the approach initially taken for venetoclax (a potent, selective 
inhibitor of Bcl-2) in patients with CLL (Cheson et al 2017, Davids et al 2017) and AML 
(DiNardo et al 2018, DiNardo et al 2019). The AZD0466 schedule involved dose ramp-up in 


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Cycle 1 from a starting dose on Day 1, with subsequent titration to the intermediate dose on 
Day 4, and to the target dose on Day 8, with weekly IV administration thereafter at the target 
dose.
Study D8240C00003, now closed, enrolled patients with advanced solid malignancies, who 
were dosed with 50, 100, or 200 mg of AZD0466. The three dose levels were declared safe by 
the SRC, which allowed the current study to start dosing patients at 300 mg (dose level 1). A 
de-escalation to dose level -1 is included as part of the study design with a target dose level of 
150 mg. Dose escalation will not be greater than a 2-fold increase of a dose declared tolerable 
by the SRC.
11.1.3.2
Part A Dose Escalation Scheme 
The dose escalation part of the study will enrol up to 48 patients with a histologically 
confirmed AML, ALL, or intermediate or higher risk MDS to ensure approximately 
36 DLT-evaluable patients. At least 3 DLT-evaluable patients are required at each dose level 
and, up to 12 patients may be enrolled in any dose level. Up to an additional 18 patients may 
be enrolled to backfill earlier cohorts at lower dose levels with the intent of enabling pre- and 
on-treatment peripheral blood samples and bone marrow aspirates and biopsies to aid 
characterisation of the PD of AZD0466 and to provide additional data on safety, tolerability, 
PK, and biological activity (n = 66 in total). If a dose escalation cohort and a backfill 
expansion cohort are simultaneously open to enrolment, precedence will be given to 
enrolment into the dose escalation cohort.
11.1.3.3
Dose Escalation, De-escalation, and Stopping Decision Rules
A SRC (Appendix A 5) will be responsible for making recommendations for dose-escalation 
or de-escalation after each dose level, including decisions on opening cohorts for backfill, in 
accordance with the SRC charter. The intra-patient dose ramp-up and/or dose schedule for 
each cohort may be modified based on safety, PK, and PD findings of a previous 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.
A recommended dose level for each subsequent cohort of patients will be made by the SRC, 
guided by pre-defined decision rules. The decision rules are based on a mTPI-2 design (Guo et 
al 2017) with a 30% (± 5%) target DLT rate for maximum tolerated dose (MTD). Depending 
on the number of patients treated at a dose level, and the number of DLTs observed in those 
patients, the possible decisions will be: to escalate, stay at current dose, de-escalate, or 
de-escalate and do not use current dose again due to unacceptable toxicity. Decision rules 
based on mTPI-2 for dose escalation are shown in Table 10.
The decisions on the adequacy of the dose escalation portion of the design were based on 
outcomes from an internal AZ simulation package which calculates estimates of the likelihood 
of selecting the true MTD under a range of different scenarios. Operating characteristics are 


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presented in Table 11.
Table 10
Decision Rules Based on mTPI-2 for Dose Escalation
Number
of DLTs
Number of Patients Treated at Current Dose Level
n = 1
n = 2
n = 3
n = 4
n = 5
n = 6
n = 7
n = 8
n = 9
n = 10 n = 11 n = 12
0
Sa
Sa
E
E
E
E
E
E
E
E
E
E
1
Sb
Sb
S
S
E
E
E
E
E
E
E
E
2
DNT
D
D
D
S
S
S
E
E
E
E
3
DNT
DNT
D
D
D
D
S
S
S
E
4
DNT
DNT
DNT
D
D
D
D
D
D
5
DNT
DNT
DNT
DNT
DNT
D
D
D
6
DNT
DNT
DNT
DNT
DNT
DNT
D
7
DNT
DNT
DNT
DNT
DNT
DNT
a
Adapted from Guo et al 2017 from E to S as a minimum of 3 evaluable patients are needed to make a dose 
escalation decision.
b
Adapted from Guo et al 2017 from D to S as a minimum of 3 evaluable patients are needed to make a dose 
de-escalation decision. 
D, de-escalation to the next lower dose level; DLT, dose -limiting toxicity; DNT, dose not tolerated; E, escalation 
to the next higher dose level; mTPI-2, modified toxicity probability interval; S, stay at the current dose level.
Table 11
Operating Characteristics for Selecting Maximum Tolerated Dose
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A dose level will be considered as having unacceptable toxicity (with no additional patients to 
be enrolled at that dose level) if there is an estimated > 95% probability (P) of exceeding the 
target DLT rate of 30% (ie, P [DLT > 30% data] > 95%) with at least 3 patients treated at that 
dose level. 
If a ‘stay’ decision is made, additional patients may be enrolled (usually in cohorts of 3) up to 
a maximum of 12 DLT-evaluable patients for a given dose level.
11.1.3.4
Dose Expansion Design
The dose expansion part of the study will enrol approximately 88 response-evaluable patients, 
into one of 4 cohorts according to the specific haematological malignancy. Patients will have a 
histologically confirmed AML or ALL as described below. Cohorts may open either in parallel 
or sequentially at the sponsor’s discretion. 
Expansion Cohort B1: Approximately 21 response-evaluable patients with 
relapsed/refractory AML secondary to myeloproliferative neoplasm (MPN) +/- TP53
mutation. At least 30% of the cohort should be venetoclax-naïve.
Expansion Cohort B2: Approximately 21 response-evaluable patients with 
relapsed/refractory AML with TP53 mutation and no prior history of MPN. At least 30% of 
the cohort should be venetoclax-naïve. 
Expansion Cohort B3: Approximately 25 response-evaluable patients with 
relapsed/refractory AML without TP53 mutation or a prior history of MPN (ie, ineligible for 
Cohort B1 and B2) but have previously been treated with venetoclax. 
Expansion Cohort B4: Approximately 21 response-evaluable patients with 
relapsed/refractory ALL including B-ALL and T-ALL. At least 25% of the cohort should be 
patients with relapsed and/or refractory T-ALL.
All patients in each cohort will receive study treatment until progressive disease, unacceptable 
toxicity, or withdrawal of consent.
11.1.4
Benefit-risk Assessment for Module 1
See Section 2.2 of the core protocol for an overall benefit-risk assessment for AZD0466 in the 
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study population.
The study design for Module 1 includes inter-patient dose escalation and intra-patient dose 
ramp-up. The dose escalation will commence administration of AZD0466 in patients with 
AML or ALL at a dose level for which the 2 ramp-up doses are below the dose tolerated as 
repeated weekly infusions in patients with advanced solid malignancies in Study 
D8240C00003 (data on file, AstraZeneca). The available nonclinical and clinical information 
supports an acceptable benefit-risk assessment for investigation of AZD0466 monotherapy in 
patients with advanced haematological malignancies for which there are limited treatment 
options.
11.2
OBJECTIVES AND ENDPOINTS - MODULE 1
11.2.1
Primary Objectives
The primary objectives and endpoints for this module are listed in Section 3 of the core 
protocol; additional endpoints for Part A are listed in Table 12.
Table 12
Primary Objectives - Module 1 - Part A
Objectives
Endpoints/Variables
•
To assess the safety and tolerability of 
AZD0466 in patients with advanced 
haematological malignancies
•
DLT
•
MTD
•
RP2D and schedule
DLT, dose-limiting toxicity; MTD, maximum tolerated dose; RP2D, recommended Phase II dose
11.2.2
Secondary Objectives
The secondary objectives and endpoints for this module are listed in Table 13. See Section 3
of the core protocol for all other secondary objectives. 
Table 13
Secondary Objectives - Module 1
Objectives
Estimand description
Complete Response Rate (CR+CRi)


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Table 13
Secondary Objectives - Module 1
Objectives
Estimand description
•
To estimate the preliminary antitumor activity 
of AZD0466 by assessment of Complete 
response rate (CR+CRi) in patients with 
advanced haematological malignancies
•
Complete response rate (CR+CRi) is defined as 
the proportion of patients who have a complete 
remission (CR) or incomplete haematological 
response (CRi), as determined by criteria 
described in Appendix J, Appendix K and 
Appendix O).
•
The analysis will include all dosed patients as 
intended.  
•
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 CR+CRi, regardless of 
whether the patient withdraws from study 
treatment. Patients who go off treatment without 
a response or progression, receive a subsequent 
therapy, and then respond will not be included 
as responders in this evaluation. 
•
The measure of interest is the estimate of 
CR+CRi. 
Time to Response (TTR)
•
To estimate the preliminary antitumor activity 
of AZD0466 by assessment of time to complete 
response (TTR) in patients advanced 
haematological malignancies
•
Time to response is defined as the time from 
date of first dose until the date of first 
documented CR or CRi.
•
The analysis will include all dosed patients as 
intended, who have a complete remission.
•
Patients who go off study treatment without a 
clinical response and receive a subsequent 
therapy and then respond will not be included. 
•
The measure of interest is median TTR.
Duration of Response (DoR)
•
To estimate the preliminary antitumor activity 
of AZD0466 by assessment of DoR in patients 
with advanced haematological malignancies.
•
DoR will be defined as the time from the date of 
first documented response (CR+CRi) until date 
of documented progression, relapse or failure 
per Appendix J and Appendix K or death due to 
any cause.
•
The analysis will include all dosed patients as 
intended who have a confirmed response (CR or 
CRi), regardless of whether the patient 
withdraws from study treatment or receives 
another anticancer therapy.
•
The measure of interest are the percentiles of 
DoR.




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of Module 1 (Module 1 Part B) are listed below in Section 11.3.1. Please note that per core 
inclusion criterion 4, patients must have received at least one prior line of therapy, and an 
established standard of care with proven benefit, and for which the patient is eligible, must not 
be available at the time of enrolment. There are no additional inclusion criteria specific to the 
dose escalation part of Module 1 (Module 1 Part A). There are no additional exclusion criteria 
specific to Module 1.
Patients are eligible to be included in the dose escalation part of Module 1 (Module 1 Part A) 
if they meet all of the inclusion criteria in Section 5.1 and none of the exclusion criteria in 
Sections 5.2. Under no circumstances can there be exceptions to this rule.
Patients are eligible to be included in the dose expansion part of Module 1 (Module 1 Part B) 
if they meet all of the inclusion criteria in Section 5.1 and one of the inclusion criteria in 
Section 11.3.1, and none of the exclusion criteria in Section 5.2. Under no circumstances can 
there be exceptions to this rule.
Note: Each patient may only be enrolled in one module of this study. A patient who enrols in 
one module of this study is not eligible to participate in another module.
11.3.1
Inclusion Criteria
Refer to Section 5.1 of the core protocol for the common inclusion criteria applicable to 
Module 1 Part A dose escalation and Module 1 Part B dose expansion. Additional inclusion 
criteria for each cohort of Module 1 Part B dose expansion are listed below. Eligible patients 
with relapsed or refractory AML or ALL will be enrolled to the cohorts according to the 
inclusion criteria described below.
Expansion Cohort B1
1. Patients must have a diagnosis of AML with a prior history of MPN which is histologically 
proven based on criteria established by the WHO as documented by medical records. 
2. Patients must have received ≤2 prior lines of treatment for AML; prior treatment with 
venetoclax is permitted. A line of treatment is defined as a recognised regimen, as per local or 
national guidelines, of which the patient has received at least one dose, following which they 
have relapsed or had refractory disease as defined in Appendix J.
Expansion Cohort B2
1. Patients must have a histologically proven diagnosis of AML, which is based on criteria 
established by WHO as documented by medical records with a TP53 mutation. TP53 status 
already determined in accordance with local/institutional practice can be used for enrolment 
but needs to be confirmed centrally. Patients with AML who have had a prior history of MPN 
are ineligible. 


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2. Patients must have received ≤3 prior lines of treatment for AML; prior treatment with 
venetoclax is permitted. A line of treatment is defined as a recognised regimen, as per local or 
national guidelines, of which the patient has received at least one dose, following which they 
have relapsed or had refractory disease as defined in Appendix J. 
Expansion Cohort B3
1. Patients must have a diagnosis of AML, which is histologically proven based on criteria 
established by WHO as documented by medical records. Patients with AML with the TP53
mutation (as described for Cohort B2) or AML who have had a prior history of MPN (as 
described in Cohort B1) are ineligible. 
2. Patients must have been previously treated with venetoclax (either as monotherapy or in 
combination) and have received ≤3 prior lines of treatment. A line of treatment is defined as a 
recognised regimen, as per local or national guidelines, of which the patient has received at 
least one dose, following which they have relapsed or had refractory disease as in Appendix J.
Expansion Cohort B4
1. Patients must have a diagnosis of ALL, which is histologically proven based on criteria 
established by WHO as documented by medical records. Patients with T-ALL or B-ALL are 
eligible for inclusion.
2. Patients must have received ≤3 prior lines of treatment. A line of treatment is defined as a 
recognised regimen, as per local or national guidelines, of which the patient has received at 
least one dose, following which they have relapsed or had refractory disease as defined in 
Appendix K.
11.3.2
Exclusion Criteria
Refer to the core protocol (Section 5.2).
11.3.3
Lifestyle Considerations
Patients must comply with the restrictions described in the core study protocol (Section 5.3).
11.3.4
Concomitant Medications
Patients must comply with the restrictions described in the core study protocol (Section 6.5)
11.3.5
Screen Failures
Refer to the core protocol (Section 5.4).
11.4
STUDY TREATMENT - MODULE 1
Information on the preparation, handling, storage, accountability of study treatment measures 


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to minimise bias, and study treatment compliance and accountability is either provided in 
Table 15 and/or referenced in the core protocol (Section 6).
11.4.1
Study Treatment – AZD0466 
The study treatment investigationalAZD0466 is described in Table 15. 
Table 15
Study Treatment for Module 1
Study Treatment
AZD0466
Dosage Form
‘AZD0466 powder for concentrate for solution for infusion’ supplied with 
‘Solvent for AZD0466 powder for concentrate for solution for infusion’.
Unit Dose Strength(s)
‘AZD0466 powder for concentrate for solution for infusion’:
500 mg per viala
‘Solvent for AZD0466 powder for concentrate for solution for infusion’:
20 mL per viala
Dose Level
As per dose escalation schema (Section 11.1.3.1)
Route of 
Administration
Intravenous
Handling Instructions
Refer to Handling Instructions
Provider
AstraZeneca R&D
Packaging and 
Labelling
AZD0466 powder for concentrate for solution for infusion will be provided in 
500 mg vials. Each vial will be labelled as per country requirement.
Solvent for AZD0466 powder for concentrate for solution for infusion will be 
provided in 20 mL vials. Each vial will be labelled as per country requirement.
a
AZD0466 powder for concentrate for solution for infusion 500 mg/vial is intended to be reconstituted with 
20 mL custom solvent to produce AZD0466 concentrate for solution for infusion, 25 mg/mL. If required, 
AZD0466 concentrate for solution for infusion may be further diluted with custom solvent to produce 
AZD0466 solution for infusion for clinical dosing. Multiple vials of drug product and custom solvent may 
be used to achieve the required doses.
The dosing and dose escalation scheme are described in Section 11.1.3.1 and the SoA of this 
module (Section 11.5.1). 
Treatment with AZD0466 will commence with a one-week ramp-up followed by weekly 
administration at the target dose. During ramp-up and while patients are considered at risk of 
TLS, patients must commence oral allopurinol and encouraged to drink 1.5 to 2 L of fluids at 
least 24 hours prior to AZD0466 infusion (Appendix F). Intravenous hydration is given on 
admission as outlined in Appendix F.
This intra-patient dose ramp-up comprises a starting dose on Day 1, subsequent titration to the 
intermediate dose on Day 4, and to the target dose on Day 8, with weekly IV administration 
thereafter at the target dose. 


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The duration of Cycle 1 is 35 days and consists of the 7-day dose ramp-up followed by 
28 days of observation during weekly administration at the target dose level (35-day DLT 
evaluation period, Section 11.4.7). Subsequent cycles are 28 days in duration in which 
AZD0466 is administered once weekly. All patients will be treated until progressive disease, 
unacceptable toxicity or withdrawal of consent. 
11.4.2
Preparation, Handling, Storage, and Accountability of Study 
Treatment
Refer to the core protocol (Section 6.2).
11.4.3
Measures to Minimise Bias
Refer to the core protocol (Section 6.3).
11.4.4
Study Treatment Compliance
Refer to the core protocol (Section 6.4).
11.4.5
Concomitant Therapy
Refer to the core protocol (Section 6.5).
11.4.6
Dose Modification
Refer to the core protocol (Section 6.6).
11.4.7
Dose-limiting Toxicity
11.4.7.1
Definition of DLT-evaluable Patients
A DLT-evaluable patient is defined as a patient that has received AZD0466 in Part A and 
either:
!
Has completed the 35-day DLT evaluation period in Cycle 1 and has received at least 
75% (3 doses at target dose from Day 8 to Day 29) of the total amount of the planned 
dose of AZD0466
Or
!
Has experienced a DLT during the 35-day DLT evaluation period in Cycle 1.
Patients who have not had a DLT but do not complete the 35-day DLT evaluation period may 
be replaced to achieve the required minimum number of DLT-evaluable patients for each 
cohort (Section 11.1.3.4). All DLT-evaluable patients enrolled during the dose-escalation stage 
will be evaluated in order to determine the MTD and RP2D. 


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11.4.7.2
Dose-limiting Toxicity
Any event that meets the DLT criteria in the opinion of the Investigator should be reported to 
the Medical Monitor within 24 hours of knowledge of the event. Events will be assessed for 
DLT criteria according to the CTCAE National Cancer Institute (NCI) v5.0 (Section 8.3.2) 
except for TLS, which will be assessed for DLT criteria using the Howard modification of 
Cairo-Bishop criteria (Appendix G). Toxicity that is clearly and directly related to the 
underlying malignancy or to an extraneous cause is excluded from the definition of a DLT. A 
DLT will be defined as the occurrence of any of the following: 
!
Any CTCAE Grade 3 non-haematological toxicity lasting > 7 days OR any CTCAE 
Grade 4 non-haematological toxicity, with the exception of: 
∀
CTCAE Grade 4 nausea, vomiting, or diarrhoea lasting < 7 days in the absence of 
maximum supportive therapy,
∀
Elevation in serum amylase and/or lipase without clinical or radiographic evidence of 
pancreatitis,
∀
CTCAE Grade 3 fatigue, asthenia, fever, anorexia, or constipation.
!
Any other cardiac findings of CTCAE Grade ≥ 2 if considered by the Investigator to be 
clinically significant. 
!
AZD0466 should be permanently discontinued if a CTCAE Grade ≥ 3 cardiac AE of any 
duration occurs at any time during study treatment, if considered by the Investigator to be 
related to study treatment. 
!
AZD0466 should be permanently discontinued if liver function test abnormalities meets 
Hy’s Law (HL) or Potential Hy’s Law (PHL) criteria, and considered by the Investigator 
to be related to study treatment (see Appendix E).
!
Prolonged myelosuppression: as myelosuppression and cytopenias are expected outcomes 
of leukaemia treatment, only the criteria defined below will be a DLT:
∀
Lack of haematological recovery (ANC remaining <0.5x 109/L, platelets remaining 
< 50 x 109/L) in the absence of active leukaemia in bone marrow (blasts < 5%) and 
with marrow hypocellularity at < 5% by Day 42. 
!
Cairo-Bishop Grade ≥ 3 Clinical TLS (Appendix G) that occurs despite 
protocol-recommended management.
!
Cairo-Bishop Laboratory TLS (Appendix G) with metabolic abnormalities that do not 
resolve within 5 days despite protocol-recommended management.
!
Any other toxicity that
∀
is greater than at baseline, is clinically significant and/or unacceptable, and is judged 
to be a DLT by the SRC, or
∀
results in a disruption of dosing schedule of more than 21 days.


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Dose-limiting toxicities will not include the following:
!
Transient isolated laboratory abnormalities, which are not considered clinically 
significant and resolve to baseline within 72 hours without any intervention.
!
Any documented infection (including COVID-19), bleeding or other direct complication 
of cytopenia due to active underlying disease.
The DLT evaluation period remains at 35 days for patients with active bone marrow disease 
by Day 35, irrespective of the blood counts. The DLT evaluation period may be extended to 
include a repeat bone marrow assessment on Day 42, in the event of myelosuppression (see 
Table 6).
11.4.7.3
Definition of Maximum Tolerated Dose
The MTD evaluation will be based on the DLT-evaluable population. The MTD will be 
determined by isotonic regression analysis applied to DLT rates observed during the 
dose-escalation phase. The estimated MTD will be selected as the dose with the smallest 
absolute value of difference between the estimated DLT rate and the target DLT rate of 30% 
among all doses. If 2 or more doses tie for the smallest difference, the following rules will be 
applied:
!
If the estimated DLT rate is < 30% for all doses, then select the higher dose among the 
tied doses.
!
In the case of dose levels with estimated toxicity of equal distance from the target toxicity 
of 30% (tied dose levels), the following approach will be used (Ji et al 2010); among all 
tied dose levels the highest dose level with target toxicity ≤ 30% will be selected, unless 
all tied dose levels have estimated toxicity > 30%, in which case the lowest dose level 
will be selected.
!
If the estimated DLT rate is > 30% for all doses, then select the lower dose among the tied 
doses.
11.4.7.4
Definition of Recommended Phase II Dose
The RP2D and schedule will be determined in discussion among the SRC (Appendix A 5) and 
the sponsor. Observations related to PK, PD, and AEs may be included in the rationale 
supporting the RP2D and schedule. 
11.4.7.5
Definition of Maximum Feasible Dose
A dose and schedule will be considered non-feasible and escalation will cease where the
maximum dose permitted based on the Chemistry Manufacturing and Controls (CMC) quality
specifications (currently set against a maximum weekly dose of 6000 mg) has been reached.


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11.4.7.6
Safety Review Committee
Once there are at least 3 evaluable patients at the dose level during the dose escalation phase 
of the study, the SRC (Appendix A 5) will evaluate all available safety, tolerability, and PK of 
AZD0466, as well as the recommendation from the mTPI-2 model, to decide the next dose. 
This decision may be to escalate, to stay at the current dose, de-escalate, or to de-escalate and 
declare that the current dose is unsafe. If a stay decision is made, additional subjects may be 
enrolled up to a maximum of 12 subjects for a given dose cohort. The mTPI-2 has been 
employed to improve the rate of accrual of patients to cohorts nearer the presumed therapeutic 
dose by reducing the need for late replacement of patients who become non-evaluable during 
the 35-day assessment period while not compromising collection of safety data (Davids et al 
2017). When there are other patients that are ongoing at the time of this review, the SRC may 
decide to defer their decision until these further patients become evaluable.
Any patient started on treatment in error, who has failed to comply with all of the selection 
criteria but meets the criteria of an evaluable patient, will be reviewed on a case-by-case basis
by the SRC to determine if the patient should be included or excluded in the decision for dose 
escalation.
The decisions and decision-making of the SRC on the next dose level will be documented and 
provided to the Investigators prior to dosing any new patients.
11.4.7.7
Expansion Cohorts (Part B) - Module 1
Sponsor approval will be required to open the individual expansion cohorts. 
11.4.7.8
Discontinuation of AZD0466 and Patient Withdrawal from Study
Refer to the core protocol (Section 7).
11.4.8
Intervention After the End of the Study 
Refer to the core protocol (Section 6.8).
11.5
STUDY PLAN AND TIMING OF PROCEDURES – MODULE 1 
11.5.1
Schedule of Activities 
The SoA for Cycle 1, Cycles 2 onwards, and follow-up periods are shown respectively in 
Table 16 and Table 17 for both Part A and Part B. Whenever vital signs and blood draws are 
scheduled for the same nominal time, the assessments should occur in the following order: 
vital signs and then blood draws. Whenever ECGs, vital signs, and blood draws are scheduled 
for the same nominal time, the assessments should occur in the following order: ECG, vital 
signs, and then blood draws. The timing of the first 2 assessments should be such that it allows 
the blood draw (eg, PK blood sample) to occur at the timepoints indicated in the SoAs.


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Table 16
Module 1 - Schedule of Activities for Screening and Cycle 1 (Parts A and B)
Procedure
Screening
Cycle 1 (35 days)
Details in 
CSP 
Section
Ramp-up 1
Ramp-up 2a
Target dose
Day
-28 to -1
1
2
3
4
5
6
7
8
9
10
11
15
16
22
23
29
30
Visit window
± 2 daysb
± 1 
day
Informed consent
X
Appendix 
A 3
Inclusion and exclusion 
criteria
X
5.1; 5.2;
11.3.1; 
11.3.2
Demography
X
8
Medical history
X
8
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
11.6.2.1
Height
X
11.6.2.3
Weight
X
X
X
X
11.6.2.3
Chest X-rayc
X
11.6.2.4
Vital signsd
X
X*
X*
X*
X
X
X
X*
X*
X*
Xe
11.6.2.5
ECOG performance status
X
X
11.6.2.8
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3
 
X
8.6.1.1
Safety ECGs (triplicate)f
X
X*
X
X*
X
X*
X
X
X
X*
X
X*
X
X*
X
11.6.2.6
24 h continuous 12-lead 
ECG recording for PK 
(Holter)
X
X
11.6.2.6
Cardiac MUGA/MRI/
ECHOg
X
11.6.2.7
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Table 16
Module 1 - Schedule of Activities for Screening and Cycle 1 (Parts A and B)
Procedure
Screening
Cycle 1 (35 days)
Details in 
CSP 
Section
Ramp-up 1
Ramp-up 2a
Target dose
Day
-28 to -1
1
2
3
4
5
6
7
8
9
10
11
15
16
22
23
29
30
Visit window
± 2 daysb
± 1 
day
Laboratory Tests
COVID-19 test
X
11.6.2.9.1
Hepatitis B and C, HIV and 
CMV
X
11.6.2.9.2
Pregnancy test (WOCBP)
X
X
11.6.2.9.3
CBC with differential 
h
X
X*
X
X*
X
X*
X
X
X
X
X
X
Xe
11.6.2.9.6
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
11.6.2.9.4
TLS Monitoringi
X*
X*
X*
X*
X*
X*
X*
X*
X*
X*
X*
X*
11.6.2.9.12
and 
11.6.2.9.13
CPK
X
X
X
X
X
X
X
X
X
X
X
X
X
11.6.2.9.4
Coagulation indices 
X
X
X
X
X
X
X
11.6.2.9.7
Cardiac troponin Ij
X
11.6.2.9.8
BNP (or NTproBNP)
X
11.6.2.9.8
Cortisol, ACTH, TSH 
X
X
11.6.2.9.9
Amylase and lipase
X
X
X
X
X
X
X
11.6.2.9.5
Serum immunoglobulinsk
X
X
11.6.2.9.10
Urinalysis
X
X
X
X
X
X
X
11.6.2.9.11
 
 
 
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Table 16
Module 1 - Schedule of Activities for Screening and Cycle 1 (Parts A and B)
Procedure
Screening
Cycle 1 (35 days)
Details in 
CSP 
Section
Ramp-up 1
Ramp-up 2a
Target dose
Day
-28 to -1
1
2
3
4
5
6
7
8
9
10
11
15
16
22
23
29
30
Visit window
± 2 daysb
± 1 
day
Overnight inpatient stay
X**
X**
X**
X**
X**
X**
11.6.2.9.12
Administer AZD0466
X
X
X
X
X
X
6.1
Pharmacokinetic Assessmentsl
Blood sample for plasma 
PK
X*
X*
X*
X
X
X
Xm
Part B
11.6.3.1.2
Urine PK collection (Part A 
select cohort(s) only)
X*
X
X*
X
X*
X
11.6.3.1.1
Pharmacodynamic Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for peripheral blood 
smears (Part A only 
cohorts)
X
X*
X
X*
X
X*
X
11.6.3.2.3
 
 
 
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Table 16
Module 1 - Schedule of Activities for Screening and Cycle 1 (Parts A and B)
Procedure
Screening
Cycle 1 (35 days)
Details in 
CSP 
Section
Ramp-up 1
Ramp-up 2a
Target dose
Day
-28 to -1
1
2
3
4
5
6
7
8
9
10
11
15
16
22
23
29
30
Visit window
± 2 daysb
± 1 
day
 
 
 
 
Disease Assessment
Mandatory bone marrow 
biopsy and aspirate for 
disease assessment
 
X
X
11.6.1; 
MRD (Part B expansion 
only)
X
X
11.6.1.4
CT/MRI/PET scans (only if 
extramedullary disease)
X
X
8.1.1
a
Any visits (eg, Day 6 and Day 7) that do not require attendance at the site for blood draw or physical examination can be conducted by telephone, at the 
Investigator’s discretion.
b
The Days 1, 4 and 8 ramp-up dose administration should be at least 72 h apart.
c
Chest X-rays may also be performed at other timepoints during the study at the Investigator’s discretion, when clinically indicated.
d
On PK sampling days, blood pressure readings to be taken at each PK sample timepoint. All blood pressure readings can be taken ±10 minutes from the 
designated PK sample collection.
e
At disease assessment if disease assessment is not on Day 30.
f
On PK sampling visits, triplicate ECGs will be collected before the PK sample is taken (please refer to Section 11.6.3.1.2 for additional PK assessments). 
g
Cardiac MUGA/MRI/ECHO to assess left ventricular ejection fraction will be conducted. Ensure the same modality is used for each patient. 
h
.
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Table 17
Module 1 - Schedule of Activities for Treatment Cycle 2 and Beyond and Follow-up Periods (Part A and B)
Procedure
Cycle 2 (28 days)
Cycle 3 and beyond (28 days)
Follow-up
Details in 
CSP Section
EoT
Post 
treatment 
follow-upa
Survival 
follow-up
Day
1
2
8/15/22
9/16/23
1
2
8
9/16/23
15/22
28 days after 
last dose
Every 1 
month after 
last dose
Visit window
±2 days
±7 days
±7 days
±14 days
Physical examination
X
X
X
X
X
X
X
X
X
X
11.6.2.1
Weight
X
D15
X
D15
X
11.6.2.3
Vital signsb
X* 
X
X*
D23-28 
with 
disease 
assessment
X*
X*
D23-28 with 
disease 
assessment
X*
X
11.6.2.5
ECOG performance status
X
X
X
11.6.2.8
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
6.5
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
8.3
Safety ECGs (triplicate)
X*
X* (even 
cycles 
only 
from C4)
X
11.6.2.6
Cardiac MUGA/MRI/ECHOc
D8
Every 3 
cycles 
from C5
X
11.6.2.7
Laboratory Tests
COVID-19 test
X
X
X
11.6.2.9.1
Pregnancy test (WOCBP)
X
X
X
11.6.2.9.3
CBC with differential 
d
X
X
X
Xe
X
X
X
Xe
X
X
11.6.2.9.6
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Table 17
Module 1 - Schedule of Activities for Treatment Cycle 2 and Beyond and Follow-up Periods (Part A and B)
Procedure
Cycle 2 (28 days)
Cycle 3 and beyond (28 days)
Follow-up
Details in 
CSP Section
EoT
Post 
treatment 
follow-upa
Survival 
follow-up
Day
1
2
8/15/22
9/16/23
1
2
8
9/16/23
15/22
28 days after 
last dose
Every 1 
month after 
last dose
Visit window
±2 days
±7 days
±7 days
±14 days
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
11.6.2.9.4
CPK
X
X
X
X
X
X
X
X
X
X
11.6.2.9.4
Coagulation indices 
X
X
X
X
X
X
11.6.2.9.7
Cortisol, ACTH, TSH
X
11.6.2.9.9
Amylase and Lipase
X
X
X
X
X
X
11.6.2.9.5
Serum immunoglobulins
X
11.6.2.9.10
Urinalysis
X
X
X
X
X
X
11.6.2.9.11
Administer AZD0466
X
X
X
X
X
6.1
Pharmacokinetic Assessments
Blood sample for plasma PK
X*
X
D23-28
(Part B)f
X* 
D23-28
(Part B)f
11.6.3.1.2
Pharmacodynamic Assessments
 
 
 
 
 
 
 
Blood for peripheral blood 
smears (Part A cohorts only)
X
X
X
11.6.3.2.3
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Table 17
Module 1 - Schedule of Activities for Treatment Cycle 2 and Beyond and Follow-up Periods (Part A and B)
Procedure
Cycle 2 (28 days)
Cycle 3 and beyond (28 days)
Follow-up
Details in 
CSP Section
EoT
Post 
treatment 
follow-upa
Survival 
follow-up
Day
1
2
8/15/22
9/16/23
1
2
8
9/16/23
15/22
28 days after 
last dose
Every 1 
month after 
last dose
Visit window
±2 days
±7 days
±7 days
±14 days
 
 
 
 
 
 
 
 
 
 
 
Disease Assessment
Mandatory bone marrow 
biopsy and aspirate for disease 
assessment 
 
g
D23-28
D23-28
Xh
11.6.1; 
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Table 17
Module 1 - Schedule of Activities for Treatment Cycle 2 and Beyond and Follow-up Periods (Part A and B)
Procedure
Cycle 2 (28 days)
Cycle 3 and beyond (28 days)
Follow-up
Details in 
CSP Section
EoT
Post 
treatment 
follow-upa
Survival 
follow-up
Day
1
2
8/15/22
9/16/23
1
2
8
9/16/23
15/22
28 days after 
last dose
Every 1 
month after 
last dose
Visit window
±2 days
±7 days
±7 days
±14 days
MRD (Part B expansion only)
D23-28 at 
disease 
assessment
C4 D23-28 at 
disease 
assessment 
and every 3 
cycles until 
disease 
progression 
(D23-28 at 
disease 
assessment)h
Xh
11.6.1.4
CT/MRI/PET scans (only if 
extramedullary disease) 
Every 3 
cycles from 
C3, D23-28
X
8.1.1
Survival follow up
X
8
a
Patients will be followed during the off-treatment period until all treatment related toxicity resolves, or for at least 28 days post-study drug discontinuation 
or until new therapy. This can be done via telephone contact at the Investigator’s discretion.
b
On PK sampling days, blood pressure readings to be taken at each PK sample timepoint. All blood pressure readings can be taken ± 10 minutes from the 
designated PK sample collection.
c
Cardiac MUGA/MRI/ECHO to assess left ventricular ejection fraction will be conducted. Ensure the same modality is used for each patient. Unscheduled 
assessment if deemed clinically warranted.
d
 
e
If disease assessment is not on Day 23, an additional CBC sample is required.
f
g
If performed on day of infusion must be at least 6 hours post-infusion.
h
Bone marrow evaluation at EoT only required if not performed in the preceding 21 days.
*Indicates more than one assessment is to be performed at the visit.
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11.6
STUDY ASSESSMENTS AND PROCEDURES - MODULE 1
Study procedures and their timings for this module are summarised in the SoA 
(Section 11.5.1). Patient demographic characteristics, medical history, and disease 
characteristics will be recorded as described in Section 8, Enrolment and Screening.
11.6.1
Efficacy Assessments
11.6.1.1
Peripheral Blood
Peripheral blood will be collected for complete blood count (CBC) (laboratory safety 
assessment) as indicated in the SoA (Table 16 and Table 17).
 
11.6.1.2
Extramedullary Disease
Refer to the core protocol (Section 8.1.1) for details on disease assessment for extramedullary 
disease. 
11.6.1.3
Bone Marrow
Bone marrow core biopsy and bone marrow aspirate should be performed (as specified in 
Table 16 and Table 17) as below. In Module 1 Part A, in the event that a patient is otherwise 
eligible but extenuating circumstances preclude obtaining a new on-study bone marrow 
biopsy, a historic bone marrow biopsy sample may be used if collected within 28 days of first 
dose, but within 14 days is preferred, with the approval of the Medical Monitor. 
Mandatory biomarker analysis (Section 11.6.4.1.6) will be performed any time a bone marrow 
analysis is performed. If performed on a dosing day, this must be at least 6 hours post-
infusion. 
!
Screening (between Day -28 and -1)
!
Cycle 1 Day 30 ± 1 day
!
Cycle 2 and subsequent cycles between Days 23 to 28
!
Disease progression or EoT visit
The disease progression sample collection may occur at the safety follow-up visit (if 
conducted in person) if not collected previously. Additional bone marrow or peripheral blood 
samples may be collected, as clinically indicated.
11.6.1.4
Minimal/Measurable Residual Disease (Part B Only)
Bone marrow sample collections for minimal/measurable residual disease (MRD) assessments 
will be performed (as specified in Table 16 and Table 17) at the following times for Part B 
only:
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!
Screening
!
Cycle 1 Day 30 ± 1 day at the time of disease assessment
!
Cycle 2 between Days 23 to 28 at the time of disease assessment
!
Cycle 4 between Days 23 to 28 at the time of disease assessment
!
At any morphologic remission timepoint. If unable to collect the bone marrow sample on 
the day of CR/CRi, additional sample need to be collected either within 4 weeks, or at the 
next visit. 
!
 
 
!
 
 
 
!
Patients will be monitored every 3 cycles (or at the discretion of the Investigator, in line 
with scheduled response assessments) thereafter until disease progression (or up to 2 
years after CRMRD-NEG confirmation, at the discretion of the Investigator).
!
End of Treatment/Disease progression.
11.6.1.5
Survival Follow-up
Refer to the core protocol (Section 8, Follow-up Period)
11.6.2
Safety Assessments
11.6.2.1
Physical Examination 
A complete physical examination will be performed and include assessments of the following: 
general appearance, abdomen, skin, head, and neck (including ears, eyes, nose, and throat), 
lymph nodes, thyroid, respiratory, cardiovascular, musculoskeletal (including spine and 
extremities), and neurological systems. Investigators should pay special attention to clinical 
signs related to previous serious illnesses. New or worsening abnormalities may qualify as 
AEs (see Section 8.3.5 for details). Targeted physical examinations will be performed 
throughout the treatment period, at the discretion of the Investigator eg, for new or worsening 
symptoms and/or signs.
Physical examinations in the Part A and Part B should be performed (as specified in the SoA 
in Table 16 and Table 17) as follows: 
!
Screening
!
Cycle 1: pre-infusion on each dosing day and on the calendar day after the dosing day
!
Cycle 2 and beyond: pre-infusion on each dosing day and on the calendar day after the 
dosing day
!
EoT visit.
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11.6.2.2
Medical History
Refer to the core protocol Section 8, Enrolment and Screening.
11.6.2.3
Height and Body Weight
Height will be recorded at screening.
Body weight will be assessed (as specified in the SoA in Table 16 and Table 17) as follows: 
!
Screening
!
Cycle 1 Day 1, 8, and 22: pre-infusion 
!
Cycle 2 and beyond Day 1 and Day 15: pre-infusion
!
EoT visit
11.6.2.4
Chest X-ray
Chest x-ray will be performed at screening to provide a baseline against which potential 
treatment-emergent lung abnormalities may be evaluated. Chest x-rays may also be performed 
at other timepoints during the study at the Investigator’s discretion, when clinically indicated.
11.6.2.5
Vital Signs
Vital signs will include heart rate, pulse, systolic and diastolic blood pressure (BP), respiration 
rate, height (at screening), and temporal temperature. Blood pressure and pulse measurements 
will be assessed in a seated or semi-supine position with a completely automated device. 
Manual techniques will be used only if an automated device is not available. Measurements 
should be preceded by at least 10 minutes of rest for the patient in a quiet setting without 
distractions (eg, television, cell phones).
On PK sampling days, BP readings to be taken at each PK sample timepoint. All BP readings 
can be taken ±10 minutes from the designated PK sample collection.
Vital signs should be assessed (as specified in the SoA in Table 16 and Table 17) as follows:
!
Screening
!
Cycle 1 Day 1: pre-infusion, 30 minutes (±5 minutes) after the start of the infusion, at the 
end of the infusion (+10 minutes)
!
Cycle 1 Day 4: pre-infusion, 30 minutes (±5 minutes) after the start of the infusion, at the 
end of the infusion (+10 minutes)
!
Cycle 1 Day 8: pre-infusion, 30 minutes (±5 minutes) after the start of the infusion, at the 
end of the infusion (+10 minutes), 2 hours (±15 minutes), 6 hours (±30 minutes), and 9 
hours (±1 hour) after the start of the infusion 


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!
Cycle 1 Day 9: 24 hours (±2 hours) after the start of the Day 8 infusion
!
Cycle 1 Day 10: 48 hours (±3 hours) after the start of the Day 8 infusion
!
Cycle 1 Day 11: 72 hours (±7 hours) after the start of the Day 8 infusion
!
Cycle 1 Day 15, 22, and 29: pre-infusion, 30 minutes (±5 minutes) after the start of the 
infusion, at the end of the infusion (+10 minutes)
!
Cycle 1 Day 30 ± 1 day at the time of disease assessment
!
Cycle 2 Day 1: pre-infusion, 30 minutes (±5 minutes) after the start of the infusion, at the 
end of the infusion (+10 minutes), 2 hours (±15 minutes), 6 hours (±30 minutes), and 
9 hours (±1 hour) after the start of the infusion
!
Cycle 2 Day 2: 24 (±2 hours) hours after the start of the Day 1 infusion
!
Cycle 2 Day 8, 15, and 22: pre-infusion, 30 minutes (±5 minutes) after the start of the 
infusion, at the end of the infusion (+10 minutes)
!
Cycle 2 between Days 23 to 28 at the time of disease assessment
!
At each cycle from Cycle 3 and beyond Day 1, 8, 15, and 22: pre-infusion, 30 minutes 
(±5 minutes) after the start of the infusion, at the end of the infusion (+10 minutes)
!
Cycle 3 and beyond Days 23 to 28 at the time of disease assessment
!
EoT visit
11.6.2.6
Electrocardiograms
Digital 12-lead ECGs (triplicate ECGs, all 3 within a 5-minute time period) will be obtained 
after the patient has been resting in a supine position for at least 10 minutes. ECGs will be 
measured before vital signs and prior to PK blood draws at all matched PK sample timepoints. 
A standardised ECG machine provided by the central ECG vendor should be used and the 
patient should be examined using the same machine throughout the study, where feasible. 
If an unscheduled ECG is done at any time, then an electrolyte panel (Section 11.6.2.9) must 
be collected to coincide with ECG testing.
Central ECG reads will be utilised during this study. Standard ECG parameters to be 
determined will include HR/RR, PR, QRS, QT, and QTcF (QT interval corrected for HR using 
Fridericia’s formula) intervals.
After the ECGs have been recorded, the Investigator or designated physician will review each 
of the ECGs at all timepoints for the presence of abnormalities (including rhythm, ECG 
intervals, or repolarisation abnormalities) and may refer to a local cardiologist if appropriate. 
A paper copy of the ECG should be filed in the patient’s medical records. For all ECGs, an 
overall evaluation and interpretation should be recorded by the Investigator or designated 
physician. Any clinically significant abnormalities detected require a confirmatory ECG. In 


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case that the centrally provided ECG machine is unavailable or technical issues occur that 
preclude correct measurement, local ECGs (using the site owned device) may be performed 
instead.
See Section 6.6.5 for management of cardiac findings and cardiovascular parameters that 
require treatment to be withheld or increased monitoring. Twelve-lead centrally-read digital 
ECGs will be performed in triplicate and should be assessed as specified in the SoA (Table 16
and Table 17), and in Table 18).
Table 18
Safety ECG Timepoints and Holter ECG extractions (Module 1)
Part A and Part B
Study 
period
Day
Timepoint
Holter 
ECG 
extractions
(for PK 
purpose)
Triplicate 
Safety ECGs
(for safety 
purpose)
Screening
-28 to -1 Baseline
-
X
Cycle 1
1
Pre-infusion
-
Xa
End of the infusion (+10 min)
-
Xa
2
24 hours after the start of the Day 1 infusion (± 2 hours)
X
4
Pre-infusion
-
Xa
End of the infusion (+10 min)
-
Xa
5
24 hours after the start of the Day 4 infusion (±2 hours)
X
8
Pre-infusion
X
Xa
30 min after start of infusion (±5 min)
X
-
End of the infusion (+10 min)
X
Xa
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
-
9
24 hours after the start of the Day 8 infusion (±2 hours)
X
Xa
10
48 hours after the start of the Day 8 infusion (± 3 hours)
-
Xa
11
72 hours after the start of the Day 8 infusion (±7 hours)
-
Xa
15
Pre-infusion
-
X
End of the infusion (+10 min)
-
X
16
24 hours after the start of the Day 15 infusion (±2 hours)
-
X
22
Pre-infusion
-
X
End of the infusion (+10 min)
-
X


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a
At PK sampling visits, triplicate ECGs will be collected before the PK sample is collected (please refer to 
Section 11.6.3.1.2 for additional PK assessments).
b
Beyond Cycle 2 ECGs will be collected on Day 1 of even cycles only, ie, Cycle 4, 6, 8 etc.: pre-infusion 
and at the end of the infusion (+10 minutes). 
11.6.2.6.1
Continuous 12-lead ECG Recordings (Holter)
Continuous recordings of 12-lead ECGs (12-lead Holter devices) will be performed for the 
purpose of PK modelling, which allows monitoring of PR, QRS, QT, QTcF, RR intervals, and 
arrhythmia and to allow extraction of replicate 12-lead ECGs. The timing of ECGs may be 
altered depending on the emerging PK profile. Recording should be performed (as specified in 
the SoA in Table 16 and Table 18) on Day 8 of Cycle 1, with recording commencing 
pre-infusion to cover the 24-hour timepoint (prior to PK sampling). 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.
11.6.2.7
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 treatment, 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. 
23
24 hours after the start of the Day 22 infusion (±2 hours)
-
X
29
Pre-infusion
-
X
End of the infusion (+10 min)
-
X
30
24 hours (±2 hours) after the start of the Day 29
-
Xa
Cycle 2 and 
even cycles 
thereafter
1
Pre-infusion 
-
Xa,b
End of the infusion (+10 min)
-
Xa,b
End of Treatment
-
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Cardiac MUGA/MRI/ECHO should be performed (as specified in the SoA in Table 16 and 
Table 17) as follows:
!
Screening
!
Cycle 2 Day 8 
!
Every third cycle from Cycle 5 (ie, Cycle 5, 8, 11, etc) on Day 8
!
EoT visit
11.6.2.8
Performance Status
ECOG performance status (Appendix L) will be assessed at the times specified in the SoA 
(Table 16 and Table 17) as follows:
!
Screening
!
Every Cycle Day 1
!
EoT visit
11.6.2.9
Clinical Safety Laboratory Assessments
Clinical laboratory safety tests, including urine or serum pregnancy tests, will be performed in 
a licensed clinical laboratory according to local standard procedures. Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values, units, and reference ranges) will 
be recorded on the appropriate eCRF. 
Laboratory values will be repeated, confirmed, and followed up as appropriate.
Safety laboratory assessments will be performed at the timepoints specified in the SoA 
(Table 16 and Table 17) Collection times begin from the start of the infusion.
Following SRC review of emerging data, the timing of laboratory safety assessment samples 
may be adjusted for subsequent cohorts. Additional sampling times may be added or removed 
if indicated by the emerging data.
11.6.2.9.1
COVID-19 Testing
COVID-19 tests will be conducted where appropriate and in accordance with local 
procedures. COVID-19 testing may include nucleic acid/PCR and/or serological approaches. 
This should be performed as follows:
!
Screening: patients with a positive PCR test results must be antigen negative with 
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!
At each cycle from Cycle 2 onwards Day 1: pre-infusion
!
EoT visit
11.6.2.9.2
Viral Serology
A Hepatitis B, Hepatitis C, HIV, and CMV viral serology sample will be collected at 
screening. If a patient was found to have positive anti-HBc antibody and a negative HBsAg, a 
DNA PCR test will be done to determine eligibility criteria.
11.6.2.9.3
Pregnancy Test (Women of Childbearing Potential Only)
A urine/serum sample for a pregnancy test will be collected from all women of childbearing 
potential (defined in Section 5.3) as follows: 
!
Screening
!
Day 1 of each treatment cycle: pre-infusion 
!
EoT visit
11.6.2.9.4
Clinical Chemistry
Blood samples for determination of clinical chemistry will be collected as specified in 
Table 16 and Table 17. Unscheduled samples may be collected if deemed clinically warranted, 
and results of unscheduled assessment should be recorded in the eCRF.
If an unscheduled ECG is performed for patient assessment, an electrolyte panel (ie, calcium, 
magnesium potassium) must be done. If clinically indicated, a troponin assay should coincide 
with this evaluation. Cardiac troponin I is preferred when available, however if not, cardiac 
troponin T is acceptable. To allow comparison with baseline, sites are requested to maintain 
consistency with the troponin assay used. Isolated troponin elevations are not sufficient to 
trigger dosing changes and should be evaluated in the context of other cardiac findings.
The following clinical chemistry tests will be performed (Table 19): 


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Table 19
Clinical Chemistry
Albumin 
Cholesterola
Magnesium
Alkaline phosphatase
C-reactive protein
Phosphate
Alanine aminotransferase
Creatinine
Potassium
Amylaseb
Gamma-glutamyl transferase
Sodium
Aspartate aminotransferase
Glucosea
Triglyceridesa
Bicarbonate
Glutamate dehydrogenaseb
Total protein
Bilirubin (total and direct)
Lactate dehydrogenase
Chloride
Blood urea nitrogen
Lipasec
Uric acid
Calcium
a
Fasting cholesterol, triglyceride and glucose values are not required. However, if non-fasting values are 
abnormal, a repeat sample should be obtained when the patient is fasting.
b
Glutamate dehydrogenase testing is optional, but should be performed where sites have the capability to 
perform the test locally.
c
Collected at screening, pre-infusion on each dosing day, and end of treatment visit.
NB. Refer to Appendix E if alanine amino transferase or aspartate aminotransferase ≥3 × ULN together with 
total bilirubin ≥2 × ULN. 
ULN, upper limit of normal range.
Results for LFTs must be available and reviewed before infusion of study treatment 
throughout Cycle 1 and review of results is recommended before each administration of study 
treatment from Cycle 2 and beyond. Values must have returned to the patient’s baseline before 
infusion of AZD0466. 
Clinical chemistry, including creatine phosphokinase, should be performed for Part A and B 
according to the schedule below. 
!
Screening
!
Pre-infusion on each dosing day
!
24 hours (±2 hours) after each dosing
!
EoT visit
11.6.2.9.5
Amylase and Lipase
Amylase and lipase will be collected for Part A and Part B according to the schedule below.
!
Screening
!
Pre-infusion on each dosing day
!
EoT visit


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11.6.2.9.6
Complete Blood Count with Differential 
 
Complete blood counts with differential 
 (Table 20) will be 
collected for Part A and Part B. Part of the blood sample collected for CBC will be used for 
peripheral blood smears as detailed in Section 11.6.1.
Table 20
Haematology Assessments
Absolute leucocyte differential count: neutrophils, 
lymphocytes, monocytes, basophils, eosinophils
Blood (B)-haemoglobin 
Haematocrit
Leucocytes
Platelet count
Collection times for Part A and Part B are indicated below (collection time begins from start 
of infusion). 
!
Screening
!
Cycle 1 Day 1: pre-infusion, end of infusion (+10 minutes), 6 hours (±30 minutes) after 
the start of the infusion
!
Cycle 1 Day 2: 24 hours (±2 hours) after the Day 1 infusion
!
Cycle 1 Day 4: pre-infusion, end of infusion (+10 minutes)
!
Cycle 1 Day 5: 24 hours (±2 hours) after the Day 4 infusion
!
Cycle 1 Day 8: pre-infusion, at the end of infusion (+10 minutes), 2 hours (±30 minutes) 
6 hours (±30 minutes), 9 hours (±1 hour) after the start of the infusion
!
Cycle 1 Day 9: 24 hours (±2 hours) after the Day 8 infusion
!
Cycle 1 Day 15: pre-infusion
!
Cycle 1 Day 16: 24 hours (±2 hours) after the Day 15 infusion
!
Cycle 1 Day 22: pre-infusion
!
Cycle 1 Day 23: 24 hours (±2 hours) after the Day 22 infusion
!
Cycle 1 Day 29: pre-infusion
!
Cycle 1 Day 30: 24 hours (±2 hours) after the Day 29 infusion (and at disease assessment 
if disease assessment is not on Day 30)
!
At each cycle from Cycle 2 onwards: pre-infusion on each dosing day 
!
At each cycle from Cycle 2 onwards: 24 hours (±2 hours) after each dosing
!
At each disease assessment
!
EoT visit 
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11.6.2.9.7
Coagulation Indices
Prothrombin time (PT), international normalisation ratio (INR), and partial thromboplastin 
time (PTT) will be collected as specified in the individual modules. INR assessment should be 
repeated if any abnormalities above ULN in liver biochemistry occur, at 6-8 hours and 
24 hours after occurrence of the abnormality. If INR is elevated at either timepoint, a 
subsequent INR assessment should be performed at 72 hours to ensure resolution.
Coagulation (PT/INR/PTT) will be collected for Part A and Part B at the times indicated 
below: 
!
Screening
!
Pre-infusion on each dosing day
!
EoT visit
11.6.2.9.8
Cardiac Troponin and BNP (or NTproBNP) 
Blood samples for cardiac troponin and brain natriuretic peptide (BNP) or n-terminal pro 
b-type natriuretic peptide (NTproBNP) measurements will be collected for Part A and Part B 
(as specified in Table 16 and Table 17) as follows:
!
Screening
!
As clinically indicated
Cardiac troponin I is preferred when available, however if not, cardiac troponin T is 
acceptable. To allow comparison with baseline, sites are requested to maintain consistency 
with the troponin assay used. Isolated troponin elevations are not sufficient to trigger dosing 
changes and should be evaluated in the context of other cardiac findings.
If an unscheduled ECG is performed for patient assessment, an electrolyte panel (ie, calcium, 
magnesium potassium) must be done. If clinically indicated, a troponin assay should coincide 
with this evaluation including referral to a cardiac specialist. 
11.6.2.9.9
Cortisol, ACTH, and TSH
A blood sample for cortisol, adrenocorticotropic hormone (ACTH) and thyroid-stimulating 
hormone (TSH) will be collected for Part A and Part B (as specified in Table 16) as follows:
!
Screening (between Day -28 and -1)
!
Cycle 1 Day 8; pre-infusion
!
EoT visit


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11.6.2.9.10
Serum Immunoglobulins
Samples for serum immunoglobulins will be collected for Part A and Part B (as specified in 
Table 16) as follows:
!
Screening (between Day -28 and -1)
!
Cycle 1 Day 8: pre-infusion
!
EoT visit
11.6.2.9.11
Urinalysis
Urinalysis will be performed to assess glucose, protein, blood, ketones, and leucocyte esterase. 
Results must be available prior to dosing.
Samples for urinalysis will be collected for Part A and Part B at the times indicated below:
!
Screening (-28 to -1)
!
Pre-infusion on each dosing day
!
EoT visit
11.6.2.9.12
Overnight Stays for TLS Monitoring
Overnight stays are recommended on infusion days during Cycle 1, but patients may be 
discharged prior to 24 hours post-dose, as per Investigator discretion, if their TLS laboratory 
values are appropriate, and if the patient is able to return for a follow-up clinic visit to 
complete required safety and laboratory assessments within the specified time windows. 
Thereafter, dosing as an inpatient will be as per Investigator discretion, based on prior 
tolerability and risk of TLS.
Tumour lysis syndrome monitoring should be performed (as specified in Table 16) at least 
twice in the first 24 hours after each administration of study treatment, and thereafter as 
clinically indicated.
11.6.2.9.13
Clinical and Laboratory Assessments for TLS
The classification of laboratory TLS and clinical TLS is described in Appendix G. Patients 
will be evaluated for clinical signs and symptoms of TLS during treatment with AZD0466, 
and blood samples for laboratory assessments will be collected according to the respective 
module SoA. 
Laboratory parameters from the clinical chemistry panel, which are indicative of TLS 
(according to the Howard modification of Cairo-Bishop criteria, Appendix G), including 
serum levels of uric acid, potassium, phosphate, calcium, and creatinine, will be evaluated. 
Blood urea nitrogen and lactate dehydrogenase may also be evaluated to aid assessment. Fluid 


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balance must be monitored per institutional standards. Blood samples for monitoring TLS will 
be collected at the timepoints as indicated in Table 16 and as clinically indicated. 
Recommended prophylaxis for TLS is outlined in Appendix F.
11.6.2.10
Adverse Events and Serious Adverse Events
Refer to the core protocol (Section 8.3).
11.6.2.10.1
Pregnancy
Refer to the core protocol (Section 8.3.13).
11.6.2.10.2
Medication Error
Refer to the core protocol (Section 8.3.14).
11.6.2.10.3
Overdose
Refer to the core protocol (Section 8.4).
11.6.3
Human Biological Samples
11.6.3.1
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.
11.6.3.1.1
Urine Pharmacokinetics (in select cohort(s) only)
Samples for PK characterisation and potential analysis of urine metabolites will be collected 
in a select cohort(s) (based on emerging data) at the following times for Part A only. Note: 
Collection time begins from start of infusion:


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Urine PK
Study period
Day
Timepoint
Cycle 1
Day 1
0-2 hours (+10 min)
2-6 hours (±15 min)
6-10 hours (±1 hour)
10-24 hours (±2 hours)
Day 2
24-36 hours (±2 hours)
Day 4
0-2 hours (+10 min)
2-6 hours (±15 min)
6-10 hours (±1 hour) 
10-24 hours (±2 hours)
Day 5
24-36 hours (±2 hours) 
Day 8
0-2 hours (+10 min)
2-6 hours (±15 min)
6-10 hours (±1 hour) 
10-24 hours (±2 hours)
Day 9 
24-36 hours (±2 hours)
11.6.3.1.2
Blood Sample for Plasma Pharmacokinetics
Blood samples should be taken from a different part of the body than where the study 
treatment is being infused, including if central line access is available, to prevent erroneous 
drug concentration readings. For example, if AZD0466 is being infused into the patient’s right 
arm, then the blood sample should be collected from the left arm. 
Blood samples for will be collected at the following times (collection time begins from start of 
infusion):


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Blood Sample for Plasma Pharmacokinetics
Study period
Day
Timepoint
Part A
Part B
Cycle 1
Day 1
Pre-infusion 
X
X
End of the infusion (+10 min)a
Day 4
Pre-infusion 
X
X
End of the infusion (+10 min)a
Day 8
Pre-infusion 
X
X
30 min after start of infusion (±5 min)
X
X
End of the infusion (+10 min)a
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)b
X
X
Day 9
24 hours after the start of the Day 8 infusion (±2 hours)
X
X
Day 10
48 hours after the start of the Day 8 infusion (±3 hours)
X
X
Day 11
72 hours after the start of the Day 8 infusion (±7 hours)
X
X
Day 
30/31
At MRD timepoint
X
Cycle 2
Day 1
Pre-infusion 
X
X
End of the infusion (+10 min)a
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
Day 2
24 hours after the start of the Day 1 infusion (±2 hours)
X
X
Day 
23-28
At MRD timepoint
X
Cycle 3 and beyond
Day 1
Pre-infusion 
X
X
End of the infusion (+10 min)a
X
X
Day 
23-28
At MRD timepoint
X
Note: Please refer to Section 11.6.2.6 for ECGs measured at all matched PK sample timepoints.
a
As close as possible to the end of the infusion, but permissible up to 10 minutes.
b
In the event that a planned collection is no longer possible at the scheduled timepoint, the Medical Monitor 
must be informed, and any collection outside allotted window must be discussed with the Medical Monitor. 
11.6.3.1.3
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11.6.3.2
Pharmacodynamics
11.6.3.2.1
Mandatory whole blood samples will be collected from all patients at the timepoints indicated 
in the SoA (Table 16 and Table 17) and as shown below.
 
 
Note: Collection time begins with the start of infusion.
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11.6.3.2.2
Pharmacodynamic 
Mandatory whole blood samples will be collected from all patients at the timepoints indicated 
in the SoA (Table 16 and Table 17) and as shown below. 
 
 
 
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Blood for Pharmacodynamic 
Study 
period
Day
Ramp-up (RU) or Target 
Dose (TD)
Timepoint
Part 
A
Part 
B
Screening
-
-
-
X
X
Cycle 1
Day 1
RU1 Day 1
Pre-infusion
X
X
End of infusion (+10 min)
X
X
6 hours after start of infusion (± 30 min)
X
X
Day 2
RU1 Day 2
24 hours after start of Day 1 infusion 
(± 2 hours)
X
-
Day 4
RU2 Day 1
Pre-infusion
X
X
End of infusion (+10 min)
X
X
Day 5
RU2 Day 2
24 hours after start of Day 4 infusion 
(± 2 hours)
X
-
Day 8
TD Day 1
Pre-infusion
X
X
End of infusion (+10 min)
X
X
6 hours after start of infusion (± 30 min)
X
-
Day 9
TD Day 2
24 hours after start of Day 8 infusion 
(± 2 hours)
X
-
Cycle 2
Day 1
-
Pre-infusion
X
-
6 hours after start of infusion (± 30 min)
X
-
Day 2
-
24 hours after start of Day 1 infusion 
(± 2 hours)
X
-
Disease 
Progression/
End of 
treatment
-
-
End of treatment
X
X
11.6.3.2.3
Peripheral Blood Smears 
Mandatory peripheral blood smears will be collected at the timepoints indicated in the SoA 
(Table 16 and Table 17) and as shown below to evaluate 
 and normal blood 
cells and detect morphologic apoptotic responses in the blood. Blood smears will be obtained 
from CBC samples collected for Part A only. Note: Collection time begins with the start of 
infusion. 
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Peripheral Blood Smears - Part A Only
Study period
Day
Ramp-up (RU) or 
Target Dose (TD)
Timepoint
Screening
-
-
-
Cycle 1 
Day 1
RU1 Day 1
Pre-infusion
End of infusion (+10 min)
Day 2
RU1 Day 2 
24 hours after start of Day 1 infusion (± 2 hours)
Day 4
RU2 Day 1
Pre-infusion
End of infusion (+10 min)
Day 5
RU2 Day 2
24 hours after start of Day 4 infusion (± 2 hours)
Day 8
TD Day 1
Pre-infusion
End of infusion (+10 min)
6 hours after start of infusion (± 30 min)
Day 9
TD Day 2
24 hours after start of Day 8 infusion (± 2 hours)
Cycle 2
Day 1
-
Pre-infusion
Day 2
-
24 hours after start of Day 1 infusion (± 2 hours)
Disease 
Progression/End 
of treatment
-
-
End of treatment
11.6.4
Human Biological Sample Biomarkers
11.6.4.1
Collection of Mandatory Samples for Biomarker Analysis
By consenting to participate in the study, the patient consents to the mandatory research 
components of the study. 
Samples for biomarker research are required and will be collected from all patients in this 
study as specified in the SoA (Table 16 and Table 17).
11.6.4.1.1
 
 
 
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11.6.4.1.2
 
 
 
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11.6.4.1.3
 
 
11.6.4.1.4
 
 
11.6.4.1.5
 
 
 
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11.6.4.1.6
Bone Marrow Biopsy and Aspirate 
 
A mandatory pretreatment bone marrow biopsy and aspirate will be required for standard 
disease profiling and 
 (Section 11.6.1). Bone marrow 
biopsy samples will be collected in accordance with local/institutional guidelines and as per 
the process delineated in the laboratory manual.
 
 
Mandatory biomarker analysis will be also performed for any bone marrow aspirate and 
biopsy collected for disease assessment and at disease progression, according to the timepoints 
in Table 16 and Table 17. Note: The disease progression sample may be taken at the safety 
follow-up visit if not collected previously.
11.6.4.2
Collection of Optional Biomarker Samples
Refer to the core protocol (Section 8.6.1.1)
11.6.5
Other Study Related Biomarker Research
11.6.5.1
 
 
. 
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For storage, re-use, and destruction of biomarker samples see Appendix C. 
11.6.6
Optional Genomics Initiative Sample
Refer to the core protocol (Section 8.7). 
11.7
STATISTICAL CONSIDERATIONS - MODULE 1 
11.7.1
Statistical Hypotheses
No formal statistical hypothesis testing is planned.
11.7.2
Sample Size Determination
11.7.2.1
AZD0466 Monotherapy Escalation - Part A
The primary objective of Part A is to identify the MTD and RP2D of AZD0466 monotherapy. 
In Part A, 3 to 12 DLT-evaluable patients may be treated in each dose level using an mTPI-2 
design (Guo et al 2017) permitting approximately 36 DLT-evaluable patients for dose 
exploration. In addition, any tolerated dose level may be expanded at the discretion of the 
sponsor in discussion with the SRC to include up to a total of 18 patients for further evaluation 
of PK, PD, safety, or biological efficacy. Up to a total of 66 patients will be enrolled to yield 
approximately 36 DLT-evaluable patients and 18 patients for further exploration in Part A. 
This limits the number of patients exposed to AZD0466 consistent with the expected safety 
profiles of the study treatment, but includes sufficient patients to explore safety of the 
treatment, PK and effects on pharmacodynamic biomarkers, and to collect preliminary 
efficacy data.
11.7.2.2
Part B Monotherapy Dose Expansion
Separate expansion cohorts will enrol 4 distinct populations of patients with advanced 
haematological malignancies. Three of these expansion cohorts (Expansion Cohorts B1, B2, 
and B4) will recruit at least 21 patients, and one (Expansion Cohort B3) will recruit at least 
25 patients. The total number of patients treated in Part B will be at least 88. These sample 
sizes have been determined to ensure confidence intervals constructed around the complete 
response rate (CR+CRi), as calculated after all patients have had the opportunity to complete 
one treatment cycle, will provide sufficient information to enable decisions to be made around 
the likely success of future studies in these patient populations, using methodology described 
in Frewer et al 2016. 
Thresholds for decision making were set for each expansion cohort based on range of 
literature and expert opinion. For Expansion Cohort B1, a target value for response was set at 
35%, with a lower reference value of 20%. If 7 or more responders are observed from 
21 patients, there will be at least an 80% chance that the true response rate is at least 20%, 
which may promote a positive decision. If 4 or fewer responders are observed, then there is a 
10% or less chance that the true rate is at least 35%, which may lead to a futility decision. If 


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the true rate of response is 15%, then, with 21 patients, there is an 80.3% probability of a 
result that may trigger a decision to stop further development in this population due to futility.
This analysis will be performed using the ITT population.
An IA as described in Section 11.7.9 will be performed in each expansion cohort when 
12 patients have had the opportunity for one cycle of treatment and is response evaluable as 
per Table 21. The number of patients is based on the operating characteristics of the 
cohort-specific decisions using the approach as described in Frewer et al 2016.
In Expansion Cohort B1, if 5 or more responders are observed from 12 patients, then there is 
at least an 80% chance that the true response rate is at least 20%, which may promote a 
decision to continue to full recruitment. It may be considered futile to continue development 
of this cohort if there is < 10% probability for the response rate to be greater than 35%. This 
translates to observing one or zero responders out of 12 patients.
For the other expansion cohorts, Expansion Cohorts B2, B3, and B4, the target values and 
lower values for response were set at (40%, 25%), (25%, 13%) and (40%, 25%) respectively. 
Descriptive statements for these expansion cohorts are given below, with values for the final 
(and interim) analyses presented using brackets for the IA.
For Expansions Cohorts B2 and B4, a target value for response was set at 40%, with a lower 
reference value of 25%. In either of these cohorts, if 8 (5) or more responders are observed 
from 21 (12) patients, there will be at least an 80% chance that the true response rate is at least 
25%, which may promote a positive decision. If 5 (1) or fewer responders are observed, then 
there is a 10% or less chance that the true rate is at least 40%, which may lead to a futility 
decision. If the true rate of response is 20%, then with 21 (12) patients, there is a 76.9% 
(55.8%) probability of a result that may trigger a decision to stop further development in these 
populations for futility.
For Expansion Cohort B3, a target value for response was set at 25%, with a lower reference 
value of 13%. If 6 (3) or more responders are observed from 25 patients there will be at least 
an 80% chance that the true response rate is at least 13%, which may promote a positive 
decision. If 3 (0) or fewer responders are observed, then there is a 10% or less chance that the 
true rate is at least 25%, which may lead to a futility decision. If the true rate of response is 
8%, then with 25 (12) patients, there is an 86.5% (36.7%) probability of a result that may 
trigger a decision to stop further development in these populations due to futility.
11.7.3
Populations for Analyses
The following populations for analyses are defined in Table 21. 


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Table 21
Populations for Analysis
Population/Analysis set
Description
Safety
All patients who received at least one dose of AZD0466
Intention-to-treat
All patients who received at least one dose of AZD0466
Evaluable for Response
All patients who have received at least 3 doses of AZD0466 at the target 
dose level in Cycle 1
DLT-evaluable
Patients enrolled in the dose-escalation that have received at least 3 doses of 
AZD0466 at the target dose level (75% of target doses from Day 8 to 
Day 29 in Cycle 1) and have completed the safety follow-up through the 
DLT evaluation period 
Or
Have experienced a DLT
Pharmacokinetics
Dosed patients with at least one reportable plasma concentrations and no 
important AEs or protocol deviations that may impact PK
AE, adverse event; DLT, dose-limiting toxicity; PK, pharmacokinetics.
11.7.4
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 specific to this 
module. 
11.7.5
General Considerations
For the dose escalation, Part A, a final analysis will be performed when the MTD has been 
determined and the last patient to be recruited (including any backfill patients) has had the 
opportunity to complete 2 cycles of treatment, or has discontinued or withdrawn from 
treatment. Response and survival data will continue to be collected for ongoing patients until 
this milestone is reached for the final patient.
For Part B, an IA will be performed when the twelfth patient has had the opportunity to 
complete one cycle of treatment and is response evaluable as per Table 21. This analysis will 
include evaluation of clinical response and AEs leading to discontinuation. Provided 
recruitment is not stopped due to futility or safety concerns, a second IA will be performed 
once all patients recruited have had the opportunity to complete one cycle of treatment, with 
efficacy analyses based on the ITT population. The final analysis of the expansion cohorts will 
be undertaken when either the last patient from all expansion cohorts has had the opportunity 
to complete 6 months of treatment, or all patients have withdrawn from the study or died. 
Thereafter, patients who are still on study treatment may remain on treatment and individual 
patients will continue to be assessed for safety as specified in the protocol.


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11.7.6
Efficacy 
Part B: Calculation or Derivation of Efficacy Variables 
Patients will be assigned a response of CR, CRi, MLFS, PR, CRc, CRm, Relapse or Failure for 
according to the criteria described in Appendix J for AML or CR, CRi, Failure, or Relapse 
according to the criteria in Appendix K for ALL. This is regardless of whether visits were 
scheduled or unscheduled and also regardless of whether a patient discontinues study 
intervention or receives another anticancer therapy. 
The disease response endpoints (CR+CRi, time to response [TTR], and DoR) will then be 
derived from the bone marrow biopsy dates and overall visit responses.
Complete response rate is defined as the proportion of patients with a best response of CR or 
CRi. Any treated patient who has not satisfied the criteria for CR or CRi will be treated as a 
non-responder for this analysis.
Time to response is defined as the time from date of first dose until the date of first 
documented CR or CRi. The analysis will include all dosed patients who have a complete 
response. Patients who go off treatment without a clinical response, receive a subsequent 
therapy, and then respond will not be included. 
Duration of response will be defined as the time from the date of first documented response 
(CR or CRi) until date of documented progression, relapse or failure according Appendix J for 
AML and Appendix K for ALL or death due to any cause. Patients who are not known to have 
reached one of these endpoints at the time of data cut-off (DCO) will be censored at the last 
overall response assessment on or before the start of subsequent therapy. 
Overall survival is defined as time from date of first dose until the date of death due to any 
cause. For patients who are alive at the time of DCO, OS will be censored on the last date 
when patients were known to be alive. Note: Survival calls will be made following the date of 
DCO for the analysis (these contacts should generally occur within 7 days of the DCO). If 
patients are confirmed to be alive or if the death date is after the DCO date, then these patients 
will be censored at the date of DCO. 
Analysis Methods
The primary efficacy variable will be the Complete Response Rate (CR+CRi). Complete 
response rate will be estimated with exact 95% confidence intervals based on the exact 
binomial distribution. Lower one-sided 80% and upper one-sided 90% limits will also be 
calculated. 
For AML patients, other outcomes such as overall response rate (ORR) (best response of 
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summarised with two-sided 95% confidence intervals based on the exact binomial 
distribution. 
Changes in platelets, blasts and neutrophils will be summarised over time.
All response outcomes will be listed. 
Time to response, DoR, and OS will be analysed using the Kaplan-Meier method. Quartiles, 
including the median, will be calculated along with 95% confidence intervals as well as rates 
at 3, 6, 9, and 12 months post first dose.
11.7.7
Safety
There are no module-specific safety analyses planned.
11.7.8
Other Analyses 
11.7.8.1
Pharmacokinetics
Calculation or Derivation of Pharmacokinetic Variables
Pharmacokinetic analysis of the plasma and urine 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.
PK 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:


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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
AUC0-72
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
AUCcml
Area under the plasma concentration-curve from time 0 on Day 1 through the first 
full dose on Day 8 and extrapolated through infinity.
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)
Urine
Urine PK parameters will be calculated for total AZD4320 including renal clearance and 
amount excreted unchanged. Plasma and urine data:
Ae0-72
Cumulative amount of unchanged drug excreted into urine from time 0 to 72 hours 
after the start of infusion
Fe
Percentage of dose excreted unchanged in urine 


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Ae0-72
Cumulative amount of unchanged drug excreted into urine from time 0 to 72 hours 
after the start of infusion
CLR 
Renal clearance of drug from plasma
Additional PK parameters may be calculated as appropriate.
PK 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 (CV, 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 
!
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) 
!
CV, 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 pharmacokinetic data for AZD4320 will also be displayed graphically. Displays will 
include AZD4320 (total and released) plasma concentration subject profiles (on the linear and 
log scale) versus time and Gmean concentration (±standard deviation) versus time, stratified by 


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dose. 
Scatter plots of PK parameters versus dose, or log-dose, may also be considered to assess dose 
proportionality.
 
 
 
 
11.7.9
Interim Analyses 
Each cohort in Part B will have an internal IA for futility, with the potential to stop or trigger a 
combination expansion (to be added via a protocol amendment), followed by a sponsor 
decision towards further development if the cohort proceeds to full recruitment. During the 
IA, enrolment may be paused in order to fully evaluate the results. Data for the IA will include 
all data collected up to the point when the twelfth patient within the cohort has had the 
opportunity to complete one cycle of treatment with AZD0466 and is response evaluable as 
per Table 21. The Evaluable for Response population will be used for this analysis. Contingent 
on the outcome of the IA, recruitment will then continue to full recruitment.
The interim analyses for efficacy will consist of summaries rates of best response (CR+CRi) 
with one-sided lower 80% and upper 90% exact confidence limits compared to the 
cohort-specific target response rates as described in Section 11.7.2.
An IA for safety in Part B will take place at the same time as the analysis for efficacy, based 
on the Safety population. Rates of AEs leading to study treatment discontinuation will be 
compared to pre-specified criteria to inform a ‘stop’ or ‘consider’ decision. The unacceptable 
rate of AEs leading to study treatment discontinuation is set at 30%. For example, in 
12 patients, one or fewer of these AEs would provide at least an 80% chance that the true rate 
is not greater than 30%. If 4 or more events are observed in 12 patients at the interim then 
there will be a lower than 10% chance that the rate is under 15% and the study may be stopped 
due to safety. If the IA takes place with a number other than 12 patients then the threshold 
rates of AEs leading to discontinuation may differ from the example provided.
The SAP will describe the planned interim analyses in greater detail.
11.7.10
Data Monitoring Committee
There will be no DMC for this study. The sponsor in discussion with the SRC (Appendix A 5) 
in accordance with its charter will be responsible for making recommendations for 
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dose-escalation or dose de-escalation decisions after each dose level, including decisions on 
opening cohorts for backfill. 


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11.8
REFERENCES - MODULE 1 
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.
Davids et al 2017
Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, et al. Phase 1 
first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin’s 
lymphoma. J Clin Onc. 2017;35(8):826-33.
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. 
Döhner et al 2017
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and 
management of AML in adults: 2017 ELN recommendations from an international expert 
panel. Blood. 2017;129(4):424-47.
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 addressing 
Ockham's razor: mTPI-2. Contemp Clin Trials. 2017;58:23-33.
Ji et al 2010
Ji Y, Liu P, Li Y, B, Bekele N. A modified toxicity probability interval method for dose-finding 
trials. Clin Trials. 2010;7(6):653-63.


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12
MODULE 2: INVESTIGATION OF DRUG-DRUG 
INTERACTION BETWEEN AZD0466 AND VORICONAZOLE 
IN PATIENTS WITH ADVANCED HAEMATOLOGICAL 
MALIGNANCIES
12.1
BACKGROUND - MODULE 2
12.1.1
Study Treatment 
Refer to Section 6 and Section 12.4 for information on AZD0466; further details are provided 
in the IB.
12.1.1.1
Non-investigational Product –Voriconazole
Voriconazole is a triazole antifungal medication used to treat serious fungal infections 
(including invasive candidiasis, invasive aspergillosis, and emerging fungal infections) that 
occur commonly in patients who are immunocompromised. Voriconazole and other azole 
antifungal agents are substrates and inhibitors of CYP3A isoforms, and are commonly used 
for prophylaxis and treatment of fungal infections in patients with acute leukaemia. 
The safety profile of voriconazole in adults is based on an integrated safety database of more 
than 2000 subjects (including 1603 adult patients in therapeutic trials) and an additional 
270 adults in prophylaxis trials. This represents a heterogeneous population, containing 
patients with haematological malignancies, patients with HIV infection with oesophageal 
candidiasis and refractory fungal infections, non-neutropenic patients with candidaemia or 
aspergillosis, and healthy volunteers. The most commonly reported adverse reactions during 
treatment with voriconazole were visual impairment, pyrexia, rash, vomiting, nausea, 
diarrhoea, headache, peripheral oedema, LFT abnormal, respiratory distress, and abdominal 
pain. The severity of the adverse reactions was generally mild to moderate. No clinically 
significant differences were seen when the safety data were analysed by age, race, or gender 
(Voriconazole Prescribing Information). 
12.1.2
Nonclinical Information and Correlative Studies
Preclinical studies of AZD4320 indicate that CYP3A4 may have a major role in the metabolic 
clearance of AZD4320, the active moiety of AZD0466. 
12.1.3
Rationale for Module 2
Drug interactions with CYP3A4 can lead to its inhibition, which can increase drug effect, or to 
its induction, which can decrease the drug effect. Medicines that are potent CYP3A4 
inhibitors include azole antifungals such as voriconazole or itraconazole. Preclinical studies of 
AZD0466 have identified CYP3A4 as likely to have a significant role in the metabolic 
clearance of AZD4320. 


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Drugs that act as inducers or inhibitors of CYP3A4 may affect circulating levels of the active 
moiety AZD4320 and could alter the efficacy or tolerability of study treatment. Use of 
voriconazole and other azole antifungal agents is prohibited in Module 1 of this study as it is 
not known whether a DDI exists between AZD0466 and azole antifungal agents. This 
prohibition restricts the therapeutic options for management of fungal infections in the 
population of patients enrolled in Module 1.
Module 2 will investigate the safety, PK, and tolerability of AZD0466 when co-administered 
with voriconazole, a strong inhibitor of CYP3A4. The investigation of a potential DDI 
between AZD0466 and voriconazole will inform the continuation or removal of restrictions on 
use of azole antifungal agents in ongoing and future study modules. 
12.1.4
Justification for Module 2 Dose
Module 2 will be initiated by the SRC (Appendix A 5) after a tolerated dose of AZD0466 has 
been determined in Module 1. 
12.1.5
Module 2 Study Design 
Module 2, a Phase I DDI study of AZD0466 and the azole antifungal agent voriconazole, will 
be conducted in patients with AML or ALL to determine the effect of voriconazole on the PK 
of AZD0466. This module will be conducted in selected sites in parallel with Module 1. 
During periods of parallel enrolment, patient entry into Module 1 will be prioritised at sites 
conducting both Module 1 and Module 2 of this protocol.
The Module 2 Cycle 1 schedule includes Periods 1, 2 and 3. Period 1 involves dose ramp-up 
in from a starting dose of AZD0466 on Day 1, with subsequent titration to the intermediate 
dose on Day 4, and to the target dose on Day 8. In Period 2, patients will receive a loading 
dose of oral voriconazole on Day 11 followed by maintenance dosing on Days 12, 13, and 14,
as specified in the prescribing information for voriconazole (Voriconazole Prescribing 
Information). In Period 3, the dose of AZD0466 administered on Day 15 in combination with 
voriconazole (at maintenance dose) will be a dose reduction of the target dose (ie, the Day 1 
equivalent dose), to mitigate against a potential increase in exposure to the active moiety 
AZD4320 if a DDI exists between AZD0466 and voriconazole, with a return to the full target 
dose at the next AZD0466 administration day.
A visual representation of the DDI component of Module 2 (Cycle 1) is shown in Figure 4.


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Figure 4
Schema for Cycle 1 of Module 2
* The target dose (TD) of AZD0466 is the highest dose level determined as tolerated by the SRC in Part A of 
Module 1 at the point of first patient enrolment in Module 2.
**After reaching AZD0466 TD at D8 there will be a dose reduction on D15 to the D1 equivalent dose, with a 
return to full TD at the next AZD0466 administration day.
*** Voriconazole administration will be discontinued on Day 19 after collection of the last PK blood sample.
BID, twice a day; D, Day; IV, intravenous; PK, pharmacokinetic; PO, by mouth; RU1: first ramp-up dose; 
RU2: second ramp-up dose; SRC, Safety Review Committee; TD, target dose.
A minimum of 10 and up to 14 patients overall will be enrolled at selected sites to investigate 
the potential DDI between AZD0466 and voriconazole. 
The DDI part of Module 2 (Cycle 1) will be performed in 3 periods over 21 days (Table 25), 
as follows:
!
Period 1 (Days 1-10): AZD0466 infusion on Days 1, 4, and 8
!
Period 2 (Days 11-14): Voriconazole administration bid
!
Period 3 (Days 15-21): AZD0466 infusion on Day 15 (at the Day 1 equivalent dose) in 
combination with voriconazole bid on Days 15-19. 
Module 2 Cycle 1 (DDI Part) will utilise a target dose of AZD0466 that has been declared 
tolerable in the dose escalation Part A of Module 1 (Table 22). After reaching the target dose 
at Day 8, there will be a dose reduction at Day 15 to the Day 1 equivalent dose, and thereafter 
there will be a return to the full target dose.
In Module 2 Cycle 2 (after the DDI part), patients may receive AZD0466 as monotherapy at a 
higher target dose, if a new higher AZD0466 dose level was declared tolerable in Module 1. 
This dose increase may be implemented without a dose ramp-up. This will allow patients to 
continue to receive study treatment at a tolerated dose within the predicted efficacious dose 
range in humans (see Section 11.1.3.1). 
Patients who do not wish to continue receiving AZD0466 will undertake the follow-up 
assessments detailed in Section 7.


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Table 22
Module 2 AZD0466 Dose Guidance
AZD0466 Dose*
Module 2, Cycle 1
Module 2, Cycle 2 and 
Beyond
D1 RU 
D4 RU
D8 TD
D15 (dose 
equivalent to D1 
dose)
D1, D8, D15, D22
75 mg
150 mg
300 mg a
75 mg
300 mg weekly b
150 mg
300 mg
600 mg a
150 mg
600 mg weekly b
300 mg
600 mg
1200 mg a
300 mg
1200 mg weekly b
600 mg
1200 mg
2400 mg a
600 mg
2400 mg weekly b
1200 mg
2400 mg
3600 mg a
1200 mg
3600 mg weekly b
2400 mg
3600 mg
5400 mg a
2400 mg
5400 mg weekly b
a
Module 2 Cycle 1 will utilise a target dose of AZD0466 that has been declared tolerable in the dose 
escalation Part A of Module 1.
b
Patients may receive AZD0466 after Cycle 1 of Module 2 at a higher target dose, without dose ramp up 
required, if a subsequent AZD0466 dose level has been declared tolerable in Part A of Module 1.
* Doses displayed are for guidance only. Definitive target and ramp-up doses will be decided by the SRC in 
Module 1 and communicated accordingly.
D, day; RU, ramp up; SRC, Safety Review Committee; TD, target dose.
In Cycle 1, patients will be admitted as inpatients for 36 hours on Days 1-2, 4-5, 8-9, and 
overnight on Day 15. Additional inpatient admission days will be at the Investigator’s 
discretion. During Period 2, voriconazole administration will occur on an outpatient basis.
Overnight stays will be required during Cycle 2 Day 1 and Day 8. Thereafter, dosing as an 
inpatient will be as per Investigator discretion, based on prior tolerability and risk of TLS. 
The SoA for the DDI part (Cycle 1) of Module 2, including PK sampling times, is provided in 
Section 12.5.1. 
The SRC may assess safety data from Module 2 that could affect the conduct of Module 1.
12.1.6
Benefit-risk Assessment
See Section 2.2 of the core protocol for an overall benefit-risk assessment for AZD0466 in the 
study population.
Module 2 will utilise a dose of AZD0466 that has been declared tolerable in patients with 
AML or ALL during the dose escalation Part A of Module 1. With the exception of abnormal 
LFTs, the most common adverse reactions during treatment with voriconazole do not overlap 
with the potential risks of treatment with AZD0466. The study protocol incorporates 
mandatory safety monitoring procedures, including intensive more frequent assessments of 


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liver biochemistry than for other clinical chemistry parameters, dose modification guidelines, 
and additional guidance for management of specific AEs.
The available nonclinical and clinical information supports an acceptable benefit-risk 
assessment for investigation of potential DDI between AZD0466 and voriconazole in patients 
with advanced haematological malignancies for which there are limited treatment options.
12.2
OBJECTIVES AND ENDPOINTS - MODULE 2
12.2.1
Primary Objectives
See Section 3 of the core protocol.
12.2.2
Secondary Objectives
The secondary objective and endpoint for this module is listed in Table 23. See Section 3 of 
the core protocol for all other secondary objectives.
Table 23
Secondary Objective – Module 2
Objectives
Endpoints/Variables
Secondary
•
To assess the drug-drug interaction potential 
between AZD0466 and the azole antifungal 
voriconazole.
•
AUC and Cmax of AZD4320 after administration 
of AZD0466 alone and in combination with 
voriconazole
12.2.3
Exploratory Objectives
See Section 3 of the core protocol for all other exploratory objectives.
12.3
STUDY POPULATION - MODULE 2
Core inclusion and exclusion criteria applicable to all patients enrolled in the study are listed 
in Section 5.1 and Section 5.2. There are no additional inclusion or exclusion criteria specific 
to Module 2.
Patients are eligible to be included in the dose escalation part of Module 2 if they meet all of 
the inclusion criteria in Section 5.1 and none of the exclusion criteria in Sections 5.2. Under 
no circumstances can there be exceptions to this rule.
Note: Each patient may only be enrolled in one module of this study. A patient who enrols in 
one module of this study is not eligible to participate in another module.
12.3.1
Inclusion Criteria
Refer to Section 5.1 of the core protocol for the common inclusion criteria applicable to 
Module 2.


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12.3.2
Exclusion Criteria
Refer to the core protocol (Section 5.2). In addition, patients for whom treatment with 
voriconazole is contraindicated per the local prescribing information must not enter the study.
12.3.3
Lifestyle Considerations
Patients must comply with the restrictions described in the core study protocol (Section 5.3).
12.3.4
Concomitant Medications
Patients must comply with the restrictions described in the core protocol (Section 6.5)
12.3.5
Screen Failures
Refer to the core protocol (Section 5.4).
12.4
Study Treatment - Module 2
Information on the preparation, handling, storage, accountability of study treatment, measures 
to minimise bias, and study treatment compliance and accountability is either provided in 
Table 24 and/or referenced in the core protocol (Section 6). 
12.4.1
Study Treatment(s) – AZD0466 and Voriconazole
AZD0466 and voriconazole are described in Table 24. 


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Table 24
Study Treatment for Module 2
Study Treatment
AZD0466
Voriconazole
Dose Formulation
‘AZD0466 powder for concentrate for 
solution for infusion’ supplied with
‘Solvent for AZD0466 powder for 
concentrate for solution for infusion’.
Film-coated tablet
Unit Dose 
Strength(s)
‘AZD0466 powder for concentrate for 
solution for infusion’: 500 mg per viala
‘Solvent for AZD0466 powder for 
concentrate for solution for infusion’:
20 mL per viala
50 mg, 100 mg, and 200 mg 
Dose Level
Dose level of AZD0466 that has been 
declared tolerable in Module 1 Part A
See Figure 4
Route of 
Administration
Intravenous
Oral
Dosage 
preparation and 
administration
Refer to Handling Instructions
Product should be administered in 
accordance with the prescribing information.
Provider
AstraZeneca R&D
Provided locally by the study site, 
subsidiary, or designeeb
Packaging and 
Labelling
AZD0466 powder for concentrate for 
solution for infusion will be provided 
in 500 mg vials. Each vial will be 
labelled as per country requirement.
Solvent for AZD0466 powder for 
concentrate for solution for infusion 
will be provided in 20 mL vials. Each 
vial will be labelled as per country 
requirement.
Voriconazole will be provided as a 
commercial film-coated tablet presentation 
in a commercial pack.
a
AZD0466 powder for concentrate for solution for infusion 500 mg/vial is intended to be reconstituted with 
20 mL custom solvent to produce AZD0466 concentrate for solution for infusion, 25 mg/mL. If required 
AZD0466 concentrate for solution for infusion may be further diluted with custom solvent to produce 
AZD0466 solution for infusion for clinical dosing. Multiple vials of drug product and custom solvent may 
be used to achieve the required doses.
b
Under certain circumstances when local sourcing is not feasible treatment may be supplied centrally 
through AstraZeneca. In the event of central supply voriconazole will be labelled as per country 
requirement for clinical trial use. 
During ramp-up and while patients are considered at risk of TLS, patients must commence 
oral allopurinol and be encouraged to drink 1.5 to 2 L of fluid at least 24 hours prior to 
AZD0466 infusion (Appendix F). 


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Patients will receive study treatment in Cycle 1 of Module 2 as follows:
!
Period 1: AZD0466 ramp-up 
Patients will be admitted to hospital and receive a starting ramp-up dose of AZD0466 on 
Day 1, with subsequent intra-patient ramp-up to an intermediate dose on Day 4, and to the 
target dose on Day 8. The Day 1 and Day 4 ramp-up doses will be equivalent to those 
used for that target dose in Module 1.
!
Period 2: Voriconazole administration 
Patients will receive voriconazole 400 mg twice daily (BID) on Day 11 and voriconazole 
200 mg BID on Day 12-14.
!
Period 3: AZD0466 in combination with voriconazole
Patients will be admitted to hospital and receive AZD0466 on Day 15 at a reduced dose 
(ie, dose equivalent to the Day 1 dose) and voriconazole 200 mg BID will continue from 
Day 15 until Day 19. Voriconazole administration on Day 19 will not continue beyond 
the time of last PK sample collection.
Voriconazole tablets should be taken at least one hour before or one hour after a meal, on each 
of the voriconazole dosing days. 
Patients who continue to receive AZD0466 in Cycle 2 may receive AZD0466 at a higher 
target dose if a new higher dose level was declared tolerable in the dose escalation part of 
Module 1. Cycle 2 and subsequent cycles are 28 days in duration in which AZD0466 is 
administered once weekly on Days 1, 8, 15, and 22 of each cycle. All patients will be treated 
until progressive disease, unacceptable toxicity or withdrawal of consent.
12.4.2
Preparation, Handling, Storage, and Accountability of Study 
Treatment
Refer to the core protocol (Section 6.2) for AZD0466. Voriconazole should be stored 
according to the storage conditions indicated on the product label.
12.4.3
Measures to Minimise Bias
Refer to the core protocol (Section 6.3).
12.4.4
Study Treatment Compliance
Refer to the core protocol (Section 6.4).
12.4.5
Intervention After the End of the Study
Refer to the core protocol (Section 6.8).


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12.5
STUDY PLAN AND TIMING OF PROCEDURES – MODULE 2
12.5.1
Schedule of Activities
The SoA for Periods 1, 2, and 3 (Cycle 1) and for subsequent cycles are shown in Table 25
and Table 26. 


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Table 25
Module 2 - Schedule of Activities for Screening and Cycle 1
Procedure
Screening
Cycle 1 (21 days)
Details in 
CSP 
Section or 
Appendix
Period 1 AZD0466a
Period 2
Voriconazole
Period 3
AZD0466 + Voriconazole
Day 
-28 to -1
1
2
3
4
5
6
7
8
9
10
11-14
15
16
17
18
19
Informed consent
X
Appendix 
A 3
Inclusion and exclusion 
criteria
X
5.1; 5.2;
12.3.1; 
12.3.2
Demography
X
8
Medical history
X
8
Physical examination
X
X
X
X
X
X
X
X
X
12.6.2.1
Height
X
12.6.2.3
Weight
X
X
X
X
12.6.2.3
Vital signsb
X
X*
X
X
X*
X*
X*
X
X
X
X
12.6.2.5
Chest X-rayc
X
12.6.2.4
ECOG performance status
X
X
12.6.2.7
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12.3.4
Adverse events (AE)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3
 
Safety ECG (triplicate)
X
X*
X
X*
X
X*
X
X*
X
X
X
12.6.2.6
Cardiac 
MUGA/MRI/ECHOd
X
12.6.2.7
Laboratory Tests
COVID-19 test
X
12.6.2.9.1
CCI


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Table 25
Module 2 - Schedule of Activities for Screening and Cycle 1
Procedure
Screening
Cycle 1 (21 days)
Details in 
CSP 
Section or 
Appendix
Period 1 AZD0466a
Period 2
Voriconazole
Period 3
AZD0466 + Voriconazole
Day 
-28 to -1
1
2
3
4
5
6
7
8
9
10
11-14
15
16
17
18
19
Hepatitis B and C, HIV and 
CMV
X
12.6.2.9.2
Pregnancy test (WOCBP 
only)
X
X
12.6.2.9.3
CBC with differential 
)e
X
X*
X
X*
X
X*
X
X*
X
12.6.2.9.6
Clinical chemistry
X
X
X
X
X
X
X
X
X
12.6.2.9.4
TLS monitoringf
X*
X*
X*
X*
X*
X*
X*
X*
12.6.2.9.12
and 
12.6.2.9.13
CPK
X
X
X
X
X
X
X
X
X
12.6.2.9.4
Coagulation indices
X
X
X
X
X
12.6.2.9.7
Cardiac troponin Ig
X
12.6.2.9.8
BNP (or NTproBNP)
X
12.6.2.9.8
Cortisol, ACTH, TSH 
X
X
12.6.2.9.9
Amylase and lipase
X
X
X
X
X
12.6.2.9.5
Serum immunoglobulins 
X
X
12.6.2.9.10
Urinalysis
X
X
X
X
X
12.6.2.9.11
 
Overnight inpatient stayh
X
X
X
X
12.6.2.9.12
Administer AZD0466
X
X
X
X
6.1 and 
12.1.5
CCI
CCI


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Table 25
Module 2 - Schedule of Activities for Screening and Cycle 1
Procedure
Screening
Cycle 1 (21 days)
Details in 
CSP 
Section or 
Appendix
Period 1 AZD0466a
Period 2
Voriconazole
Period 3
AZD0466 + Voriconazole
Day 
-28 to -1
1
2
3
4
5
6
7
8
9
10
11-14
15
16
17
18
19
Administer voriconazole
X
X
X
X
X
X
12.4.1
Pharmacokinetic Assessments
Blood sample for plasma PK
X*
X
X
X*
X*
X*
X
X
X
X
12.6.3.1
Pharmacodynamic Assessments
 
 
 
Blood for peripheral blood 
smears 
X
X*
X
X*
X
X*
X
X*
X
12.6.1
 
Disease Assessment
Mandatory bone marrow 
biopsy and aspirate for 
disease assessment 
 
Xi
12.6.1;
CT/MRI/PET scans (only if 
extramedullary disease)
X
8.1.1
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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a
Any visits (eg, Day 6 and Day 7) that do not require attendance at the site for blood draw or physical examination can be conducted by telephone, at the Investigator’s 
discretion.
b
On PK sampling days, blood pressure readings to be taken at each PK sample timepoint. All blood pressure readings can be taken ± 10 minutes from the designated PK 
sample collection.
c
Chest X-rays may also be performed at other timepoints during the study at the Investigator’s discretion, when clinically indicated.
d
Cardiac MUGA/MRI/ECHO to assess left ventricular ejection fraction will be conducted. Ensure the same modality is used for each patient. Unscheduled assessment if 
deemed clinically warranted.
e
.
f
At least twice in the first 24 hours after each administration of AZD0466, and as clinically indicated thereafter as per institutional protocol.
g
Cardiac troponin to be collected at screening (baseline) and at other timepoints in the study, as clinically indicated. Cardiac troponin I is preferred if available, if not, cardiac 
troponin T is acceptable. To allow comparison with baseline, sites are requested to maintain consistency with the troponin assay used.
h
Additional inpatient admission days at Investigator discretion. 
i
To be collected at screening between Day -28 and -1. When it is not possible to obtain a new bone marrow biopsy, a historic bone marrow biopsy sample may be used if 
collected within 28 days of first dose of AZD0466, but a historic bone marrow biopsy sample collected within 14 days of the first dose is preferred.
*Indicates more than one assessment is to be performed at the visit. 
ACTH, adrenocorticotropic hormone; AE, Adverse event; BNP, brain natriuretic peptide; CBC, complete blood count; CMV, cytomegalovirus; COVID-19, coronavirus disease 
2019; CPK, creatine phosphokinase; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; HIV, human immunodeficiency virus; 
MRI, magnetic resonance imaging; MUGA, multigated acquisition; 
; PET, positron emission tomography; PK, pharmacokinetic; 
TSH, thyroid stimulating hormone; TLS, tumour lysis syndrome; WOCBP, women of childbearing potential.
Table 26
Module 2 - Schedule of Activities for Cycle 2 and beyond
Procedure
Cycle 2
Cycle 3 onwards (28-day cycles)
Follow-up
EoT
Post 
treatment 
follow-upa
Survival 
follow-up
Details in 
CSP 
Section or 
Appendix
Day
1
2
8/15/22
9/16/23
1
2
8
9/16/23
15/22
28 days 
after last 
dose
Every 
1 month 
after last 
dose
Visit window
±2 days
±7 days
±7 days
±14 days
Physical 
examination
X
X
X
X
X
X
X
X
X
X
12.6.2.1
Weight
X
D15
X
D15
X
12.6.2.3
CCI
CCI


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Table 26
Module 2 - Schedule of Activities for Cycle 2 and beyond
Procedure
Cycle 2
Cycle 3 onwards (28-day cycles)
Follow-up
EoT
Post 
treatment 
follow-upa
Survival 
follow-up
Details in 
CSP 
Section or 
Appendix
Day
1
2
8/15/22
9/16/23
1
2
8
9/16/23
15/22
28 days 
after last 
dose
Every 
1 month 
after last 
dose
Visit window
±2 days
±7 days
±7 days
±14 days
Vital signsb
X*
X
X*
D9
X*
X*
Every 
disease 
assessment 
in (D23-
D28)
X*
X
12.6.2.5
ECOG performance 
status
X
X
X
12.6.2.8
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
12.3.4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
8.3
Safety ECG 
(Triplicate)
X*
X
D8* 
D9
X* (even 
cycles only 
from C4)
X
12.6.2.6
Cardiac 
MUGA/MRI/ECHOc 
D8
Every 3 
Cycles 
from C5 
X
12.6.2.7
Laboratory Tests
COVID-19 test
X
X
X
12.6.2.9.1
Pregnancy test 
(WOCBP only)
X
X
X
12.6.2.9.3


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Table 26
Module 2 - Schedule of Activities for Cycle 2 and beyond
Procedure
Cycle 2
Cycle 3 onwards (28-day cycles)
Follow-up
EoT
Post 
treatment 
follow-upa
Survival 
follow-up
Details in 
CSP 
Section or 
Appendix
Day
1
2
8/15/22
9/16/23
1
2
8
9/16/23
15/22
28 days 
after last 
dose
Every 
1 month 
after last 
dose
Visit window
±2 days
±7 days
±7 days
±14 days
CBC with 
differential 
 
d
X
X
X
Xe
X
X
X
Xe
X
X
12.6.2.9.6
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
12.6.2.9.4
TLS monitoringf
X*
X*
D8*
D9*
12.6.2.9.12
and 
12.6.2.9.13
CPK
X
X
X
X
X
X
X
X
X
X
12.6.2.9.4
Coagulation indices
X
X
X
X
X
X
12.6.2.9.7
Cortisol, ACTH and 
TSH
X
12.6.2.9.9
Amylase and lipase
X
X
X
X
X
X
12.6.2.9.5
Serum 
immunoglobulins
X
12.6.2.9.10
Urinalysis
X
X
X
X
X
X
12.6.2.9.11
Overnight inpatient 
stay
X
D8
12.6.2.9.12
Administer 
AZD0466
X
X
X
X
X
6.1
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Table 26
Module 2 - Schedule of Activities for Cycle 2 and beyond
Procedure
Cycle 2
Cycle 3 onwards (28-day cycles)
Follow-up
EoT
Post 
treatment 
follow-upa
Survival 
follow-up
Details in 
CSP 
Section or 
Appendix
Day
1
2
8/15/22
9/16/23
1
2
8
9/16/23
15/22
28 days 
after last 
dose
Every 
1 month 
after last 
dose
Visit window
±2 days
±7 days
±7 days
±14 days
Pharmacokinetic assessments
Blood sample for 
plasma PK
X*
X*
12.6.3.1.1
Pharmacodynamic assessments
 
 
 
Blood for 
pharmacodynamic 
 
 
X
X
X
12.6.3.2.2
Blood for 
peripheral blood 
smears
X
X
X
12.6.1
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Table 26
Module 2 - Schedule of Activities for Cycle 2 and beyond
Procedure
Cycle 2
Cycle 3 onwards (28-day cycles)
Follow-up
EoT
Post 
treatment 
follow-upa
Survival 
follow-up
Details in 
CSP 
Section or 
Appendix
Day
1
2
8/15/22
9/16/23
1
2
8
9/16/23
15/22
28 days 
after last 
dose
Every 
1 month 
after last 
dose
Visit window
±2 days
±7 days
±7 days
±14 days
 
 
 
 
Disease Assessment
Mandatory bone 
marrow biopsy and 
aspirate for disease 
assessment
 
g
D16-17
D23-28
X
12.6.1; 
12.6.4.1.3
CT/MRI/PET scans 
(only if 
extramedullary 
disease) 
D23-28, 
C3 and 
every 3 
cycles
X
8.1.1
Survival follow up
X
8
a
Patients will be followed during the off-treatment period until all treatment related toxicity resolves, or for at least 28 days post-study drug discontinuation 
or until new therapy. This can be done via telephone contact at the Investigator’s discretion.
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b
On PK sampling days, blood pressure readings to be taken at each PK sample timepoint. All blood pressure readings can be taken ± 10 minutes from the 
designated PK sample collection.
c
Cardiac MUGA/MRI/ECHO to assess left ventricular ejection fraction will be conducted. Ensure the same modality is used for each patient. Unscheduled 
assessment if deemed clinically warranted.
d
Part of collection to be used for peripheral blood smears. 
e
If disease assessment is not on Day 23, an additional CBC sample is required.
f
At least twice in the first 24 hours after each administration of AZD0466, and as clinically indicated thereafter as per institutional protocol.
g
To be taken at Cycle 2 Day 16 or 17 and Cycle 3 Day 23-28 or as clinically indicated. If bone marrow is performed on day of infusion must be at least 6 
hours post-infusion.
*Indicates more than one assessment is to be performed at the visit.
ACTH, adrenocorticotropic hormone; AE, Adverse event; C, cycle; CBC, complete blood count; COVID-19, coronavirus disease 2019; CPK, creatine 
phosphokinase; D, Day; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; EoT, end of treatment; 
INR, international normalised ratio; MRI, magnetic resonance imaging; MUGA, multigated acquisition; 
; PET, 
positron emission tomography; PK, pharmacokinetic; PT, prothrombin time; PTT, partial thromboplastin time; TSH, thyroid stimulating hormone; TLS, tumour 
lysis syndrome; WOCBP, women of childbearing potential.
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12.6
STUDY ASSESSMENTS AND PROCEDURES - MODULE 2
Study procedures and their timings for this module are summarised in the SoA 
(Section 12.5.1). Patient demographic characteristics, medical history and disease 
characteristics will be recorded as described in Section 8, Enrolment and Screening.
12.6.1
Efficacy Assessments
12.6.1.1
Peripheral Blood
Peripheral blood will be collected for CBC (laboratory safety assessment) as indicated in the 
SoA (Table 25 and Table 26).
 
 
12.6.1.2
Extramedullary Disease
Refer to the core protocol (Section 8.1.1) for details on disease assessment for extramedullary 
disease.
12.6.1.3
Bone Marrow
Bone marrow core biopsy and bone marrow aspirate should be performed (as indicated in 
Table 25 and Table 26) as below. Mandatory biomarker analysis (Section 12.6.4.1.3) will be 
performed any time a bone marrow analysis is performed. If a bone marrow aspirate and 
biopsy is performed on a dosing day, it must be at least 6 hours post infusion. In Module 2, in 
the event that a patient is otherwise eligible but extenuating circumstances preclude obtaining 
a new on-study bone marrow biopsy, a historic bone marrow biopsy sample may be used if 
collected within 28 days of first dose, but within 14 days is preferred, with the approval of the 
Medical Monitor.
!
Screening (between Day -28 and -1)
!
Cycle 2 Day 16 or 17
!
Cycle 3 and subsequent cycles between Day 23 to 28
!
Disease progression or EoT visit
The disease progression sample collection may occur at the safety follow-up visit (if 
conducted in person) if not collected previously. Additional bone marrow or peripheral blood 
samples may be collected, as clinically indicated.
12.6.1.4
Survival Follow-up
Refer to the core protocol (Section 8, Follow-up Period).
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12.6.2
Safety Assessments
12.6.2.1
Physical Examination
A complete physical examination will be performed and include assessments of the following: 
general appearance, abdomen, skin, head, and neck (including ears, eyes, nose, and throat), 
lymph nodes, thyroid, respiratory, cardiovascular, musculoskeletal (including spine and 
extremities), and neurological systems. Investigators should pay special attention to clinical 
signs related to previous serious illnesses. New or worsening abnormalities may qualify as 
AEs (see Section 8.3.5 for details). Targeted physical examinations will be performed 
throughout the treatment period, at the discretion of the Investigator eg, for new or worsening 
symptoms and/or signs.
Physical examinations should be performed (as specified in the SoA in Table 25 and Table 26) 
as follows: 
!
Screening
!
Cycle 1 Period 1 and Period 3: pre-infusion on each dosing day 
!
Cycle 1 Period 1 and Period 3: 24 hours after each infusion
!
Cycle 2 and beyond: pre-infusion on each dosing day
!
Cycle 2 and beyond: 24 hours after each infusion
!
EoT visit
12.6.2.2
Medical history
Refer to the core protocol (Section 8, Enrolment and Screening).
12.6.2.3
Height and Body Weight
Height will be recorded at screening.
Body weight will be assessed (as specified in the SoA in Table 25 and Table 26) as follows: 
!
Screening
!
Cycle 1 Day 1, 8, and 15: pre-infusion 
!
Each Cycle thereafter Day 1 and Day 15: pre-infusion
!
EoT visit
12.6.2.4
Chest X-ray
Chest x-ray will be performed at screening to provide a baseline against which potential 
treatment-emergent lung abnormalities may be evaluated. Chest x-rays may also be performed 
at other timepoints during the study at the Investigator’s discretion, when clinically indicated.


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12.6.2.5
Vital Signs
Vital signs will include heart rate, pulse, systolic and diastolic BP, respiration rate, height (at 
screening), and temporal temperature. Blood pressure and pulse measurements will be 
assessed in a seated or semi-supine position with a completely automated device. Manual 
techniques will be used only if an automated device is not available. Measurements should be 
preceded by at least 10 minutes of rest for the patient in a quiet setting without distractions 
(eg, television, cell phones).
On PK sampling days, BP readings to be taken at each PK sample timepoint. All BP readings 
can be taken ±10 minutes from the designated PK sample collection.
Vital signs should be assessed (as specified in the SoA in Table 25 and Table 26) as follows:
!
Screening
!
Cycle 1 Period 1, Day 1: pre-infusion, 30 minutes (±5 minutes) after the start of the 
infusion, at the end of the infusion (+10 minutes), and 2 hours (±15 minutes), 6 hours 
(±30 minutes), 9 hours (±1 hour) after the start of the infusion 
!
Cycle 1 Period 1, Day 2: 24 hours (±2 hours) after the start of the Day 1 infusion
!
Cycle 1 Period 1, Day 3: 48 hours (±3 hours) after the start of the Day 1 infusion
!
Cycle 1 Period 1, Day 4: 72 hours after the start of the Day 1 infusion (up to 3 hours 
before Day 4 infusion), 30 minutes (±5 minutes) after the start of the infusion, and at the 
end of the infusion (+10 minutes)
!
Cycle 1 Period 1, Day 8: pre-infusion, 30 minutes (±5 minutes) after the start of the 
infusion, and at the end of the infusion (+10 minutes)
!
Cycle 1 Period 3, Day 15: pre-infusion, 30 minutes (±5 minutes) after the start of the 
infusion, at the end of the infusion (+10 minutes), and 2 hours (±15 minutes), 6 hours 
(±30 minutes), 9 hours (±1 hour) after the start of the infusion
!
Cycle 1 Period 3, Day 16: 24 hours (±2 hours) after the start of the Day 15 infusion
!
Cycle 1 Period 3, Day 17: 48 hours (±3 hours) after the start of the Day 15 infusion
!
Cycle 1 Period 3, Day 18: 72 hours (±3 hours) after the start of the Day 15 infusion
!
Cycle 1 Period 3, Day 19: 96 hours (±3 hours) after the start of the Day 15 infusion
!
Cycle 2 Day 1: pre-infusion, 30 minutes (±5 minutes) after the start of the infusion, and at 
the end of the infusion (+10 minutes)
!
Cycle 2 Day 2: 24 hours (±2 hours) after the start of the Day 1 infusion
!
Cycle 2 Day 8: pre-infusion, 30 minutes (±5 minutes) after the start of the infusion, and at 
the end of the infusion (+10 minutes)
!
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!
Cycle 2 Day 15: pre-infusion, 30 minutes (±5 minutes) after the start of the infusion, and 
at the end of the infusion (+10 minutes)
!
Cycle 2 Day 16 or 17: at time of disease assessment 
!
Cycle 2 Day 22: pre-infusion, 30 minutes (±5 minutes) after the start of the infusion, and 
at the end of the infusion (+10 minutes)
!
Cycle 3 and beyond Day 1, 8, 15 and 22: pre-infusion, 30 minutes (±5 minutes) after the 
start of the infusion, and at the end of the infusion (+10 minutes)
!
At each cycle: at time of disease assessment
!
EoT visit
12.6.2.6
Electrocardiograms
Digital 12-lead ECGs (triplicate ECGs, all 3 within a 5-minute time period) will be obtained 
after the patient has been resting in a supine position for at least 10 minutes. ECGs will be 
measured before vital signs and prior to PK blood draws at all matched PK sample timepoints. 
A standardised ECG machine provided by the central ECG vendor should be used and the 
patient should be examined using the same machine throughout the study, where feasible. 
If an unscheduled ECG is done at any time, then an electrolyte panel (Section 12.6.2.9) must 
be collected to coincide with ECG testing.
Central ECG reads will be utilised during this study. Standard ECG parameters to be 
determined will include HR/RR, PR, QRS, QT and QTcF (QT interval corrected for HR using 
Fridericia’s formula) intervals.
After the ECGs have been recorded, the Investigator or designated physician will review each 
of the ECGs at all timepoints for the presence of abnormalities (including rhythm, ECG 
intervals, or repolarisation abnormalities) and may refer to a local cardiologist if appropriate. 
A paper copy of the ECG should be filed in the patient’s medical records. For all ECGs, an 
overall evaluation and interpretation should be recorded by the Investigator or designated 
physician. Any clinically significant abnormalities detected require a confirmatory ECG. In 
case that the centrally provided ECG machine is unavailable or technical issues occur that 
preclude correct measurement, local ECGs (using the site owned device) may be performed 
instead.
See Section 6.6.5 for management of cardiac findings and cardiovascular parameters that 
require treatment to be withheld or increased monitoring. Twelve-lead centrally-read digital 
ECGs will be performed in triplicate; collection times are from the start of AZD0466 infusion.
ECGs should be performed as specified in the SoA Table 25 and Table 26, and Table 27. 


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Table 27
PK Timepoints and Corresponding Safety ECG Timepoints (Module 2) 
a
At PK sampling visits, triplicate ECGs will be collected before the PK sample is taken (please refer to 
Section 12.6.3.1.1 for additional PK assessments).
b
Beyond Cycle 2 ECGs will be collected on Day 1 of even cycles only, ie, Cycle 4, 6, 8 etc: pre-infusion and 
at the end of the infusion (+10 minutes). 
Study period
Day
Timepoint
Triplicate Safety 
ECGs
Screening
-28 to -1
Baseline
X
Cycle 1
Period 1
1
Pre-infusion
Xa
End of the infusion (+10 min)
Xa
2
24 hours after the start of the Day 1 infusion (±2hours)
Xa
4
Pre-infusion
Xa
End of the infusion (+10 min)
Xa
5
24 hours after the start of the Day 4 infusion (±2 hours)
X
8
Pre-infusion
Xa
End of the infusion (+10 min)
Xa
9
24 hours after the start of the Day 8 infusion (±2 hours)
X
Period 3
15
Pre-infusion
Xa
End of the infusion (+10 min)
Xa
16
24 hours after the start of the Day 15 infusion 
(±2hours)
Xa
17
48 hours after the start of the Day 15 infusion 
(±2hours)
Xa
18
72 hours after the start of the Day 15 infusion (±2 
hours)
Xa
Cycle 2
1
Pre-infusion 
Xa
End of the infusion (+10 min)
Xa
2
24 hours after the start of the Cycle 2 Day 1 infusion 
(±2 hours)
X
8
Pre-infusion 
X
End of the infusion (+10 min)
X
9
24 hours after the start of the Cycle 2 Day 8 infusion 
(±2 hours)
X
Cycle 4 and even cycles 
thereafter
1
Pre-infusion 
Xa,b
End of the infusion (+10 min)
Xa,b
End of Treatment
X


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12.6.2.7
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 treatment, 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 at the times specified in the SoA (Table 25
and Table 26) as follows: 
!
Screening
!
Cycle 2, Day 8
!
Every 3 cycles from Cycle 5 (ie, Cycle 5, 8, 11, etc), Day 8
!
EoT visit
12.6.2.8
Performance Status
ECOG performance status (Appendix L) will be assessed at the times specified in the SoA 
(Table 25 and Table 26) as follows. 
!
Screening
!
Every Cycle Day 1
!
EoT visit 
12.6.2.9
Clinical Safety Laboratory Assessments
Clinical laboratory safety tests, including urine or serum pregnancy tests, will be performed in 
a licensed clinical laboratory according to local standard procedures. Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values, units, and reference ranges) will 
be recorded on the appropriate eCRF. 
Laboratory values will be repeated/confirmed and followed up as appropriate.


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Safety laboratory assessments will be performed at the timepoints specified in the SoA 
(Table 25 and Table 26). Additional sampling times may be added or removed if indicated by 
the emerging data. 
12.6.2.9.1
COVID-19 Testing
COVID-19 tests will be conducted where appropriate and in accordance with local 
procedures. COVID-19 testing, may include nucleic acid/PCR and/or serological approaches. 
This should be performed as follows:
!
Screening: patients with a positive PCR test, must be antigen negative with confirmed 
IgG antibodies to COVID-19 to be able to start treatment
!
At each cycle from Cycle 2 onwards Day 1: pre-infusion
!
EoT visit
12.6.2.9.2
Viral Serology
A Hepatitis B, Hepatitis C, HIV and CMV viral serology sample will be collected at 
screening. If a patient was found to have positive anti-HBc antibody and a negative HBsAg, a 
DNA PCR test will be done to determine eligibility criteria.
12.6.2.9.3
Pregnancy Test (Women of Childbearing Potential Only)
A urine/serum sample for a pregnancy test will be collected from all women of childbearing 
potential (defined in Section 5.3) as follows: 
!
Screening
!
Day 1 of each cycle: pre-infusion 
!
EoT visit
12.6.2.9.4
Clinical Chemistry
Blood samples for determination of clinical chemistry will be collected as specified in 
Table 25 and Table 26. Unscheduled samples may be collected if deemed clinically warranted, 
and results of unscheduled assessment should be recorded in the eCRF.
If an unscheduled ECG is performed for patient assessment, an electrolyte panel (ie, calcium, 
magnesium potassium) must be done. If clinically indicated, a troponin assay should coincide 
with this evaluation. Cardiac troponin I is preferred when available, however if not, cardiac 
troponin T is acceptable. To allow comparison with baseline, sites are requested to maintain 
consistency with the troponin assay used. Isolated troponin elevations are not sufficient to 
trigger dosing changes and should be evaluated in the context of other cardiac findings.
The following clinical chemistry tests will be performed (Table 28).


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Table 28
Clinical Chemistry
Albumin 
Cholesterola
Magnesium
Alkaline phosphatase
C-reactive protein
Phosphate
Alanine aminotransferase
Creatinine
Potassium
Amylaseb
Gamma-glutamyl transferase
Sodium
Aspartate aminotransferase
Glucosea
Triglyceridesa
Bicarbonate
Glutamate dehydrogenaseb
Total protein
Bilirubin (total and direct)
Lactate dehydrogenase
Chloride
Blood urea nitrogen
Lipasec
Uric acid
Calcium
a
Fasting cholesterol, triglyceride and glucose values are not required. However, if non-fasting values are 
abnormal, a repeat sample should be obtained when the patient is fasting.
b
Glutamate dehydrogenase testing is optional, but should be performed where sites have the capability to 
perform the test locally.
c
Collected at screening, pre-infusion on each dosing day, and end of treatment visit.
NB. Refer to Appendix E if alanine amino transferase or aspartate aminotransferase ≥3 × ULN together with 
total bilirubin ≥2 × ULN. 
ULN, upper limit of normal range.
Results for LFTs must be available and reviewed before each infusion of study treatment 
throughout Cycle 1 and review of results is recommended before each infusion of study 
treatment from Cycle 2 and beyond. Values must have returned to the patient’s baseline before 
infusion of AZD0466. 
Clinical chemistry, including creatine phosphokinase, should be performed according to the 
schedule below (collection time begins from start of infusion).
!
Screening
!
Cycle 1 Period 1 and Period 3: Pre-infusion on each dosing day 
!
Cycle 1 Period 1 and Period 3: 24 hours (±2 hours) after each dosing 
!
At each cycle from Cycle 2 onwards: Pre-infusion on each dosing day
!
At each cycle from Cycle 2 onwards: 24 hours (±2 hours) after each dosing 
!
EoT visit
12.6.2.9.5
Amylase and Lipase
Amylase and lipase will be collected according to the schedule below.
!
Screening
!
Pre-infusion on each dosing day 


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!
EoT visit
12.6.2.9.6
Complete Blood Count with Differential 
 
Complete blood counts with differential 
 (Table 29) will be 
collected. Part of the blood sample collected for CBC will be used for peripheral blood smears 
as detailed in Section 12.6.1.
Table 29
Haematology Assessments
Absolute leucocyte differential count: neutrophils, 
lymphocytes, monocytes, basophils, eosinophils
Blood (B)-haemoglobin 
Haematocrit
Leucocytes
Platelet count
Collection times are indicated below (collection time begins from start of infusion). 
!
Screening
!
Cycle 1 Period 1, Day 1: pre-infusion, at the end of the infusion (+10 minutes), and 
6 hours (±30 minutes) after the start of the infusion
!
Cycle 1 Period 1, Day 2: 24 hours (±2 hours) after the start of the Day 1 infusion
!
Cycle 1 Period 1, Day 4: pre-infusion and at the end of the infusion (+10 minutes)
!
Cycle 1 Period 1, Day 5: 24 hours (±2 hours) after the start of the Day 1 infusion
!
Cycle 1 Period 1, Day 8: pre-infusion, at the end of the infusion (+10 minutes), and 
2 hours (±30 minutes), 6 hours (±30 minutes) and 9 hours (±1 hour) after the start of 
infusion
!
Cycle 1 Period 1, Day 9: 24 hours (±2 hours) after the start of the Day 8 infusion
!
Cycle 1 Period 3, Day 15: pre-infusion, at the end of the infusion (+10 minutes), and 
2 hours (±30 minutes), 6 hours (±30 minutes) and 9 hours (±1 hour) after the start of 
infusion
!
Cycle 1 Period 3, Day 16: 24 hours (±2 hours) after the start of the Day 15 infusion 
!
At each cycle from Cycle 2 onwards: Pre-infusion on each dosing day 
!
At each cycle from Cycle 2 onwards: 24 hours (±2 hours) after each dosing 
!
At each disease assessment
!
EoT visit
12.6.2.9.7
Coagulation Indices
Prothrombin, INR and PTT will be collected as specified in the individual modules. 
International normalised ratio assessment should be repeated if any abnormalities above ULN 
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in liver biochemistry occur, at 6-8 hours and 24 hours after occurrence of the abnormality. If 
INR is elevated at either timepoint, a subsequent INR assessment should be performed at 72 
hours to ensure resolution.
Coagulation (PT/INR/PTT) will be collected at the times indicated below: 
!
Screening
!
Pre-infusion on each dosing day
12.6.2.9.8
Cardiac Troponin and BNP (or NTproBNP) 
Blood samples for cardiac troponin and BNP or NTproBNP measurements will be collected 
(as specified in Table 25 and Table 26) as follows: 
!
Screening
!
As clinically indicated
Cardiac troponin I is preferred when available, however if not, cardiac troponin T is 
acceptable. To allow comparison with baseline, sites are requested to maintain consistency 
with the troponin assay used. Isolated troponin elevations are not sufficient to trigger dosing 
changes and should be evaluated in the context of other cardiac findings.
If an unscheduled ECG is performed for patient assessment, an electrolyte panel (ie, calcium, 
magnesium potassium) must be done. If clinically indicated, a troponin assay should coincide 
with this evaluation including referral to a cardiac specialist. 
12.6.2.9.9
Cortisol, ACTH, and TSH
Cortisol, ACTH, and TSH will be collected (as specified in Table 25 and Table 26) as follows:
!
Screening (between Day -28 and -1)
!
Cycle 1 Period 1, Day 8: pre-infusion
!
EoT visit
12.6.2.9.10
Serum Immunoglobulins
Samples for serum immunoglobulins will be collected (as specified in Table 25) as follows:
!
Screening (between Day -28 and -1)
!
Cycle 1 Period 1, Day 8: pre-infusion
!
EoT visit


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12.6.2.9.11
Urinalysis
Urinalysis will be performed to assess glucose, protein, blood, ketones, and leucocyte esterase. 
Results must be available prior to dosing.
Samples for urinalysis will be collected at the times indicated below:
!
Screening (between Day -28 and -1) 
!
Pre-infusion on each dosing day
!
EoT visit
12.6.2.9.12
Overnight Stays for TLS Monitoring
During Cycle 1 Period 1, study treatment will be administered on an inpatient basis on Day 1, 
Day 4 and Day 8 to allow TLS monitoring and PK assessments. Overnight stays are also 
recommended for dosing on Day 15 during Cycle 1 Period 3 and during Cycle 2 for Days 1 
and 8, but patients may be discharged prior to 36 hours post-dose as per Investigator 
discretion, if their TLS laboratory values are appropriate, and if the patient is able to return for 
a follow-up clinic visit to complete the required safety and laboratory assessments. Thereafter, 
dosing as an inpatient will be as per Investigator discretion, based on prior tolerability and risk 
of TLS.
Tumour lysis syndrome monitoring should be performed (as specified in Table 25 and 
Table 26) at least twice in the first 24 hours after each administration of study treatment, and 
thereafter as clinically indicated.
12.6.2.9.13
Clinical and Laboratory Assessments for TLS
The classification of laboratory TLS and clinical TLS is described in Appendix G. Patients 
will be evaluated for clinical signs and symptoms of TLS during treatment with AZD0466, 
and blood samples for laboratory assessments will be collected according to the respective 
module SoA. 
Laboratory parameters from the clinical chemistry panel, which are indicative of TLS 
(according to the Howard modification of Cairo-Bishop criteria, Appendix G), including 
serum levels of uric acid, potassium, phosphate, calcium, and creatinine, will be evaluated. 
Blood urea nitrogen and lactate dehydrogenase may also be evaluated to aid assessment. Fluid 
balance must be monitored per institutional standards. Blood samples for monitoring TLS will 
be collected at the timepoints as indicated in Table 25 and Table 26 and as clinically indicated. 
Recommended prophylaxis for TLS is outlined in Appendix F.
12.6.2.10
Adverse Events and Serious Adverse Events
Refer to the core protocol (Section 8.3).


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12.6.2.10.1
Pregnancy
Refer to the core protocol (Section 8.3.13).
12.6.2.10.2
Medication Error
Refer to the core protocol (Section 8.3.14).
12.6.2.10.3
Overdose
Refer to the core protocol (Section 8.4).
12.6.3
Human Biological Samples
12.6.3.1
Pharmacokinetics
The PK of AZD0466 will be assessed when administered alone and in combination with 
voriconazole as described in the SoA (Table 25). 
12.6.3.1.1
Blood Sample for Plasma Pharmacokinetics
Blood samples should be taken from a different part of the body than where study the 
treatment is being infused, including if central line access is available, to prevent erroneous 
drug concentration readings. For example, if AZD0466 is being infused into the patient’s right 
arm, then the blood sample should be collected from the left arm.


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Blood Samples for Plasma Pharmacokinetics
Study period
Day
Timepoint
Cycle 1 Period 1
Day 1
Pre-infusion
30 minutes after the infusion the start of infusion (±5 minutes)
End of the infusion (+10 minutes)a
2 hours from start of Day 1 infusion (±15 min)
6 hours from start of Day 1 infusion (±30 min)
9 hours from start of Day 1 infusion (±1 hour)
Day 2
24 hours after the start of the Day 1 infusion (±2 hours)
Day 3
48 hours after the start of the Day 1 infusion (±3 hours)
Day 4
72 hours after the start of the Day 1 infusion (up to 3 hours before 
infusion on Day 4)
End of the infusion on Day 4 (+10 minutes)a
Day 8
Pre-infusion
End of the infusion (+10 minutes)a
Cycle 1 Period 3
Day 15
Pre-infusion
30 minutes after the infusion the start of infusion (±5 minutes)
End of the infusion (+10 minutes)a
2 hours from start of Day 15 infusion (±15 min)
6 hours from start of Day 15 infusion (±30 min)
9 hours from start of Day 15 infusion (±1 hour)b
Day 16
24 hours after the start of the Day 15 infusion (±2 hours)
Day 17
48 hours after the start of the Day 15 infusion (±3 hours)
Day 18
72 hours after the start of the Day 15 infusion (±3 hours)
Day 19
96 hours after the start of the Day 15 infusion (±3 hours)
Cycle 2
Day 1
Pre-infusion
End of the infusion (+10 minutes)a
Cycle 3 and 
beyond
Day 1
Pre-infusion 
End of the infusion (+10 minutes)a
a
As close as possible to the end of the infusion, but permissible up to 10 minutes.
b
In the event that a planned collection is no longer possible at the scheduled timepoint, the Medical Monitor 
must be informed, and any collection outside allotted window must be discussed with the Medical Monitor. 
12.6.3.2
Pharmacodynamics
12.6.3.2.1
 
Mandatory whole blood samples will be collected from all patients at the timepoints indicated 
in the SoA (Table 25 and Table 26) and as shown below.
 
 
CCI
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Note: Collection time begins with the start of infusion.
12.6.3.2.2
Blood for Pharmacodynamic 
Mandatory whole blood samples will be collected from all patients at the timepoints indicated 
in the SoA (Table 25 and Table 26) and as shown below.
 
 
CCI
CCI
CCI


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Blood for Pharmacodynamic 
Study period
Day
Ramp-up (RU) or 
Target Dose (TD)
Timepoint
Screening
-
-
-
Cycle 1 Period 1
Day 1
RU1 Day 1
Pre-infusion
End of infusion (+10 min)
6 hours after start of infusion (± 30 min)
Day 2
RU1 Day 2
24 hours after start of Day 1 infusion (± 2 hours)
Day 4
RU2 Day 1
Pre-infusion
Day 5
RU2 Day 2
24 hours after start of Day 4 infusion (± 2 hours)
Day 8
TD Day 1
Pre-infusion
End of infusion (+10 min)
6 hours after start of infusion (± 30 min)
Day 9
TD Day 2
24 hours after start of Day 8 infusion (± 2 hours)
Cycle 1 Period 3
Day 15
-
Pre-infusion
End of infusion (+10 min)
6 hours after start of infusion (± 30 min)
Day 16
-
24 hours after start of Day 15 infusion (± 2 hours)
Cycle 2
Day 1
-
Pre-infusion
Day 2
-
24 hours after start of Day 1 infusion (± 2 hours)
Disease Progression/ 
End of treatment
-
-
End of treatment
12.6.3.2.3
Peripheral Blood Smears 
Mandatory peripheral blood smears will be collected at the timepoints indicated in the SoA 
(Table 25 and Table 26) and as shown below to evaluate 
 normal blood 
cells and detect morphologic apoptotic responses in the blood. Blood smears will be obtained 
from collected CBC samples. Note: Collection time begins with the start of infusion.
Peripheral Blood Smears 
Study period
Day
Ramp-up (RU) or 
Target Dose (TD)
Timepoint
Screening
-
-
-
Cycle 1 Period 1
Day 1
RU1 Day 1
Pre-infusion
End of infusion (+10 min)
Day 2
RU1 Day 2
24 hours after start of Day 1 infusion (± 2 hours)
CCI
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12.6.4.1.2
 
 
 
12.6.4.1.3
Bone Marrow Biopsy and Aspirate 
A mandatory pretreatment bone marrow biopsy and aspirate will be required for standard 
disease profiling 
 (Section 12.6.1). Bone marrow 
biopsy samples will be collected in accordance with local/institutional guidelines and as per 
the process delineated in the laboratory manual. 
 
 
Mandatory biomarker analysis will be also performed for any bone marrow biopsy and 
aspirate collected for disease assessment and at disease progression, according to the 
timepoints in Table 25 and Table 26.
Note: The disease progression sample may be taken at the safety follow-up visit if not 
collected previously.
12.7
Statistical Considerations – Module 2
12.7.1
Statistical Hypotheses 
No formal statistical hypothesis testing is planned. 
12.7.2
Sample Size Determination
The number of subjects is based on the desire to gain adequate information on the effect of 
voriconazole on the exposure of AZD4320, while exposing as few subjects as possible to 
study procedures.
Interpretation of the results will be based on the estimated effect (geometric mean ratio; 
GMR) and associated 90% CI. 
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Assuming an intrapatient CV of 30%, 10 PK evaluable participants are expected to give a 
relative precision of 2.0 (ratio between the upper and lower limits of the 90% CI) with a 
probability greater than 80%. This corresponds to a 90% CI of 2.83 to 5.66 if the observed 
ratio is 4.00 (based on in-vitro data). Up to 14 patients will be enrolled to ensure that at least 
10 evaluable patients complete the study.
12.7.3
Populations for Analysis
The following populations for analyses are defined in Table 30. 
Table 30
Populations for Analysis
Population/Analysis set
Description
Safety
All patients who received at least one dose of AZD0466
Intention-to-treat
All patients who received at least one dose of AZD0466
Pharmacokinetics
Dosed patients with reportable plasma concentrations and no important AEs 
or protocol deviations that may affect PK
12.7.4
Statistical Analyses
The SAP will include a more technical and detailed description of the statistical analyses 
described in this section.
12.7.5
General Considerations
Refer to the core protocol (Section 9.5) for details of summary analyses. A clinical report will 
be produced from the database when all patients have had the opportunity to be treated and 
followed-up for 6 months. 
12.7.6
Efficacy
Refer to the core protocol (Section 9.6).
12.7.7
Safety
Refer to the core protocol (Section 9.7).
12.7.8
Other Analyses
12.7.8.1
Pharmacokinetics
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.


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PK 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
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
AUCcml
Area under the plasma concentration-curve from time 0 on Day 1 through the first 
full dose on Day 8 and extrapolated through infinity.
tlast
Time of last observed (quantifiable) concentration
Ctrough
Concentration prior to dosing
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.
PK 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 


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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 (CV, 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 
!
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) 
!
CV, 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 pharmacokinetic data for AZD4320 will also be displayed graphically. Displays will 
include AZD4320 (total and released) plasma concentration subject profiles (on the linear and 
log scale) versus time and Gmean concentration (±standard deviation) versus time, stratified by 
dose. 
Statistical Analysis of Pharmacokinetic Data
For the statistical analyses, only patients who provide eligible PK data for both AZD0466 
(Period 1) and AZD0466 + Voriconazole (Period 3) interventions will be included for 
statistical comparison. A comparison of the AZD0466 PK parameters Cmax and AUC will be 
performed for AZD0466 + Voriconazole versus AZD0466 interventions.
Where data allow, the statistical analysis will be performed via a linear mixed effect model 
using the natural logarithm of AZD4320 Cmax and AUC as the response variables with 


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intervention as a fixed effect, and patient as a random effect. Transformed back from the 
logarithmic scale, geometric means together with CIs (2-sided 95%) for Cmax and AUC will be 
estimated and presented. Also, ratios of geometric means together with CIs (2-sided 90%) will 
be estimated and presented.
12.7.9
Interim Analyses 
No IA is planned.
12.8
References - Module 2
Voriconazole Prescribing Information
Highlights of Voriconazole Prescribing Information, VFEND (Revised 1/2019). Available 
from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021630s034,021266s045,021267s
055lbl.pdf. Accessed 28 October 2020.
13
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
None.


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences 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 Institutional Review Board/ 
Independent Ethics Committee (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 
Contract Research Organisation 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 treatment 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 treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators.
!
For all studies except those utilising medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to Investigators as necessary.


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∀
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
!
An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the 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 
(HIPAA) requirements, where applicable, and the IRB/IEC or study centre.
!
The medical record must include a statement that written informed consent was obtained 
before the 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 re-consented to the most current version of the ICF(s) during their 
participation in the study.
!
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorised 
representative.
A patient who is re-screened is not required to sign another ICF if the re-screening occurs 
within 28 days from the previous ICF signature date. A patient may be re-screened up to 
2 times to determine eligibility in this study.


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


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!
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
A study-specific Safety Review Committee 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 (PI) or delegate from the investigational sites that have enrolled 
patients
!
Medical Monitor 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://astrazenecaclinicaltrials.com, 
https://www.clinicaltrialsregister.eu and http://www.clinicaltrials.gov as will the summary of 
the study results when they are available. The clinical study and/or summary of study results 
may also be available on other websites according to the regulations of the countries in which 
the study is conducted.


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A 7
Data Quality Assurance
!
All patient data relating to the study will be recorded on eCRF unless transmitted to the 
sponsor or designee electronically (eg, laboratory data). The Investigator is responsible 
for verifying that data entries are accurate and correct by electronically signing the eCRF.
!
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.
!
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organisations).
!
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of 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 entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.


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!
All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the construction 
and evaluation of the study are defined as source documents. Source data are contained in 
source documents (original records or certified copies).
!
A digital copy of all imaging scans should be stored as source documents.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
patients.
The first act of recruitment is the first site activated and will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or Investigator may include but are 
not limited to:
!
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines
!
Inadequate recruitment of patients by the Investigator
!
Discontinuation of further study treatment development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the patient and 
should assure appropriate patient therapy and/or follow-up.
Patients from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy
!
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the sponsor 


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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 (ICMJE) authorship requirements.


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


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


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Intensity Rating Scale:
!
Mild (awareness of sign or symptom, but easily tolerated)
!
Moderate (discomfort sufficient to cause interference with normal activities)
!
Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
The grading scales found in the revised National Cancer Institute CTCAE version 5 will be 
utilised for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate, and 
severe events into CTCAE grades should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?
!
No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
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!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognised feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as ‘no reasonable possibility’.
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 treatment that either causes harm to the patient 
or has the potential to cause harm to the patient. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient.
Medication error includes situations where an error: 
!
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
!
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!
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 
!
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 
!
Wrong 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 that lead to one of the above 
listed events, which 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 medication or SoC medication in open-label studies, even if 
an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.


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


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AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is 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
!
Pathogens are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances that do not contain infectious substances or substances that are unlikely 
to cause disease in humans or animals are not subject to these regulations unless they meet the 
criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf)
!
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content


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Appendix D
Optional Genomics Initiative Sample
D 1
 
CCI
CCI


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CCI


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CCI


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


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥3 × ULN
!
AST ≥3 × ULN
!
TBL ≥2 × ULN
Local Laboratories Being Used:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative 
!
Determine whether the patient meets PHL criteria (see Section E 2 for definition) by 
reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory eCRF
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient has not met PHL criteria
!
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP
E 4.2
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
!
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (see Section E 6)
!
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!
Within one day of PHL criteria being met, the Investigator will report the case as a SAE 
of Potential HL; 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 Medical Monitor 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 Medical Monitor
∀
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 TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Medical Monitor 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 Medical 
Monitor contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP, to 
ensure timely analysis and reporting to health authorities within 15 calendar days from date 
PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global Safety 
Physician will also be involved in this review together with other subject matter experts as 
appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:


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!
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 HL 
SAE and AE eCRFs accordingly with the new information (reassessing event term; 
causality and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
!
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
∀
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
∀
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:
!
Provides any further update to the previously submitted SAE of PHL, (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to the investigational medicinal 
product (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 Treatment
This section is applicable to patients with liver involvement who meet PHL criteria on study 
treatment, having previously met PHL criteria at a study visit prior to starting study treatment.


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At the first on-study treatment occurrence of PHL criteria being met the Investigator will 
determine if there has been a significant change in the 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 treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following 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 
treatment and at their first on-study treatment visit as described in Section 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 TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Medical Monitor if there is any uncertainty.


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E 8
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests, which are 
recommended but not mandatory. The list may be modified based on clinical judgement. Any 
test results need to be recorded.
Hy’s Law Lab Kit for Laboratories 
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
HBsAg
IgM and IgG anti-HBc
HBV DNAa
IgG anti-HCV
HCV RNAb
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)
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
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 
E 9
References
Aithal et al, 2011
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H,et al Case definition 
and phenotype standardization in drug-induced liver injury. Clinical Pharmacology and 


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Therapeutics. 2011; 89(6):806-15.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation


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Appendix F
Management of Specific Adverse Events
F 1
Guidance for Management of Tumour Lysis Syndrome
Patients will be evaluated for clinical signs and symptoms of TLS during treatment with 
AZD0466, and blood samples will be collected according to the individual module SoA.
Recommendations for prophylaxis, management, dose modification, and adverse event 
reporting pertaining to TLS are summarised below.
F 1.1
Prophylaxis for TLS
Assessment of TLS risk is based on disease type, as summarised in Table 31. 
Table 31
Risk Assessment for Tumour Lysis Syndrome
Risk of tumour lysis syndromea
Malignancy
High
Intermediate
Low
Acute myeloid 
leukaemia
WBC ≥100 ×109/L
WBC ≥25 and ≤100 ×109/L
or 
WBC < 25 ×109/L and 
LDH ≥2x ULN 
WBC < 25 ×109/L and LDH 
< 2x ULN
Acute 
lymphoblastic 
leukaemia
WBC ≥100 ×109/L and 
LDH ≥2x ULN
WBC < 100 ×109/L and 
LDH < 2x ULN
-
a
WBC < 10 ×109/L is required for study eligibility and hydroxyurea (AML) and high-dose steroids (ALL 
and leukaemia of ambiguous lineage) are permitted during screening and Cycle 1 to achieve this; 
consequently patients will be intermediate or low risk of TLS.
Risk classification adapted from MD Anderson Cancer Center guidance.
LDH, lactate dehydrogenase; TLS, tumour lysis syndrome; ULN, upper limit of normal range; WBC, white 
blood cell count.
Prophylaxis for TLS (hydration and anti-hyperuricaemic agents) is required for all patients 
receiving study treatment and should be implemented according to the TLS risk level assessed 
for each patient (Table 31). Specific recommendations are outlined in this section, but details 
of management may vary per institutional practice. Patients with creatinine clearance < 80 
mL/min, and patients with renal involvement from underlying disease and/or urinary outflow 
obstruction, may be at higher risk of TLS and complications of TLS, and should be managed 
accordingly. Hospitalisation may be considered for hydration management requirements 
occurring outside of the protocol-scheduled inpatient hospitalisation period.
Prophylaxis is summarised by TLS risk score in Table 32, according to the following 
principles:
!
Adequate oral fluid intake (Table 32) is required for all patients receiving study 
treatment, in particular around the times of AZD0466 dosing, and patients should be 


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encouraged to drink sufficient fluid (total of 1.5 to 2 L/day) before and after each infusion 
of AZD0466. 
!
IV hydration is required for all patients during the ramp-up in Cycle 1 (total > 2 L/day of 
IV and oral hydration). From Cycle 1 Day 15 onwards, IV hydration should be 
administered based on risk of TLS. Infusion of sodium chloride 0.9% IV (fluid 
composition may change based on patient need and Investigator discretion) should 
commence 2 to 4 hours before each infusion of AZD0466. At least 1 L of IV hydration 
should be administered over a 24-hour period. Additional IV hydration may be 
administered as clinically indicated in patients with diarrhoea and/or nausea and 
vomiting. Diuretics should be used with care and prophylactic use of diuretics should be 
used only if patients have signs of volume overload.
!
Allopurinol (or other xanthine oxidase inhibitor) should be administered to all patients 
receiving study treatment and it is recommended to initiate it one calendar day before the 
first dose of AZD0466. 100 to 300 mg every 8 hours is suggested, but allopurinol dose 
may require adjustment as described in the allopurinol prescribing information or 
institutional guidelines.
!
Rasburicase should be considered as an alternative to allopurinol for patients with 
elevated uric acid at baseline, or high tumour burden. Rasburicase should be administered 
4 hours prior to AZD0466 infusion, and as described in the rasburicase prescribing 
information. It is recommended that investigators check for 
Glucose-6-Phosphate-Dehydrogenase (G6PD) as Rasburicase is contraindicated in 
patients with G6PD deficiency.


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Table 32
Recommended Prophylaxis for Tumour Lysis Syndrome
Risk of tumour lysis syndrome
High
Intermediate
Low
Recommended prophylaxis
Hydration
Increased hydration: 
oral 1.5 to 2 L/day and 
IV 150 to 200 mL/h
Maintain urine output
IV hydration required during ramp-up (total IV and oral 
fluids > 2 L/day)
From Cycle 1 Day 15: oral hydration 1.5 to 2 L/day; 
consider IV hydration based on risk of TLS
Anti-
hyperuricaemics
Allopurinol 100 to 300 mg every 8 hours
Early consideration of rasburicasea as an alternative, based 
on baseline uric acid and tumour burden
Allopurinol 100 to 300 mg 
every 8 hours
Criteria for use of rasburicase
Serum uric acid 
at baseline
> 475.8 μmol/Lb + 1 risk 
factor
≤475.8 μmol/Lb + 2 risk 
factors
> 475.8 μmol/Lb + 2 risk 
factors
≤475.8 μmol/Lb + 3 risk 
factors
-
Risk factors
Serum creatinine > 1.3 mg/dL (> 88.4 μmol/L)
WBC > 50 ×109/L
LDH > 2x ULN
-
a
Rasburicase is contraindicated in patients with glucose-6 phosphate dehydrogenase deficiency, known 
hypersensitivity to rasburicase, haemolytic anaemia or methemoglobinemia
b
Uric acid cut-off may be adjusted according to local guidance.
Recommended prophylaxis adapted from University of Texas MD Anderson Cancer Center 2018, Cairo and 
Bishop 2004,Cairo and Bishop 2004
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. 
Br J Haematol 2004;127(1):3-11.
, and Howard et al 2011.
IV, intravenous; LDH, lactate dehydrogenase; ULN, upper limit of normal range; TLS, tumour lysis syndrome; 
WBC, white blood cell count.
F 1.2
AZD0466 Dose Modifications for TLS
AZD0466 dose modifications for TLS are summarised in Table 33.


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Table 33
AZD0466 Dose Modifications for TLS
Abnormality 
Action with AZD0466
Laboratory findings (serum)
Uric acid ≥ 475.8 μmol/L
•
Initiate supportive therapy as per standard clinical 
practice, additional guidance provided in Table 34.
•
Delay AZD0466 for up to 7 days (if finding present 
before administration of AZD0466)
•
If resolution to within specified threshold in ≤7 
days, restart AZD0466 at the same dose level
•
If resolution after 7 days, restart AZD0466 at one 
lower dose than the current dose.
Potassium ≥ 6.0 mmol/L
Phosphate ≥ 1.6 mmol/L (5.0 mg/dL) with 
≥0.16 mmol/L (0.5 mg/dL) increase*
Corrected calcium < 1.75 mmol/L
Creatinine increase by > 26.5 μmol/L from 
baseline (creatinine > 1.5 x ULN if no baseline)
All laboratory abnormalities must resolve to within specified threshold before AZD0466 is restarted, with the 
exception of an isolated phosphate abnormality, in which instance restarting the dose may be discussed with 
the Medical Monitor.
Clinical findings
Signs suggestive of clinical TLS (eg, acute 
kidney injury, cardiac arrhythmia/dysrhythmiaa, 
hypotensionb, heart failureb)
•
Initiate supportive therapy as per standard clinical 
practice
•
Delay AZD0466 for up to 14 days (if finding present 
before administration of AZD0466)
•
Restart AZD0466 at one lower dose than the current 
dose following resolution
Symptoms suggestive of clinical TLSa (eg, 
oliguriac, seizure, nausea, vomiting, muscle 
crampsb, neuromuscular instabilityb)
•
For clinical TLS, initiate supportive therapy and 
withhold AZD0466 until resolution of symptoms. 
AZD0466 can be withheld up to 14 days.
•
Restart AZD0466 at one lower dose than the current 
dose level 
•
Patients should be encouraged to maintain oral 
hydration 
a
Probably or definitely caused by hyperkalaemia or hypocalcaemia
b
Probably or definitely caused by hypocalcaemia
c
Average urine output of < 0.5 mL/kg/h, lasting for > 6 hours.
TLS, tumour lysis syndrome; ULN, upper limit of normal range.
*Recommended prophylaxis adapted from University of Texas MD Anderson Cancer Center 2018, Cairo and 
Bishop 2004, Coiffier et al 2008, and Howard et al 2011.
.
F 1.3
Treatment of TLS
Signs and symptoms of clinical TLS (including but not limited to acute kidney injury, oliguria, 
nausea, vomiting, seizure, muscle cramps, neuromuscular irritability, cardiac 
arrhythmia/dysrhythmia, hypotension, or heart failure) should be managed according to 
standard clinical practice. Additional IV hydration may be administered as clinically indicated 
in patients with diarrhoea and/or nausea and vomiting.
Recommendations for management of specific laboratory abnormalities is summarised in 
Table 34. 


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Table 34
Recommended Management of Electrolyte Abnormalities in TLS
Abnormality
Management recommendations
Hyperphosphataemia
Moderate (≥2.1 mmol/L)
Avoid IV and oral phosphate and limit dietary sources
Administer phosphate binder 
Severe
Dialysis or haemofiltration may be required
Hypocalcaemia (≤1.75 mmol/L)
Asymptomatic
No therapy
Patients with acute hypocalcaemia and hyperphosphataemia should not 
receive calcium repletion until phosphate level has normalised
Symptomatic
Calcium gluconatea 50 to 100 mg/kg by slow IV infusion with ECG 
monitoring
Calcium-phosphate product
≥ 50 mg2/dL2
Ensure hydration is maintained and alkalinisation is discontinued
Hyperkalaemia
Moderate (≥6.0 to < 7.0 mmol/L) 
and asymptomatic
Avoid IV and oral potassium
ECG monitoring
Administer sodium polystyrene sulfonate
Severe (≥7.0 mmol/L) or 
symptomatic 
As above, plus
Calcium gluconatea 100 to 200 mg/kg by slow IV infusion if concurrent 
ECG changes (including life-threatening arrhythmias)
Regular IV insulin and dextrose, monitor blood glucose closely
Consider sodium bicarbonatea if patient is acidaemic
Consider albuterol (to be avoided in patients with acute coronary 
disease)
Dialysis may be required
Renal dysfunction (uraemia)
Fluid and electrolyte management
Uric acid and phosphate management
Adjust doses of renally excreted medication
Dialysis or haemofiltration may be required
a
Sodium bicarbonate and calcium gluconate should not be administered through the same line.
Recommended management adapted from University of Texas MD Anderson Cancer Center 2018, and Coiffier 
et al 2008. ECG, electrocardiogram; IV, intravenous.
Laboratory parameters indicating TLS (including blood urea nitrogen, creatinine, 
phosphate/phosphorus, uric acid, calcium, potassium, and lactate dehydrogenase [LDH]) will 
be evaluated. Fluid balance must be monitored per institutional standards. If more aggressive 
hydration management is indicated, patient hospitalisation will be considered at Investigator 
discretion. Allopurinol prophylaxis should be considered based on institutional guidelines.
F 1.4
Reporting Adverse Events of TLS
The Investigator will report TLS as an adverse event or serious adverse event of "laboratory 


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TLS" or "clinical TLS" according to the classification of TLS in Appendix G 1. For the 
purposes of adverse event reporting, a CTCAE grade for TLS should also be recorded, as 
follows:
!
CTCAE Grade 3: TLS present
!
CTCAE Grade 4: TLS with life-threatening consequences; urgent intervention indicated
!
CTCAE Grade 5: Death
TLS will also be graded according to Cairo-Bishop criteria for the purposes of dose-limiting 
toxicity assessment and summary of adverse events of special interest (Appendix G 2; Cairo 
and Bishop 2004).
F 2
Guidance for Management of haematological 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 Medical 
Monitor. 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, according to institutional standards 
provided the patient has < 5% blasts in bone marrow and it is discussed with the Medical 
Monitor. The use of long-acting pegylated G-CSF (eg, pegfilgrastim) is not permitted during 
study treatment.
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marrow assessments.
F 2.3
Leucocyte Count
With the exception of hydroxyurea (AML) and high-dose steroids (ALL and leukaemia of 
ambiguous lineage) during screening and Cycle 1 up to 4 days (maximum dexamethasone IV 
40 mg/day or equivalent), no other direct anti-leukaemia therapy is permitted once study 
treatment has begun. Both medications are to be used for white blood cell count control and 
can be started or stopped any point during this period. 
F 2.4
Anaemia
Patients already receiving erythropoietin at screening may continue to receive it during study 
treatment, provided they have been receiving erythropoietin for > 1 month at the time study 
treatment 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 treatment.
Blood transfusions may be administered at the discretion of the Investigator.
F 3
Guidance for Management of Fungal Infection
In vitro data have shown that the principal CYP enzyme responsible for the Phase I 
metabolism of AZD0466 is CYP3A4. Azole antifungal agents including ketoconazole, 
itraconazole, voriconazole, posaconazole, and fluconazole are strong or moderate inhibitors of 
CYP3A4. As there is no data available at the time of initiation of this protocol on in vivo 
interactions between azole antifungal agents and AZD0466, use of this class of agents is 
prohibited during study treatment (with the exception of per protocol administration of 
voriconazole in Module 2).
Therapeutic: Non-azole antifungal agents (eg, caspofungin) should be given in the first 
instance. However, should an azole antifungal be necessary, it may be administered a 
minimum of 24 hours after the last dose of AZD0466 and AZD0466 should be discontinued. 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 Medical Monitor.
Prophylactic: Non-azole antifungal agents (eg, caspofungin) should be considered for 
patients at risk of prolonged neutropenia (> 10 days) to reduce the risk of fungal infections.


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The potential drug-drug interaction between AZD0466 and an azole antifungal agent will be 
investigated in Module 2 of this protocol. Guidance on concomitant use of azole antifungal 
agents will be updated by protocol amendment, if applicable based on emerging data. 
F 4
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 B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of 
pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008;
26(16):2767-78.
Howard et al 2011
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med 2011;364(19):1844-
54.
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.


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Appendix G
Classification of Tumour Lysis Syndrome
G 1
Classification
The criteria for classification of laboratory and clinical TLS in adults are described below. 
These criteria are based on the Howard et al 2011 modification of Cairo and Bishop 2004, and 
have been adapted from Cheson et al 2017.
Clinical TLS assumes the laboratory evidence of metabolic changes and an adverse event that 
requires clinical intervention. Clinical TLS is defined as the presence of laboratory TLS and 
any one or more of the clinical criteria, as specified in Table 35 below.
Table 35
Criteria for Laboratory and Clinical Tumour Lysis Syndrome
Abnormality
Criteria
Laboratory TLS
Two or more of the following metabolic abnormalities occurring during the same 24-hour period, and within 
3 days before until 7 days after infusion of study treatment:
Hyperuricaemia 
Uric acid ≥ 475.8 μmol/L (≥ 8.0 mg/dL)
Hyperkalaemia
Potassium ≥ 6.0 mmol/L
Hyperphosphataemia
Phosphate ≥ 1.5 mmol/L (≥ 4.5 mg/dL)
Hypocalcaemia
Corrected calcium < 1.75 mmol/L (< 7.0 mg/dL), or 
Ionised calcium < 0.3 mmol/L 
Clinical TLS
Laboratory TLS plus one or more of the following:
Acute kidney injury
Serum creatinine increase by > 26.5 μmol/L (or a single value 
> 1.5 × ULN if no baseline measurement), or oliguria (average urine 
output of < 0.5 mL/kg/h) lasting for > 6 hours
Cardiac arrhythmia/dysrhythmia 
or sudden death
Probably or deﬁnitely caused by hyperkalaemia or hypocalcaemia
Seizure
Probably or deﬁnitely caused by hypocalcaemia
Neuromuscular irritability, 
hypotension, or heart failure
Probably or deﬁnitely caused by hypocalcaemia
TLS, tumour lysis syndrome; ULN, upper limit of normal.
G 2
Grading
TLS should be graded according to the Cairo-Bishop criteria for the purposes of dose-limiting 
toxicity assessment (Cairo and Bishop 2004). The grade of the maximal clinical manifestation 
defines the overall grade of TLS, as summarised below in Table 36.


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Table 36
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 creatininea
< 1.5 x ULN
1.5 x ULN
> 1.5 – 3.0 x 
ULN
> 3.0 – 6.0 x ULN
> 6.0 x ULN
Deathb
Cardiac 
arrhythmiaa
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)
Deathb
Seizurea
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)
Deathb
a
Not directly or probably attributable to a concomitant therapeutic agent.
b
Probably or definitely attributable to clinical TLS.
Modified from Cairo and Bishop 2004. 
ADL, activities of daily living; CHF, congestive heart failure; TLS, tumour lysis syndrome; ULN, upper limit of 
normal.
G 3
References
Cairo and Bishop 2004
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. 
Br J Haematol 2004;127(1):3-11
Cheson et al 2017
Cheson BD, Enschede SH, Cerri E, Desai M, Potluri J, Lamanna N et al. Tumor lysis 
syndrome in chronic lymphocytic leukemia with novel targeted agents. Oncologist. 
2017;22(11):1283-91.
Howard et al 2011
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med 2011;364(19):1844-
54.


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Appendix H
Drugs That Prolong QT Interval and/or Induce Torsades De 
Pointes
Drugs with known or possible risk of TdP (cardiac arrhythmia due to drug-induced QTc 
prolongation) are withheld for 5 half-lives prior to the first dose of study treatment and will 
continue to be withheld during the study, and for 14 days after the last dose of AZD0466. 
Table 37
Drugs with a known risk of Torsades de Pointes
Contraindicated drug
Withdrawal period prior to the start of study 
treatment
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 weeksb
Arsenic trioxidea, ibogaine
3 weeksb
Pentamidine
3 weeksb
Astemizole, probucol, vandetanib
3 weeksb
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 Medical Monitor regarding the risk/benefit ratio.
CredibleMeds® (www.crediblemeds.org) is the standard reference for drugs with known or 
possible risk of TdP. 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.


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Some of the medications listed as a possible risk of TdP may be allowed at the Investigator’s 
discretion after approval by the Medical Monitor when the patient has unmet medical need to 
continue receiving prohibited medication(s), no suitable alternative treatments are available, 
and the benefit-risk ratio is acceptable in the Investigator’s opinion. 


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Appendix I
Contraception Guidance
I 1
Definitions
!
A female of childbearing potential is defined as a female who is not permanently 
surgically sterilised or postmenopausal.
!
Surgical sterilisation includes hysterectomy and/or bilateral oophorectomy and/or 
bilateral salpingectomy but excludes bilateral tubal occlusion (the term occlusion refers to 
both occluding and ligating techniques that do not physically remove the oviducts).
!
Postmenopausal is defined as amenorrhoeic for 12 months without an alternative medical 
cause. The following age-specific requirements apply:
∀
Women under 50 years of age would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments AND with luteinising hormone and follicle-stimulating hormone levels in 
the postmenopausal range
∀
Women over 50 years of age would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments
!
A highly effective method of contraception is defined as a method that results in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly.
I 2
Contraception Methods
Highly effective methods of contraception are described in Table 38. 


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Table 38
Highly Effective Methods of Contraception
Barrier/Intrauterine Methods
Hormonal Methods
•
Intrauterine device
•
Intrauterine hormone-releasing system (IUS)
•
Bilateral tubal occlusion
•
Vasectomised partner a
•
Sexual abstinence b
Combined (oestrogen and progestogen containing c
hormonal contraception)
%
Oral (combined pill)
%
Injectable
%
Transdermal (patch)
Progestogen-only hormonal contraception associated 
with inhibition of ovulation d
%
Injectable
%
Implantable
a
With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate).
b
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the subject. 
However, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.
c
Hormonal contraception may be susceptible to interaction with study or other drugs, which may reduce the 
efficacy of the contraception method. Women using hormonal contraceptives must add a barrier method.
d
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action 
(eg, minipill), is not accepted as a highly effective method.






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Appendix K
Response Assessment for Acute Lymphoblastic Leukaemia
Disease Status Criteria for acute lymphoblastic leukaemia (ALL):
At least 20% lymphoblasts present in blood or marrow at baseline. Immunophenotyping must 
be performed to determine lineage (B-cell, T-cell, or mixed B/T-cell).
Extramedullary Disease in ALL:
1
Measurable Extramedullary Disease: Lesions that can be accurately measured in 2 
dimensions by CT or MRI.
2
Non-measurable Extramedullary Disease: All other lesions including unidimensional 
lesions, lesions too small to be considered measurable, pleural or pericardial effusion, 
ascites, bone disease, leptomeningeal disease, lymphangitis, pulmonitis, abdominal 
masses not confirmed or followed by imaging techniques or disease documented by 
indirect evidence only (eg, lab values).
For patients with extramedullary disease, baseline disease assessments will be performed 
using radiologic imaging by CT with contrast covering neck, chest, abdomen, and pelvis 
within 30 days before the first dose of study treatment. Radiologic scans (ie, contrast CT) will 
be repeated approximately every 12 weeks ±7 days. Up to 6 measurable extramedullary 
disease lesions (only target lesions >1.0 cm in the longest diameter may be assessed), clearly 
measurable in 2 perpendicular dimensions, will be followed as target lesions for each patient. 
Measurable sites of disease should be chosen such that they are representative of the patient’s 
disease. In addition, selection of target lesions should be from as disparate regions of the body 
as possible when these areas are significantly involved. If additional non-measurable 
extramedullary disease lesions are present, they can be added as non-target lesions and 
followed throughout the study. For patients with baseline hepatosplenomegaly, the cranial-
caudal measurement of the spleen and longest diameter of the liver will be assessed at 
screening and all subsequent response evaluations. MRI 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. 
Patients without extramedullary disease will be assessed for response every 4 weeks (±7 days)
Response Assessment (Advani et al 2022
Advani AS, Moseley A, O’Dwyer KM, Wood BL, Fang M, Wieduwilt MJ, et al. SWOG 
1318: A Phase II Trial of Blinatumomab Followed by POMP Maintenance in Older Patients 
With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic 
Leukemia. J Clin Oncol 2022; 40(14):1574-82
SWOG 2020; Advani et al 2022):
C1 extramedullary disease status: Complete disappearance of all measurable and non-


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measurable extramedullary disease with the exception of lesions for which the following must 
be true: for patients with ≥1 measurable lesion, all nodal masses > 1.5 cm in greatest 
transverse diameter (GTD) at baseline must have regressed to ≤1.5 cm in GTD and all nodal 
masses ≥1 cm and ≤1.5 cm in GTD at baseline must have regressed to < 1 cm GTD or they 
must have reduced by 75% in sum of products of greatest diameters (SPD). No new lesions. 
Spleen and other previously enlarged organs must have regressed in size and must not be 
palpable. All disease must be assessed using the same technique as at baseline.
C2 extramedullary disease status: Patient does not qualify for C1 status.
Complete Remission (CR)
1
< 5% marrow aspirate blasts. Blasts can be ≥ 5% if the blasts are found to be myeloid and 
there is no evidence of lymphoblasts by flow cytometry or immunostaining.
2
ANC ≥ 1,000 cells/mm3; platelets > 100,000 cells/mm3; and no blasts in the peripheral 
blood.
3
C1 extramedullary disease status as described above.
Complete Remission with Incomplete Recovery (CRi)
Same as CR but platelet count may be ≤ 100,000 cells/mm3 and/or ANC ≤ 1,000 cells/mm3
Partial Remission (PR)
Improvement or no worsening of ALL, as indicated by all of the following:
1
No blasts in the peripheral blood
2
ANC ≥ 1,000 cells/mm3; platelets > 100,000 cells/mm3
3
Either or both of the following:
∀
At least a 50% decrease in the marrow blast percentage, compared to the 
pretreatment value, and marrow blast percentage ≥5% and ≤25%.
∀
C2 extramedullary disease status as described above.
FAILURE - Resistant Disease (RD) 
Resistant Disease: Patient survives ≥ 7 days following completion of initial treatment course 
with persistent leukaemia in the last peripheral blood smear or bone marrow, or with persistent 
extramedullary disease. 
FAILURE - Aplasia 
Aplasia: Patient survives ≥ 7 days following completion of initial treatment course then dies 
while cytopenic, with the last post induction bone marrow aplastic or hypoplastic (ie, < 20% 
cellularity) and without leukaemia blasts.


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FAILURE - Indeterminate 
Indeterminate: 
(a) Patient survives < 7 days after completion of initial treatment course; or 
(b) patient survives ≥ 7 days following completion of initial treatment course then dies with no 
persistent leukaemia in the peripheral smear but no post-induction bone marrow examination.
RELAPSE FROM CR or CRi
Relapse: Reappearance of leukaemia blasts in the peripheral blood; or > 5% blasts in the bone 
marrow not attributable to another cause (eg, recovery of normal cells following 
chemotherapy-induced aplasia); or appearance or reappearance of extramedullary disease.
K 1
References
Advani et al 2022
Advani AS, Moseley A, O’Dwyer KM, Wood BL, Fang M, Wieduwilt MJ, et al. SWOG 
1318: A Phase II Trial of Blinatumomab Followed by POMP Maintenance in Older Patients 
With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic 
Leukemia. J Clin Oncol 2022; 40(14):1574-82
SWOG 2020
SWOG Data Operations Center. Oncology Research Professional (ORP) Manual. Version 6.0 
October 2020. 
https://crawb.crab.org/txwb/CRA_MANUAL/Vol1/chapter%2011a_Response%20Assessment
-Leukemia.pdf (Accessed 8 Dec 2020).


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Appendix L
Eastern Cooperative Oncology Group Performance Status 
Scoring
Eastern Cooperative Oncology Group (ECOG) performance status is scored as follows:
0 = 
Fully active, able to carry out all pre-disease activities without restrictions
1 = 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (eg, light housework, office work)
2 = 
Ambulatory and capable of self-care, but unable to carry out any work activities. Up 
and about more than 50% of waking hours
3 = 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4 = 
Completely disabled, cannot carry on self-care, totally confined to bed or chair


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Appendix M Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with COVID-19 or similar pandemic infection) during which 
patients may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
M 1
Re-screening of Participants to Reconfirm Study Eligibility
Up to 2 additional re-screenings per patient can be performed for screen failures due to study 
disruption in previously screened patients. The Investigator should confirm this with the 
designated Medical Monitor.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with study treatment. 
If this delay is outside the screening window specified in the individual module SoA, the 
patient will need to be re-screened to reconfirm eligibility before commencing study 
procedures. This will provide another opportunity to re-screen a patient in addition to that 
detailed in Section 5. The procedures detailed in Section 5 must be undertaken to confirm 
eligibility using the same patient number for the same patient.


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Appendix N
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, dyspnoea 
(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, dyspnoea 
(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 dyspnoea.
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.
Reference: https://www.heart.org/en/health-topics/heart-failure/what-is-heart-failure/classes-of-heart-failure 
Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria 
Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, 
MA: Lippincott Williams and Wilkins; March 1, 1994.


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Appendix O
Prognostic Scoring for Myelodysplastic Syndrome
O 1
Prognostic Scoring System for MDS: The International Prognostic 
Scoring System – Revised (IPSS-R)
IPSS-R prognostic score values
Prognostic variable
0
0.5
1.0
1.5
2.0
3.0
4.0
% Bone Marrow blasts
≤2
-
> 2–< 5
-
5–10
> 10
-
Cytogenetics
Very good
-
Good
-
Intermediate
Poor
Very Poor
Hemoglobin (g/dL)
≥10
-
8–< 10
< 8
-
-
-
Platelets (×109/L)
≥100
50–
< 100
< 50
-
-
-
-
Neutrophils (×109/L)
≥0.8
< 0.8
-
-
-
-
-
IPSS-R prognostic risk categories
IPSS-R risk score
Very low
≤1.5
Low
> 1.5–3
Intermediate
> 3– 4.5
High
> 4.5–6
Very high
> 6
O 2
MDS Cytogenetic Scoring System
MDS cytogenetic prognostic 
subgroups
Cytogenetic abnormalities
Very good 
−Y, del(11q)
Good 
Normal, del(5q), del(12p), del(20q), double including del(5q)
Intermediate 
del(7q), +8, +19, i(17q), any other single or double independent clones
Poor 
−7, inv(3)/t(3q)/del(3q), double including −7/del(7q), complex: 3 
abnormalities
Very poor 
Complex: > 3 abnormalities
O 3
References
Greenberg et al 2012
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised 
international prognostic scoring system for myelodysplastic syndromes. Blood 
2012;120(12):2454-65.


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Appendix P
Response Criteria for Myelodysplastic Syndrome
P 1
Response Criteria (IWG 2006)
Category 
(IWG2006)
Response Criteria (response must last at least 4 weeks)
Complete remission
Bone marrow: 
•
≤ 5% myeloblasts with normal maturation of all cell lines a
Persistent dysplasia will be noteda,b
Peripheral blood c:
•
Hgb ≥ 11 g/dL
•
Platelets ≥ 100 × 109/L
•
Neutrophils ≥ 1.0 × 109/Lb
•
Blasts 0%
Partial remission
All CR criteria if abnormal before treatment except:
•
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5%
Cellularity and morphology not relevant
Marrow CR b
Bone marrow CR: 
•
≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment b
Peripheral blood: 
•
if HI responses, they will be noted in addition to marrow CR b
Stable disease
Failure to achieve at least PR, but no evidence of progression for > 8 weeks
Failure
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in percentage of bone marrow blasts, or progression to a more 
advanced MDS FAB subtype than pretreatment
Relapse after CR or 
PR
At least 1 of the following:
•
Return to pretreatment bone marrow blast percentage
•
Decrement of ≥50% from maximum remission/response levels in 
granulocytes or platelets
•
Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence
Cytogenetic response
Complete cytogenetic response:
•
Disappearance of the chromosomal abnormality without appearance of new 
ones
Partial cytogenetic response:
•
At least 50% reduction of the chromosomal abnormality
Disease progression
For patients with:
•
Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts
•
5%-10% blasts: ≥ 50% increase to > 10% blasts
•
10%-20% blasts: ≥ 50% increase to > 20% blasts
•
20%-30% blasts: ≥ 50% increase to > 30% blasts
Any of the following:
•
At least 50% decrement from maximum remission/response in granulocytes or 
platelets


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Category 
(IWG2006)
Response Criteria (response must last at least 4 weeks)
•
Reduction in Hgb by ≥ 2 g/dL
•
Transfusion dependence
a
Dysplastic changes should consider the normal range of dysplastic changes (modification).
b
Modification to IWG response criteria.
c
In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, 
maintenance) before the 4-week period. Such patients can be included in the response category into which 
they fit at the time the therapy is started. Transient cytopenias during repeated chemotherapy courses should 
not be considered as interrupting durability of response, as long as they recover to the improved counts of 
the previous course.
AML, acute myeloid leukaemia; CR, complete remission; DFS, disease-free survival; FAB, French-American-
British; Hgb, haemoglobin; HI, haematologic improvement; MDS, myelodysplastic syndromes; PR, partial 
remission; PFS, progression-free survival.
P 2
Haematological Improvement (IWG 2018)
Response evaluation criteria: Haematological Improvement - Erythrocytes, Platelets, 
and Neutrophils
Haematological
improvement 
(IWG 2018)
Response criteria (response must last at least 8 weeks)
Baseline criteria
Definition of transfusion-
burden categories
3 groups:
•
NTD (0 RBCs in 16 weeks)a
•
LTB (3-7 RBCs in 16 weeks in at least 2 transfusion episodes, maximum 3 
in 8 weeks) a
•
HTB (≥8 RBCs in 16 weeks, ≥4 in 8 weeks)
Pretreatment RBC 
transfusion policy
Transfusion policy for the individual patient prior to therapy should be maintained 
on treatmentb
Response evaluation criteria: HI-E
NTD (0 RBCs in 
16 weeks) a
At least 2 consecutive Hb measurements ≥1.5 g/dL for a period of minimum 8 
weeks in an observation period of 16 to 24 weeks compared with the lowest mean 
of 2 Hb measurements (apart from any transfusion) within 16 weeks before 
treatment onsetc; only a response duration of at least 16 weeks, however, is 
considered clinically meaningful
LTB (3-7 RBCs in 
16 weeks in at least 
2 transfusion episodes, 
maximum 3 in 8 wk) a
HI-E in LTB patients corresponds to transfusion independence, defined by the 
absence of any transfusions for at least 8 weeks in an observation period of 16-24 
weeks with the same transfusion policy (defined below) compared with 16 weeks 
prior to treatment; only a response duration of at least 16 weeks, however, is 
considered clinically meaningful
HTB (≥8 RBCs in 
16 weeks, ≥4 in 
8 weeks)
Major response: 
Major HI-E response in HTB patients corresponds to transfusion independence, 
defined by the absence of any transfusions over a period of minimum 8 weeks in 
an observation period of 16-24 weeks with the same transfusion policy (defined 


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Haematological
improvement 
(IWG 2018)
Response criteria (response must last at least 8 weeks)
below) compared with 16 weeks prior to treatment; only a response duration of at 
least 16 weeks, however, is considered clinically meaningful
Minor response: 
Minor HI-E response in HTB patients is defined as a reduction by at least 50% of 
RBCs over a minimum of 16 weeks with the same transfusion policy (defined 
below) compared with 16 weeks prior to treatment
On-treatment RBC 
transfusion policyd
Transfusion policy for the individual patient prior to therapy should be maintained 
on treatment if not otherwise clinically indicated (documentation by the treating 
physician required); we suggest a maximum variation between pre- and on-study 
practice of 1 g/dL (or 0.6 mmol/L) in terms of transfusion threshold
Dose adjustment 
thresholds for high Hb 
levels
If the drug under investigation is stopped or its dose reduced in a responding 
patient for protocol-defined reasons leading to a loss of response, this should not 
be counted as such if reintroduction at the same or lower dose of the drug induces 
a new response; if reintroduction of the drug at a lower dose does not reinduce a 
response, this should be documented as such
Response evaluation criteria: HI-P
Platelet response 
(pretreatment, 
< 100 x 109/L
!
Absolute increase of 30 x 109/L for patients starting with > 20 x 109/L PLTs
or
!
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100%
In addition,
!
Evolution of bleeding symptoms is to be taken into account
!
Increments of platelets also for patients with a pretreatment PLT count of 
> 100 x 109/L are to be reported
Dose-adjustment policy 
for PLT counts on 
treatment
!
If the drug under investigation is being stopped or its dose is being reduced in 
a responding patient for protocol-defined reasons leading to a loss of 
response, this should not be counted as such, if reintroduction at the same or 
lower dose of the drug induces a new response
!
When the investigational drug is stopped or reduced in dose, weekly blood 
counts are required to monitor the PLT levels
!
2 subsequent PLT counts > 450 x 109/L are a sufficient reason for treatment 
discontinuation in the case of treatment with TPO agonists
Response evaluation criteria: HI-N
Neutrophil response 
(pretreatment, all 
patients)
At least 100% increase and an absolute increase > 0.5 x 109/L (pretreatment, 
< 1.0 x 109/L)
Increments of neutrophils also for patients with a pretreatment ANC > 1.0 x 109/L 
are to be reported
a
HI-E achievement requires not only transfusion independence but also an increase of Hb by at least 
1.5 g/dL (= 0.9 mmol/L).


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b
As in IWG 2006 criteria, only RBC transfusions administered for an Hb level below 9 g/dL are taken into 
account. Exceptions to this rule may be accepted in cases of well-documented moderate or severe angina 
pectoris, cardiac or pulmonary insufficiency, or ischemic neurologic diseases. In these cases, a higher 
transfusion trigger level may be established for an individual patient. These patients may require special 
attention when analysing responses within clinical trials. Transfusions for intercurrent diseases (bleeding, 
surgical procedure, etc) are not considered.
c
Oscillations (eg, natural or due to drug intervals) within this period are accepted as long as the patient 
remains off any transfusions and the same transfusion policy has been maintained. We suggest accepting 
1 drop to an increase of between 1.0 and 1.5 g/dL over a period of 8 wk. We recommend that intervals 
between blood counts do not exceed 2 wk.
d
Exceptions to this rule may be accepted in cases of well-documented moderate or severe angina pectoris, 
cardiac or pulmonary insufficiency, or ischemic neurologic diseases. In these cases, a higher transfusion 
trigger level may be established for an individual patient. These patients may require special attention when 
analysing responses within clinical trials. Transfusions for intercurrent diseases (bleeding, surgical 
procedure, etc) should not be taken into account.
ANC, absolute neutrophil count; Hb, haemoglobin; HI-E, haematological improvement-erythroid; HI-N, 
haematological improvement-neutrophils; HI-P, haematological improvement-platelets; HTB, high transfusion 
burden; IWG, International Working Group; LTB, low transfusion burden; NTB, not transfusion dependent; 
PLT, platelet; RBC, red blood cell; TPO, thrombopoietin.
P 3
References
Cheson et al 2006
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. 
Clinical application and proposal for modification of the International Working Group (IWG) 
response criteria in myelodysplasia. Blood 2006;108(2):419-25.
Platzbecker et al 2018
Platzbecker U, Fenaux P, Ades L, Giagounidis A, Santini V, van de Loosdrecht AA, et al. 
Proposals for revised IWG 2018 hematological response criteria in patients with MDS 
included in clinical trials. Blood 2019;133(10):1020-30.


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Appendix Q
Abbreviations
Abbreviation or 
special term
Explanation
ACTH
adrenocorticotropic hormone 
AE
adverse event
AESI
adverse event of special interest
ALL
Acute Lymphoblastic Leukaemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase/transaminase
AML
Acute Myeloid Leukaemia
ANC
absolute neutrophil count
AST
aspartate aminotransferase/transaminase
Bcl-2
B-cell lymphoma 2
Bcl-xL
B-cell lymphoma-extra large
BCRP
breast cancer resistance protein
BMMC
bone marrow mononuclear cells
BNP
brain natriuretic peptide
BP
blood pressure
CAR-T
chimeric antigen receptor T cell therapy
CBC
complete blood count
cfDNA
circulating free DNA
CLL
chronic lymphocytic leukaemia
Cmax
maximum concentration
CMML
chronic myelomonocytic leukaemia
CMV
Cytomegalovirus
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease 2019
CR
complete remission
CRc
cytogenetic CR
CrCl
creatinine clearance
CRi
complete remission with incomplete platelet recovery
CRm
molecular CR
CRMRD-NEG
CR with minimal/measurable residual disease negativity
CRMRD-POS
CR with minimal/measurable residual disease positivity
CSP
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Abbreviation or 
special term
Explanation
CSR
Clinical Study Report
CT
computerised tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumour DNA
CTEP
Cancer Therapy Evaluation Program 
CYP
cytochrome P450
DCO
data cut-off
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid 
DoR
duration of response
DUS 
disease under study
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EoT
end of treatment
G6PD
Glucose-6-Phosphate-Dehydrogenase
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GM-CSF
granulocyte-macrophage colony-stimulating factor 
GVHD
graft versus host disease
HIV
human immunodeficiency virus
HL
Hy’s Law
IA
interim analysis
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational medicinal product


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Abbreviation or 
special term
Explanation
INR
international normalisation ratio
IPSS-R
Revised International Prognostic Scoring System
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
intent-to-treat
IV
intravenous(ly)
LDH
lactate dehydrogenase
LFT
liver function test
LVEF
left ventricular ejection fraction
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MFDS
Ministry of Food and Drug Safety
MLFS
morphologic leukaemia free state
MPN
myeloproliferative neoplasm
MRD
minimal/measurable residual disease
MRI
magnetic resonance image
MTD
maximum tolerated dose
mTPI-2
modified toxicity probability interval
MUGA
multigated acquisition
NCI
National Cancer Institute
NTproBNP
n-terminal pro b-type natriuretic peptide
NYHA
New York Heart Association
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
Pharmacodynamic
PEG
polyethylene glycol
PET
positron emission tomography
PHL
Potential Hy’s Law
PI
Principal Investigator 
PK
pharmacokinetic(s)
PR
partial remission
PT
prothrombin time
PTT
partial thromboplastin time
Q2W
every 14 days


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Abbreviation or 
special term
Explanation
RANKL
receptor activator of nuclear factor kappa-B ligand
RD
resistant disease
RNA
ribonucleic acid
RP2D
recommended Phase II dose
SAE
serious adverse event 
SAP
statistical analysis plan
SoA
Schedule of Activities
SoC
standard of care
SRC
Safety Review Committee
TBL
total bilirubin
TD
target dose
TdP
Torsades de Pointes
TLS
Tumour lysis syndrome
TSH
thyroid-stimulating hormone
TTR
time to response
ULN
upper limit of normal
WHO
World Health Organization


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Appendix R
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the TOC.
Amendment 2 [29 March 2022]
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the council of the European Union.
Overall Rationale for the Amendment:
The global protocol was amended to address comments received from various health 
authorities, ethics committees, and clarification requested from study sites. A summary of 
changes and the rationale for each change are tabulated below.
Section # and 
Name
Description of Changes
Brief Rationale
Substantial/ 
Non-substantial
2.1.1 Apoptosis and 
Cancer, 2.3 Study 
Rationale
Added background for 
high-risk MDS
To provide context for the inclusion 
of high-risk MDS patients in this 
study.
Substantial
4.5 Criteria for 
Stopping or Pausing 
Study Recruitment
Added a new section to 
describe the criteria for 
stopping or pausing study 
recruitment.
In response to HA/EC request to 
provide criteria for study-wide 
stopping or pausing study 
recruitment. 
Substantial
5.1 Core Inclusion 
Criteria (#3, #6)
Included high-risk MDS, in 
Part A only (Criterion 3).
Added Criterion 6 to specify 
that eligible high-risk MDS 
patients must have no 
available therapies to provide 
clinical benefit.
Patients with high-risk MDS are on a 
clinical continuum with AML with 
equally very poor prognosis and may 
also receive benefit from AZD0466. 
Substantial
5.1 Core Inclusion 
Criteria (#5)
Criterion updated to clarify 
“for AML and ALL 
patients”.
To clarify that inclusion criterion 
applies to AML and ALL patients; 
whereas for high-risk MDS patients, 
separate criteria and included in 
inclusion criterion 6.
Substantial
5.1 Core Inclusion 
Criteria (#9);
5.2 Core Exclusion 
Criteria (#4c, #14);
6.5.1 Permitted 
Concomitant 
Medications and 
Treatments;
Clarified hydroxyurea usage 
and patient population it 
should be used in and added 
high-dose steroid usage for 
white blood cell count 
control in patients with ALL 
and leukemia of ambiguous 
lineage. Also, specified the 
maximum dose and duration 
White blood cell count can fluctuate 
until the disease is under control. 
Therefore, treatment may be required 
during screening until the start of 
Cycle 2 to mitigate TLS risk. AML 
patients can be given hydroxyurea; 
however, this is insufficient in ALL 
patients, for whom steroids are 
standardly used for control of high 
Substantial


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Section # and 
Name
Description of Changes
Brief Rationale
Substantial/ 
Non-substantial
F2.3 Leukocyte 
Count
of high-dose steroids 
allowed.
white blood cell counts. In addition, 
strict count-based rules for stopping 
hydroxyurea therapy result in 
implementation challenges due to 
expected fluctuations of the white 
blood cell counts. 
5.2 Core Exclusion 
Criteria (#9) and 
11.6.2.9.1 COVID-
19 testing
Exclusion Criterion 9 was 
expanded to include details 
on study population inclusion 
based on COVID-19 history. 
Expanded to allow inclusion of 
patients that have had a past infection
but are still testing positive on 
sensitive PCR tests, which can 
remain positive for a long period of 
time despite not having an active 
infection. These patients must have a 
negative antigen test and presence of 
IgG antibodies.
Substantial
5.2 Core Exclusion 
(#20, #21)
Exclusion Criteria 20 and 21 
were added to expand on 
populations excluded from 
participation.
Added in response to an EC request.
Substantial
5.2 Core Exclusion 
(#14);
6.5.2 Prohibited 
Concomitant 
Medications and 
Treatments
Revised text to state a 
maximum of 14 days 
washout periods for 
reversible CYP3A inhibitors 
and moderate or strong 
mechanism-based inhibitors 
or inducers of CYP3A4.
A duration of 14 days is considered 
an adequate washout period to 
account for any clinically relevant 
contribution from prescription or 
non-prescription small molecule 
drugs (including CYP3A 
inhibitors/inducers) to overall risk-
benefit of AZD0466. Drug with half-
life longer than 14 days (eg, 
isavuconazole) exhibit a biphasic 
plasma concentration-time profile, 
which results in significantly reduced 
systemic concentrations by Day 14 
(post-dose) and therefore have a 
minimal impact on the risk-benefit of 
AZD0466.
Substantial
5.3 Lifestyle 
Considerations
Removed reference to “2” 
highly effective 
contraception.
As highly effective methods have 
less than 1% failure rate, it is not 
required to stipulate the number 
required.
Substantial
Added text to indicate that 
male patients should use a 
condom with all sexual 
partners to avoid potential 
To prevent exposure to a developing 
embryo.


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Section # and 
Name
Description of Changes
Brief Rationale
Substantial/ 
Non-substantial
exposure to drug from the 
semen.
6.6 Dose 
Modification and 
Toxicity 
Management
Added text and table for dose 
reduction (Table 4)
For clarification of dose reductions 
(see below).
Substantial
Added text to indicate that 
patients diagnosed with 
COVID-19 while on study 
may continue if getting 
clinical benefit in the opinion 
of the investigator but must 
pause treatment if they meet 
pause or discontinuation 
criteria for dose 
modifications based on 
haematological parameters 
(Section 6.6.1, neutropenia), 
or CTCAE grade 2 or higher 
non-haematologic toxicities 
(Section 6.6.3), which would 
include pneumonia or other 
infectious complications.
COVID-19 language added in 
response to an EC request. If a 
patient is diagnosed with COVID-19 
during treatment, but is deriving 
clinical benefit from the study 
treatment in the opinion of the 
Investigator, the patient may 
continue on study based on guidance 
provided in toxicity management 
therefore preventing patients 
discontinuing a potentially beneficial 
treatment.


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Section # and 
Name
Description of Changes
Brief Rationale
Substantial/ 
Non-substantial
6.6.1 Dose 
Modifications Based 
on Haematological 
Parameters;
6.6.2 Retreatment 
Criteria (Table 7);
6.6.3 Dose 
Modifications for 
Non-haematological 
Toxicities (Table 8);
6.6.4 Dose 
Modifications for 
Hepatotoxicity 
(Table 9);
F1.2 AZD0466 
Dose Modifications 
for TLS (Table 33)
Replaced % reductions by 
reductions based on previous 
dose levels and added dose 
modification guidelines 
during ramp up.
Alignment of dose modification 
guidelines with doses used in 
previous dose settings by replacing 
% reductions by reductions to lower 
doses; ie, '50% reduction' was 
replaced by ‘one lower dose’ and 
'75% reduction' was replaced by 'two 
lower doses'. This enables the patient 
to continue on a dose that has been 
considered safe in all cohorts. Avoids 
the use of intermediate doses that 
complicate dose findings.
Substantial
6.6.5 Cardiac 
Findings
Cardiac findings were 
clarified to specify that 
patients should not be 
discharged and continuously 
monitoring should be 
provided until patient is seen 
by a cardiologist for safety 
assessment.
In response to HA request for close 
and appropriate ECG monitoring 
(continuously) in hospital until a 
cardiologist’s opinion is issued for 
patients who discontinue treatment 
due to QT interval 
> 500 milliseconds.
Substantial
8.3.9 New Cancers
Changes made to regard as 
SAEs rather than AEs, and 
seriousness criteria clarified.
For clarification.
Substantial
8.7 Optional 
Genomics Initiative 
Sample
 
 
 
 
Non-substantial
CCI
CCI


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Section # and 
Name
Description of Changes
Brief Rationale
Substantial/ 
Non-substantial
11.1.3.3 Dose 
Escalation, 
De-escalation, and 
Stopping Decision 
Rules
Removed the 3-day interval 
between dosing patient 1 at 
target dose (11 days from 
Day 1) and dosing 
subsequent patients in a 
cohort
Due to the rapidly progressive nature 
of relapsed/refractory acute 
leukemias, starting treatment as soon 
as possible after relapse is confirmed 
is highly important, as even small 
delays can lead to uncontrolled 
disease. A 3-day delay from target 
dose in patient 1 to enrollment of 
subsequent patients was incorporated 
as a conservative approach to address 
the unknown initial safety profile of 
the drug. In this study one key 
implication is that due to the dosing 
ramp-up during the first week, the 
delay between patient 1 and 
subsequent patients in a cohort is 
actually a total of 11 days (or more 
should the first patient not proceed 
with treatment as scheduled). While 
offering an incremental gain in safety 
data prior to dosing subsequent 
patients in the cohort, this delay puts 
subsequent patients at significant 
disadvantage should their disease 
progress.
Substantial
 
 
 
 
 
11.3 Study 
Population –
Module 1
Emphasized Core Inclusion 
Criterion 4.
In response to an HA request for 
clarity that patients must have 
exhausted standard of care prior to 
entering the study. No change was 
made to the inclusion criteria, but 
this item was highlighted wherever 
relevant in the protocol, to ensure it 
would not be missed.
Non-substantial
11.4.7.2 Dose 
Limiting Toxicity
Clarification to add 
COVID-19 as a documented 
infection due to active 
underlying disease will not 
be classified as a DLT.
To clarify that COVID-19 would be 
included as an infection.
Non-substantial
11.4.7.5 Maximum 
Feasible Dose
Added section defining 
maximum feasible dose. 
For clarification of the Chemistry 
Manufacturing and Controls (CMC) 
quality specifications, which is 
Non-substantial
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Section # and 
Name
Description of Changes
Brief Rationale
Substantial/ 
Non-substantial
currently set against a maximum 
weekly dose of 3600 mg.
11.5.1 Schedule of 
Activities (Table 25)
 
 
 
Non-substantial
11.5.1 Schedule of 
Activities (Table 
17);
11.6.2.9.8 Cardiac 
Troponin and BNP 
(or NTproBNP);
12.5.1 Schedule of 
Activities (Table 
25);
12.6.2.9.8 Cardiac 
Troponin and BNP 
(or NTproBNP)
Removed the Cycle 1 Day 8 
assessment of cardiac 
troponin I. Revised 
text/footnote to indicate that 
troponin I is preferred but 
troponin T is acceptable if 
troponin I is not available at 
the site.
The Sponsor’s cardiology experts 
have confirmed that both troponin I 
and troponin T are acceptable to 
assess acute cardiac abnormalities. 
Therefore, language changed to 
clarify that troponin I highly 
preferred, however troponin T 
acceptable if sites do not have access 
to troponin I testing. However, at any 
abnormal troponin result, further 
investigations required. Troponin to 
be evaluated at screening (to obtain a 
baseline value) and as clinically 
indicated thereafter.
Substantial
11.5.1 Schedule of 
Activities (Table 
15);
11.6.2.6 
Electrocardiograms;
12.6.2.6 
Electrocardiograms
Replaced single safety ECG 
option at Holter visits with 
triplicate ECGs requirement 
at all ECG-required visits. In 
addition, revised footnote 
(Table 15) to indicate that on 
PK sampling visits, triplicate 
ECGs will be collected prior 
to PK sampling. 
Holter recordings will not show 
instant ECG values, which are 
required prior to infusion. Triplicate 
ECG is more appropriate to identify 
any abnormal values prior to infusion 
decision.
Non-substantial
11.5.1 Schedule of 
Activities 
(Table15);
11.6.2.9.12 
Overnight Stays for 
TLS Monitoring 
Added text to indicate that 
patients may be discharged 
prior to 24 hours post-dose if 
they are able to complete 
required safety and 
laboratory assessments 
within the specified time 
windows.
This update was made to allow 
flexibility for reducing in-patient 
stays, as long as required safety 
evaluations are performed. White 
blood cell parameters remain in place 
to ensure all enrolled patients are at 
low risk for TLS. No SAEs 
associated with tumor lysis occurred 
in the 300 mg cohort. 
Substantial
11.6.1.4 Minimal/ 
Measurable Disease 
(Part B Only);
Appendix J 
Response 
Evaluation Criteria
Added text to indicate that 
MRD negative or positive 
status (or conversion from 
negative to positive MRD) 
will need to be confirmed 
with a second MRD negative 
For clarification.
Non-substantial
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Section # and 
Name
Description of Changes
Brief Rationale
Substantial/ 
Non-substantial
for Acute Myeloid 
Leukaemia (Table)
or positive sample devoid of 
blasts obtained within the 
interval specified, and that 
MRD status of patients will 
be monitored every 3 cycles 
(or at the discretion of the 
Investigator, in line with 
scheduled response 
assessments) thereafter.
11.6.2.9.2 Viral 
Serology;
12.6.2.9.2 Viral 
Serology
Added the following text: “If 
a patient was found to have 
positive anti-HBc antibody 
and a negative HBsAg, a 
DNA PCR test will be done 
to determined eligibility 
criteria.”
Clarification to distinguish patients 
who have prior versus active 
infection and no undetected active 
disease at enrolment.
Non-substantial
11.6.2.9.4 Clinical 
Chemistry;
12.6.2.9.4 Clinical 
Chemistry
Revised text to indicate that 
if an unscheduled ECG is 
performed, an electrolyte 
panel (ie, calcium, 
magnesium, potassium) must 
be done and troponin 
performed as clinically 
indicated to coincide with the 
ECG assessment, and referral 
to a cardiac specialist if 
required.
Rephrased sentence for clarity.
Non-substantial
11.6.3.1.1 Blood 
Sample for Plasma 
Pharmacokinetics;
12.6.3.1.1 Blood 
Sample for Plasma 
Pharmacokinetics
Added the following text: 
“including if central line 
access is available”.
For clarification of how PK samples 
should be taken, to avoid sampling 
artifacts
Non-substantial
11.6.3.1.1 Blood 
Sample for Plasma 
Pharmacokinetics;
12.6.3.1.1 Blood 
Sample for Plasma 
Pharmacokinetics
Added “as close to the end of 
the infusion, but permissible 
up to 10 minutes” for the 
sample collected at the end of 
the infusion. 
To better characterize maximum 
plasma concentration.
Non-substantial
11.6.3.1.3 Blood 
Samples for 
Metabolite 
Identification
Removed sample collection 
on Cycle 1 Days 1, 4, 9, 10, 
and 11 and Cycle 2 Day 2.
To reduce patient burden and it is 
unnecessary to obtain so many 
samples for metabolite identification. 
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Section # and 
Name
Description of Changes
Brief Rationale
Substantial/ 
Non-substantial
11.6.3.2.2 and 
12.6.3.2.2 
Pharmacodynamic 
 
 
Added assessment timepoints 
to table.
To better characterise the PD 
response in patients, aligning 
collections to PK timepoints.
Non-substantial
11.6.5.1
 
 
 
 
 
 
Non-substantial
12.6.2.9.12 
Overnight Stays for 
TLS Monitoring
Added PK assessments as 
part of the rationale for 
in-patient treatment 
administration.
For clarification that patients have 
frequent PK sampling during Module 
2, therefore preventing discharge 
over night
Non-substantial
12.7.2 Sample Size 
Determination
Updated text from a sample 
size determined empirically 
to that based on statistical 
criteria. 
To provide statistical justification of 
sample size based on within-subject 
coefficients of variation/power 
calculations. 
Non-substantial
12.7.3 Populations 
for Analysis 
Clarified that 
pharmacokinetic population 
will include subjects with “at 
least one” reportable plasma 
concentration
To be more specific with description 
of the population
Non-substantial
Appendix I2 (Table 
37)
Updated table footnotes.
For clarification.
Non-substantial
Appendix O 
Prognostic Scoring 
for Myelodysplastic 
Syndrome;
Appendix P 
Response Criteria 
for Myelodysplastic 
Syndrome
Added prognostic and 
response criteria for MDS.
These criteria were added given that 
patients with MDS are now eligible 
for enrolment in this study.
Substantial
Not applicable
Minor editorial changes were made to the document, to correct 
formats and spelling, to clarify protocol instruction, and to align text 
with related sections of the protocol
Non-substantial
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Amendment 1 [14 July 2021]
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the council of the European Union.
Overall Rationale for the Amendment:
The global protocol was amended to address comments received from various health 
authorities, ethics committees and clarification requested from study sites. A summary of 
changes and the rationale for each change are tabulated below.
Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Synopsis, 2 Introduction 
– Core, 2.3 Study 
Rationale, 4.1 Overall 
Design, 4.2.1 Regulatory 
Amendments for 
Additional Modules, 6.1 
Study Treatment(s) 
Administered
This section was updated with 
text regarding potential for 
4 additional modules to the 
study where permissible by 
local regulations. 
Text was added regarding 
the potential additional of 
modules to the protocol, 
to further support the 
scientific rationale and the 
overall goal of the study 
to generate clinically 
meaningful data -
including combination 
therapies - which in turn 
would guide the course of 
development of AZD 
0466. A caveat was added 
that these modules maybe 
added only if permissible 
by local regulations.
Non-substantial
2.1.2 Rationale for 
AZD0466 in treatment 
of haematological 
malignancies
Text regarding ongoing study 
D8240C00003 was updated
The D8240C00003 study 
has now changed status 
(enrolment complete), 
hence the referring text 
was updated in this 
protocol amendment. 
Non-substantial
4.4 End of Study 
Definition
This section was updated with 
definitions of End of Module 
and with a plan for reporting 
results for each module, as 
well as after the final study 
analyses for all modules.
These updates were of an 
administrative nature.
Non-substantial
5.1 Core Inclusion 
Criteria
Inclusion criterion 2 was 
edited to clarify that subjects 
who are 18 years of age in 
some countries may be 
eligible for the study, but may 
need to sign assent forms, 
This clarification was 
added to accommodate 
countries where 18 years 
may be below the age 
limit for consent.
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
together with parental consent 
forms. 
Inclusion criterion 4 was 
updated to clarify that eligible 
patients must not have an 
established standard of care 
with proven benefit at the time 
of enrolment
This clarification was 
provided in response to 
query from South Korean 
Ministry of Food and 
Drug Safety (MFDS).
Non-substantial
Inclusion criterion 7 was 
updated to reduce the 
predicted life expectancy of 
eligible patients from 
12 weeks to 8 weeks.
This inclusion criterion 
was updated in line with 
realistic clinical 
characteristics seen in 
patients with leukaemia.
Substantial
Inclusion criterion 9 was 
edited to omit the eligibility 
requirement of the absence of 
a prior history of pancreatitis, 
and add a requirement of 
absence of clinical pancreatitis 
at the time of enrolment. 
This inclusion criterion 
was updated in line with 
realistic clinical 
characteristics seen in 
patients with leukaemia.
Substantial
The exclusion criterion about 
reproduction was updated to 
clarify that women of 
childbearing potential must be 
willing to use highly effective 
contraceptive measured, and 
that they should have a 
negative serum pregnancy test.
These updates were made 
for clarity, and 
consistency with Section 
5.3 of this protocol. 
Non-substantial
5.2 Core Exclusion 
Criteria
Exclusion criterion 3 was 
corrected to exclude patients 
with a history of 
haematopoietic stem cell 
transplantation within 
100 days prior to the first dose 
of study treatment. 
This exclusion criterion 
was updated to provide 
more clarity on the 
eligibility of patients with 
a history of 
haematopoietic stem cell 
transplantation.
Substantial
Exclusion criterion 4 was 
updated to clarify eligibility 
requirements amongst patients 
receiving immunosuppressants 
for graft versus host disease
(GVHD) and primary 
malignancy control.
This exclusion criterion 
was updated to provide 
more granularity about 
terms of exclusion of 
patients taking 
immunosuppressants for 
GVHD and primary 
malignancy control.
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Exclusion criterion 8 was 
edited to clarify that patients 
with known uncontrolled 
cytomegalovirus (CMV) 
infection will be excluded 
from the study.
This exclusion criterion 
was updated to remove 
the eligibility testing 
requirement for CMV 
infection, and to clarify 
that subjects with known 
active CMV infection will 
be excluded.
Non-substantial
Exclusion criterion 11 was 
updated to
1.
add the New York Heart 
Association (NYHA) 
Functional Classification 
for the assessment of 
cardiac eligibility criteria
2.
allow for investigator 
discretion in assessing the 
eligibility of 
abnormalities in 
electrograms (ECGs)
3.
edit the risk of arrhythmic 
events to omit heart 
failure and hypokalaemia
This exclusion criterion 
was updated to add a 
standardised method for 
the testing of cardiac 
eligibility criteria and 
provide clarity on how 
risk assessment will be 
done for abnormalities in 
rhythm and arrhythmic 
events. 
Substantial
Exclusion criterion 12 was 
updated to clarify that patients 
with a history of 
myelodysplastic syndrome or 
myeloproliferative neoplasm 
(including chronic 
myelomonocytic leukaemia 
[CMML]), will be eligible for 
enrolment in this study.
This exclusion was 
updated to clarify that the 
exclusion criterion of 
“history of 
life-threatening 
malignancy ≤2 years 
prior to first dose of study 
treatment” did not apply 
to myelodysplastic 
syndrome or 
myeloproliferative 
neoplasm.
Substantial
In exclusion criterion 13, the 
exclusion conditions of prior 
or concomitant congestive 
heart failure, ventricular 
arrythmias and 
supraventricular arrythmias 
were omitted.
This exclusion criterion 
was updated because it
was repetitive of the 
cardiac criteria in #11.
Non-substantial
Exclusion criterion 14 was 
updated to clarify that patients 
This exclusion criterion 
was edited to make it 
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
receiving high dose steroids 
for primary malignancy 
control would be eligible if 
these steroids are discontinued 
2 days before the first dose of 
study treatment.
consistent with the 
conditions for high dose 
steroid use in exclusion 
criterion 4.
Exclusion criterion 14 was 
also updated to provide more 
detail on the allowable use of 
hydroxyurea until the start of 
cycle 2, and direction about 
therapy discontinuation at 
least 7 days prior to the first 
dose of study treatment for 
patients who relapse while on 
maintenance therapy.
This exclusion criterion 
was edited to provide 
more detail and clarity on 
the use of these 
concomitant drugs.
Substantial
Exclusion criterion 14 was 
also updated to provide clearer 
direction about exclusion of 
subjects for whom the 
following types of medications 
cannot be discontinued within 
5 half-lives of the first dose of 
study treatment, and withheld 
until 14 days after the last 
dose of AZD0466:
1.
reversible cytochrome 
P450 3A (CYP3A) 
inhibitors,
2.
sensitive substrates of 
BCRP, OCT2, OAT3, 
OATP1B1, OATP1B3, 
CYP2B6, CYP2C8, 
CYP2C9, or CYP2D6, or 
3.
moderate or strong 
mechanism-based 
inhibitors or inducers of 
CYP3A4
4.
medications with known 
risk of Torsades de 
Pointes.
Exclusion criterion 14 was 
also updated to clarify that 
heparin required for vascular 
This exclusion criterion 
was edited to add more 
detail and clarity on the 
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
line management was not an 
exclusion criterion. 
concurrent use of 
anticoagulants.
5.3 Lifestyle 
Considerations
This section was updated to 
clarify that male patients with 
a partner of non-child bearing 
potential should use a condom 
for 35 days after the last dose 
of study treatment.
This exclusion criterion 
was edited to add more 
clarity on the required 
time period for the use of 
condoms in this study
Non-substantial
5.4 Screen Failures and 8 
Study Assessments and 
Procedures – Core, 
Appendix A3 Informed 
Consent Process, 
Appendix M1 
Rescreening of 
Participants to 
Reconfirm Study 
Eligibility
This section was updated to 
clarify that patients who fail 
screening may be re-screened 
up to 2 times for study 
eligibility.
This text was edited to 
add an allowance of up to 
2 re-screening per patient.
Non-substantial
6.5.1 Permitted 
Concomitant 
Medications and 
Treatments 
This section was edited to 
clarify that allopurinol must be 
used for tumour lysis 
syndrome (TLS) prophylaxis 
per institutional guidelines
This text was edited to 
clarify the terms of 
allopurinol use in the 
study.
Non-substantial
This section was also edited to 
clarify that patients who get 
vaccinated for Coronavirus 
disease 2019 (COVID-19) 
must do so at least 7 days 
before the first dose of study 
treatment, where possible.
This text was updated to 
add COVID-19 vaccine 
language to permitted 
medications 
Non-substantial
6.5.2 Prohibited 
Concomitant 
Medications and 
Treatments
The table listing strong 
inducers of CYP3A, moderate 
inducers of CYP3A and 
mechanism-based strong 
inhibitors of CYP3A was 
updated with new drugs 
enasidenib and midostaurin 
ivosidenib.
This table was updated 
with drugs which were 
likely prescribed to 
patients who would be 
eligible for the study
Non-substantial
6.6.1 Dose 
Modifications Based on 
Haematological 
Parameters
The recommended dose 
modifications for 
haematological changes of 
toxicity grade “Grade 3 or 4 
neutropenia” and “Febrile 
neutropenia/neutropenic 
This section was updated 
to reflect clinical practice 
in patients with 
neutropenia, in discussion 
with lead investigator. 
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
infection (any grade lasting 
> 2 days)” were replaced by 
new recommendations with 
updated actions in an added 
row “Grade 4 neutropenia, 
with or without fever or 
infection”. The absolute 
neutrophil count (ANC) 
threshold was reduced from 
> 1.0 × 109/L to ≥ 0.5 × 109/L
6.6.3 Dose 
Modifications for Non-
haematological 
Toxicities
It was specified that non-
haematological toxicities will 
be graded according to the 
Common Terminology 
Criteria for Adverse Events 
(CTCAE) version 5
The CTCAE criteria 
version was added for 
clarity.
Non-substantial
6.6.5 Cardiac findings
This section was updated to 
add that AZD0466 should be 
permanently discontinued if a 
CTCAE ≥ Grade 3 cardiac 
adverse event (AE) of any 
duration occurs during study 
treatment, if considered by the 
Investigator to be related to 
study treatment.
This section was updated 
with more specific 
treatment discontinuation 
criteria in patients with 
cardiac findings.
Substantial
6.6.6 Infusion-site 
reactions
This section was added with 
guidance about drug 
interruption in the event of 
infusion site reactions
This section was added to 
guide the investigator 
with specific criteria for 
management of infusion 
site reactions.
Substantial
8.3.13.2 Paternal 
Exposure
This section was edited to 
clarify that the outcome of all 
pregnancies occurring from 
the date of first dose and for 
35 days after the last dose of 
study treatment, plus 6 
months, should be 
documented.
This section was edited to 
make the language for 
pregnancy follow-up 
clearer.
Non-substantial
8.6.1.1
 
 
 
 
 
 
 
.
 
 
Non-substantial
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
9.7.1 Adverse Events
The defined follow-up period 
for AEs was changed from 30 
days to 28 days.
This section was edited to 
keep it consistent with the 
time period and frequency 
for collecting AE and 
serious adverse event 
(SAE) information in 
Section 8.3.1.
Non-substantial
10 REFERENCES -
CORE
A new reference “Ji et al 2010 
Ji Y, Liu P, Li Y, B, Bekele N. 
A modified toxicity 
probability interval method for 
dose-finding trials. Clin Trials. 
2010;7(6):653-63.” was added
A new reference used to 
update text in this 
protocol amendment was 
added.
Non-substantial
11.1.3.1 Justification for 
Starting Dose and 11.4.1 
Study Treatment –
AZD0466
This section was updated with 
text from the ongoing study 
D8240C00003 (that AZD0466 
200 mg intravenous (IV) is 
tolerated in patients with 
advanced solid malignancies, 
and that the study has 
completed recruitment) and by 
making the text about dose 
ramp-up on Day 1 and Day 4 
consistent with Figure 3.
Section 11.4.1 was also 
updated with the text about 
dose ramp-up.
This text was edited to 
clarify the planned dose 
ramp-up in the protocol.
Non-substantial
11.1.3.3 Dose escalation, 
de-escalation, and 
stopping decision rules
This section was edited to 
clarify that the decisions on 
dose escalation were based on 
outcomes from an internal AZ 
simulation package, the 
operating characteristics of 
which were also added to the 
protocol in Table 10.
This change was made in 
response to a site query 
for clarity regarding 
operating characteristics 
on the mTPI-2 design.
Non-substantial.
11.3 STUDY 
POPULATION -
MODULE 1 and 12.3 
STUDY POPULATION 
- MODULE 2
A note was added that each 
patient may only be enrolled 
in one module of this study. A 
patient who enrols in one 
module of this study is not 
eligible to participate in 
another module.
These sections were 
updated to make explicit 
that a patient who has 
participated in one 
module of this study 
cannot then participate in 
another. 
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
11.4.7.2 Dose-limiting 
Toxicity
This section was updated to 
add more detail on what would 
be considered a dose-limiting 
toxicity (DLT) in this study, to 
specify that AZD0466 should 
be permanently discontinued if 
a drug-related CTCAE Grade 
≥ 3 cardiac AE of any duration 
occurs at any time during 
study treatment, and to define 
the period of DLT evaluation.
This section was updated 
to refine the definition 
and actions taken with 
dose-limiting toxicity in 
this study, and to keep 
consistency with Section 
11.4.7.1.
Substantial
11.4.7.3 Definition of 
Maximum Tolerated 
Dose
This section was updated with 
the rules for 2 or more tied 
doses that are equidistant from 
the target toxicity dose of 
30%. 
This update was made in 
order to take a more 
conservative approach if 
the estimated DLT rate 
for the tied doses are a 
combination of < 30% 
and > 30%.
Substantial
Table 15: Module 1 -
Schedule of Activities 
for Screening and Cycle 
1 (Parts A and B)
Footnote a was added in the 
ramp-up 2 column to allow for 
visits to be conducted over the 
telephone if it does not require 
attendance for blood draws or 
physical examination
This footnote was added 
to allow for flexibility in 
the study, where site visits 
are not required.
Non-substantial
Footnote b was added to the 
cycle 1 visit window row to 
clarify that the Days 1, 4 and 8 
ramp-up dose administration 
should be at least 72 h apart.
This footnote was added 
to clarify that dose ramp-
ups should be no more 
frequent than 72 hours to 
allow for a suitable safety 
assessment.
Non-substantial
Footnote c was added to the 
Chest X-ray row to note that 
Chest X-rays may also be 
performed at other timepoints 
during the study at the 
Investigator’s discretion, when 
clinically indicated. 
This update was made in 
response to a query from 
the South Korea MFDS.
Non-substantial
Day 8 assessments were 
marked, and Day 11 
assessments deleted for 
cardiac troponin and brain 
natriuretic peptide (BNP) (or 
n-terminal pro b-type 
natriuretic peptide 
The schedule of 
assessments for cardiac 
troponin and BNP (or 
NTproBNP) was updated 
to evaluate cardiac 
troponin levels before 
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
[NTproBNP]). The associated 
footnote j was also updated to 
add that cardiac troponin 
samples on Day 8 should be 
collected pre-infusion, and 
may be collected at other 
timepoints in the study if 
clinically indicated.
patients receive the target 
dose on Day 8.
Footnote k was added to the 
serum immunoglobulins row 
to clarify that a routine serum 
immunoglobulin profile (IgA, 
IgG, IgM) would be assessed.
This footnote was added 
for clarity about the serum 
immunoglobulin 
assessments.
Non-substantial
Footnote l was added to the 
pharmacokinetic (PK) 
assessments row to refer to 
Section 11.6.3.1 for 
information on timepoints for 
PK assessment.
This footnote was added 
for clarity about PK 
assessment timepoints.
Non-substantial
It was clarified that blood 
 
 
 
 
 
will 
be collected at disease 
assessment (Part A and B) and 
minimal/measurable residual 
disease (MRD) timepoint in 
Part B. Footnote n was added 
to the Table with this 
instruction.
The schedule of 
assessments 
 
 
 
 
was 
updated to enable an 
analysis of orthogonal 
biomarkers on 
biospecimen collected at 
the same time.
Substantial
The collection of blood 
 
 using 
plasma and serum was omitted 
from this table.
This previously planned 
assessment has now been 
omitted from the study.
Non-substantial
 
 
 
 
 
 
 
 
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
 
 
 
Footnote o was updated to 
note that the window for bone 
marrow biopsy at screening is 
28 days, and that when it is 
not possible to obtain a bone 
marrow biopsy sample, a 
historic bone marrow biopsy 
sample may be used.
The allowance and 
acceptable window for a 
historic bone marrow 
biopsy sample was added 
for screening.
Substantial
Table 16: Module 1 -
Schedule of Activities 
for Treatment Cycle 2 
and Beyond and Follow-
up Periods (Part A and 
B)
All assessments for cardiac 
troponin and BNP (or 
NTproBNP) from Cycle 2 and 
beyond were deleted. It was 
specified that troponin may be 
assessed at investigators’ 
discretion (throughout the 
study period, including 
Cycle 2 and beyond).
The schedule of 
assessments for cardiac 
troponin and BNP (or 
NTproBNP) was updated 
for evaluation prior to 
getting the target dose a 
Cycle 1 Day 8, and 
thereafter at any other 
timepoint through the 
study at the Investigator’s 
discretion. 
Substantial
The rows for blood 
 
 
 
analysis were 
updated with assessments at 
each disease assessment (Part 
A and B)/MRD timepoint 
(Part B). Footnote f was added 
to the Table with this 
instruction.
 
 
The schedule of 
assessments for 
 
 
 
 
 
was updated to 
enable an analysis of 
biomarkers on 
biospecimen collected at 
the same time.
Substantial
An MRD assessment for Part 
B (expansion) was deleted at 
The schedule of 
assessments for MRD 
assessments was updated 
Substantial
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Brief Rationale
Substantial/Non-
substantial
Cycle 1 Day 1 and added at 
the EoT visit.
to clarify that a bone 
marrow sample will not 
be collected on Cycle 1 
Day 1.
11.6.1.3 Bone Marrow 
and 12.6.1.3 Bone 
Marrow
These sections were updated 
to allow for a historic bone 
marrow biopsy sample if an 
eligible patient is unable to 
give a fresh bone marrow 
biopsy sample due to 
extenuating circumstances, 
with the approval of the 
Medical Monitor.
The allowance and 
acceptable window for a 
historic bone marrow 
biopsy sample was added 
for screening.
Substantial
These sections were also 
updated to clarify that the 
window for these screening 
assessments is 28 days.
This section was updated 
to make the screening 
window for all screening 
assessments consistent.
Non-substantial
11.6.1.4 
Minimal/Measurable 
Residual Disease (Part B 
Only)
An MRD assessment for 
Part B (expansion) was 
deleted at Cycle 1 Day 1 and 
added at the end of treatment 
(EoT) visit. It was also 
clarified that MRD 
assessments will be made at 
any morphologic remission 
timepoint, and that patients 
with confirmed CR without 
measurable residual disease 
(CRMRD) will be monitored 
every 3 cycles, and thereafter 
until disease progression, per 
the investigator’s discretion.
This section was updated 
with text for MRD 
assessments at any 
morphological remission 
timepoint, and in patients 
with confirmed CRMRD, 
up to 2 years after CRMRD
confirmation, at the 
discretion of the 
Investigator.
Substantial
11.6.2.1 Physical 
Examination
This section was updated to 
clarify that physical 
examination will be done pre-
infusion and on the calendar 
day after the dosing day 
during each cycle.
The text for the schedule 
of assessments for 
physical examination in 
this study was clarified.
Non-substantial
11.6.2.4 Chest X-ray and 
12.6.2.4 Chest X-ray
These sections were updated 
to add that a Chest X-ray may 
also be performed at other 
timepoints during the study at 
the Investigator’s discretion, 
when clinically indicated. 
This update was made in 
response to a query from 
the South Korea MFDS.
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Description of Change
Brief Rationale
Substantial/Non-
substantial
11.6.2.5 Vital Signs and 
12.6.2.5 Vital Signs
These sections were updated 
to clarify that temporal instead 
of oral temperature assessment 
will be done, and that blood 
pressure (BP) and pulse 
measurements may be made in 
a seated position.
These sections were 
updated to provide new 
guidance on vital sign 
assessments at the sites.
Non-substantial
11.6.2.6 
Electrocardiograms and 
12.6.2.6 
Electrocardiograms
These sections were updated 
by replacing a bullet pointed 
list of assessments timepoints 
with a tabulated list of ECG 
assessment timepoints, and to 
clarify that Day 1 pre-infusion 
and end of infusion ECGs will 
be conducted during each 
cycle. 
Section 12.6.2.6 for Module 2 
ECG assessments was updated 
with additional ECG 
timepoints (Cycle1 Period 3 
Days 17 and 18).
This update was made for 
better presentation of 
ECG assessments 
The additional ECG 
timepoints (Cycle1 
Period 3 Days 17 and 18) 
were added to Module 2 
for safety monitoring after 
infusion of target dose of 
AZD0466 in combination 
with voriconazole.
Non-substantial
11.6.2.6.1 Continuous 
12-lead ECG Recordings 
(Holter)
It was clarified that continuous 
recordings of 12-lead ECGs 
will be performed for the 
purpose of PK modelling, 
which in turn would allow for 
monitoring of PR, QRS, QT, 
QTcF, RR intervals.
This section was updated 
to provide clarification on 
the purpose of continuous 
12-lead ECG Recordings
Non-substantial
Table 18 Clinical 
Chemistry and Table 26 
Clinical Chemistry
Footnote b was added to each 
table clarify that glutamate 
dehydrogenase testing is 
optional, but should be 
performed where sites have 
the capability to perform the 
test locally.
The clinical chemistry 
table was modified to 
reflect the test as not 
mandatory, but optional, 
given the exploratory 
nature of the glutamate 
dehydrogenase testing.
Substantial
11.6.2.9.8 Cardiac 
troponin and BNP (or 
NTproBNP) and 
12.6.2.9.8 Cardiac 
troponin and BNP (or 
NTproBNP)
This section was updated to 
add that cardiac troponin and 
BNP (or NTproBNP) samples 
on Day 8 should be collected 
pre-infusion, to omit all 
planned assessments during 
Cycle 2 and every 3 cycles 
The schedule of 
assessments for cardiac 
troponin and BNP (or 
NTproBNP) was updated 
for evaluation prior to 
getting the target dose a 
Cycle 1 Day 8. Thereafter 
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Brief Rationale
Substantial/Non-
substantial
thereafter, and to add that 
cardiac troponin I samples 
may be collected at other 
timepoints in the study if 
clinically indicated.
Troponin can be assessed 
at investigators’ discretion 
(throughout the study 
which includes Cycle 2 
and beyond).
These sections were also 
updated to clarify that isolated 
troponin elevations are not 
sufficient to trigger dosing 
changes and should be 
evaluated in the context of 
other cardiac findings.
This update was made for 
patient safety purposes, 
and to provide additional 
guidance on dose changes 
due to elevated cardiac 
troponin levels.
Substantial
11.6.2.9.9 Cortisol, 
ACTH and TSH, 
11.6.2.9.10 Serum 
immunoglobulins, and 
11.6.2.9.11 Urinalysis
12.6.2.9.9 Cortisol, 
ACTH and TSH, 
12.6.2.9.10 Serum 
immunoglobulins, and 
12.6.2.9.11 Urinalysis
These sections were updated 
to clarify that the window for 
these screening assessments is 
28 days.
This section was updated 
to make the screening 
window for all screening 
assessments consistent.
Non-substantial
11.6.2.9.12 Overnight 
stays for TLS monitoring 
and 12.6.2.9.12 
Overnight stays for TLS 
monitoring
These sections were updated 
to clarify that Overnight stays 
will be recommended, instead 
of mandatory, for dosing on 
Days 15, 22, and 29 during 
Module 1 Cycle 1 and Day 15 
Cycle 1 (Period 3) and Cycle 2 
for Days 1 and 8 during 
Module 2, allowing for 
patients to be discharged prior 
to 24 hours post-dose as per 
Investigator discretion, and 
with planned clinic follow-up 
within 12 hours after 
discharge, if their TLS 
laboratory values are 
appropriate.
This update was made to 
allow flexibility for 
reducing inpatient stays 
beyond the first 3 doses in 
Cycle 1, per the 
Investigator’s discretion.
Substantial
These sections were also 
updated to clarify that TLS 
monitoring should be 
This update was made to 
clarify that TLS 
monitoring should be 
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Brief Rationale
Substantial/Non-
substantial
performed (as specified in 
Table 15 for Module 1 and 
Tables 23 and 24 for Module 
2) at least as frequently as 
every 12 hours during the first 
24 hours after each 
administration of study 
treatment, and thereafter as 
clinically indicated.
done at least once every 
12 hours instead of twice 
every 24 hours, which 
may be ambiguous.
11.6.3.1.1 Blood Sample 
for Plasma 
Pharmacokinetics
In Section 11.6.3.1.1 the table 
for blood samples for plasma 
PK was updated with a 
footnote referring the reader to 
Section 11.6.2.6 for ECGs 
measured at matched PK 
timepoints.
This update was 
administrative, and was 
made to refer the reader to 
a related section of the 
protocol.
Non-substantial
11.6.3.1.1 Blood Sample 
for Plasma 
Pharmacokinetics and 
12.6.3.1.1 Blood Sample 
for Plasma 
Pharmacokinetics
A new footnote was added to 
the Table for Blood Sample 
for Plasma PK, at the 9 hour 
post-infusion timepoint on 
Cycle 1 Day 8 (Module 1) and 
the 9 hour post-infusion 
timepoint on Cycle 1 Period 3 
Day 15 (Module 2), to clarify 
that if a planned collection is 
no longer possible at the 
scheduled timepoint, the 
Medical Monitor must be 
informed, and any collection 
outside allotted window must 
be discussed with the Medical 
Monitor
This footnote was added 
to provide flexibility and 
guidance around this 
blood collection 
timepoint.
Non-substantial
11.6.4.1.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substantial
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.6.4.1.6 Bone marrow 
biopsy and aspirate 
 
 and 
12.6.4.1.3 Bone marrow 
biopsy and aspirate 
 
This section was updated to 
clarify that bone marrow 
biopsy samples will be 
collected in accordance with 
local/institutional guidelines 
and as per the process 
delineated in the laboratory 
manual.
This update was made to 
clarify that 
local/institutional 
guidelines will be used to 
conduct bone marrow 
biopsies and aspirate, but 
using a process delineated 
in the laboratory manual.
Non-substantial
11.7.6
Efficacy
This section was updated to 
omit the word 
“programmatically” when 
speaking of assigning a 
response of complete 
remission (CR), CR with 
incomplete platelet recovery 
(CRi), morphologic leukaemia 
free state (MLFS), partial 
This update was made
because a response of CR, 
CRi, MLFS, PR, CRc, 
CRm, Relapse or Failure is 
not being assigned 
programmatically
Non-substantial
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
remission (PR), Cytogenetic 
CR (CRc), Molecular CR 
(CRm), Relapse or Failure
12.1.5 Module 2 Study 
Design
The dose ramp-up schedules 
in Periods 1, 2 and 3 were 
updated. 
This update clarified the 
schedule and strategy for 
dose ramp-ups during 
Module 2. 
Non-substantial
12.3.2 Exclusion Criteria
This section was updated to 
add an exclusion criterion for 
Module 2, making patients for 
whom voriconazole is 
contraindicated ineligible for 
the study.
Module 2 investigates a 
potential drug-drug 
interaction between 
AZD0466 and 
voriconazole, hence 
patients for whom 
voriconazole is 
contraindicated cannot 
participate in the study.
Non-substantial
Table 23: Module 2 -
Schedule of Activities 
for Screening and Cycle 
1
Footnote a was added in the 
ramp-up 2 column to allow for 
visits to be conducted over the 
telephone if attendance for 
blood draws or physical 
examination is not required
This footnote was added 
to allow for flexibility in 
the study, where site visits 
are not required.
Non-substantial
Footnote c was added to the 
Chest X-ray row to note that 
Chest X-rays may also be 
performed at other timepoints 
during the study at the 
Investigator’s discretion, when 
clinically indicated. 
This update was made in 
response to a query from 
the South Korea MFDS.
Non-substantial
Day 8 assessments were 
marked, and Day 11 
assessments deleted for 
cardiac troponin and BNP (or 
NTproBNP). The associated 
footnote g was also updated to 
add that cardiac troponin 
samples on Day 8 should be 
collected pre-infusion, and 
may be collected at other 
timepoints in the study if 
clinically indicated.
The schedule of 
assessments for cardiac 
troponin and BNP (or 
NTproBNP) was updated 
for evaluation prior to 
getting the target dose a 
Cycle 1 Day 8, and 
thereafter at any other 
timepoint through the 
study at the Investigator’s 
discretion
Substantial
Footnote i was updated to note 
that the window for bone 
The allowance and 
acceptable window for a 
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
marrow biopsy at screening is 
28 days, and that when it is 
not possible to obtain a bone 
marrow biopsy sample, a 
historic bone marrow biopsy 
sample may be used.
historic bone marrow 
biopsy sample was added 
for screening.
Table 24: Module 2 -
Schedule of Activities 
for Cycle 2 and beyond
Visit windows were added to 
this table.
This table was updated 
with clarity about the visit 
windows
Non-substantial
All assessments for cardiac 
troponin and BNP (or 
NTproBNP) from Cycle 2 and 
beyond were deleted. It was 
specified that troponin may be 
assessed at investigators’ 
discretion (throughout the 
study period, including Cycle 
2 and beyond).
The assessments for 
cardiac troponin and BNP 
(or NTproBNP) will now 
be done at any timepoint 
through the study at the 
Investigator’s discretion.
Substantial
An MRD assessment for Part 
B (expansion) was deleted at 
Cycle 1 Day 1 and added at 
the EoT visit.
The schedule of 
assessments for MRD 
assessments was updated 
during this amendment.
Substantial
12.6.2.9.6 Complete 
blood count with 
differential including 
This section was updated with 
wider widows (30 minutes 
instead of 15 minutes) for 
blood collection at the Cycle 1 
Period 1 Day 8, 2 hours post-
dose timepoint, and the Cycle 
1 Period 3, Day 15, 2 hours 
post-dose timepoint.
This change was made for 
consistency with the 
2-hour timepoint in 
Section 11.6.2.9.6.
Non-substantial
Appendix F 1.1 
Prophylaxis for TLS
This Appendix was updated to 
add more detail about specific 
recommendations for 
prophylaxis for TLS with 
regard to IV hydration and 
allopurinol use, but to clarify 
that details of TLS 
management may vary per 
institutional practice, .
This Appendix was 
updated to provide 
additional detail regarding 
TLS prophylaxis, but also 
allow flexibility per 
institutional practice.
Non-substantial
Appendix F 1.2 
AZD0466 Dose 
Modifications for TLS
Table 31 AZD0466 Dose 
Modifications for TLS was 
updated to clarify that 
AZD0466 may be delayed up 
to 7 days if an abnormal 
This section was edited to 
align with clinical 
practice in the 
management of TLS in 
low or intermediate risk 
Non-substantial
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
laboratory finding is present 
before study drug 
administration. The laboratory 
value for abnormal phosphate 
levels was changed to 
“Phosphate ≥1.6 mmol/L 
(5.0 mg/dL) (0.5 mg/dL) 
increase”, with an added note 
that in the event of an isolated 
phosphate abnormality, 
restarting the dose may be 
discussed with the Medical 
Monitor. 
Two references to support 
these changes were added to 
the footnote. 
The rows for “Abnormality 
(present before admin of 
AZD0466)” were deleted.
leukaemia patients, and to 
allow for flexibility due to 
patient variability.
Appendix F 2.3 
Leucocyte Count
Text regarding prior cytotoxic 
chemotherapy was omitted 
and the following statement 
was added: Treatment with 
low dose prednisone (10 mg or 
less) or equivalent dose of 
alternative steroid is 
permitted. 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 
treatment.
This appendix was 
updated to align text 
about treatment with low 
dose prednisone with 
clinical practice, where 
steroid use is permissible 
for disease control - but 
other cytotoxic agents 
would be considered new 
treatment.
Non-substantial
Appendix G 
Classification of Tumour 
Lysis Syndrome
In Table 33 Criteria for 
Laboratory and Clinical 
Tumour Lysis Syndrome, the 
criteria for 
hyperphosphataemia was 
corrected from 1.5 to 
4.5 mg/dL.
This edit was a correction.
Non-substantial.
Appendix H: Drugs That 
Prolong QT Interval 
and/or Induce Torsades
De Pointes
It was clarified that drugs with 
a known risk of Torsades de 
Pointes should be withheld for 
5 half-lives prior to the first 
dose of study treatment and 
This section was updated 
to provide clarity for the 
study sites regarding the 
restricted use of drugs that 
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
for 14 days after the last. A 
tabulated list of drugs with a 
known risk of Torsades de 
Pointes was added. 
have a known risk of 
Torsades de Pointes . 
Appendix J: Response 
Evaluation Criteria for 
Acute Myeloid 
Leukaemia
The table for response 
evaluation criteria in this 
appendix was replaced by 
revised recommendations, 
with categories of response, 
treatment failure and relapse. 
All irrelevant literature 
references were deleted.
In this appendix response 
criteria were updated to 
reflect current guidelines, 
and to address internal 
inconsistencies 
Non-substantial
Appendix N: New York 
Heart Association 
Functional Classification
This new appendix was added 
to support the exclusion 
criterion of patients with a 
history of myocarditis or heart 
failure NYHA Functional 
Classification Class 3 or 4.
This new appendix was 
added to support a cardiac 
eligibility assessment
Non-substantial
NA
Minor editorial changes were made the document, to 
correct formats and spelling, to clarify protocol instruction 
and to align text with related sections of the protocol
Non-substantial


SIGNATURE PAGE
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Document Name: d8241c00001-csp-v4
Document Title:
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Doc ID-004378682
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Server Date
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Signed by
Meaning of Signature
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Content Approval
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Content Approval
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PPD
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SAP_001.pdf: 
Parexel International
AstraZeneca
D8241C00001
Statistical Analysis Plan
TP-GDO-WW-133-02
CONFIDENTIAL
Project Document Version No. Final 2.0
Effective Date:  26 Nov 19
Project Document Effective Date: <Date of last signature>
Related to:  SOP-GDO-WW-019
Page 1 of 58
Parexel International
AstraZeneca
D8241C00001
A Modular Phase I/II, Open-Label, Multi-Centre Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Preliminary Efficacy of AZD0466 Monotherapy or in Combination in 
Patients with Advanced Haematological Malignancies
Statistical Analysis Plan
Version: Final 2.0
Parexel Project Number: 254945


Parexel International
AstraZeneca
D8241C00001
Statistical Analysis Plan
TP-GDO-WW-133-02
CONFIDENTIAL
Project Document Version No. Final 2.0
Effective Date:  26 Nov 19
Project Document Effective Date: <Date of last signature>
Related to:  SOP-GDO-WW-019
Page 2 of 58
TABLE OF CONTENTS
1
INTRODUCTION - Core
12
2
STUDY OBJECTIVES – Core
12
2.1
Primary Objective
12
2.2
Secondary Objectives
12
2.3
Exploratory Objective(s)
13
3
INVESTIGATIONAL PLAN - Core
14
3.1
Overall Study Design
14
3.2
Endpoints and Associated Variables
14
3.2.1
Efficacy Variables
14
3.2.1.1 Response Evaluation Criteria – AML
14
3.2.1.2 Response Evaluation Criteria – ALL
15
3.2.2
Pharmacokinetic Variables
16
3.2.3
Safety and Tolerability Variables
16
4
STATISTICAL METHODS - Core
16
4.1
Data Quality Assurance
16
4.2
General Presentation Considerations
16
4.3
General Variables
18
4.3.1
Data cut-off
18
4.3.2
Study Day Definitions
18
4.3.3
Time Windows
18
4.3.4
Handling of Missing Data
18
4.3.4.1 Imputations of Partial Dates
18
4.3.5
Imputation Rules for Laboratory Values Outside of Quantification Range
19
4.4
Software
19
4.5
Analysis Sets
19
4.6
Study Patients
19
4.6.1
Disposition of Patients
19
4.6.2
Protocol Deviations
19
4.6.2.1 Important Protocol Deviations
20
4.6.2.2 Monitoring of Important Protocol Deviations
20


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Statistical Analysis Plan
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4.7
Demographics and Baseline Characteristics
21
4.8
Medical/Surgical History
21
4.9
Prior Treatments for Leukaemia
21
4.10
Previous and Concomitant Medications and Other Treatments
21
4.11
Disallowed Concomitant Medications
22
4.12
Efficacy Evaluation
22
4.13
Pharmacokinetics
22
4.13.1
Pharmacokinetic Concentrations
22
4.13.2
Pharmacokinetic Parameters Calculation and Summary
23
4.13.3
Criteria for Handling Concentrations Below the Limit of Quantification or Missing 
Concentrations in Pharmacokinetic Analysis
24
4.13.4
Treatment of Outliers in Pharmacokinetic Analysis
24
4.14
Safety and Tolerability Evaluation
24
4.14.1
Exposure and treatment administration
24
4.14.2
Dose limiting toxicities (DLTs)
25
4.14.3
Definition of Maximum Tolerated Dose and Definition of Recommended Phase II Dose 25
4.14.4
Adverse Events
25
4.14.5
Deaths
27
4.14.6
Clinical Laboratory Evaluation
28
4.14.7
Vital Signs
29
4.14.8
ECGs
29
4.14.9
LVEF
30
4.14.10 Eastern Cooperative Oncology Group Performance Status (ECOG PS)
30
4.14.11 Tumour lysis syndrome (TLS)
30
4.14.12 Determination of Sample Size
31
4.14.13 Interim Analyses
31
5
INTRODUCTION – Module 1 Part A
32
6
STUDY OBJECTIVES - Module 1 Part A
33
6.1
Primary Objective
33
6.2
Secondary Objectives
33
6.3
Exploratory Objective(s)
34
7
INVESTIGATIONAL PLAN - Module 1 Part A
35
7.1
Overall Study Design
35
7.2
Endpoints and Associated Variables
37


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Statistical Analysis Plan
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7.2.1
Efficacy Variables
37
7.2.1.1 Overall Survival (OS)
37
7.2.1.2 Peripheral Blood
37
7.2.1.3 Extramedullary Disease
37
7.2.1.4 Bone Marrow
38
7.2.2
Pharmacokinetic Variables
38
7.2.3
Safety and Tolerability Variables
39
8
STATISTICAL METHODS - Module 1 Part A
40
8.1
Data Quality Assurance
40
8.2
General Presentation Considerations
40
8.3
General Variables
40
8.3.1
Study Day Definitions
40
8.3.2
Time Windows
40
8.3.3
Handling of Missing Data
40
8.3.4
Imputation Rules for Laboratory Values Outside of Quantification Range
40
8.4
Software
40
8.5
Analysis Sets
40
8.6
Study Patients
42
8.6.1
Disposition of Patients
42
8.6.2
Protocol Deviations
42
8.7
Demographics and Baseline Characteristics
43
8.8
Medical/Surgical History
43
8.9
Concomitant Medications and Other Treatments
43
8.10
Efficacy Evaluation
43
8.10.1
Analysis and Data Conventions
43
8.10.1.1 Multi-centre Studies
43
8.10.1.2 Adjustments for Covariates
43
8.10.1.3 Handling of Dropouts or Missing Data
43
8.10.2
Primary Efficacy Endpoints
43
8.10.2.1 Complete Response (CR+CRi) Rate
43
8.10.2.2 Overall Survival (OS)
44
8.11
Pharmacokinetics
44
8.12
Safety and Tolerability Evaluation
44


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8.12.1
Exposure and treatment administration
44
8.12.2
Dose limiting toxicities (DLTs)
44
8.12.3
Definition of Maximum Tolerated Dose and Definition of Recommended Phase II Dose 44
8.12.4
Adverse Events
44
8.12.5
Deaths
45
8.12.6
Clinical Laboratory Evaluation
45
8.12.7
Vital Signs
45
8.12.8
ECGs
45
8.12.9
LVEF
45
8.12.10 Eastern Cooperative Oncology Group performance status (ECOG PS)
45
8.12.11 Tumour lysis syndrome (TLS)
45
8.13
Determination of Sample Size
45
8.13.1.1 AZD0466 Monotherapy Escalation - Part A
45
8.14
Interim Analyses (Not applicable)
45
9
INTRODUCTION – Module 2
46
10
STUDY OBJECTIVES - Module 2
47
10.1
Secondary Objectives
47
11
INVESTIGATIONAL PLAN - Module 2
48
11.1
Overall Study Design
48
11.2
Endpoints and Associated Variables
49
11.2.1
Efficacy Variables
49
11.2.1.1 Peripheral Blood
49
11.2.1.2 Extramedullary Disease
49
11.2.1.3 Bone Marrow
49
11.2.2
Pharmacokinetic Variables
50
11.2.3
Safety and Tolerability Variables
52
12
STATISTICAL METHODS - Module 2
52
12.1
Data Quality Assurance
52
12.2
General Presentation Considerations
52
12.3
General Variables
52
12.3.1
Data cut-off
52
12.3.2
Study Day Definitions
53
12.3.3
Time Windows
53


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12.3.4
Handling of Missing Data
53
12.3.5
Imputation Rules for Laboratory Values Outside of Quantification Range
53
12.4
Software
53
12.5
Analysis Sets
53
12.6
Study Patients
54
12.6.1
Disposition of Patients
54
12.6.2
Protocol Deviations
54
12.7
Demographics and Baseline Characteristics
54
12.8
Medical/Surgical History
54
12.9
Concomitant Medications and Other Treatments
54
12.10
Efficacy Evaluation
55
12.11
Pharmacokinetics
55
12.12
Safety and Tolerability Evaluation
55
12.12.1 Exposure and treatment administration
55
12.12.2 Adverse Events
55
12.12.3 Deaths
55
12.12.4 Clinical Laboratory Evaluation
55
12.12.5 Vital Signs
55
12.12.6 ECGs
55
12.12.7 Eastern Cooperative Oncology Group performance status (ECOG PS)
55
12.12.8 Tumour lysis syndrome (TLS)
55
12.13
Determination of Sample Size
56
12.14
Interim Analyses
56
13
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS
57
14
REFERENCES
57








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AMENDMENT HISTORY
Date
Brief description of change
7 September 2021
Initial version 1.0
14 December 2023
Version 2.0 includes the following changes from V1.0:
!
Study was prematurely terminated on 28 July 2023; 
!
Sections and paragraphs which were dedicated to module 1 part B 
were removed.
!
Analysis descriptions were aligned to the tables, listings, figures 
as planned to be included into the synoptic CSR
!
Section 3.2.1.1 Response Evaluation Criteria – AML 
!
Divided response categories for Module 1 Part A and Part B.
!
Section 4.6.2.1 Important Protocol Deviations
!
Deviation 4 rephrased.
!
Section 4.14.1 Exposure and treatment administration
!
Exposure is also measured by the number of cycles received.
!
Section 4.13.2 Pharmacokinetic Parameters Calculation and
Summary
!
Added to summarize PK concentrations also by actual dose level
!
Section 4.14.1 Exposure and treatment administration.
!
Added exposure is also measured by the number of cycles.
!
Section 4.14.4 Adverse events
!
Period for AEs observed as treatment emergent after study 
treatment changed from 30 to 28 days,
!
OAEs (other significant AEs) removed.
!
Section 4.14.8 ECGs
!
ECG parameters will be summarized and plotted for the average 
from the triplicate ECG measurements.
!
Section 6.3 Exploratory Objective(s)
!
Exploratory objective added: haematological improvement in 
intermediate and higher risk MDS patients.
!
Section 7.2.1.5 Minimal Residual Disease (Part B only) was removed
!
Section 7.2.2 Pharmacokinetic Variables
!
Several parameters added AUCs (0-36), (0-24) added.
!
Section 8.3.1 Data cut-off removed
!
Section 8.10 Efficacy Evaluation
!
Removed parameters CR, TTR, DoR from the list of objectives
!
Section 8.10.2.1 Complete Response (CR+CRi) Rate removed
!
Section 8.10.2.2 Time to Response (TTR) removed
!
Section 8.10.2.3 Duration of Response (DoR) removed


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Date
Brief description of change
!
Sections 8.10.2.2, 8.10.2.3, 8.10.3.1 Efficacy evaluation
!
Disease progression revised as treatment failure and relapse, as 
applicable.
!
Section 8.10.3.3 Minimal/Measurable Residual Disease (Part B Only)
removed
!
Section 8.10.3.4 added for haematological response in intermediate 
and higher risk MDS patients (Part A Only)
!
Section 8.13.1.2 Part B Monotherapy Dose Expansion removed
!
Section 8.14 Interim Analysis changed to (Not applicable)
!
Minor editorial changes


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1
INTRODUCTION - Core
This is a modular, Phase I/II study of AZD0466 as monotherapy or in combination with other 
treatments in patients with advanced haematological malignancies.  The core sections of the SAP
contains information applicable to all analyses planned in this study, more specific details are 
provided in the sections related to the individual modules. 
The sponsor made the decision to terminate the study on July 28, 2023. Recruitment was stopped on 
June 16, 2023 and patients were followed up until the planned LPLV date of August 8, 2023.  At the 
time of stopping recruitment, Module 1 Part A, and Module 2 were ongoing.  The decision was also 
made not to initiate Module 1 Part B.  Therefore, this statistical analysis plan (SAP) provides the 
technical elaboration of the statistical analyses for Module 1 Part A, and Module 2.
The analyses described for Module 1 and 2 in this SAP are based upon the following study documents
and reporting standards:
!
Study Protocol, Version 4.0 (September 29, 2022)
!
Electronic Case Report Form (eCRF), Version 8.0 (March 13, 2023)
!
AZ Corporate CSRHLD Reporting Standards v3.3
!
Oncology Guidance Version 3.0
!
Early Phase Oncology Guidance Version 1.0
!
AZ Guideline: Pharmacokinetic Evaluations in Clinical Studies v2.3
Specifications for tables, figures, and listings are contained in a separate document.
2
STUDY OBJECTIVES – Core
2.1
Primary Objective 
Objectives
Endpoints/Variables
To assess the safety and tolerability of 
AZD0466 in patients with advanced 
haematological malignancies
Incidence of AEs and SAEs
Changes from baseline in laboratory findings, 
physical examinations, performance status, 
electrocardiograms, and vital signs
For further and more detailed definitions of primary study objectives refer to the individual modules.
2.2
Secondary Objectives
Objectives
Endpoints/Variables
To characterise the PK profile of AZD0466 
following intravenous administration (via PK 
profiles of the active moiety AZD4320 in 
plasma)
Plasma concentrations and derived PK 
parameters for total and released AZD4320, to 
be specified for each module
For further and more detailed definitions of the secondary study objectives refer to the individual 
modules.




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3
INVESTIGATIONAL PLAN - Core
3.1
Overall Study Design
This is a modular Phase I/II, open-label, multi-centre study in patients with advanced haematological 
malignancies with limited treatment options.  Each module will evaluate the safety, tolerability, PK,
and preliminary efficacy of AZD0466 as monotherapy or in combination with other treatments in the 
patient population.
For further details refer to the individual modules.
3.2
Endpoints and Associated Variables
3.2.1
Efficacy Variables
Disease assessments will be based on bone marrow biopsy and aspirate, peripheral blood collected 
for complete blood count (CBC), and blood smear with leukaemic blast count, if clinically indicated.  
Baseline assessments will be performed within 28 days before the first dose/administration of study 
medication and ideally as close as possible to the start of study treatment.  Post-baseline disease 
assessments will be performed following the SoA in Tables 14, 15 and Tables 21, 22 in the study 
protocol.
In case of unscheduled disease assessments, these will also be included into the analysis.
3.2.1.1
Response Evaluation Criteria – AML
Patients will be assigned to a response category by the investigator according to the criteria described 
in Appendix J in the study protocol for AML as for Module 1 Part A:
!
CR (Complete remission),
o
CRmrd- (Complete remission without minimal residual disease negativity),
o
CRmrd+ (Complete remission without minimal residual disease positivity),
o
CRmrd unknown (Complete remission with minimal residual disease unknown),
!
CRi (CR with incomplete recovery),
!
MLFS (Morphologic leukaemia-free state),
!
PR (Partial remission),
!
CRc (Cytogenetic CR, Part A only),
!
CRm (Molecular CR, Part A only),
!
SD (Stable disease),
!
PD (Progressive disease),
!
Treatment Failure, as: 
o
Resistant disease, 
o
New extramedullary disease,
o
Resistant disease or new extramedullary disease,
o
Death in aplasia,
o
Death from indeterminate cause,
!
Relapse.
This assignment is regardless of whether visits were scheduled or unscheduled and also regardless of 
whether a patient discontinues study intervention or receives another anticancer therapy. 
Reasons for overall response classification (supporting data leading to the classification of response, 
multiple options may be selected) will be listed as follows:


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!
Radiological imaging,
!
Bone marrow,
!
Peripheral blood,
!
Other.
Reasons for determining treatment failure, relapse, or disease progression (multiple options may be 
selected) will be listed as follows:
!
Increased/new extramedullary disease,
!
Increased blast cells in bone marrow,
!
Increased blast cells in peripheral blood,
!
Other.
3.2.1.2
Response Evaluation Criteria – ALL
Patients will be assigned to a response category by the investigator according to the criteria in 
Appendix K in the study protocol for ALL as: 
!
CR (Complete remission), 
!
CRi (CR with incomplete recovery), 
!
PR (Partial remission), 
!
Treatment Failure (specified as either Resistant Disease, Death in aplasia, or Death from 
indeterminate cause),
!
Relapse (specified as either Relapse from CR, Relapse from CRi, or Relapse from PR).
This assignment is regardless of whether visits were scheduled or unscheduled and also regardless of 
whether a patient discontinues study intervention or receives another anticancer therapy. 
Reasons for overall response classification (supporting data leading to the classification of response, 
multiple options may be selected) will also be summarised as follows:
!
Radiological imaging,
!
Bone marrow,
!
Peripheral blood,
!
Other.
Reasons for determining treatment failure or relapse (multiple options may be selected) will also be 
summarised as follows:
!
Increased/new extramedullary disease,
!
Increased blast cells in bone marrow,
!
Increased blast cells in peripheral blood,
!
Other.
Extramedullary disease
Extramedullary disease status will be obtained by assessments made by the investigator based on the 
use of CT/MRI/PET scans during the screening period within 28 days before the first 
dose/administration of study medication.  Post-baseline assessments for the response status (C1/C2) 
will be performed following the SoA in Tables 14, 15 and Tables 21, 22 in the study protocol.  
Patients with hepatosplenomegaly at baseline will have spleen and liver measured at screening and at 
all subsequent response evaluations


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For further details for derivation of the extramedullary disease status refer to the study protocol 
Appendix K. 
For further details on efficacy variables refer to the individual modules.
3.2.2
Pharmacokinetic Variables
For the definitions of the pharmacokinetic variables refer to the individual modules.
3.2.3
Safety and Tolerability Variables
The primary objective is to assess the safety and tolerability of the AZD0466 in patients with 
advanced haematological malignancies.
The following assessments will be performed:
•
Adverse event (AE) assessments,
•
Clinical chemistry (including creatine phosphokinase) and haematology as described in 
Section 4.14.6,
•
Amylase and lipase, coagulation indices, serum immunoglobulins, urinalysis, cardiac 
troponin and BNP (or NTproBNP), cortisol, ACTH and TSH parameters described in 
Section 4.14.6,
•
Vital signs (systolic blood pressure [SBP] and diastolic blood pressure [DBP], pulse rate, 
oral body temperature), height and weight,
•
12-lead Electrocardiograms (ECG),
•
Tumour lysis syndrome (TLS; clinical and laboratory assessments),
•
Eastern Cooperative Oncology Group performance status (ECOG PS),
•
Left ventricular ejection fraction (echocardiograms [ECHO] / multi-gated acquisition scan 
[MUGA]).
The full list of laboratory measurements performed during the study that are used to evaluate safety 
and tolerability variables can be found in Table 1 and Table 2.
For further module specific definitions of the safety and tolerability variables refer to the individual 
modules.
4
STATISTICAL METHODS - Core
4.1
Data Quality Assurance
All tables, figures and listings to be included in the clinical study report will be independently checked 
for consistency, integrity and in accordance with standard Parexel procedures.
4.2
General Presentation Considerations
The following considerations will be applicable to all modules.
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, 25th and 
75th percentiles (where appropriate), minimum, maximum and number of observations.  For 
log-transformed data it is more appropriate to present geometric mean (gmean), geometric coefficient 
of variation (CV), median, minimum and maximum. 
With continuous data, any calculation of descriptive statistics or other derived parameters will be
performed without rounding, but only for presentation in the output.  The original values, as to be 
presented for minimum and maximum, will be rounded as applicable in order to enable readability 


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with 5 to a maximum of 7 significant digits depending on the dimensional range of the original data, 
e.g.:
Data of a range
Presented as
From
To
Minimum
Maximum
     12.34
    56.789
   12.340
    56.789
   1234.5678
12345.6789
1234.6
12345.7
      0.1234
  1234.5678
    0.123
  1234.568
The mean, median and geometric mean (gmean) will be rounded to one additional decimal place 
compared to the presentation of the original data.  The SD will be rounded to two additional decimal 
places compared to the presentation of the original data.  Geometric CV will be presented with one 
decimal place. The maximum number of decimal places reported will be four for any summary 
statistic.
Categorical data will be summarized by frequency counts and percentages for each category.  
Percentages will be presented to one decimal place.  Percentages will not be presented for zero counts.  
Unless otherwise stated, percentages will be calculated out of the analysis set total and each dose 
level/cohort as appropriate for the respective module.
Confidence intervals (CIs) and p-values, when presented, will generally be constructed at 2-sided 
80% and 95% level.  CIs will be presented to one additional place than presented for the original data.  
Unless otherwise stated, summaries will be presented by dose level or by cohort, as applicable for the 
respective module. 
Baseline measurements and change from baseline variables 
Baseline will generally be the last value obtained prior to the first dose of study medication.  
Alternatively, 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), the average will be taken as a baseline 
value.  In the scenario where there are two assessments pre-dose on day 1, one with time recorded 
and the other without time recorded, the one with time recorded will be selected as the baseline value. 
Where safety data are summarized over time, study day will be calculated in relation to date of first 
dose.
For assessments performed on the day of first dose for which time is not captured a nominal pre-dose 
indicator as the variable label will serve as evidence that the assessment occurred prior to first dose.  
Assessments on the day of first dose where 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 first dose.
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%


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For considerations for analysis of pharmacokinetic data refer to sections 4.13.1, and 4.13.2.
4.3
General Variables
4.3.1
Data cut-off
A data cut-off is not applicable.  There will be one data analysis performed for both modules after the 
data base was locked.  All data will be used as available. 
4.3.2
Study Day Definitions
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). 
“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 on the 
same day as the last dose will be described as occurring zero days from last dose of study treatment.
4.3.3
Time Windows
Time windows for a reassignment of visits are not applicable for this study. The visit schedule is 
defined with the study protocol and the eCRF is set up to follow this scheme as defined. If 
measurements are repeated outside of the current schedule due to abnormalities, these will be 
recorded as unscheduled visits. Extreme value summaries use all values collected after baseline, 
including those collected at unscheduled visits. By-visit summaries only consider the scheduled 
assessments.
Listings will display all values contributing to each scheduled time point and unscheduled visits for 
a patient.
4.3.4
Handling of Missing Data
In general, other than for the below described, or where otherwise specified in the particular analysis, 
missing data will not be imputed and will be treated as missing.
4.3.4.1
Imputations of Partial Dates
Concomitant medication and adverse events start dates
!
Missing day: imputed with the 1st of the month, unless month and year are the same as month
and year of first dose of study treatment, then impute with first dose date.
!
Missing day and month: imputed with the 1st of January unless the year is the same as the year 
of first dose of study treatment, then imputed with first dose date.
!
Completely missing: imputed with date of first dose of study treatment, unless the end date
suggests it could have started prior to this in which case it is imputed 1st January of the same year 
as at the end date.
When imputing a start date care should be taken to ensure the start date is sensible, i.e., prior to the 
end date.
Concomitant medication and adverse events end dates


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!
Missing day: imputed with the last day of the month, unless month and year are the same as month 
and year of last dose of study treatment, then imputed with the last treatment date in that month.
!
Missing day and month: imputed with the 31st of December unless the year is the same as the 
year of last dose of study treatment, the imputed with the last treatment date in that year.
!
Completely missing: no date imputed (the event is assumed to be ongoing).
No study day or duration will be calculated for imputed dates.
4.3.5
Imputation Rules for Laboratory Values Outside of Quantification Range
Values of the form “< x” (i.e., below the lower limit of quantification [LLQ]) or “> x” (i.e., above the 
upper limit of quantification [ULQ]) will be imputed as “x” in the calculation of summary statistics 
but displayed as “< x” or “> x” in the listings.
4.4
Software
All report outputs will be produced using SAS® version 9.4 in a secure and validated environment.
PK analyses will be produced using Phoenix® WinNonLin (WNL) version 8.1 or later in a secure 
and validated environment. 
4.5
Analysis Sets
For the definitions of the analysis sets refer to the individual modules.
4.6
Study Patients
4.6.1
Disposition of Patients
Patient disposition from screening to study completion will be listed and summarised for the Enrolled 
analysis set.  Summaries will include:
!
Number of patients screened (informed consent received)
!
Number of subjects assigned to study treatment
!
Number and percentage of patients who did not receive study treatment (including reasons)
!
Number and percentage of patients who received study treatment
!
Number and percentage of patients who completed study treatment (including reasons for those 
that did not)
!
Number and percentage of patients who completed study (including reasons for those that do not)
Study treatment discontinuations will be listed, including dose level/cohort/study treatment as 
appropriate for the respective module, the date of study treatment discontinuation, total treatment 
duration (days), actual treatment duration (days) and reason for discontinuation.  Total treatment 
duration and actual treatment duration will be derived as described in Section 4.14.1. 
An additional listing will be provided for study completion status.
A summary of the number and percentage of patients that were screened will be presented by country 
and site.
4.6.2
Protocol Deviations
General protocol deviation categories will be programmatically pulled from the electronic case report 
form (eCRF) data.  These deviations and deviations identified from monitoring notes or reports will 
be reviewed and assessed by AZ on a case by-case basis to determine importance.  Important protocol 


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deviations are defined as those deviations from the protocol likely to have an impact on the perceived 
efficacy and/or safety of study treatments.  All decisions on importance will be made ahead of 
database lock and will be documented. 
The important protocol deviations will be listed and summarised by dose level /cohort on the safety 
analysis set.    
A full list of protocol deviations can be found in the study-specific protocol deviation specification.
4.6.2.1
Important Protocol Deviations
According to ICH E3 guidelines version dated 1995 (ICH 1995), 
“Protocol deviations consist of any change, divergence or departure from the study design or 
procedures defined in the protocol. Important protocol deviations (IPDs) are a subset of protocol 
deviations that may significantly affect the completeness, accuracy, and/or reliability of the study 
data or that may significantly affect a patient’s rights, safety or well-being.” 
For this study, the following 4 general categories will be considered IPDs and will be summarised in 
the CSR:
!
Deviation 1: Patients who received treatment and who deviated from the entry criteria in the 
study protocol.
!
Deviation 2: The patient met discontinuation criteria but did not discontinue AZD0466 (e.g. 
patient withdrew consent, patient became pregnant).
!
Deviation 3: The patient received a prohibited concomitant medication or procedure as 
detailed in Section 6.5.1 of the study protocol or any other concomitant medication or 
procedure which, upon physician review of all medications and procedures prior to database 
lock , is considered to have a potential effect on study outcomes. 
!
Deviation 4: Administration of study treatments, treatment compliance or dose level 
assignment was not according to protocol, and considered to have a potential effect on study 
outcomes.
   
Details for the protocol deviations criteria with potential to be assessed as an IPD will be specified in 
the protocol deviations specifications document.
4.6.2.2
Monitoring of Important Protocol Deviations
Programmable protocol deviations will be detected from the data recorded in the clinical database 
and will be reviewed at regular protocol deviations review meetings. 
At this meeting, the 
programmatically-derived protocol deviations will be checked to ensure that they have been correctly 
classified as major or minor protocol deviations. 
On an ongoing basis throughout the study, monitoring notes or summaries will also be reviewed to 
determine any important post entry deviations that are not identifiable via programming. 
If the number of deviations which are considered to have the potential to impact the primary analysis 
is considered important, sensitivity analyses may be performed on subgroups. This will be decided 
during the data review meeting and before the database lock. 
The final classification of IPDs will be made prior to database lock or data cut-off for final analysis. 
Any other deviations from monitoring notes or reports will be reported in an appendix to the CSR.


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4.7
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarised and listed for all patients in the Safety 
analysis set by dose level/cohort as appropriate: 
!
Demographic characteristics (age [years], age group [< 65 years; ≥ 65 years], sex [female; male], 
race, ethnicity and country); height (cm), weight (kg)
!
Any other patient/disease characteristics at baseline as specified below:
o
Disease type,
o
WHO classification of acute leukaemia,
o
Molecular and cytogenetic characteristics of AML/ALL,
o
Eastern Cooperative Oncology Group (ECOG) performance status,
o
Extramedullary disease will be listed for target/non-target lesions for ALL.
4.8
Medical/Surgical History
Medical history and surgical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA).  Disease related medical history will be listed and the number and percentage of patients 
with any disease-related medical history will be summarised for the Safety analysis set by system 
organ class (SOC) and preferred term (PT), by dose level/cohort and overall as appropriate.
Surgical history will be summarised, if applicable.
4.9
Prior Treatments for Leukaemia
Prior therapies are defined as started and stopped prior to the first dose of the study treatment based 
on imputed start and stop dates. Incomplete therapy start and stop dates will be imputed as detailed 
in section 4.3.4.1.
Radiotherapy and all cancer therapies prior to the study will be listed.
The following summaries will be produced for prior therapies for leukaemia disease under study:
!
Prior anti-cancer therapy class 
!
Prior anti-cancer radiotherapy
!
Number of prior lines of anti-cancer therapy
!
Number of prior regimens of anti-cancer therapy 
!
Anti-cancer therapy agent by ATC and generic drug name
Treatment status (Consolidation, Palliative, Maintenance, Induction Therapy) will be listed.
In addition to prior therapies for leukaemia, post-study cancer treatment will be listed.  Post-study 
anti-cancer treatments are defined as treatments started after a patient discontinued study treatment.
4.10 Previous and Concomitant Medications and Other Treatments
Treatments received prior to, concomitantly or post-treatment will be coded using the World Health 
Organisation-Drug Dictionary (WHODRUG) and will be classified by Anatomical Therapeutic 
Chemical (ATC) categories. 
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 4.3.4.1.
Prior medications, concomitant and post-study medications are defined based on imputed start and 
stop dates as follows:


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!
Prior medications are those that started and stopped prior to the first dose of the study treatment
!
Concomitant medications are those with a stop date on or after the first dose date of study 
treatment (and could have started prior to or during treatment)
!
Post-study medications are those with a start date after the last dose of the study treatment.
All concomitant medication will be listed by patient and will include the reported name, coded name , 
(ATC), route of administration, dose, frequency, start date/time, duration and indication (PT).  
Concomitant medication will be summarised by ATC and PT, dose level/cohort as appropriate.
All prior, concomitant and post study treatment medication data (including surgical procedures) will 
be listed.  Missing coding terms (ATC or PT) will be listed and summarised as uncoded terms.  
All listings and tables will be based on the Safety analysis set.
4.11 Disallowed Concomitant Medications
Patient may have received prohibited concomitant medication as detailed in Section 6.5.2 of the study 
protocol or any other concomitant medication which, upon physician review of all medications and 
procedures prior to database lock, is considered to have a potential effect on study outcomes.
Disallowed concomitant medications will be summarised and listed.
4.12 Efficacy Evaluation
Refer to the individual modules.
4.13 Pharmacokinetics
4.13.1
Pharmacokinetic Concentrations
Plasma concentrations of total and released AZD4320 will be listed by actual and relative (to dose 
administration) sampling time.  The following summary statistics will be presented for the 
concentrations and PK parameters at each time point separately per cohort and actual dose level: 
!
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 logarithmic scale)
!
Arithmetic Mean
!
Arithmetic 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:


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! 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 
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 (gSD calculated as exp[μ±s])
!
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. 
4.13.2
Pharmacokinetic Parameters Calculation and Summary 
Derived PK parameters will be summarized by cycle, separately per cohort and actual dose level.  
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 
logarithmic scale) 
!
Arithmetic mean calculated using untransformed data 
!
Arithmetic SD calculated using untransformed data 
!
Minimum 
!
Median
!
Maximum 
!
Number of observations 
The descriptive statistics for diagnostic parameters are n, arithmetic mean, SD, median, min, and max. 
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. 


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!
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. 
!
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. 
4.13.3
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.
4.13.4
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. 
4.14 Safety and Tolerability Evaluation
Refer to the individual modules.
4.14.1
Exposure and treatment administration
Exposure to investigational product i.e. total amount of study drug received will be listed for all 
patients.
Total treatment duration will be summarized by the following: mean, standard deviation, minimum, 
maximum, median and number of observations.  Exposure is also measured by the number of cycles 
received. A cycle corresponds to a period of 28 days from cycle 2 and 35 days for cycle 1. If a cycle 
is prolonged due to toxicity, this should still be counted as one cycle. A cycle will be counted if 
treatment is started even if the full dose is not delivered.  In addition, the number and percentage of 


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patients with at least one dose reduction will be presented separately for the initial period of 
evaluability defined as 35 days and for any cycle in the study.
Relative dose intensity (RDI) of AZD0466 will be derived as the percentage of the actual dose 
delivered relative to the intended dose up to treatment discontinuation as:
RDI(%)= 100 x d/D
where:
d is the actual cumulative dose delivered up to the last dosing, and 
D is the intended cumulative dose up to the last day of dosing 
(i.e. that would have been delivered without a modification of the dose or schedule).
Summaries by mean, standard deviation, minimum, maximum, median and number of observations 
will be produced for RDI of AZD0466.
4.14.2
Dose limiting toxicities (DLTs) 
A DLT is defined as an AE or abnormal laboratory value that meets the predefined study DLT criteria 
as described in Section 11.4.7.2 in the study protocol.  The DLT evaluation period is defined from 
first dose of study treatment, up to the end of Cycle 1 (Day 35).  DLTs occurring during this period 
will be used for determination of the maximum tolerated dose (MTD) during Part A in Module 1.  
The number of patients evaluable for determination of DLTs and the number of patients with any 
DLT (and their categorisation) during the DLT evaluation period will be summarised by dose 
level/cohort, and by SOC and PT, as appropriate.  
The listings and tables will be based on the DLT-evaluable analysis set.  
4.14.3
Definition of Maximum Tolerated Dose and Definition of Recommended Phase II
Dose
The MTD evaluation will be based on the DLT-evaluable population.  The MTD will be determined 
by isotonic regression analysis applied to DLT rates observed during the dose-escalation phase.  The 
estimated MTD will be selected as the dose with the smallest absolute value of difference between 
the estimated DLT rate and the target DLT rate of 30% among all doses.  If 2 or more doses tie for 
the smallest difference, the following rules will be applied:
If the estimated DLT rate is < 30% for all doses, then select the higher dose among the tied doses
If the estimated DLT rate for the tied doses are a combination of < 30% and > 30% then select the 
higher dose among the tied doses
If the estimated DLT rate is > 30% for all doses, then select the lower dose among the tied doses.
The MTD evaluation will not be part of this analysis and thus related methods are not further be 
described in this analysis plan.  The RP2D and schedule will be determined in discussion among the 
SRC (Appendix A 5 of the study protocol) and the sponsor.  Observations related to PK, PD, and AEs 
may be included in the rationale supporting the RP2D and schedule.
4.14.4
Adverse Events
Any AE occurring on or after first dose of study treatment and within 28 days after discontinuation 
of study treatment will be included in the AE summaries.  Any AEs in this period that occur after a 
patient has received further therapy for cancer (following discontinuation of study treatment) will be 


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flagged in the data listings.  AEs occurring before first dose of study treatment or after 28 days after 
discontinuation of study treatment will be listed separately, but not included in the summaries.
AEs will be coded using the most recent Medical Dictionary for Regulatory Activities (MedDRA) 
Version as available at data cut-off and will be graded according to the National Cancer Institute of 
Common Terminology Criteria for AEs (CTCAE version 5.0).
AEs of special interest
In this study, the following are considered to be AESIs:
!
Tumour lysis syndrome (Appendix G of the study protocol)
!
Hepatotoxicity, including potential Hy’s Law, drug-induced liver injury (DILI), and bilirubin 
increase with transaminase (ALT or AST or both ALT and AST) increase
!
QRS amplitude decrease
All AEs will be listed individually by patient and dose level/cohort as appropriate with the inclusion 
of the patient identifier, centre, country, age, race, sex, preferred term, reported term, time of onset, 
duration (days), CTCAE, seriousness (serious/non-serious), action taken (dose not changed, dose 
increased, dose reduced, drug interrupted, drug permanently discontinued, N/A), outcome 
(recovered/resolved, recovering/resolving, recovered/resolved with sequelae, not recovered/not 
resolved), related assessed by investigator, DLT as well as a flag in the case of AEs occurring after 
additional cancer therapy.  AEs of special interest (AESI) will be listed.
The following summaries for the number and percentage of patients with AEs will be created by dose 
level/cohort and overall as appropriate: 
!
Overall summary of adverse events for the categories:
o
Any AE
o
Any SAE
o
Any SAE with outcome death
o
Any AE leading to discontinuation of AZD0466
o
Any possibly related AE 
o
Any possibly related SAE 
o
Any AE leading to AZD0466 dose reduction
o
Any AE leading to AZD0466 dose interruption
o
Any AE of >= CTCAE grade 3 
o
Any SAE and/or >= CTCAE grade 3 AE 
o
Any AE classified as a DLT 
o
Any possibly related deaths 
!
AEs by SOC and PT
!
AEs sorted by decreasing frequency by PT
!
AEs by SOC, PT and maximum reported CTCAE grade 
!
AEs of CTCAE grade 3 or higher by SOC and PT
!
AEs 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.
!
Time to onset of first AE (days) by SOC and PT
!
Duration of first AE (days) by SOC and PT
!
AEs leading to hospitalisation by SOC and PT
!
AEs by PT and maximum reported CTCAE grade


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!
AEs by PT and relationship to study treatment
!
AEs with outcome death by SOC and PT
!
AEs assessed by investigator as possibly related with outcome death by SOC and PT
!
SAEs by SOC and PT
!
SAEs leading to discontinuation of study treatment by SOC and PT
!
SAEs leading to discontinuation of study treatment assessed by investigator as possibly 
related to study treatment by SOC and PT
!
Non-serious AEs sorted by decreasing frequency by PT.
!
SAEs assessed by investigator as possibly related to study treatment by SOC and PT 
!
AEs leading to discontinuation of study treatment by SOC and PT
!
AEs assessed by investigator as possibly related to study treatment leading to discontinuation 
of study treatment by SOC and PT
!
AEs leading to reduction of study treatment by SOC and PT
!
AEs leading to interruption of study treatment by SOC and PT
For patients with multiple AEs of the same SOC and/or PT, only the AE with the highest CTCAE 
grade per system organ class and preferred term will be included in the summaries presented by 
maximum CTCAE grade.  Similarly, for multiple AEs differing in causality, only the AE with
causality will be included in by-causality summaries.  If causality is missing, the AE will be 
considered related in all summaries.
In summaries including SOC or PT, the summaries are sorted by international order for SOC and in 
alphabetical order for PT.
The following summaries for the number and percentage of patients will be created for AESIs if 
applicable: 
!
By PT 
!
By outcome
!
By time of resolution
o
On-treatment, which is defined as AEs with onset date on or after first study treatment, 
but before or on date of end of treatment;
o
Follow-up, which is defined as AEs with onset after, but within 28 days after end of 
treatment;
o
Post-treatment, which is defined as AEs with onset after 28 days after end of treatment.
4.14.5
Deaths
A summary will be provided with the number and percentage of patients who died, and death event 
was categorised as: 
!
AEs with outcome of death only
!
Related to disease under investigation only
!
Both related to disease under investigation and an AE with outcome of death only
!
AEs with a start date after 28 days after treatment discontinuation with an outcome of death
!
Other deaths
A corresponding listing will also be produced.


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4.14.6
Clinical Laboratory Evaluation
All local laboratory results collected will be listed according to the SoA in Tables 14, 15 and Tables 
21, 22 in the study protocol.
Summaries for safety laboratory will include the parameters as specified in Table 1 and Table 2.
Table 1 Laboratory Safety Variables - Clinical Chemistry
Albumin 
Cholesterola
Magnesium
Alkaline phosphatase
C-reactive protein
Phosphate
Alanine aminotransferase
Creatinine
Potassium
Amylaseb
Gamma-glutamyl transferase
Sodium
Aspartate aminotransferase
Glucosea
Triglyceridesa
Bicarbonate
Glutamate dehydrogenase
Total protein
Bilirubin (total and direct)
Lactate dehydrogenase
Chloride
Blood urea nitrogen
Lipaseb
Uric acid
Corrected calcium
a
Fasting cholesterol, triglyceride and glucose values are not required.  However, if non-fasting values are abnormal, 
a repeat sample should be obtained when the patient is fasting.
b
Collected at screening, pre-infusion on each dosing day, and end of treatment visit.
Table 2 Laboratory Safety Variables - Haematology
Absolute leucocyte differential count: 
neutrophils, lymphocytes, monocytes, basophils, 
eosinophils
Blood (B)-haemoglobin 
Haematocrit
Leucocytes
Platelet count
All values will be classified as low (below normal range), normal (within normal range), or high 
(above normal range) based on local laboratory normal reference ranges.  Results will be converted 
to standard units.  For assessments included in CTCAE version 5.0, the CTCAE grade will be
determined.
All clinical laboratory results will be listed. 
For all continuous laboratory assessments, the absolute values and the change from baseline will be 
summarised using descriptive statistics at each time point by dose level/cohort as appropriate.  
For clinical chemistry and haematology, shift tables from baseline to worst on-treatment value 
according to reference range classification will be created.  CTCAE grade changes from baseline to 
the maximum on-treatment grade will also be provided.  Corresponding shift tables (“Negative”, 
“Trace”, “Positive”, “0”, “+”, “++”, “+++”) will be produced for urinalysis
Liver biochemistry test results over time for patients with elevated ALT or AST (≥ 3 x ULN) and 
elevated bilirubin (≥ 2 x ULN,) regardless of whether or not these elevations occurred at the same 
visit, or ALT or AST of ≥ 5 x ULN, will be tabulated and plotted.
CCI


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All parameters as used for summaries including amylase and lipase, coagulation indices, serum 
immunoglobulins, urinalysis, cardiac troponin and BNP (or NTproBNP), clinical and laboratory 
assessments for TLS, Cortisol, ACTH and TSH parameters will be listed as appropriate. 
Following 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.  
4.14.7
Vital Signs
The following vital signs will be assessed and listed:
!
Systolic blood pressure (SBP) [mmHg]
!
Diastolic blood pressure (DBP) [mmHg]
!
Pulse rate (bpm)
!
Oral body temperature (°C)
!
Respiration rate (breaths/min)
!
Body weight (kg)
Change from baseline in vital signs variables will be calculated for each post-dose visit.
Descriptive statistics for absolute values and changes from baseline will be presented by dose 
level/cohort as appropriate. 
Blood pressure and pulse rate will be plotted as subject profiles.
4.14.8
ECGs
The following parameters will be assessed in 12-lead ECGs:
!
PR-interval (msec).
!
QRS-duration (msec). 
!
QT-interval (msec).
!
QT-interval corrected using the Fridericia correction formula (QTcF) (msec).
!
RR-interval (msec).
!
Heart rate (beats per minute [bpm]).
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal.
All ECG parameters will be listed by patient including changes from baseline for numeric ECG 
parameters. 
Descriptive statistics for the means of the triplicate ECG measurements in absolute values and 
changes from baseline will be presented by dose level/cohort as appropriate. The values used for 
this summary are the average of the three measurements of the triplicate ECG.
A shift table for the overall ECG assessment from baseline to the worst (abnormal) on-treatment 
assessement will be created.  
Subject profiles will be plotted for the means of the triplicate ECG measurements in absolute values.
QTcF outliers (defined as values following study treatment that are greater than 470 msec or increases 
from baseline greater than 30 msec) will be summarised using cumulative counts and percentages 
under the following categories:
!
Absolute value > 470 msec


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!
Absolute value > 480 msec
!
Absolute value > 500 msec
!
Change from baseline > 30 msec
!
Change from baseline > 60 msec
!
Absolute value > 470 msec and change from baseline > 30 msec
!
Absolute value > 500 msec and change from baseline > 60 msec.
4.14.9
LVEF
Descriptive statistics for left ventricular ejection fraction (LVEF) for absolute values and changes 
from baseline will be presented by dose level/cohort as appropriate.
Summary tabulations of frequencies will be presented for:
!
Baseline CTCAE grade, as defined by:
-
≥ 50% (CTCAE Grade 0)
-
40% to < 50% (CTCAE grade 2)
-
20% to < 50% (CTCAE grade 3)
-
< 20% (CTCAE grade 4). 
!
Maximum on-treatment CTCAE grade, as defined by:
-
≥50% (CTCAE Grade 0)
-
40% to < 50% or 10 to 19% drop from baseline (CTCAE grade 2)
-
20% to < 50% or 20 to 29% drop from baseline (CTCAE grade 3)
-
< 20% (CTCAE grade 4). 
In addition, the results of (echocardiograms [ECHO] / multi-gated acquisition scan [MUGA]) scans 
for LVEF will be listed.  
4.14.10
Eastern Cooperative Oncology Group Performance Status (ECOG PS)
ECOG performance status scores will be assessed at screening and before each dose of AZD0466
according to ECOG criteria as follows:
0 =
Fully active, able to carry out all pre-disease activities without restrictions
1 =
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g. light housework, office work
2 =
Ambulatory and capable of self-care, but unable to carry out any work activities.  Up and about 
more than 50% of waking hours
3 =
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 =
Completely disabled, cannot carry on self-care, totally confined to bed or chair
5 =
Death.
The ECOG performance status will be listed and summarised as frequency counts by dose 
level/cohort and visit as appropriate.
4.14.11
Tumour lysis syndrome (TLS)
Table of key subject information for patients with tumour lysis syndrome will be provided.  This 
listing will comprise 


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!
Disease history (AML/ALL), age, gender, cohort
!
Baseline risk of TLS as specified in Table 3
!
WBC, LDH, BUN at baseline
!
Allopurinol, and Rasburicase prophylaxis (identified by ATC-code list from prior or 
concomitant medications)
!
Date and time of TLS assessment
!
Parameters contributing to the laboratory TLS 
!
Parameters contributing to the clinical TLS with Cairo-Bishop Grade
!
Overall Cairo-Bishop Grade (as assessed by the investigator)
!
AE term and number, AE recorded as a DLT, AE serious, AE start and stop dates, and AE 
outcome.
Table 3 Risk of tumour lysis syndrome
Risk of tumour lysis syndromea
Malignancy
High
Intermediate
Low
Acute myeloid 
leukaemia
WBC ≥100 ×109/L
WBC ≥25 and ≤100 ×109/L
or 
WBC < 25 ×109/L and 
LDH ≥2x ULN 
WBC < 25 ×109/L and LDH 
< 2x ULN
Acute 
lymphoblastic 
leukaemia
WBC ≥100 ×109/L and 
LDH ≥2x ULN
WBC < 100 ×109/L and 
LDH < 2x ULN
-
c
WBC < 10 ×109/L is required for study eligibility and hydroxyurea is permitted during screening and Cycle 1 to 
achieve this; consequently patients will be intermediate or low risk of TLS.
Risk classification adapted from MD Anderson Cancer Center guidance.
Summary tabulations of frequencies for Overall Cairo-Bishop Grade (as assessed by the investigator) 
will be presented at patient- and event-level for:
!
Laboratory TLS
!
Clinical TLS
!
Cairo-Bishop TLS Grade
!
TLS classified as a DLT
Time to first onset of Laboratory TLS and Time to first onset of Clinical TLS will be presented as 
categorical groupings by cycle, and as summary statistics, including Kaplan-Meier statistics (Q1, 
median and Q3).
4.14.12
Determination of Sample Size
Refer to the individual modules.
4.14.13
Interim Analyses
Refer to the individual modules.


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5
INTRODUCTION – Module 1 Part A
Module 1 will evaluate the safety, tolerability, PK, and efficacy of AZD0466 as monotherapy.  Part A 
is a dose escalation assessment of the safety and tolerability of AZD0466 to determine the 
recommended dose and schedule for further evaluation.  
As Module 1 Part B was not initiated, Sections 6, 7 and 8 describe the analyses to be conducted for 
Module 1 Part A.
For further general study information refer to Section 1.


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6
STUDY OBJECTIVES - Module 1 Part A
The core objectives and endpoints for the study are listed in Sections 2.1, 2.2, and 2.3; additional 
endpoints for Module 1 Part A are listed in Sections 6.1, 6.2, and 6.3.
6.1
Primary Objective
Objectives
Endpoints/Variables
To assess the safety and tolerability of 
AZD0466 in patients with advanced 
haematological malignancies
DLT
MTD
RP2D and schedule
DLT, dose-limiting toxicity; MTD, maximum tolerated dose; RP2D, recommended Phase II dose
6.2
Secondary Objectives
Objectives
Endpoints/Variables
Complete Response Rate (CR+CRi)
To estimate the preliminary antitumor activity 
of AZD0466 by assessment of Complete 
response rate (CR+CRi) in patients with 
advanced haematological malignancies
Complete response rate (CR+CRi) is defined as 
the proportion of patients who have a complete 
remission (CR) or incomplete haematological 
response (CRi), as determined by criteria 
described in Appendix J and Appendix K of the 
study protocol.
The analysis will include all dosed patients as 
intended.  
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 CR+CRi, regardless of 
whether the patient withdraws from study 
treatment.  Patients who go off 
treatment without a response or progression, 
receive a subsequent therapy, and then respond 
will not be included as responders in this 
evaluation. 
The measure of interest is the estimate of 
CR+CRi. 
Time to Response (TTR)
To estimate the preliminary antitumor activity 
of AZD0466 by assessment of time to complete 
Time to response is defined as the time from 
date of first dose until the date of first 
documented CR or CRi.


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Objectives
Endpoints/Variables
response (TTR) in patients advanced 
haematological malignancies
The analysis will include all dosed patients as 
intended, who have a complete remission.
Patients who go off study treatment without a 
clinical response and receive a subsequent 
therapy and then respond will not be included. 
The measure of interest is median TTR.
Duration of Response (DoR)
To estimate the preliminary antitumor activity 
of AZD0466 by assessment of DoR in patients 
with advanced haematological malignancies.
DoR will be defined as the time from the date of 
first documented response (CR+CRi) until date 
of documented progression, relapse, failure 
(relapse and failure as determined by criteria 
described in Appendix J and Appendix K of the 
study protocol) or death due to any cause.
The analysis will include all dosed patients as 
intended who have a confirmed response (CR or 
CRi), regardless of whether the patient 
withdraws from study treatment or receives 
another anticancer therapy.
The measure of interest are the percentiles of 
DoR.
Overall Survival (OS)
To estimate the preliminary antitumor activity 
of AZD0466 by assessment of OS in patients 
with advanced haematological malignancies.
OS is defined as time from date of first dose 
until the date of death due to any cause.  
The comparison will include all dosed patients 
as intended, regardless of whether the patient 
withdraws from therapy or receives another 
anticancer therapy.
The measures of interest are the median OS and 
landmarks at 6 and 12 months of OS.
ALL, acute lymphocytic leukaemia; AML, acute myeloblastic leukaemia; CR, complete remission; CRi, incomplete 
haematological response; DoR, duration of response; OS, overall survival; TTR, time to response
6.3
 
CCI
CCI
CCI
CCI
CCI




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Figure 1 Schema for Module 1
a
AZD0466 doses shown are illustrative. Actual doses will not exceed a 2-fold increase of a dose declared tolerable 
by the SRC, or the maximum feasible dose as specified in in the study protocol section 11.4.7.5.
Dotted paths contingent on emerging data.
ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; DL, dose level; IA, interim analysis; MPN, 
myeloproliferative neoplasm; TP53, gene encoding tumour protein p53.
Part A, the dose escalation part of the study, will enrol up to 40 patients with a histologically 
confirmed AML or ALL to ensure 30 DLT-evaluable patients in total.  At least 3 DLT-evaluable 
patients are required at each dose level and, up to 12 patients overall may be enrolled at each dose 
level.  Up to additional 18 patients may be enrolled to backfill earlier cohorts at lower dose levels 
with the intent of enabling pre- and on-treatment peripheral blood samples and bone marrow aspirates 
and biopsies to aid characterisation of the PD of AZD0466 and to provide additional data on safety, 
tolerability, PK, and biological activity (n = 58 in total).  If a dose escalation cohort and a backfill 
expansion cohort are simultaneously open to enrolment, precedence will be given to enrolment into 
the dose escalation cohort.
A SRC will be responsible for making recommendations for dose-escalation or de-escalation after 
each dose level, including decisions on opening cohorts for backfill, in accordance with the SRC 
charter.  From day of target dose, a delay of at least 3 days will be mandatory between the first and 
second patient at each dose level.  This separation between the dosing of patients will ensure that any 
acute toxic effects of the AZD0466 infusion will have sufficient time to be identified before additional 
patients are exposed.  The intra-patient dose ramp-up and/or dose schedule for each cohort may be 
modified based on safety, PK, and PD findings of a previous 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.




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7.2.1.4
Bone Marrow
Bone marrow core biopsy and bone marrow aspirate should be performed as specified in in the SoA 
in Tables 16, 17 in the study protocol. 
!
Screening (between Day -14 and -1)
!
Cycle 1 Day 30 ± 1 day
!
Cycle 2 and subsequent cycles between Days 23 to 28
!
Disease progression or EoT visit
The disease progression sample collection may occur at the safety follow-up visit (if conducted in 
person) if not collected previously.  Additional bone marrow or peripheral blood samples may be 
collected, as clinically indicated.
7.2.2
Pharmacokinetic Variables
Pharmacokinetic parameters will be calculated by non-compartmental analysis methods using 
Phoenix® WinNonlin® (Version 8.1) or higher as data applicable.  
The PK parameters are calculated/estimated according to AstraZeneca standards.
PK analysis will, where data allow, be carried out using actual elapsed times determined from the PK 
sampling and dosing times recorded 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 concentrations supporting doses on Cycle 1 Day 8 and Cycle 2 Day 1.
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
AUC0-72
Partial area under the plasma concentration-time curve from time 0 to 72 hours after 
the start of infusion (Cycle 1 Day 8 only)
AUC0-36
Partial area under the plasma concentration-time curve from time 0 to 36 hours after 
the start of infusion (to match urine collection interval) (Cycle 1 Day 8 only)
AUC0-24
Partial area under the plasma concentration-time curve from time 0 to 24 hours after 
the start of infusion (to support comparisons between C1D8 and C2D1)
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


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Dose normalised 
AUClasta
Area under the plasma concentration-time curve from time 0 to time of last 
quantifiable analyte concentration divided by the administered AZD4320 dose in mg
Dose normalised 
AUC0-24a
Area under the plasma concentration-time curve from time 0 to 24 hours after the 
start of infusion divided by the administered AZD4320 dose in mg
Dose normalised 
AUC0-72a
Area under the plasma concentration-time curve from time 0 to 72 hours after the 
start of infusion divided by the administered AZD4320 dose in mg (Cycle 1 Day 8 
only)
Dose normalised Cmaxa
Maximum observed plasma (peak) drug concentration divided by the administered 
AZD4320 dose in mg
a
Calculated for total AZD4320 only; AZD4320 dose calculated as 29% w/w of the AZD0466 dose in mg, based on 
average batch results, unless an alternate value is specified.
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)
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.
Urine
Data permitting, the following urine PK parameters will be calculated for total AZD4320 for 
Cycle 1 Days 1, 4, and 8, as appropriate:
Table 4 Urine PK parameters
Ae(t1-t2)
Cumulative and by interval amount of unchanged drug excreted in urine from time
t1 to t2
fe(t1-t2)
Cumulative and by interval percentage of adjusted AZD4320 dose excreted 
unchanged in urine from time t1 to t2. For fe, adjusted dose will be calculated as
(AZD0466 dose / AZD0466 mol weight * AZD4320 mol weight)
CLR 
Renal clearance of drug from plasma (Day 8 only)
Additional PK parameters may be calculated as appropriate.
7.2.3
Safety and Tolerability Variables
Part A
The primary objective of Part A is to assess the safety and tolerability, describe the DLTs, and identify 
the MTD and/or RP2D of AZD0466 in patients with advanced haematological malignancies.


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As referenced in Section 3.2.3 the safety assessments performed will be:
•
Adverse event (AE) assessments
•
Clinical chemistry (including creatine phosphokinase) and haematology as described in 
Section 4.14.6.
•
Amylase and lipase, coagulation indices, serum immunoglobulins, urinalysis, cardiac 
troponin and BNP (or NTproBNP), clinical and laboratory assessments for TLS, cortisol, 
ACTH and TSH parameters described in Section 4.14.6.
•
Vital signs (systolic blood pressure [SBP] and diastolic blood pressure [DBP], pulse rate, 
oral body temperature), height and weight
•
12-lead Electrocardiograms (ECG)
•
Tumour lysis syndrome (TLS) 
•
Eastern Cooperative Oncology Group performance status (ECOG PS)
•
Left ventricular ejection fraction (echocardiograms [ECHO] / multi-gated acquisition scan 
[MUGA]).
The full list of laboratory measurements performed during the study that are used to evaluate safety 
and tolerability variables can be found in Table 1 and Table 2.
8
STATISTICAL METHODS - Module 1 Part A
8.1
Data Quality Assurance
Refer to Section 4.1.
8.2
General Presentation Considerations
Refer to Section 4.2.
8.3
General Variables
8.3.1
Study Day Definitions
Refer to Section 4.3.2.
8.3.2
Time Windows
Refer to Section 4.3.3.
8.3.3
Handling of Missing Data
Refer to Section 4.3.4.
8.3.4
Imputation Rules for Laboratory Values Outside of Quantification Range
Refer to Section 4.3.5.
8.4
Software
Refer to Section 4.4.
8.5
Analysis Sets
Details of the analysis sets are presented in Table 5.


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Table 5 Analysis Sets – Module 1
Population/Analysis set
Description
Screened
All patients that signed the informed consent form (ICF)
Safety
All patients who received at least one dose of AZD0466
Intention-to-treat
All patients who received at least one dose of AZD0466
Evaluable for Response
All patients who have received at least 3 doses of AZD0466 at the 
target dose level in Cycle 1
DLT-evaluable
Patients enrolled in the dose-escalation part of Module 1 that have 
received at least 3 doses of AZD0466 at the target dose level (75% of 
target doses from Day 8 to Day 29 in Cycle 1) and have completed 
the safety follow-up through the 35-day DLT evaluation period 
Or
Have experienced a DLT during the 35-day DLT evaluation period 
in Cycle 1.
Pharmacokinetics
Dosed patients with at least one reportable plasma concentration and 
no important AEs or protocol deviations that may impact PK
A summary on which analysis set will be used for each outcome variable is provided in Table 6.


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Table 6 Summary of outcome variables and analysis sets
Outcome variable
Analysis Set
Study Population/Demography Data
Disposition                                                                                      Enrolled
Demography and baseline characteristics 
Safety
Important protocol deviations
Safety
Medical History
Safety
Prior/Concomitant Medication
Safety
Safety data
Exposure
Safety
Adverse Events
Safety
Laboratory measurements
Safety
Vital Signs/ECG/Physical examination
Safety
ECOG PS
Safety
DLTs 
DLT-evaluable
Efficacy Data
CR rate
Evaluable for response; 
Intention-to-treat
TTR
Evaluable for response
DoR      
Evaluable for response
OS
Intention-to-treat
ORR      
Evaluable for response; 
Intention-to-treat
Pharmacokinetics
Pharmacokinetic variables
PK
CR complete response; DLT dose-limiting toxicity; DoR duration of response; ECOG PS Eastern Co-operative Oncology Group performance status; 
OS overall survival; PK pharmacokinetic. 
The number of enrolled patients included/excluded from each of the analysis sets will be summarized.  
Patients and data excluded from each analysis set will be listed with the reason for exclusion.
8.6
Study Patients
8.6.1
Disposition of Patients
Refer to Section 4.6.1.
8.6.2
Protocol Deviations
Refer to Section 4.6.2.


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8.7
Demographics and Baseline Characteristics
Refer to Section 4.7.
8.8
Medical/Surgical History
Refer to Section 4.8.
8.9
Concomitant Medications and Other Treatments
Refer to Section 4.10.
8.10 Efficacy Evaluation
The preliminary antitumor activity of AZD0466 will be estimated using the following endpoints:
o
Complete response,
o
OS.
All of the collected response related data, such as from complete blood count (CBC), extramedullary 
disease status, bone marrow core biopsy and aspirate will be listed for all patients in the Intention-to-
treat analysis set. Summaries will not be produced.
8.10.1
Analysis and Data Conventions
No hypotheses are planned to be tested.
8.10.1.1
Multi-centre Studies
No adjustments for centre will be performed.
8.10.1.2
Adjustments for Covariates
No adjustments for covariates will be performed.
8.10.1.3
Handling of Dropouts or Missing Data
Summary statistics will be based on non-missing values unless otherwise specified. 
8.10.2
Primary Efficacy Endpoints 
8.10.2.1
Complete Response (CR+CRi) Rate
Complete response rate (CR+CRi) for AML and ALL patients is defined as the proportion of patients 
with best response as complete remission (CR) or incomplete haematological response (CRi), as 
determined by criteria described in Section 3.2.1 and in Appendix J and Appendix K in the study 
protocol.  Any treated patient who has not satisfied the criteria for CR or CRi will be treated as a non-
responder for this analysis.
Data obtained from first dose up until treatment failure or disease progression, or the last evaluable 
assessment in the absence of treatment failure or disease progression, will be included in the 
assessment of CR+CRi, regardless of whether the patient withdrew from study treatment.  
The complete response rate will be presented along with all remaining response categories, as defined 
in Section 3.2.1 by means of the proportion (%).
The analyses will include all patients from the Evaluable for Response analysis set. Patients who 
went off treatment without a response or who received a subsequent therapy after treatment failure or 
disease progression, and then respond will not be included as responders in this evaluation.  


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Secondarily, the analyses will be repeated for the Intention-to-treat analysis set, for that the 
denominators for the calculation of percentages will refer to the number of patients in the Intention-
to-treat analysis set.  Patients who are not evaluable for response analysis will not be assigned to a 
response category and frequencies for missing data items will not be presented.
8.10.2.2
Overall Survival (OS)
The number of deaths will be summarised.  The number of censored patients, and reason for censoring, 
will also be summarised.
OS will be summarised using the Kaplan-Meier technique.  The quartiles (Q1, median, and Q3) of 
OS will be summarised, including 95% CIs.  The percentage of patients survival rate at 3, 6, 9 and 12 
months along with the 95% CI will be presented. The median (range) duration of follow-up among 
censored subjects (months) will also be presented.
8.11 Pharmacokinetics
For the definitions of handling, calculation and presentation of pharmacokinetic concentrations and 
parameters refer to Section 4.13. For PK parameters and calculations supporting Module 1, see 
section 7.2.2.
There are no formal statistics planned for Module 1 PK results; these will be 
summarized descriptively by cohort, and sampling interval, or other appropriate subsetting.
Amount and cumulative amount of AZD4320 excreted will be listed and summarized by urine 
collection intervals per day of infusion during cycle 1, as appropriate.  In addition, individual urine 
PK parameters will be listed.
8.12 Safety and Tolerability Evaluation
Safety, tolerability and DLT data will be listed and summarised as defined by the current AZ 
standards (oncology early phase study outputs).
Safety analysis set will be used for all safety and tolerability analyses.  All listings and tables, other 
than those to assess DLTs during Cycle 1 in Part A, will be based on the safety analysis set.  To 
describe the DLTs during Cycle 1 in Part A, the DLT-evaluable analysis set will be used.
Part A includes the AEs, AESIs, laboratory data, vital signs, ECG, LVEF (by MUGA/ MRI/ ECHO) 
as safety assessments.  The listings and tables of all safety data for Part A will be created as described 
in this section.  In addition, for Part A, DLTs will be listed and summarised; MTD (if determined) 
will be reported. 
8.12.1
Exposure and treatment administration
For the calculation and presentation of exposure and treatment administration refer to Section 4.14.1.
8.12.2
Dose limiting toxicities (DLTs) 
Refer to Section 4.14.2.
8.12.3
Definition of Maximum Tolerated Dose and Definition of Recommended Phase II
Dose
Refer to Section 4.14.3.
8.12.4
Adverse Events
Refer to Section 4.14.4.


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8.12.5
Deaths
Refer to Section 4.14.5.
8.12.6
Clinical Laboratory Evaluation
Refer to Section 4.14.6.
8.12.7
Vital Signs
Refer to Section 4.14.7.
8.12.8
ECGs
Refer to Section 4.14.8.
8.12.9
LVEF
Refer to Section 4.14.9.
8.12.10
Eastern Cooperative Oncology Group performance status (ECOG PS)
Refer to Section 4.14.10.
8.12.11
Tumour lysis syndrome (TLS)
Refer to Section 4.14.11.
8.13 Determination of Sample Size 
8.13.1.1
AZD0466 Monotherapy Escalation - Part A
The primary objective of Part A is to identify the MTD and RP2D of AZD0466 monotherapy.  In Part 
A, 3 to 12 DLT-evaluable patients may be treated in each dose level using an mTPI-2 design (Guo et 
al 2017) permitting up to a maximum of 30 DLT-evaluable patients for dose exploration.  In addition, 
any tolerated dose level may be expanded at the discretion of the sponsor in discussion with the SRC 
to include up to a total of 18 patients for further evaluation of PK, PD, safety, or biological efficacy.  
Up to a total of 58 patients will be enrolled to yield a maximum of 30 DLT-evaluable patients and 18 
patients for further exploration in Part A.  This limits the number of patients exposed to AZZ0466 
consistent with the expected safety profiles of the study treatment, but includes sufficient patients to 
explore safety of the treatment, PK and effects on pharmacodynamic biomarkers, and to collect 
preliminary efficacy data.
8.14 Interim Analyses (Not applicable)


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9
INTRODUCTION – Module 2
Module 2 will be initiated by the SRC (Appendix A5 of the study protocol) after a tolerated dose of 
AZD0466 has been determined in Module 1.  This is a DDI study that will evaluate AZD0466 with 
voriconazole, a strong inhibitor of CYP3A4. 
For further general study information refer to Section 1.


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10
STUDY OBJECTIVES - Module 2
The core objectives and endpoints for the study are listed in Sections 2.1, 2.2 and 2.3; additional 
secondary endpoints for Module 2 are listed in Section 10.1
10.1 Secondary Objectives
Objectives
Endpoints/Variables
To assess the drug-drug interaction potential 
between AZD0466 and the azole antifungal 
voriconazole.
AUC (AUC0-72 and AUClast) and Cmax of 
AZD4320 (total and released) after 
administration of AZD0466 alone and in 
combination with voriconazole


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11 INVESTIGATIONAL PLAN - Module 2
11.1 Overall Study Design
Module 2, a Phase I DDI study of AZD0466 and the azole antifungal agent voriconazole, will be 
conducted in patients with AML or ALL to determine the effect of voriconazole on the PK of 
AZD0466.  This module will be conducted in selected sites in parallel with Module 1.  During periods 
of parallel enrolment, patient entry into Module 1 will be prioritised at sites conducting both Module 
1 and Module 2 of this protocol.
The schedule in Cycle 1 involves dose ramp-up in from a starting dose of AZD0466 on Day 1 (one 
quarter of the target dose), with subsequent titration to the intermediate dose on Day 4 (one half of 
the target dose), and to the target dose on Day 8.  Patients will receive a loading dosage of oral 
voriconazole followed by maintenance dosing in Cycle 1, as specified in the prescribing information 
for voriconazole (Voriconazole Prescribing Information).  The dose of AZD0466 administered in 
combination with voriconazole will be one quarter of the target dose, to mitigate against a potential 
increase in exposure to the active moiety AZD4320 if a DDI exists between AZD0466 and 
voriconazole.
A visual representation of the DDI component of Module 2 (Cycle 1) is shown in Figure 2.
Figure 2 Schema for Cycle 1 of Module 2
* The target dose (TD) of AZD0466 is the highest dose level determined as tolerated by the SRC in Part A of Module 1 
at the point of first patient enrolment in Module 2.
**After reaching AZD0466 TD at D8 there will be a dose reduction on D15 to the D1 equivalent dose, with a return to 
full TD at the next AZD0466 administration day.
*** Voriconazole administration will be discontinued on Day 19 after collection of the last PK blood sample.
BID, twice a day; D, Day; IV, intravenous; PK, pharmacokinetic; PO, by mouth; RU1: first ramp-up dose; RU2: second 
ramp-up dose; SRC, Safety Review Committee; TD, target dose.
A minimum of 10 and up to 14 patients overall will be enrolled at selected sites to investigate the 
potential DDI between AZD0466 and voriconazole. 


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The DDI part of Module 2 (Cycle 1) will be performed in 3 periods over 21 days, as follows:
Period 1 (Days 1-10): AZD0466 infusion on Days 1, 4, and 8
Period 2 (Days 11-14): Voriconazole administration bid
Period 3 (Days 15-21): AZD0466 infusion (at the Day 1 equivalent dose) on Day 15 in combination 
with voriconazole bid on Days 15-19. 
Module 2 Cycle 1 (DDI Part) will utilise a target dose of AZD0466 that has been declared tolerable 
in the dose escalation Part A of Module 1 (Table 22 in the study protocol). After reaching the target 
dose at Day 8, there will be a dose reduction at Day 15 to the Day 1 equivalent dose, and thereafter 
there will be a return to the full target dose. 
In Module 2 Cycle 2 (after the DDI part), patients may receive AZD0466 as monotherapy at a 
higher target dose, if a new higher AZD0466 dose level was declared tolerable in Module 1. This 
dose increase may be implemented without a dose ramp up. This will allow patients to continue to 
receive study treatment at a tolerated dose within the predicted efficacious dose range in humans, 
see study protocol Section 11.1.3.1.
In Cycle 1, patients will be admitted as inpatients for 36 hours on Days 1-2, 4-5, 8-9, and overnight 
on Day 15.  Additional inpatient admission days will be at the Investigator’s discretion.  During 
Period 2, voriconazole administration will occur on an outpatient basis.
The SoA for the DDI part (Cycle 1) of Module 2, including PK sampling times, is provided in Tables 
21, 22 in the study protocol. 
The SRC may assess safety data from Module 2 that could affect the conduct of Module 1.
11.2 Endpoints and Associated Variables
11.2.1
Efficacy Variables
For the definitions of the efficacy variables for the response evaluation criteria variables for ALL and 
AML, and extramedullary disease refer to the Section 3.2.1.
11.2.1.1
Peripheral Blood
Peripheral blood will be collected for complete blood count (CBC) (laboratory safety assessment) 
as indicated in the SoA in Tables 21, 22 in the study protocol.  
 
 
 
11.2.1.2
Extramedullary Disease
Refer to Sections 3.2.1.2.
11.2.1.3
Bone Marrow
Bone marrow core biopsy and bone marrow aspirate should be performed as specified in in the SoA 
CCI


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in Tables 25, 26 in the study protocol.
!
Screening (between Day -28 and -1)
!
Cycle 2 Day 16 or 17
!
Cycle 3 and subsequent cycles between Day 23 to 28
!
Disease progression or EoT visit
The disease progression sample collection may occur at the safety follow-up visit (if conducted in 
person) if not collected previously.  Additional bone marrow or peripheral blood samples may be 
collected, as clinically indicated.
11.2.2
Pharmacokinetic Variables
Pharmacokinetic analysis of the plasma concentration data for total and released AZD4320 (and its 
metabolites (if available and appropriate)) when administered alone and in combination with 
voriconazole, when applicable, will be derived using non-compartmental methods in Phoenix® 
WinNonlin® Version 8.1 or higher (Certara); analysis will be performed by Covance on behalf of 
the sponsor. 
PK analysis will, where data allow, be carried out using actual elapsed times determined from the 
PK sampling and dosing times in the database and following the schedule for plasma samples in
Table 7.
Table 7 Blood samples for plasma PK – Module 2
Study period
Day
Timepoint
Cycle 1 Period 1
Day 1
Pre-infusion
30 minutes after the infusion the start of infusion (± 5 minutes)
End of the infusion (+10 minutes)
2 hours from start of Day 1 infusion (± 15 min)
6 hours from start of Day 1 infusion (± 30 min)
9 hours from start of Day 1 infusion (± 1 hour)
Day 2
24 hours after the start of the Day 1 infusion (± 2 hours)
Day 3
48 hours after the start of the Day 1 infusion (± 3 hours)
Day 4
72 hours after the start of the Day 1 infusion (up to 3 hours before 
infusion on Day 4)
End of the infusion on Day 4 (+10 minutes)
Day 8
Pre-infusion
End of the infusion (+10 minutes)
Cycle 1 Period 3
Day 15
Pre-infusion
30 minutes after the infusion the start of infusion (± 5 minutes)
End of the infusion (+10 minutes)


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Study period
Day
Timepoint
2 hours from start of Day 15 infusion (± 15 min)
6 hours from start of Day 15 infusion (± 30 min)
9 hours from start of Day 15 infusion (± 1 hour)
Day 16
24 hours after the start of the Day 15 infusion (± 2 hours)
Day 17
48 hours after the start of the Day 15 infusion (± 3 hours)
Day 18
72 hours after the start of the Day 15 infusion (± 3 hours)
Day 19
96 hours after the start of the Day 15 infusion (± 3 hours)
Cycle 2
Day 1
Pre-infusion
End of the infusion (+10 minutes)
Cycle 3 and 
beyond
Day 1
Pre-infusion 
End of the infusion (+10 minutes)
If actual elapsed times are missing, nominal times may be used, with approval by the Sponsor; if 
this occurs, it will be described in the report.  Nominal sampling times may be used for any agreed 
interim PK parameter calculations.  Where data allow, the following PK parameters for total and 
released AZD4320 will be derived from plasma concentrations collected following doses 
administered on Cycle 1 Day 1 and Day 15.   
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
AUC0-72
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
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


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λz lower
Lower (earlier) t 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)
∀z span ratio
Time period over which ∀z was determined as ratio of t1/2λz
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.
Additional PK parameters may be calculated as appropriate.
11.2.3
Safety and Tolerability Variables
The primary objective is to assess the safety and tolerability of the AZD0466 in patients with 
advanced haematological malignancies.
As referenced in Section 3.2.3 the safety assessments performed will be:
•
AE assessments,
•
Clinical chemistry (including creatine phosphokinase) and haematology as described in 
Section 4.14.6,
•
Amylase and lipase, coagulation indices, serum immunoglobulins, urinalysis, cardiac 
troponin and BNP (or NTproBNP), cortisol, ACTH and TSH parameters described in 
Section 4.14.6,
•
Vital signs (SBP, DBP, pulse rate, oral body temperature), height and weight,
•
12-lead ECG,
•
TLS (clinical and laboratory assessments), 
•
ECOG PS,
•
Left ventricular ejection fraction (ECHO/MUGA).
The full list of laboratory measurements performed during the study that are used to evaluate safety 
and tolerability variables can be found in Table 1 and Table 2.
12
STATISTICAL METHODS - Module 2
12.1 Data Quality Assurance
Refer to Section 4.1.
12.2 General Presentation Considerations
Refer to the Section 4.2 for details of summary analyses. A clinical report will be produced from the 
database when all patients have had the opportunity to be treated and followed-up for 6 months.
12.3 General Variables
12.3.1
Data cut-off
Refer to Section 4.3.1 for general considerations.  For this module a clinical report will be produced 
when all patients have had the opportunity to be treated and followed-up for 6 months.


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12.3.2
Study Day Definitions
Refer to Section 4.3.2.
12.3.3
Time Windows
Refer to Section 4.3.3.
12.3.4
Handling of Missing Data
Refer to Section 4.3.4.
12.3.5
Imputation Rules for Laboratory Values Outside of Quantification Range
Refer to Section 4.3.5.
12.4 Software
Refer to Section 4.4.
12.5 Analysis Sets
Details of the analysis sets are presented in Table 8.
Table 8 Analysis Sets – Module 2
A summary on which analysis set will be used for each outcome variable is provided in Table 9.
Population/Analysis set
Description
Safety
All patients who received at least one dose of AZD0466
Intention-to-treat
All patients who received at least one dose of AZD0466
Pharmacokinetics
Dosed patients with reportable plasma concentrations and no 
important AEs or protocol deviations that may affect PK


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Table 9 Summary of outcome variables and analysis sets – Module 2
Outcome variable
Analysis Set
Study Population/Demography Data
Disposition                                                                                      Enrolled
Demography and baseline characteristics 
Safety
Important protocol deviations
Safety
Medical History
Safety
Prior/Concomitant Medication
Safety
Safety data
Exposure
Safety
Adverse Events
Safety
Laboratory measurements
Safety
Vital Signs/ECG/Physical examination
Safety
ECOG PS
Safety
Efficacy Data
Efficacy data listings
Intention-to-treat
Pharmacokinetics
Pharmacokinetic variables
PK
PK pharmacokinetic. 
The number of enrolled patients included/excluded from each of the analysis sets will be summarised.  
Patients and data excluded from each analysis set will be listed with the reason for exclusion.
12.6 Study Patients
12.6.1
Disposition of Patients
Refer to Section 4.6.1.
12.6.2
Protocol Deviations
Refer to Section 4.6.2.
12.7 Demographics and Baseline Characteristics
Refer to Section 4.7.
12.8 Medical/Surgical History
Refer to Section 4.8.
12.9 Concomitant Medications and Other Treatments
Refer to Section 4.10.


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12.10Efficacy Evaluation
All of the collected response related data, such as from complete blood count (CBC), extramedullary 
disease status, bone marrow core biopsy and aspirate will be listed for all patients in the Intention-to-
treat analysis set. Summaries will not be produced.
12.11Pharmacokinetics
For the definitions of handling, calculation and presentation of pharmacokinetic concentrations and 
parameters refer to Section 4.13.
12.12Safety and Tolerability Evaluation
Safety, tolerability data will be listed and summarized as defined by the current AZ standards 
(oncology early phase study outputs).  Safety analysis set will be used for all safety and tolerability 
analyses.  All listings and tables will be based on the safety analysis set
This include the AEs, AESIs, laboratory data, vital signs, and ECG as safety assessments. 
Additional assessments will be included: ECHOs and serum immunoglobulins.
12.12.1
Exposure and treatment administration
For the calculation and presentation of exposure and treatment administration for AZD0466 refer to 
Section 4.14.1.
In addition, the exposure to voriconazole received will be listed for all patients.  Actual and total 
treatment duration will be summarized by the following: mean, standard deviation, minimum, 
maximum, median and number of observations.  
12.12.2
Adverse Events
Refer to Section 4.14.4.
12.12.3
Deaths
Refer to Section 4.14.5.
12.12.4
Clinical Laboratory Evaluation
Refer to Section 4.14.6.
12.12.5
Vital Signs
Refer to Section 4.14.7.
12.12.6
ECGs
Refer to Section 4.14.8.
12.12.7
Eastern Cooperative Oncology Group performance status (ECOG PS)
Refer to Section 4.14.10.
12.12.8
Tumour lysis syndrome (TLS)
Refer to Section 4.14.11.


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12.13Determination of Sample Size 
The sample size of 14 patients has been determined empirically and is not based on statistical 
requirements.  It is expected that the proposed sample size will provide sufficient data to evaluate the 
effect of voriconazole on exposure of AZD0466 (evaluated indirectly by AZD4320) while minimizing 
the number of patients exposed to study procedures.
12.14Interim Analyses
No interim analysis is planned for this module.


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13
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS
As per the protocol, Section 11.7.6, analysis of efficacy data from Module 1 was to include data from 
Part B of Module 1.  As Module 1 Part B was not initiated, and if data allow, the analyses described 
in Section 11.7.6 of the protocol will be applied to Module 1 Part A data.
14
REFERENCES
Guo et al 2017
Guo W, Wang SJ, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design addressing 
Ockham's razor: mTPI-2. Contemp Clin Trials. 2017;58:23-33
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
Döhner et al. 2010
Döhner H, Estey EH, Amadori S, Applebaum FR, Büchner T, Burnett AK, et al. Diagnosis and 
management of acute myeloid leukemia in adults: recommendations from an international expert 
panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453-74.
Döhner et al 2017
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and 
management of AML in adults: 2017 ELN recommendations from an international expert panel. 
Blood. 2017;129(4):424-47.
Grimwade et al. 1997
Grimwade D, Walker H, Oliver F, Wheatley K, Clack R, Burnett A, et al. What happens 
subsequently in AML when cytogenetic abnormalities persist at bone marrow harvest? Results of 
the 10th UK MRC AML trial. Medical Research Council Leukaemia Working Parties. Bone 
Marrow Transplant. 1997;19 (11):1117-23.
Marcucci et al. 2004
Marcucci G, Mrózek K, Ruppert AS, Archer KJ, Pettenati MJ, Heerema NA, et al. Abnormal 
cytogenetics at date of morphologic complete remission predicts short overall and disease-free 
survival, and higher relapse rate in adult acute myeloid leukemia: results from Cancer and 
Leukemia Group B study 8461. J Clin Oncol. 2004;22(12):2410-8.
Martinelli et al. 2004
Martinelli G, Rondoni M, Buonamici S, Ottaviani E, Piccaluga PP, Malagola M, et al. Molecular 
monitoring to identify a threshold of CBFß/MYH11 transcript below which continuous complete 
remission of acute myeloid leukemia inv16 is likely. Haematologica. 2004;89(4):495-7.
Perea et al. 2006
Perea G, Lasa A, Aventín A, Domingo A, Villamor N, Paz Queipo de Llano M, et al. Prognostic 
value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable 
cytogenetics [t(8;21) and inv(16)]. Leukemia. 2006;20(1):87-94.


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Recommended prophylaxis adapted from MD Anderson Cancer Center guidance and Cairo 
& 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


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