Conditions: Advanced Haematological Malignancies
Keywords: AZD4573 Anti-cancer Agents Sequential dose-setting and expansion treatment
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
This is a modular, multicentre, open-label, non-randomised, Phase I/II, dose-setting and expansion study including an intra-participants dose ramp up. AZD4573 will be administered intravenously, in novel combinations with anti-cancer agents, to participants with relapsed/refractory (r/r) haematological malignancies.

Detailed description:
In Module 1 Part A (dose-setting), this study module will enrol participants with r/r Diffuse large B-cell lymphoma (DLBCL) or r/r Marginal zone lymphoma (MZL) who have failed prior therapy(ies), are not eligible for curative treatment options, for whom there is no standard therapy available, and will initially explore once weekly administration of AZD4573 at up to three target dose levels in combination with oral acalabrutinib 100 mg twice daily. The primary objective of Part A will be to identify the maximum tolerated dose and/or Recommended Phase II dose (RP2D) for further evaluation in Part B. A 5-week DLT-assessment period will incorporate the whole of Cycle 1 in Part A, including the dose ramp up and the first 3 weeks at the target dose. In Module 1 Part B (expansion), separate expansion cohorts for participants with Germinal Centre B-cell (GCB) and non-GCB DLBCL subtypes will be opened at the RP2D.

In Module 2, this study module will enroll participants with r/r Mantle Cell Lymphoma (MCL) who have failed at least one line of prior therapy, are not eligible for curative treatment options. Module 2, Part A consist of AZD4573 monotherapy (Period 1) followed by AZD4573 + acalabrutinib combination treatment (Period 2). Period 1: AZD4573 will be administered weekly (12 mg, infusion). Period 2: AZD4573 (RP2D from Module 1) will be administered (weekly) in combination with oral acalabrutinib 100 mg twice daily. Cycle 1 of each dosing period has a duration of 5 weeks; subsequent cycles have a duration of 3 weeks. The AZD4573 monotherapy (Period 1) includes an intra-patient ramp up; participants will receive AZD4573 at Cycle 1 Week 1, Cycle 1 Week 2, and Cycle 1 Week 3 in 3 dose escalation manner (6, 9 and 12 mg respectively). Part A, Period 1 of Module 2 aims to confirm the AZD4573 monotherapy RP2D in MCL participants. In Period 2, the safety and tolerability of the RP2D of AZD4573 + acalabrutinib established in Module 1 will be assessed in participants with MCL. The study design of Part B of Module 2 will be determined from the data emerging from Part A.

Arms:
arm 1: Participants will receive intravenous ascending doses of AZD4573 once weekly with oral acalabrutinib twice daily continuously in Part A. For Part A, cohorts 1, 2, and 3 have different target dose levels respectively.

In Part B, participants will receive the RP2D of AZD4573 from Part A. arm 2: Participants will receive AZD4573 as monotherapy for Period 1 and AZD4573 + acalabrutinib as combination therapy for Period 2.

Part B of Module 2 will be determined from the data emerging from Part A.

Interventions: intervention 1: AZD4573 intervention 2: Acalabrutinib
Intervention descriptions: intervention 1: AZD4573 will be administered as an absolute (flat) dose, 2-hour (± 15 minutes) IV infusion once weekly (as monotherapy for Module 2 only) and in combination with orally administered acalabrutinib twice daily continuously. For both Part A and Part B of this study, Cycle 1 consists of 5 weeks, with a dose ramp-up. Subsequent cycles are 21 days (3 weeks) with once weekly dosing of AZD4573 in combination with acalabrutinib twice daily continuously (in Module 1 and Module 2, period 2). intervention 2: Oral Acalabrutinib capsule will be administered twice daily continuously from Day 1 of Cycle 1 Week 1 in combination with AZD4573.

Protocol document:
SAP_007.pdf: 
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Parexel International
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A Modular Phase I/II, Open-label, Multicentre Study to Assess AZD4573 in Novel Combinations 
with Anti-cancer Agents in Patients with Advanced Haematological Malignancies
Statistical Analysis Plan
Module 1 and Module 2
Version: 5.0
Parexel Project Number: 248067


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TABLE OF CONTENTS
1
INTRODUCTION ...................................................................................................... 14
2
STUDY OBJECTIVES............................................................................................... 14
2.1
Primary Objectives...................................................................................................... 14
2.1.1
Secondary Objectives ............................................................................................. 15
2.1.2
Exploratory Objective(s) ........................................................................................ 16
3
INVESTIGATIONAL PLAN ..................................................................................... 17
3.1
Overall Study Design.................................................................................................. 17
3.2
Planned Analyses........................................................................................................ 17
3.3
Endpoints and Associated Variables............................................................................ 18
3.3.1
Efficacy Variables.................................................................................................. 18
3.3.2
Pharmacokinetic Variables ..................................................................................... 19
3.3.3
Safety and Tolerability Variables............................................................................ 22
4
STATISTICAL METHODS ....................................................................................... 24
4.1
Data Quality Assurance............................................................................................... 24
4.2
General Presentation Considerations ........................................................................... 24
4.3
General Variables ....................................................................................................... 26
4.3.1
Study Day Definitions ............................................................................................ 26
4.3.2
Visit Window......................................................................................................... 26
4.3.3
Handling of Missing Data....................................................................................... 27
4.3.3.1 Imputations of Partial Dates.................................................................................... 27
4.3.4
Imputation Rules for Laboratory Values Outside of Quantification Range.............. 28
4.4
Software. .................................................................................................................... 28
4.5
Analysis Sets .............................................................................................................. 28
4.6
Study Subjects ............................................................................................................ 31
4.6.1
Disposition of Subjects........................................................................................... 31
4.6.2
Protocol Deviations ................................................................................................ 32
4.7
Demographics and Baseline Characteristics ................................................................ 33
4.8
Medical/Surgical History ............................................................................................ 33
4.9
Concomitant Medications and Other Treatments......................................................... 34
4.10 Efficacy Evaluation..................................................................................................... 34
4.10.1
Analysis and Data Conventions .............................................................................. 35
4.10.1.1 Multi-centre Studies............................................................................................. 35
4.10.1.2 Adjustments for Covariates ................................................................................. 35
4.10.1.3 Handling of Dropouts or Missing Data................................................................ 35
4.10.2
Primary Efficacy Endpoint ..................................................................................... 35
4.10.2.1 Objective response rate (ORR)............................................................................ 36
4.10.3
Other Efficacy Variables ........................................................................................ 36
4.10.3.1 Complete Response (CR) Rate............................................................................. 37
4.10.3.2 Time to Response (TTR) ...................................................................................... 37
4.10.3.3 Duration of Response (DoR) ................................................................................ 37
4.10.3.4 Progression-free Survival (PFS) .......................................................................... 37
4.10.3.5 Overall Survival (OS)........................................................................................... 40
4.10.4
Pharmacokinetics ................................................................................................... 42
4.10.4.1 Pharmacokinetic Concentrations......................................................................... 42


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4.10.4.2 Pharmacokinetic Parameters Calculation and Summary................................... 43
4.11 Safety and Tolerability Evaluation .............................................................................. 45
4.11.1
Exposure and treatment administration................................................................... 45
4.11.2
Dose intensity......................................................................................................... 47
4.11.3
Dose limiting toxicities (DLTs) .............................................................................. 48
4.11.4
Adverse Events....................................................................................................... 49
4.11.5
Deaths .................................................................................................................... 51
4.11.6
Clinical Laboratory, Blood Sample......................................................................... 51
4.11.6.1 Definitions and Derivations.................................................................................. 51
4.11.6.2 Presentations......................................................................................................... 52
4.11.7
Clinical Laboratory, Urinalysis............................................................................... 53
4.11.7.1 Definitions and Derivations.................................................................................. 53
4.11.7.2 Presentations......................................................................................................... 53
4.11.8
Vital Signs.............................................................................................................. 53
4.11.9
ECGs...................................................................................................................... 53
4.11.10 Physical Examination ............................................................................................. 54
4.11.11 Eastern Cooperative Oncology Group performance status (ECOG PS) ................... 54
4.11.12 B Symptoms........................................................................................................... 55
4.11.13 Tumour lysis syndrome .......................................................................................... 55
4.11.14 Other Safety Assessments....................................................................................... 57
4.11.14.1
Presentations............................................................................................ 57
4.12 Interim Analyses......................................................................................................... 57
4.13 Determination of Sample Size..................................................................................... 57
4.14 Changes or Clarification to Protocol in the Conduct of the Study or Planned Analysis 57
5
REFERENCES ........................................................................................................... 58
6
APPENDICES............................................................................................................ 59


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LIST OF ABBREVIATIONS
Abbreviation / Acronym
Definition / Expansion
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic chemical
AUC
Area under the concentration-time curve
AUC(0-inf)
AUC from time zero extrapolated to infinity
AUC(0-t)
AUC from time zero to the last quantifiable concentration
AUClast
Area under the plasma concentration-curve from zero to the last 
quantifiable concentration
BICR
Blinded independent central review 
BID
Twice daily
BLQ
Below the lower limit of quantification
BMI
Body Mass Index
BoR
Best Overall Response
BP
Blood pressure
bpm
Beats per minute
COO
Cell of origin
CR
Complete response
CRF
Case report form
CTC
Common toxicity criteria
CTCAE
Common Terminology Criteria for Adverse Events
Cmax
Maximum observed concentration
CMV
Active Cytomegalovirus
CV
Coefficient of variation
DBP
Diastolic blood pressure
DLBCL
Diffuse large B-cell lymphoma


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Abbreviation / Acronym
Definition / Expansion
DLT
Dose-limiting toxicity
DoR
Duration of response
DU
Dose is unsafe
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG PS
Eastern Co-operative Oncology Group performance status
eCRF
Electronic Case Report Form 
FAS
Full analysis set
Gmean
Geometric mean
IHC
Immunohistochemistry
IP
Investigational Product
IPI score
International Prognosis Index score
ITT
Intention-to-treat
IV
Intravenous
KM
Kaplan-Meier
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum tolerated dose
MZL
Marginal zone lymphoma
mTPI-2
Modified toxicity probability interval
MUGA
Multi-gated acquisition scan
NA
Not available
NCS
Not clinically significant
NK
Natural killer
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
PD
Progressive Disease


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Abbreviation / Acronym
Definition / Expansion
PET-CT
Positron-emission tomography-computed tomography
PFS
Progression-free survival
PHL
Potential Hy’s law
PK
Pharmacokinetics
PKS
Pharmacokinetic analysis set
PR
Partial response / Partial remission
PT
Preferred term
QT
The QT interval is measured from the beginning of the QRS 
complex to the end of the T wave
QTc
Corrected QT interval
QTcF
QT corrected using Fridericia’s formula
RP2D
Recommended Phase II dose
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
Std Dev
Standard deviation or single dose
SFU
Safety follow-up
SoA
Schedule of Activities
SOC
System Organ Class
SRC
Safety Review Committee
TEAE
Treatment emergent adverse event
TLS
Tumour lysis syndrome
TTR
Time to response
ULN
Upper limit of normal
tmax,ss
Time corresponding to occurrence of Cmax,ss at steady state
Vz/F
Apparent volume of distribution during terminal phase
WHODRUG
World Health Organisation Drug Dictionary
λz
Terminal elimination rate constant


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Abbreviation / Acronym
Definition / Expansion
λz,ss
Terminal elimination rate constant at steady state


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REVISION HISTORY
Version No.
Effective Date
Summary of Change(s)
1.0
09 Aug 2021
New document
2.0
26 Apr 2022

Updated to be aligned with CSP Amendment v3.0

Updated to have abbreviations to be defined at first use 

Updated Section 1 (Introduction) to remove text about 
the use of subjects in the document

Updated Section 2.1.2 to remove footnote referring to ª 
as there is not superscript in the table 

Updated Section 3.2 to add reference note in table 
footnote

Updated Section 3.3.1 to clarify that part of the text refer 
to Part A and Part B

Updated Section 3.3.2 as per Labcorp comments
Clarified that Pk parameters are for AZD4573, 
acalabrutinib and its metabolites.
AUCextr added to the list of diagnostic parameters for 
plasma PK

Updated Section 4.2 to remove text to align more to the 
latest SAP template guidance and to add visit naming 
conventions for efficacy and non-efficacy data. 
    SD abbreviation changed to Std Dev, where applicable

Updated Section 4.3.2 to add a bullet for dose delays

Updated Section 4.3.3.1 to add a bullet for missing 
diagnostic dates, flags and end date imputations to take 
DCO dates into account.

Updated Section 4.5-Table 2 updated DLT-evaluable 
analysis set definition.
Tumour response analysis set changed with Response 
evaluable set. This update was performed across the 
document as appropriate.

Updated Section 4.6.1 (disposition of subjects):
To add screen failures
To remove completed subjects summaries and listings 
and to add summary for subjects who terminated study
To add listings and summaries on subjects impacted 
with the COVID-19 pandemic

Updated Section 4.7
(demographics and baseline 
characteristics) to change age group and to add listings 


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Version No.
Effective Date
Summary of Change(s)
and summaries on subjects impacted with the COVID-
19 pandemic.
Reference to subject recycle process document added.

Updated Section 4.8 to remove disease related and 
relevant terms and to add listings and summaries on 
subjects impacted with the COVID-19 pandemic

Updated Section 4.9 to change regimens with lines of 
therapy

Updated Section 4.10  [CR and PR] changed with [CR 
or PR 

Updated Section 4.10.3.1 to add 80% CI for CR rate

Updated Section 4.10.3.2 -Table 4 to add censoring rule 
for sensitivity analysis

Updated Section 4.10.3.3 to add 80% CI for DoR
Supportive analysis added

Updated Section 4.10.3.4 to change “The percentage of 
subjects…” text with “The proportion of subjects…”

Updated Section 4.10.3.5  to move “supportive data; 
change in target lesion tumour size” to this section and 
to add target lesion tumour size definition

Updated Section 4.11.1 to be aligned with current AZ-
SAP template 
Exposure section updated using exposure definition 
from AZ-Oncology template v0.6 (wording simplified) 
and adding swimmer plots

Updated Section 4.11.4 to update MedDRA version

Updated Section 4.10.3 to remove table 4 and to use 
same format/order the CSP has it

Updated Section 4.11.13

Updated Section 4.14 to add clarifications to CSP

Updated Appendices to remove SoA and Lab. table
3.0
11-Jul-22

Updated Section 4.2 to add additional summaries 

Updated Section 4.5 to update response evaluable 
analysis set and full analysis set definition and to add 
modified response evaluable analysis set definition. 

Updated Section 4.5 to update response evaluable 
analysis set definition


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Version No.
Effective Date
Summary of Change(s)
4.0
11-Oct-2023

Updated Introduction to specify the purpose of the 
additional 
analysis 
described 
in 
the 
document 
(conferences, publications). 

Updated Section 2.1 to remove footnote referring to 
BICR. 

Updated Section 2.1.2 to remove abbreviation for 
pharmacodynamics as per CSP v4.0 

Updated Section 3.2 to align the definition of the 
primary analysis to CSP v4.0

Updated Section 3.2 to update the requirements and 
timing for the interim analysis.

Update Section 3.3.3 to add physical examination to the 
list of safety and tolerability variables as per CSP.

Updated Section 4.1.4 to remove clarification text 
regarding discrepancies in the definition of efficacy 
analysis set(s) with previous version of the CSP. 

Updated Section 4.1.4 to clarify discrepancy with CSP 
v4.0 regarding dose delays for acalabrutinib

Updated Section 4.2 to add details regarding the 
presentation of the data for the supportive analysis. 

Updated Section 4.5 to align the definition of DLT set 
as per CSP v 4.0.

Updated Section 4.6.1 to describe the listing of subject 
populations as a supportive analysis. 

Updated Section 4.9 to remove the summary of 
regimens of previous chemotherapies. 

Updated Section
4.10
to update Initial disease 
assessment for DLBCL method from Lugano to Ann 
Arbor classification as per CSP v4.0. 

Updated Section 4.10.3 to add the description of the 
supportive efficacy analysis performed for conferences 
and publications 

Updated Section 4.10.3.3 to rephrase swimmer plot 
description.

Updated Section 4.11.1 to remove Dose Delays 
definition 
and 
presentation 
from 
acalabrutinib 
subsection and add under AZD4573. 

Updated Section 4.11.6 to update list of clinical 
chemistry parameters as per CSP v4.0


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Version No.
Effective Date
Summary of Change(s)

Updated Section 14.11.12 to add CSPv4.0 to the TLS 
table. 

Updated Section 4.12 to update the requirements and 
timing for the interim analysis 

Updated Section 4.12 to update the Analysis set for IA 
from Response evaluable set to Modified Response 
evaluable set. 

Updated Introduction to describe the purpose of Module 
2 and update CSP version. 

Updated Section 2.1 to add Module 2 Objectives. 

Updated Section 2.1 to update list efficacy endpoints for 
Module 2 as per defined scope (DoR, PFS and OS).  

Updated Section 3.2 to remove interim analysis and add 
primary analysis for Module 2. 

Updated Section 3.3.1 to rephrase the general definition 
of the efficacy endpoints as per CSP version 5.0 

Updated Section 3.3.1 to add definition of efficacy 
endpoints for Module 2. 

Updated Section 3.3.3 to add the list of Safety and 
Tolerability variables for Module 2. 

Updated Section 4.2 to align the description of the 
results presentation to the current structure of outputs. 

Updated Section 4.5 to update the definition of DLT-
evaluable as per CSP version 5.0.  

Updated Section 4.5 to add Interim response evaluable 
set as per CSP version 5.0.  

Updated Section 4.10.3 to define the handling of 
missing post-baseline target lesion measurements. 

Updated Section 4.10.3 to remove sensitivity analysis 
for PFS and OS. 

Updated Section 4.11 to specify that safety data for 
Module 2 subjects will be only listed and no summary 
tables will be provided. 

Updated Section 4.11.2 to define the rules for the 
derivation of actual dose of AZD4573 in mg. 

Updated Section 4.11.2 to add note regarding the 
protocol allowed window of 2 days for the calculation 
of cumulative planned dose. 


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Version No.
Effective Date
Summary of Change(s)

Updated Section 4.11.2 to specify that the RDI will not 
be calculated for Module 2 subjects. 

Updated Section 14.11.12 to describe the presentation 
of TLS laboratory data in Module 1.

Updated Section 4.12 to remove the presentation of the 
interim analysis and specify the reason as per CSP 
version 5.0.

Add decimal rules for data recorded in EDC

Populations for tables: No population header or flag for 
Disposition table, FAS population for important 
protocol deviations, prior/concomitant medication, and 
medical history

For OAE, per sponsor add sentence saying data will not 
be presented.

Updated Section 2.1 to remove Part B to Module 2. 
Reversed Module 1 Part A and B to show Module 1 first.

Updated Section 2.1.1 to show Module 1 first followed 
by part. 

Updated Section 2.1.2 to show Module 1 first followed 
by part.

Updated Section 4.2 to align with sponsor reporting 
standards. 

Updated Section 4.11.6.

Updated Section 4.11.7.

Added Section 4.11.14.

Updated Section 4.13 per CSP version 5.0


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Version No.
Effective Date
Summary of Change(s)
5.0
27-Oct-2023

Updated Section 4.5 to revert the DTL population to 
match SAP V3 and to define backfill subjects.


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1
INTRODUCTION
This is a modular, Phase I/II, open-label, multicentre study of AZD4573 administered intravenously in novel 
combinations with other anti-cancer agents, to subjects with advanced haematological malignancies.
Module 1 will be investigating AZD4573+acalabrutinib in subjects with relapsed or refractory diffuse large 
B-cell lymphoma (DLBCL) or relapsed or refractory marginal zone lymphoma (MZL).
Module 2 will be investigating 2 cycles (8 weeks) AZD4573 monotherapy (Period 1) followed by AZD4573 
+ acalabrutinib combination treatment (Period 2) in subjects with relapsed or refractory (r/r) Mantle Cell 
Lymphoma (MCL). 
The statistical analysis plan (SAP) provides a technical elaboration of the statistical analysis to be performed 
for Module 1 and Module 2 as outlined in the clinical study protocol (CSP). Details provided in this document 
will also support the statistical analysis for conferences and publications.
The analyses described in this SAP are based upon the following study document:

Study Protocol, Version 5.0 (June 01, 2023)
Specifications for tables, figures, and listings are contained in a separate document.
2
STUDY OBJECTIVES
2.1
Primary Objectives
Objectives
Endpoints/Variables
Module 1 – Part A

Assess the safety and tolerability, describe 
the DLTs, and identify the MTD and/or
RP2D of AZD4573 in combination with
acalabrutinib (100 mg BID).

Adverse events, DLTs, laboratory data, 
vital signs, and ECG changes.
Module 1 – Part B

Assess the efficacy of AZD4573 in 
combination with acalabrutinib by 
evaluation of objective response rate.

Endpoint based on revised response 
criteria for malignant lymphoma (Cheson 
et al 2014):
o
ORR, defined as the proportion of 
subjects who have a tumour response 
(CR or PR) a
Abbreviations: BID = twice daily; CR = Complete response; DLT = dose-limiting toxicity; ECG = electrocardiogram; 
MTD = maximum tolerated dose; ORR = Objective response rate; PR = Partial response; RP2D = recommended Phase 
II dose.
Objectives
Endpoints/Variables
Module 2

Assess the safety and tolerability of the 
RP2D of AZD4573 in combination with 
acalabrutinib (100 mg BID) for subjects 

Adverse events (including SAEs), dose 
modifications, treatment discontinuation 
due to AE, AESIs, laboratory data, vital 
signs, and ECG changes.


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Objectives
Endpoints/Variables
who are administered AZD4573 
monotherapy.

Assess the safety and tolerability and 
confirm the RP2D of AZD4573 
monotherapy in MCL.

Adverse events (including SAEs), dose 
modifications, treatment discontinuation 
due to AE, AESIs, laboratory data, vital 
signs, and ECG changes.
Abbreviations: BID = twice daily; ECG = electrocardiogram;RP2D = recommended Phase II dose; SAE=Serious Adverse 
Event, AESI=Adverse Event of Special Interest; MCL= mantle cell lymphoma. 
2.1.1 Secondary Objectives
Objectives
Endpoints/Variables
Module 1 – Part B

Assess efficacy of AZD4573 in 
combination with acalabrutinib by 
evaluation of tumour response and overall 
survival

Endpoints based on revised response criteria for 
malignant lymphoma (Cheson et al 2014):

CR rate

DoR

TTR

PFS

OS

Assess the safety and tolerability of the 
RP2D of AZD4573 in combination with 
acalabrutinib (100 mg BID)

Adverse events, laboratory data, vital signs, and 
ECG changes
Module 1 – Part A and B

Assess the plasma PK of AZD4573 and 
acalabrutinib (plus its active metabolite 
ACP-5862), when given in combination.

Plasma concentrations and derived PK parameters 
for AZD4573 summarised by cohort and dose 
level for the PK analysis set

Plasma concentrations and derived PK parameters 
for acalabrutinib and its metabolite ACP-5862 
summarised by cohort and dose level for the PK 
analysis set
Abbreviations: BID = twice daily; CR = Complete response; DoR = duration of response; ECG = electrocardiogram; 
OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; PR = partial response; 
RP2D = recommended Phase II dose; TTR = time to response.
Objectives
Endpoints/Variables
Module 2

Assess the plasma PK of AZD4573 (when 
given alone and in combination with 
acalabrutinib 100 mg) and acalabrutinib 

Plasma concentrations and derived PK parameters 
for AZD4573 for the PK analysis set. 

Plasma concentrations and derived PK parameters 


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Objectives
Endpoints/Variables
(plus its active metabolite ACP-5862). 
for acalabrutinib and its metabolite ACP-5862 for 
the PK analysis set. 
Abbreviations: PK = pharmacokinetics.
2.1.2 Exploratory Objective(s)
Objectives
Endpoints/Variables
Module 1 – Part A

Assess efficacy of AZD4573 in 
combination with acalabrutinib by 
evaluation of objective response rate, 
tumour response, and overall survival.

Endpoints based on revised response criteria for 
malignant lymphoma (Cheson et al 2014):

ORR

CR rate

DoR

TTR

PFS

OS
Module 1 – Part A and B

Assess the pharmacodynamics of
 
 

 
 

Assess 
 

 
 
 
 
 

To evaluate 
 

 

To 
 
 
 
 
 

 
 
Abbreviations: BID = twice daily; 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Objectives
Endpoints/Variables
Module 2

Explore activity of AZD4573 alone, and in 
combination with acalabrutinib by 
evaluation of tumour responses and overall 
survival.

Endpoints based on revised response criteria for 
malignant lymphoma (Cheson et al 2014):

DoR

PFS

OS

Assess 
 
 

 
 
 
 

Assess 
 

 
 
 
 
 

To 
 
 
 
 
 

 
 
DoR = duration of response; 
 
OS = overall survival; 
PFS = progression-free survival; 
 
Exploratory endpoints related to the pharmacodynamics of AZD4573 and acalabrutinib, 
 may be reported outside of the CSR and will not be described further within this SAP.
3
INVESTIGATIONAL PLAN
3.1
Overall Study Design
Refer to Section 13.1 for Module 1 and Section 22.1 for Module 2 of the CSP.
3.2
Planned Analyses
The details of the analyses planned during the conduct of this study is outlined in Table 1.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Table 1
Summary of Analyses During Study Conduct
Analysis
Trigger
Primary Analysis Module 1
The data cut-off (DCO) for the primary analysis for each 
expansion subgroup will occur approximately 6 months
following last subject first dose in the expansion subgroup or 
when 75% of subjects have progressed or died in the cohort, 
whichever occurs first.
Primary Analysis Module 2
The data cut-off for the primary analysis of Module 2 will occur 
approximately 6 months following last-subject first-dose of 
AZD4573 monotherapy or when 75% of subjects have 
progressed or died in Module 2, whichever occurs first. All 
available data from Period 1 (AZD4573 monotherapy) and 
Period 2 (AZD4573 plus acalabrutinib) will be analysed.
Final AnalysisA
At the end of each module a final analysis will be conducted to 
incorporate all data (up to and beyond the primary analysis) 
from all subjects.
A Refer to subject recycling process document in appendix for details.
If the sponsor decides to terminate the study early, the primary analysis of each module is considered final 
analysis.  
3.3
Endpoints and Associated Variables
3.3.1
Efficacy Variables
Module 1 – Part B
The primary objective is to assess the efficacy of AZD4573 in combination with acalabrutinib by 
evaluation of objective response rate (ORR) per the Lugano classification for Non-Hodgkin 
Lymphoma (NHL) (Cheson et al 2014) (hereafter referred to as Lugano classification) as assessed by 
investigators.
The secondary objectives are to:
Assess the efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response.

Complete response (CR) rate per Lugano classification as assessed by investigators

Duration of response (DoR) per Lugano classification as assessed by investigators

Time to response (TTR) per Lugano classification as assessed by investigators

Progression-free survival (PFS) per Lugano classification as assessed by investigators

Overall survival (OS)
Module 1 – Part A


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The exploratory objective is to assess the efficacy of AZD4573 in combination with acalabrutinib by 
evaluation of:

ORR per Lugano classification as assessed by investigators

CR rate per Lugano classification as assessed by investigators

DoR per Lugano classification as assessed by investigators

TTR per Lugano classification as assessed by investigators

PFS per Lugano classification as assessed by investigators

OS
Module 1 – Part A and B
The efficacy variables, all per the Lugano classification as assessed by investigators (Cheson et al 
2014), are defined as follows: 

ORR is defined as the proportion of subjects who achieve either a PR or CR.

CR rate is defined as the percentage of subjects who achieve a CR.

DoR defined as the time from the first documented objective response to the time of 
documented disease progression or death due to any cause, whichever occurs first.

TTR is defined as time from the first dose of study treatment to the first documented objective 
response observed for subjects who achieved a CR or PR.

PFS is defined as time from date of first dose to documented disease progression, or death 
from any cause, whichever occurs first.

OS is defined as the time from date of first dose until the date of death from any cause.
Module 2
An exploratory objective is to explore activity of AZD4573 alone, and in combination with 
acalabrutinib, by evaluation of tumour responses and overall response per revised response criteria 
for malignant lymphoma (Cheson et al 2014). The following efficacy endpoints will be analysed: 
Duration of response (DoR), Progression-free survival (PFS) and Overall survival (OS). 
3.3.2
Pharmacokinetic Variables
Pharmacokinetics analysis is a secondary objective for both Module 1 (Part A and Part B) and Module 
2. PK parameters for AZD4573, acalabrutinib and its metabolite ACP-5862 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.


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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 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.
For AZD4573 (IV infusion), the following PK parameters will be calculated using the PK 
concertation vs time data from Cycle 1 Day1 of Week 1-3, and Cycle 2 Day 1, as data applicable.
Cmax
Maximum observed plasma (peak) drug concentration
tmax 
Time to reach peak or maximum observed concentration following drug 
administration
z 
Terminal elimination rate constant, estimated by log-linear least squares 
regression of the terminal part of the concentration-time curve
t1/2
Half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve
AUC(0-24) 
Area under the plasma concentration-time curve from time 0 to time 
24 hours
AUClast 
Area under the plasma concentration-curve from zero to the last 
quantifiable concentration
AUCinf 
Area under plasma concentration-time curve from zero to infinity
CL
Total body clearance of drug from plasma after a single IV infusion dose
Vd
Volume of distribution after a single IV infusion (based on terminal phase)
Vss
Volume of distribution at steady-state after a single IV infusion
tlast
Time of last observed quantifiable concentration
Cmax/D
Dose-normalized Cmax
AUClast/D
Dose-normalized AUClast
AUCinf/D
Dose-normalized AUCinf
Additional PK parameters may be determined where appropriate.


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For acalabrutinib and ACP-5862, the following PK parameters will be calculated using the PK 
concentration vs time data from Cycle 1 Day 1 of Week 1, as data applicable. 
Cmax
Maximum observed plasma (peak) drug concentration
tmax
Time to reach peak or maximum observed concentration following drug 
administration
z
Terminal elimination rate constant, estimated by log-linear least squares 
regression of the terminal part of the concentration-time curve
t1/2
Half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve
AUC(0-12)
Area under the plasma concentration-time curve from time 0 to time 
12 hours
AUClast
Area under the plasma concentration-curve from zero to the last 
quantifiable concentration
AUCinf
Area under plasma concentration-time curve from zero to infinity
CL/F
Apparent total body clearance of drug from plasma after extravascular 
administration (parent drug only)
Vz/F
Apparent Volume of distribution following extravascular administration 
(based on terminal phase) (parent drug only)
MP ratio 
Metabolite: parent ratio; AUCinf metabolite/AUCinf parent, 
Cmax(metabolite)/Cmax(parent) (metabolite only)
tlast
Time of last observed quantifiable concentration
Additional PK parameters may be determined where appropriate.
For acalabrutinib and ACP-5862, the following PK parameters will be calculated using the PK 
concentration vs time data from Cycle 1 Day 1 of Week 2, 3, and Cycle 2 Day 1, as data applicable.
Cmax
Maximum observed plasma (peak) drug concentration
Tmax
Time to reach peak or maximum observed concentration or response 
following drug administration during a dosing interval at steady state
AUC
Area under plasma concentration-time curve in the dosing interval the
is 12 hours
CL/F
Apparent total body clearance of drug from plasma after extravascular
administration calculated as dose/ AUC
AUClast
Area under the plasma concentration-curve from zero to the last quantifiable 
concentration
Tlast
Time of last observed (quantifiable) concentration
Cmin
Minimum observed plasma drug concentration
Cavg
Average drug concentration during a dosing interval
Additional PK parameters may be determined where appropriate.


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The following diagnostic parameters for plasma PK analysis will be provided:
AUCextr
Extrapolated area under the curve from tlast to infinity (%)
λz lower
Lower (earlier) t used for λz determination
λz upper
Upper (later) t used for λz determination
λzN
Number of data points used for λz determination
Rsq
Statistical measure of fit for the regression used for λz determination 
Rsq adj
Statistical measure of fit for the regression used for λz determination 
adjusted for the number of used data points (n obs)
λz span ratio
Time period over which λz was determined as ratio of t½λz 
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.
3.3.3
Safety and Tolerability Variables
Module 1 – 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 AZD4573 in combination with acalabrutinib (100mg BID) in subjects with
relapsed/refractory DLBCL or MZL.
Data from all cycles of treatment will be combined in the presentation of safety data.
An overall summary table of the number of subjects experiencing each category of adverse events
will be produced.
The number of subjects experiencing treatment emergent adverse events by MedDRA system organ 
class (SOC) and MedDRA preferred term (PT) will be presented, with further splits by CTCAE grade, 
causal relationship to study medication and adverse events classed as Grade 3 or higher.
Separate tables will present dose limiting toxicities, adverse events leading to discontinuation, serious 
adverse events (SAES) and other significant adverse events. All AE data will be listed appropriately.
AEs occurring prior to first dose of investigational product (ie, before study Day 1) which 
subsequently worsen in severity following dosing will be presented in the summary tables. All other 
AEs occurring prior to first dose of investigational product (ie, before study Day 1), or after the 30-day 
follow-up period after discontinuation of investigational product will be listed separately, but not 
included in the summaries.
Module 1 – Part B


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The secondary objective of Module 1 Part B is to assess the safety and tolerability of the RP2D of 
AZD4573 in combination with acalabrutinib (100 mg BID) in subjects with relapsed or refractory 
DLBCL with GCB or non-GCB subtype.
The following assessments will be performed:

Adverse event (AE) assessments

Dose limiting toxicities (DLTs) defined in Section 4.11.3

Clinical laboratory tests described in Section 4.11.6

Vital signs (systolic blood pressure [SBP] and diastolic blood pressure [DBP], pulse rate, 
oral body temperature), height and weight

12-lead Electrocardiograms (ECG)

Tumor lysis syndrome (TLS)

B symptoms (unintentional weight loss, fevers and night sweats)

Eastern Cooperative Oncology Group performance status (ECOG PS)

Left ventricular ejection fraction (echocardiograms [ECHO] / multi-gated acquisition scan 
[MUGA])

Physical examinations
The full list of laboratory measurements performed during the study that are used to evaluate safety 
and tolerability variables can be found in Section 4.11.6.
Module 2
The secondary objective of Module 2 is to assess the safety and tolerability of the RP2D of AZD4573 
in combination with acalabrutinib (100 mg BID) in subjects administered AZD4573 monotherapy 
and to confirm the RP2D of AZD4573 monotherapy in MCL.
The following assessments will be performed:

Vital signs (blood pressure, pulse rate, temperature) 

12-lead Electrocardiogram (ECG) 

Clinical laboratory tests (haematology, clinical chemistry, coagulation, urinalysis 
parameters, CD4, CD8, CD19, CD16/NK, cardiac troponin I or troponin T measurements, 
electrolyte panel, supra-renal glands and Lipase and amylase measurements) 

Adverse event (AE) assessments 

Dose modifications

Tumour lysis syndrome (TLS) 

B symptoms (unintentional weight loss, fevers and night sweats) 

Eastern Cooperative Oncology Group performance status (ECOG PS) 

Left ventricular ejection fraction (echocardiograms [ECHO] / multi-gated acquisition scan 
[MUGA]).


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4
STATISTICAL METHODS
4.1
Data Quality Assurance
All tables, figures and listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Parexel procedures.
4.2
General Presentation Considerations
The following considerations will be applicable to all modules.
Continuous data will be summarised in terms of the mean, standard deviation (Std Dev), median, 25th 
and 75th percentiles (where appropriate), minimum, maximum and number of observations. If data 
are available for less than 3 subjects, no summary statistics other than minimum, maximum and 
number of observations will be presented. For log--transformed data it is more appropriate to present 
geometric mean (gmean), geometric coefficient of variation (CV), median, minimum and maximum. 
Categorical data will be summarised 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.
Confidence intervals (CIs), when presented, will generally be constructed at 2-sided 80% and 95% 
level. CIs will be presented to one additional place than the original data. When presented, P-values 
greater than or equal to 0.001, in general, will be presented to three decimal places. P-values less than 
0.001 will be presented as “<0.001”.
For continuous data, descriptive summary statistics (mean, median, quartiles, Std Dev, standard 
error, confidence intervals [CIs]) will be rounded to 1 additional decimal place compared to the 
original data. Minimum and maximum will be displayed with the same accuracy as the original 
data.
For categorical data, percentages will be rounded to 1 decimal place. In Module 1, summary tables
will be presented by dose level combining Module 1 Part A and Module 1 Part B subjects unless 
otherwise stated. Data from RP2D-treated Module 1 Part A subjects that meet entry criteria for 
Module 1 Part B will also be included in Module 1 Part B.
A subgroup analysis will be performed. For the purposes of recycling of data from Module 1 Part A 
subjects for analysis with Module 1 Part B subject data, cell of origin (COO data) from local 
assessment will be used. The histology subtype was assigned by local sites, and it was confirmed by 
central laboratory only for subset of GCB and non-GCB subjects were treated at RP2D (AZD4573 
12 mg) and all Module 1 Part B subjects.
Efficacy endpoints may also be summarised by other relevant subgroups (eg, Lymphoma 
classification, Histology subtype, prior anti-cancer therapies [CAR-T, BiTE and BTKi]).


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Generally, the last observation prior to the first dose of the study treatment, will be considered the 
baseline measurement. For non-numeric laboratory tests (ie some of the urinalysis parameters) where 
taking an average is not possible then best value would be taken as baseline as this is the most 
conservative. In the scenario where there are two assessments on day 1, one with time recorded and 
the other without time recorded, the one with time recorded would be selected as baseline (if it is 
earlier than the start time of study treatment). Where safety data are summarised over time, study day 
will be calculated in relation to date of first dose.
For assessments on the day of first dose where time is not captured, a nominal pre-dose indicator, if 
available, 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
Visit naming conventions are defined separately for efficacy and non-efficacy data.
Visits for efficacy summaries will be named according to the time from first dose as defined in the 
CSP. Examples are:

After 8 weeks

After 17 weeks

After 26 weeks
All other data will follow the following naming conventions:

Cycle 1 (ramp-up):
o
Cycle 1 6 mg AZD4573 dose x
o
Cycle 1 9 mg AZD4573 dose x
o
Cycle 1 12 mg AZD4573 dose x

“x” is replaced with “1”, “2”, “3”, etc. as applicable, and refers to the count 
of the dose received at that specified amount.

Cycle 2 onwards:
o
Cycle 2 Day 1
o
Cycle 2 Day 8
o
Cycle 2 Day 15
o
Cycle 3 Day 1

That is, the visit name as per schedule of activities in the CSP is followed.


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4.3
General Variables
4.3.1
Study Day Definitions
Study day 1 is defined as the date of first dose of Investigational Product (IP) (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 IP). For visits (or events) that occur on or after first dose of IP, study day is defined as (date 
of visit [event] – date of first dose of IP + 1). There is no study day 0.
“Days since last dose” is defined as (event date – date of last dose) where “date of last dose” is defined 
as the date of dosing immediately preceding the event occurrence. Thus, events on the same day as 
the last dose will be described as occurring zero days from last dose of IP.
4.3.2
Visit Window
For safety and tumour assessments, visit windows will be defined for any presentations that 
summarise values by visit. The following conventions will apply:
For tumour assessments:

The protocol assigned windows for tumour assessments will be used to assign the result to a 
particular visit.

For example, the visit windows for tumour assessments are:
o
After 8 weeks: 49-63
o
After 17 weeks: 112-126
o
After 26 weeks: 175-189
For safety assessments:

The time windows will be exhaustive so that data recorded at any timepoint has the potential 
to be summarised. Inclusion within the time window will be based on the actual date and not 
the intended date of the visit.

All unscheduled visit data will have the potential to be included in the summaries.

The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls halfway between the two visits (the lower limit of the first 
post-baseline visit will be Day 2). If an even number of days exists between two consecutive 
visits then the upper limit will be taken as the midpoint value minus 1 day.

For example, the visit window for AZD4573 administration (with 1 week between 
scheduled visits) are:
o
Cycle 1 6 mg AZD4573 Dose 1:1
o
Cycle 1 9 mg AZD4573 Dose 1: 2-11
o
Cycle 1 12 mg AZD4573 Dose 1: 12-18
o
Cycle 1 12 mg AZD4573 Dose 2: 19-25
o
Cycle 1 12 mg AZD4573 Dose 3: 26-32


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
If dose delays are experienced, the planned dosing visit windows will be modified during 
the programming to anchor to the actual visit date where intervention was administered on 
to adjust for these dose delays. The same rules apply to safety visits of other types (non-
dosing visits) where the safety visit is moved due to a dose delay. For example, if the Day 8 
dose is taken on Day 10, the visit windowing will be anchored around Day 10 for this visit.

Visit windowing will be done separately for each assessment based on the schedule of 
events specific to that assessment.

Should Study Day be missing (due to partial or missing dates), then visit will be assigned to 
the nominal visit at which that assessment was recorded, and no windowing will be 
performed.

For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on treatment (from the day of the first IP administration up to the day of the last IP 
administration) will be used (regardless of where it falls in an interval).

Listings should display all values contributing to a time point for a subject.

If multiple measurements are taken on the same day, due to inappropriate procedures or any 
other issues with the first measurement, the reassessment measurement on that day will take 
preference for analysis, should the values for that day be in the analysis after visit 
windowing rules have been applied.

If there are more than one value per subject within a time window then the closest value to 
the scheduled visit date should be summarised, or the earlier, in the event the values are 
equidistant from the nominal visit date. The listings should highlight the value for the 
subject that contributed to the summary table, wherever feasible. Note: in summaries of 
extreme values all post baseline values collected are used including those collected at 
unscheduled visits regardless of whether the value is closest to the scheduled visit date.
4.3.3
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. The imputed dates should not be used 
to calculate durations, where the results would be less accurate.
4.3.3.1
Imputations of Partial Dates

For missing diagnostic dates (eg, disease diagnosis), if the day and/or month are missing use 
01 and/or January. if year is missing, put the complete date to missing.

For missing concomitant medication and adverse events start dates, the following is applied:
o
Missing day: imputed with the 1st of the month, unless month and year are the same 
as month and year of first dose of IP, then impute with first dose date.
o
Missing day and month: imputed with the 1st of January unless the year is the same 
as the year of first dose of IP, then imputed with first dose date.
o
Completely missing: imputed with date of first dose of IP, 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.


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When imputing a start date care should be taken to ensure the start date is sensible, ie, prior to the 
end date.

For missing concomitant medication and adverse events end dates, the following is applied:
o
Missing day: imputed with the last day of the month, unless both the month and year 
are the same as month and year of last dose of IP, or the primary analysis date cut-off 
(DCO) date then imputed with the last treatment date in that month or the primary 
analysis date cut-off (DCO) date.
o
Missing day and month: imputed with the 31st of December unless the year is the 
same as the year of last dose of IP or the primary analysis DCO date, then imputed 
with the last treatment date in that year or the primary analysis DCO date. 
o
Completely missing: no date imputed (the event is assumed to be ongoing).
Flags will be retained in the database indicating where any programmatic imputation has been 
applied, and in such cases for AEs and concomitant medications, any durations will not be 
calculated.
4.3.4
Imputation Rules for Laboratory Values Outside of Quantification Range
Values of the form “< x” (ie, below the lower limit of quantification [LLQ]) or “> x” (ie, 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
Details of the analysis sets are presented in Table 2.
Table 2
Analysis Sets
Analysis Set
Definition
Enrolled
All subjects that signed the informed consent form (ICF).
Safety
All subjects who received any amount of AZD4573 and/or 
acalabrutinib. For safety analyses subjects will be reported by 
the actual treatment(s) received and grouped by their assigned 
target dose level of AZD4573.


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Analysis Set
Definition
DLT-evaluable
A DLT-evaluable subject is defined as a subject enrolled in the 
dose-setting part of the study (Part A) that has received 
AZD4573 in combination with acalabrutinib and either:

Has received at least 3 doses of AZD4573 at the 
designated target dose level, has received at least 75% 
of acalabrutinib doses during the AZD4573 treatment 
weeks and has completed sufficient safety assessments 
(as determined by SRC review) through the DLT 
assessment period.
The DLT-assessment period is assumed to have been completed 
with adequate safety assessments for SRC evaluations if 3 doses 
of AZD4573 were received at the designated target dose level. 
In case of an extended DLT period (longer than 5 weeks), where 
there has been AZD4573 dose interruption(s), the requirement 
for at least 75% of planned acalabrutinib doses will be 
applicable only to AZD4573 treatment weeks. If the time period 
between two consecutive AZD4573 infusion dates does not 
exceed 9 days, the AZD4573 treatment week is defined as: from 
the day of AZD4573 infusion until the 9th day or the next 
AZD4573 infusion, whichever comes first. In case the next 
AZD4573 dose was administered >= 10 days after the previous 
AZD4573 dose, the AZD4573 treatment week is defined as: 
from the day of AZD4573 infusion until the 7th day.
Or 

Has experienced a DLT during the DLT-assessment 
period. (For analysis reporting purposes, the DLTs are 
as approved and documented at the Safety Review 
Committee meetings.)
This excludes a subject that is part of the backfill. If a subject is 
assigned to Part A in Module 1 and has an ICF signed after 
(the date of the SRC when RP2D was declared, and 
decisions were made to open Part B and backfill Part A), then 
he/she is considered backfill.
Pharmacokinetics (PK)
All dosed subjects with reportable plasma concentration and no 
important protocol deviations that may impact PK. Subjects will 
be reported by the actual treatment(s) received and grouped by 
their assigned target dose level of AZD4573.
Response evaluable 
Subjects dosed with AZD4573 or acalabrutinib with measurable 
disease (longest diameter greater than zero) at baseline.
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Analysis Set
Definition
Interim response evaluable
Subjects dosed with AZD4573 or acalabrutinib, or both 
AZD4573 and acalabrutinib with baseline tumour assessment 
and have their first post-baseline disease assessment performed 
or have discontinued study treatment for any reasons before their 
first post-baseline disease assessment.
Full Analysis Set (ITT)
All subjects who received any amount of AZD4573 and/or 
acalabrutinib.
Abbreviations: DLT = dose-limiting toxicity; ICF = informed consent form; ITT intention-to-treat;
PK=pharmacokinetics.
Upon database release, protocol deviations and analysis set outputs will be produced and will be sent 
to AZ for review. Prior to database lock for the primary analysis, an analysis set classification meeting 
will be arranged to discuss the outputs and to decide which subjects and/or subject data will be 
excluded from certain analyses. Decisions made regarding the exclusion of subjects and/or subject 
data from analyses will be made prior to primary analysis lock and will be documented and approved 
by AZ.
A summary on which analysis set will be used for each outcome variable is provided in Table 3.
Table 3
Summary of outcome variables and analysis sets
Outcome Variable
Analysis Set
Study Population/Demography Data
Disposition
All Subjects
Demography and baseline characteristics
FAS
Important protocol deviations
FAS
Medical History
FAS
Prior/Concomitant Medication
FAS
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
Response evaluable
TTR
Response evaluable
DoR
Response evaluable


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Outcome Variable
Analysis Set
PFS
FAS
OS
FAS
ORR
Response evaluable
Pharmacokinetics
Pharmacokinetic variables
PK
Abbreviations: CRR = Complete response rate; DLT = dose-limiting toxicity; DoR = duration of response; ECOG PS=
Eastern Co-operative Oncology Group performance status; FAS = full analysis set; ORR = objective response rate; OS = 
overall survival; PFS = progression free survival; PK = pharmacokinetic; TTR: = time to objective response.
The number of enrolled subjects included/excluded from each of the analysis sets will be summarised. 
Subjects and data excluded from each analysis set will be listed with the reason for exclusion.
4.6
Study Subjects
4.6.1
Disposition of Subjects
Module 1 – Part A and Part B:
Subject disposition from screening to study completion will be listed and summarised for all subjects.
Summaries will include:

Number of subjects enrolled (informed consent received)

Number of screen failures (including reasons)

Number and percentage of subjects who received treatment (including reasons for those that 
did not receive treatment)

Number and percentage of subjects ongoing in the study at data cut-off (DCO)

Number and percentage of subjects ongoing treatment at DCO

Number and percentage of subjects who discontinued treatment (including reasons for 
discontinuation)

Number and percentage of subjects who terminated study
Subject discontinuations will be listed, including dose level/cohort, the date of study exit, 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 4.11.1.
Summaries on disposition due to COVID-19 will be added to the disposition table if applicable. The 
number and percentage of subjects for the following summaries will be added if applicable:

Subjects who discontinue intervention due to COVID-19;

Subjects who withdrew from study due to COVID-19.
The number and percentages of subjects with confirmed or suspected COVID-19 infection will be 
presented separately, including details on COVID-19 related interruptions impacting visits and IP 
administration. Listings of subjects affected by the COVID 19 pandemic will be presented detailing 


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any affect and impact on the study. Issues reported in the Clinical Trial Management System will be 
considered for presentation in listings as well.
As supportive analysis, all enrolled subjects will be presented in a listing indicating the different 
analysis sets in which these are included and flagging all those belonging to the backfill cohorts, this 
latter category includes all subjects enrolled after SRC 
 
Module 2:
All subjects enrolled in Module 2 will be presented, including the enrollment into Period 1 and Period 
2. In addition, subjects who discontinued study and /or affected by Global/country situation will be 
appropriately listed.
4.6.2
Protocol Deviations
Important protocol deviations are defined as those deviations from the protocol likely to have an 
impact on the perceived efficacy and/or safety of study intervention. Protocol deviations will be 
collected and classified as defined in the protocol deviations specification. The final assessment of 
Protocol Deviations will be performed at a Data Review Meeting (DRM) shortly before database 
lock. Results and population assignments will be summarized in a DRM report which will be signed 
off by all relevant scientific experts.
The following general deviation categories will be defined. These deviations will be reviewed on a 
case-by-case basis by AstraZeneca to determine importance. Deviations considered to be important 
will be listed and discussed in the CSR as appropriate. All decisions on importance will be made 
ahead of database lock and will be documented prior to the primary analysis being performed.

Subjects who deviate from entry criteria per CSP

No baseline Lugano assessments on or before the date of first dose

Received prohibited concomitant medications or therapies.

Subjects deviating from prescribed dosing regimen.

Missed visits, assessments, or treatments that, in the opinion of the investigator, were due to 
Coronavirus Disease 2019 (COVID-19) global pandemic, and where there was a significant 
effect on either completeness, accuracy and/or reliability of the subject’s data, or the subject’s
rights, safety or wellbeing.

Missing scheduled efficacy assessments

Deviation from Good Clinical Practice as determined by medical review (for example 
insufficient informed consent)
The important protocol deviations affecting Module 1 subjects will be listed and summarised by dose 
level on the Full Analysis Set. Important protocol deviations related to COVID-19 will be summarised 
separately.
The important protocol deviations affecting Module 2 subjects will be only presented in a listing. 
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A full list of protocol deviations can be found in the study-specific Protocol Deviation Specification.
Protocol deviations will be reviewed on a regular basis between AZ and Parexel Data Operations.
4.7
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarised and listed for all subjects in the Safety 
Analysis Set by dose level/cohort:

Demographic characteristics (age[years], age group [ (≥18 - 64, ≥65 - 74, ≥75 - 84, ≥85)], sex
[female; male], race, ethnicity and country).

Subject characteristics at baseline (height[cm], weight [kg], and body mass index [BMI] 
[kg/m2]).

Previous disease related treatment modalities by preferred group.

Any other subject/disease characteristics at baseline as specified below.
Subject/disease characteristics at baseline:

Eastern Cooperative Oncology Group (ECOG) performance status

Histology type

Lymphoma classification

Lugano Modification of Ann Arbor Staging

International Prognosis Index (IPI) score

Brain involvement

Spleen involvement

Bone marrow involvement

Liver involvement

Extranodal involvement

Bulky nodal disease

Histology subtype /cell of origin (COO)
The histology subtype will be assigned by local sites for Module 1 Part A GCB and non-GCB subjects 
who are treated at RP2D (refer to the subject recycling process document) and all Module 1 Part B 
subjects.
Demographics and subject characteristics will further be summarised separately for all subjects in the 
FAS who had confirmed or suspected COVID-19 infection. If less than 5 subjects have confirmed or 
suspected COVID-19 infection, this will be presented in a listing rather than being summarised.
4.8
Medical/Surgical History
Medical history and surgical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 24.1 (as a minimum). Disease related medical history will be listed and the 
number and percentage of subjects with any disease related medical history will be summarised for 


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the Safety Analysis Set by system organ class (SOC) and preferred term (PT), by dose level/cohort
and overall.
Surgical history will be listed and summarised similarly.
A separate summary on medical history will be presented for subjects who had confirmed or 
suspected COVID-19 infection. If less than 5 subjects have confirmed or suspected COVID-19 
infection, this will be presented in a listing rather than being summarised.
4.9
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 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 4.3.2.
Prior medications, concomitant and post- medications are defined based on imputed start and stop 
dates as follows:

Prior medications are those that started and stopped prior to the first dose of the IP.

Concomitant medications are those with a stop date on or after the first dose date of IP (and 
could have started prior to or during treatment).

Post medications are those with a start date after the last dose of the IP.
All concomitant medication will be listed by subject and will include the reported name, PT, ATC, 
route of administration, dose, frequency, start date/time, duration and indication and will be 
summarised by ATC and PT, dose level/cohort.
Radiotherapy and cancer therapies prior to the study will be listed.
The following summaries will be produced:

Previous cancer therapies

Lines of previous cancer therapies

Previous chemotherapy

All concomitant medications
Post-discontinuation cancer therapies will be listed.
All prior, concomitant and post IP medication data (including surgical procedures) will be listed.
Missing coding terms (ATC or Preferred term [PT]) will be listed and summarised as uncoded terms.
All listings and tables will be based on the Safety Analysis Set.
4.10 Efficacy Evaluation
Module 1:


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Module 1 Parts A and B include the following efficacy endpoints: objective response rate (defined as 
the proportion of subjects who have a tumour response [CR or PR] by investigator assessment), CR
rate, TTR, DoR, PFS and OS.
All assessments of anti-tumour activity will be done by the investigators using standard response 
criteria as specified in Section 17.4 of the CSP.
Initial disease assessment for DLBCL include staging by Ann Arbor classification.
Tumour assessments will be made for measurable disease, non-measurable disease, and new lesions 
on CT and combined with visual assessment of PET-CT for response assessment according to the 
revised response criteria for malignant lymphoma (refer to Table 17 of CSP).
All response assessments will be made by the investigator. All images for the assessment of response 
will be collected and stored for potential central review. Additional disease assessments may be 
performed as clinically indicated.
The following tumour assessment details will be listed by subject:

Target lesion size

Non-target lesion

New lesion

Spleen/Liver Disease
Module 2:
For Module 2 subjects, all figures and listings will be based on the FAS or Safety analysis sets, except 
the Response assessment figure that will be based on the Response Evaluable set. Data will 
appropriately be listed by treatment period.
4.10.1 Analysis and Data Conventions
No hypotheses are planned to be tested.
4.10.1.1 Multi-centre Studies
No adjustments for center will be performed.
4.10.1.2 Adjustments for Covariates
No adjustments for covariates will be performed.
4.10.1.3 Handling of Dropouts or Missing Data
Summary statistics will be based on non-missing values unless otherwise specified.
4.10.2 Primary Efficacy Endpoint
In Module 1 Part B, the primary efficacy endpoint is the objective response rate (ORR). Primary 
efficacy endpoint will be analysed and presented by dose level.


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4.10.2.1 Objective response rate (ORR)
The ORR is defined as the proportion of subjects who achieve either a partial response (PR) or 
complete response (CR) as determined by the investigator at local site per Lugano criteria prior to 
any evidence of progression and will be based on the response evaluable set, all subjects who received 
any amount of AZD4573 and acalabrutinib with measurable disease at baseline. A response does not 
need to be confirmed to be included in the calculation of ORR.
Data obtained from first dose up until progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of ORR, regardless of whether the subject withdraws 
from therapy. Subjects who discontinue study treatment without a response or progression, receive a 
subsequent anti-cancer therapy and then respond will not be included as responders in the ORR (ie,
the visit contributing to a response must be prior to subsequent therapy for the subject to be considered 
as a responder).
The ORR will be based on the investigator Lugano data and using all scans regardless of whether 
they were scheduled or not.
Summaries will be produced that present the number and percentage of subjects with a tumour 
response (CR or PR) based upon the number of subjects with measurable disease at baseline per 
investigator. ORR will be calculated and binomial exact 2-sided confidence intervals (CIs) at 80% 
and 95% will be presented for subjects in the Response Evaluable Set. 
Best overall response (BoR)
BoR is calculated based on the overall visit responses from Lugano assessments by the investigator 
recorded in the eCRF. It is the best overall response a subject has had following start of study 
treatment, but prior to starting any subsequent cancer therapy and up to and including Lugano 
progression or the latest evaluable assessment in the absence of Lugano progression. Categories of 
BoR will be based on Lugano criteria using the following response categories (CR, PR, SD, PD and 
NE).
BoR will be summarised by number of subjects and percentage for each category (CR, PR, SD, PD, 
and NE). No formal statistical analyses are planned for BoR.
4.10.3 Other Efficacy Variables
In Module 1 Part A and Module 2, all efficacy endpoints are exploratory. In Module 1 Part B, all 
efficacy endpoints other than ORR are secondary.
All listings and summaries will be based on the Response Evaluable Set, except PFS and OS that will 
be based on the FAS as defined in Table 3.
Tumour response data will be listed and summarised by dose level, if appropriate, using the Lugano 
Response Criteria for Non-Hodgkin’s Lymphoma in Table 17 of the CSP.


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4.10.3.1 Complete Response (CR) Rate
CR is defined as the proportion of subjects who achieve CR, according to the response criteria for 
malignant lymphoma reported by the investigator (Cheson et al 2014). CR Rate will be calculated 
and binomial exact 2-sided CIs at 80% and 95% will be presented for subjects in the Response 
Evaluable Set.
4.10.3.2 Time to Response (TTR)
Time to response (TTR) is defined as the time from the first dose of study treatment to the first 
documented objective response. TTR data will be listed and summarised in subjects who achieved an 
objective response. TTR (months) = (date of first objective response – date of first dose + 1) / 
(365.25/12).
Only subjects who have achieved objective response (CR or PR) are evaluated for TTR.
Subjects who discontinue study treatment without a response or progression, receive a subsequent 
anti-cancer therapy, and then respond will not be included (ie, the visit contributing to a response 
must be prior to subsequent therapy for the subject to be considered as a responder).
If numbers of responders allow, the median TTR and two-sided 95% CI will be assessed using the 
Kaplan-Meier method (without censoring because all subjects have events). The number of subjects 
with response at different disease assessment timepoints may be provided.
4.10.3.3 Duration of Response (DoR)
DoR is defined as the time from the first objective response to the time of documented disease 
progression or death due to any cause, whichever occurs first.
DoR (months) = (date of PFS event (progression/death) or censoring – date of first objective response 
+ 1) / (365.25/12)
The end of response should coincide with the date of progression or death from any cause used for 
the PFS endpoint. The time of the initial response is defined as the latest of the dates contributing 
towards the first visit response of CR or PR. If a subject does not progress following a response, then 
their DoR is censored on the PFS censoring date. Only subjects who have achieved objective response 
are evaluated for DoR.
Individual duration of treatment and duration of response will be appropriately presented in a 
swimmer plot (including non-responders subjects) and all response assessments performed by the 
investigator will be displayed.
Only subjects who have achieved objective response (CR or PR) are included in the summaries of 
DoR. If numbers of responders allow, Kaplan-Meier plots of DoR will be presented. The median DoR 
and 2-sided 80% and 95% CIs will be estimated using the Kaplan-Meier method.
4.10.3.4 Progression-free Survival (PFS)
Disease progression will be determined by the investigators according to the revised response criteria 
for malignant lymphoma (Cheson et al 2014).


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PFS is defined as the time from first dose date to documented disease progression, or death (from any 
cause in the absence of progression), regardless of whether the subject withdraws from therapy or 
receives another anti-cancer therapy prior to progression.
PFS (months) = (date of PFS event (progression/death) or censoring – first dose + 1) / (365.25/12)
Subjects who are progression free and alive at the time of data cut-off, or have unknown status, will 
be censored at the time of the latest date of assessment from their last evaluable disease assessment.
However, if the subject progresses or dies immediately after two or more consecutive missed visits, 
the subject is censored at the time of the latest evaluable disease assessment prior to the two missed 
visits. Note: a NE visit is not considered as a missed visit. 
Given the scheduled visit assessment scheme (ie, 9-weekly for the first 26 weeks then 12-weekly 
thereafter), the definition of 2 missed visits will depend on the scheme.
If the previous assessment is less than study day 113 (ie, week 16) then 2 missing visits will equate 
to 20 weeks since the previous assessment, allowing for early and late visits (ie, 2 x 9 weeks + 1 week 
for an early assessment + 1 week for a late assessment= 20 weeks).
If the 2 missed visits occur over the period when the scheduled frequency of assessment changes from 
nine-weekly to twelve-weekly this will equate to 23 weeks (ie, take the average of 9 and 12 weeks 
which gives 10.5 weeks and then apply the same rationale, hence 2 x 10.5 weeks + 1 week for early 
assessment + 1 week for late assessment =23 weeks). The time period for the previous assessment is 
from study days 113 to 175 (ie, week 16 to week 25).
From week 25 onwards (when the scheduling changes to 12-weekly assessments), two missing visits 
equates to 26 weeks (ie, 2 x 12 weeks + 1 week for an early assessment + 1 week for a late assessment 
= 26 weeks).
If the subject has no evaluable disease assessments post-baseline or does not have baseline tumour 
assessment data they are censored at Day 1 unless they die within two visits of baseline (8 weeks plus 
9 weeks plus 1 week allowing for a late assessment within the visit window) when the death date 
qualifies as a PFS event.
A summary of censoring rules and the date of PD/death or censoring are given in Table 4. Note that 
censoring overrides event in certain specified cases.
Table 4
Summary of Censoring Rules for PFS
Situation
Date of PD/Death or 
Censoring
PFS Outcome
Documented Progressive Disease (PD) or 
death in the absence of progression
Date of earliest documentation 
of PD or date of death in the 
absence of progression
Event
Either no tumour assessment at baseline 
or no evaluable assessments post-baseline Date of death
Event


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Table 4
Summary of Censoring Rules for PFS
Situation
Date of PD/Death or 
Censoring
PFS Outcome
AND death prior to second scheduled 
post-baseline disease assessment
Either no tumour assessment at baseline 
or no evaluable assessments post-baseline 
AND no Death prior to second scheduled 
post-baseline disease assessment
Date of first dose (Day 1)
Censored
PD or death (in the absence of 
progression) immediately after ≥ 2 
consecutive missed disease assessments 
as per the protocol specified assessment 
schedule
Last evaluable progression-
free disease assessment prior 
to missed assessments
Censored
On-going with neither PD nor death at 
the time of analysis or lost to follow-up 
or withdrawn consent
Date of last evaluable disease 
assessment
Censored
Abbreviations: PD = progressive disease; PFS = progression-free survival.
The PFS time is always derived based on scan/assessment dates, not visit dates.
Disease assessments/scans contributing towards a particular visit may be performed on different 
dates. The following rules are applied:

The date of progression is determined based on the earliest of the dates of the component that 
triggered the progression.

When censoring a subject for PFS the subject is censored at the latest of the dates contributing 
to a particular overall visit assessment.
Note: for target lesions only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions and similarly for non-target lesions only the latest scan date is 
recorded out of all scans performed at that assessment for the non-target lesions
The main analysis of PFS is based on the FAS. The number and percentage of subjects experiencing 
a PFS event [broken down by type of event/censoring] and Kaplan-Meier plots of PFS will be
presented. The median PFS and its 2-sided 80% and 95% confidence intervals will be estimated using 
the Kaplan-Meier method (if subject numbers allow).
The treatment status of subjects at progression will be summarised. This includes the number (%) of 
subjects who were on study treatment at the time of progression, the number (%) of subjects who 
discontinued study treatment prior to progression, the number (%) of subjects who did not progress 
and were on treatment or discontinued treatment.


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A summary of the duration of follow-up for PFS will be included using median range for censored
subjects (including all types of PFS censoring).
Duration of follow-up for PFS is applicable only for PFS censored subjects and is defined as follows:
Duration of follow-up for PFS (months) = (date of PFS event (progression/death) or censoring – date 
of first dose + 1) / (365.25/12).
The proportion of subjects progression free at every 3 months (3, 6, 9, 12, etc.) and associated 2-sided 
80% and 95% CIs will be estimated using Kaplan Meier method.
4.10.3.5 Overall Survival (OS)
OS is defined as the time from date of first dose until the date of death from any cause, regardless of 
whether the subject withdraws from therapy or received another anti-cancer therapy. 
OS (months) = (date of death or censoring – first dose + 1) / (365.25/12)
Subjects who have not died by the analysis data cut-off date will be censored at their last date known 
to be alive before the cut-off date. Subjects known to be alive or dead after the data cut-off date will 
be censored at the data cut-off date. Subjects lost to follow-up will be censored at the date the subject
is last known to have been alive.
Note: Survival calls will be made in the week following the date of DCO for the analysis, and if 
subjects are confirmed to be alive or if the death date is after the DCO date these subjects will be 
censored at the date of DCO. The status of ongoing, withdrawn (from the study) and “lost to follow-
up” subjects at the time of the final OS analysis should be obtained by the site personnel by checking 
the subject’s notes, hospital records, contacting the subject’s general practitioner and checking 
publicly-available death registries. In the event that the subject has actively withdrawn consent to the 
processing of their personal data, the vital status of the subject can be obtained by site personnel from 
publicly available resources where it is possible to do so under applicable local laws.
For any OS analysis performed prior to the final OS analysis, in the absence of survival calls being 
made, it is necessary to use all relevant eCRF fields to determine the last recorded date on which the 
subject was known to be alive for those subjects still on treatment (since SURVIVE module is only 
completed for subjects off treatment if a survival sweep is performed). The last date for each 
individual subject is defined as the latest among the following dates recorded in the eCRF:

AE start and stop dates

Admission and discharge dates of hospitalization

Study treatment date

End of treatment date

Laboratory test dates

Date of vital signs

Disease assessment dates on eCRF

Start and stop dates of alternative anti-cancer treatment

Date last known alive on survival status eCRF


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
End of study date
The analysis of OS is based on the FAS. The number and percentage of subjects experiencing an OS 
event and Kaplan-Meier plots of OS will be presented. If subject numbers allow, the median OS and 
2-sided 80% and 95% CI will be estimated using the Kaplan-Meier method. 
Summaries of the number and percentage of subjects who have died, those still in survival follow-up, 
those lost to follow-up and those who have withdrawn consent will be provided.
A summary of the duration of follow-up for OS will be included using median (range). This will be 
presented separately for censored and non-censored subjects.
Duration of follow-up for OS is reported separately for censored subjects and non-censored subjects
and is defined as follows:
Duration of follow-up for OS (months) = (date of death or censoring (date last known to be alive) –
date of first dose + 1) / (365.25/12).
The proportion of subjects alive at every 3 months (3, 6, 9, 12) and associated 2 sided 80% and 95% 
CIs will be estimated using the Kaplan-Meier method.
Supportive data: Change in Target Lesion Tumour Size
Target lesions are measurable tumour lesions. Baseline is defined to be the last evaluable assessment 
prior to starting treatment.
Target lesion tumour size for the target measurable nodes and extra-nodal sites at any timepoint is 
defined as the sum of the product of the perpendicular diameters for multiple lesions. When a lesion 
is too small to measure, 5 mm x 5 mm will be assigned as the product of the perpendicular diameters.
If target lesion measurements are missing post-baseline, then the sum of the product of perpendicular 
diameters for multiple lesions will be set to missing for that post-baseline measurements. Subsequent 
percentage changes will consequently not be calculated using post-baseline measurements where any 
target lesion measurement is missing.
The percentage change in target lesion size at each timepoint for which data are available will be 
obtained for each subject, taking the difference between each timepoint and baseline multiplied by 
100 (ie, [timepoint – baseline]/baseline x 100).
The best change in tumour size from baseline (ie, depth of response) is the largest decrease from 
baseline or the smallest increase from baseline in the absence of a reduction and includes all 
assessments:

up to and including the first visit at which the overall visit response is a PD,

prior to death in the absence of progression,

prior to the start of subsequent anti-cancer therapy,

or up to and including the last evaluable tumour assessment if the subject has not died, 
progressed, or stated subsequent anti-cancer therapy.


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Only response-evaluable subjects with measurable disease at baseline and at least one post baseline 
tumour assessment should be included in summaries of best percentage change in tumour size 
(measurable disease is as denoted on the CRF by the investigator).
The target lesion size and percentage change from baseline in target lesion size will be summarised 
using descriptive statistics and presented at each scheduled timepoint (refer to efficacy naming 
conventions in Section 4.2). Subjects who progress before the scheduled assessment at 8 weeks 
should have had a tumour assessment performed at the time of progression prior to treatment 
discontinuation. The tumour size from their latest progression assessment is used instead of the Week 
8 assessment for these subjects.
Additionally, using scheduled and unscheduled tumour assessments ‘spider’ plots of percentage 
change from baseline in target lesion size by subject will be presented. A graphical summary of the 
best percentage change in the target lesion tumour size will be presented in a vertical bar chart with 
each subject’s best percent change from baseline to nadir displayed as a vertical bar, with color coding 
that indicates best response attained (‘waterfall’ plot).
Supportive analysis:
As supportive analysis, the efficacy outcomes (ORR, CR and PR) may be presented by other relevant 
subgroups defined by AZ medical. This may include lymphoma classification, histology subtype, 
COO (GCB/non-GCB), prior CAR-T, BiTE and/or BTKi therapies. 
4.10.4 Pharmacokinetics
4.10.4.1 Pharmacokinetic Concentrations
Plasma concentrations of AZD4573 plus acalabrutinib and its metabolite ACP-5862 will be listed by 
actual and relative (to dose administration) sampling time. Data from subjects excluded from the PK 
analysis set (ie, Safety Analysis Set) will be included in the data listings, but not in the descriptive 
statistics or in the inferential statistics. The following summary statistics will be presented for these 
concentrations and PK parameters at each time point by 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 log scale)

Gmean + gSD (gSD calculated as exp[μ±s])

Gmean – gSD

Arithmetic Mean

Arithmetic Std Dev

Minimum

Median

Maximum


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
Number of observations
In listings, concentrations below the lower limit of quantification (LLOQ) will be presented as NQ. 
In listings and tables where the terms BLQ or LLOQ are included, the LLOQ (numerical value) will 
be included in a footnote.
For the calculation of statistics, concentrations that are BLQ will be handled as follows at each time 
point:

If ≤50% of the concentrations are BLQ, all BLQ values will be set to the LLOQ, and all 
descriptive statistics will be calculated.

If >50%, but not all, of the concentrations are BLQ, the geometric mean, geometric CV, 
arithmetic mean, and arithmetic Std Dev will be reported as ‘NC’ (not calculable). The 
maximum value will be reported from the individual data, and the minimum and median will 
be set as ‘BLQ’.

If all concentrations are BLQ, no descriptive statistics will be calculated. ‘NA’ (not 
applicable) will be presented for geometric CV, and arithmetic Std Dev, 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 each of AZD4573, acalabrutinib and 
its metabolite ACP-5862:

Subject Profiles, Plasma Concentration Time Data – Linear Scale

Subject Profiles, Plasma Concentration Time Data - Semi-Logarithmic Scale 

Gmean (± gSD), Plasma Concentration Time Data 

GMean, Plasma Concentration Time Data - Semi-Logarithmic Scale
Individual figures will be plotted using concentration versus actual time, and mean figures will be 
plotted using concentration versus nominal time, by treatment or dose level and cycle/PK day, as 
needed.
4.10.4.2 Pharmacokinetic Parameters Calculation and Summary
Derived PK parameters will be summarized by cycle, separately by dose levels. The following 
summary statistics will be presented for the estimated PK parameters, as appropriate: 

Gmean (calculated as exp[μ], where μ is the mean of the data on a logarithmic scale)

gCV (calculated as 100 √ [exp(s2)-1], where s is the standard deviation of the data on a log 
scale)

Gmean + gSD (gSD calculated as exp[μ±s])


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
Gmean - gSD

Arithmetic mean calculated using untransformed data

Standard deviation calculated using untransformed data

Minimum

Median

Maximum 

Number of observations 
The following rules will be followed with regards to the number of decimal places and presentation 
of data in the tables and listings for PK parameters:

Individual PK parameters will be presented to four significant digits, with the exception of 
tmax, which will be presented to two decimal places. 

Parameters derived directly from source data (eg, 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 Std Dev 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.
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 assigned a value of 0, otherwise it will be treated as missing. The 
following rules apply with special situations defined below:

Where two 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, the value will be set to zero.
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.


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Quantifiable pre-dose concentration values in the first dosing of Cycle 1 will be considered 
anomalous and set to missing for the PK analysis. 
4.11 Safety and Tolerability Evaluation
Module 1:
Safety, tolerability and DLT data will be listed and summarised as defined by the current AZ 
standards (oncology early phase study outputs).
The Safety analysis set will be used for all safety and tolerability analyses. All listings and tables, 
other than those to assess DLTs 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. To describe DLT-like events beyond 
Cycle 1 all subjects who receive any amount of study treatment after Cycle 1 will be included.
Module 1 Parts A and B include AEs, AESIs, DLTs in Module 1 Part A Cycle 1, DLT-like events
outside of the dose-setting evaluation period, laboratory data, vital signs, and ECGs as safety 
assessments. In Module 1 Part A, the safety assessments, which also include Cycle 1 DLTs for dose 
setting, are primary endpoints. In Module 1 Part B, the safety assessments are a secondary endpoint. 
Listings and summary tables and figures of all safety data for Module 1 Part A and Part B will be 
created as described in this section. In addition, for Module 1 Part A dose setting MTD (if determined) 
will be reported. 
Module 2: 
For Module 2 subjects, all safety data will be presented in separate listings and no summary tables
will be provided.
The by subject listing will include the identification of the treatment period (Period 1/ Period 2) when 
the event occurred and/or the safety assessment was performed.
4.11.1 Exposure and treatment administration
Module 1:
Exposure amounts, durations and dose modifications and interruptions/delays will be summarised for 
the following periods:

Overall treatment period

Cycle 1

Up to first tumour assessment

Cycle 2 onwards
Duration of AZD4573 exposure is defined by the last date of actual AZD4573 dosing (ie, a dose > 0 
mg was given) plus 6 days (due to the fact that AZD4573 is ordinarily dosed on a weekly schedule)
minus the date of first AZD4573 dose (> 0 mg) plus 1.


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
For subjects who die whilst on study treatment or if a DCO occurs, duration of exposure 
(months/weeks) is defined as date of death/DCO (whichever occurs first) minus the date of 
first treatment plus 1 day.

Therefore: Duration of exposure of AZD4573 (weeks) = [min (last dose date where dose > 0 
mg + 6, date of death, date of DCO) – first dose date + 1]/7.
Actual duration of exposure (weeks) = [duration of exposure (days) – total duration of dose delays 
(days)]/7. Duration of exposure is calculated as above, and dose delays are defined as any length of 
time where the subject has not taken any of the planned dose in accordance with the protocol. The 
actual exposure calculation makes no adjustment for any dose reductions that may have occurred. 
Duration of dose delays of AZD4573 will be derived for doses indicated as being delayed on the 
eCRF for subjects enrolled on CSP v3.0 and later versions. For each individual dose, the duration of 
dose delay is the number of days the dose was received outside of the original planned dosing 
schedule. Overall duration of dose delays will be calculated as the sum of all individual dose delays 
during the study. For example, assume the eCRF indicate that there was a treatment delay (question 
“Treatment delayed” indicated as “Y” by investigator) then the duration of the individual delay will 
be [date first dose received after delay – date last dose received before delay – 9]. 9 is being used to 
account for the 2-day window. For example, if dose is given on days 1 and 15 with the eCRF 
indicating a delay, the duration of the delay = 15 – 1 – 9 = 5 days.
The number of subjects with dosing delays and total dose delays will be summarised. Dose delays 
will also be summarised for number of delays with a duration < 7 days and number of delays with a 
duration ≥ 7 days. 

Duration of acalabrutinib exposure is defined by the last date of actual acalabrutinib dosing 
(ie, a dose > 0 mg was given) minus the date of first dose (> 0 mg) plus 1.
o
Duration of exposure acalabrutinib (weeks) = [min (last dose date where dose > 0 mg, 
date of death, date of DCO) – first dose date + 1]/7.
o
Actual duration of acalabrutinib exposure is the sum of duration of exposure – total 
duration of dosing delays.
Total and actual treatment duration will be summarised by descriptive statistics for each study drug
(AZD4573 and acalabrutinib) and dose level/cohort, separately for Cycle 1 (including ramp-up) and 
for other treatment cycles. In addition, the number and percentage of subjects with at least one dose 
interruption will be summarised separately for Cycle 1 (including ramp-up) and for other treatment 
cycles, for each study drug. Exposure swimmer plot(s) will be produced, with a line presented for 
each subject to display relevant exposure and disposition details.
Dosing deviations for study intervention (s) will be summarized with reasons for deviations for the 
following categories: reductions and interruptions. 
The following additional summaries will also be produced:


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
Number of subjects that completed Cycle 1 (ending a week after receiving 12 mg AZD4573 
for three times), including number of subjects that did not complete Cycle 1.

Number of doses received per subject in Cycle 1.

Total and actual duration of exposure, specific to Cycle 1.

Number of subjects that initiated Cycle 2.
Module 1 Part A:

Number of subjects that completed DLT evaluability period (all doses up to 3rd dose at target 
level), and number of subjects that did not complete DLT evaluability period

Number of doses received per subject in DLT evaluability period (including subjects that did 
not complete DLT evaluability period)

Actual treatment duration in weeks of exposure specific to DLT evaluability period (including 
subjects that did not complete DLT evaluability period)

Number of subjects that initiated Post DLT Evaluability Period
Missed or forgotten doses
Missed and forgotten doses will be included in the listings for dosing but will not be included as dose 
interruptions in summary tables. However, missed doses will be included in the calculation of actual 
treatment duration.
Module 2:
For Module 2 subjects, actual and planned doses of AZD4573 and acalabrutinib will be appropriately 
listed by identifying the treatment period (Period 1/Period2) when the actual administration occurred. 
4.11.2 Dose intensity
Module 1:
Dose intensity of AZD4573 and acalabrutinib will be addressed by considering relative dose intensity 
(RDI). RDI is the percentage of the actual dose delivered relative to the intended dose up to treatment 
discontinuation. RDI will be defined as:
The actual dose administered in mg of AZD4573 will be derived based on the actual volume (mL), 
planned dose (mg) collected in EDC, and the planned volume presented in Table 5 under “Total 
dose volume of diluted study drug (mL)”.
However, there was a high heterogeneity in the handling of AZD4573 preparations between the 
different sites (eg, some sites provided more diluted solutions which result in higher volume 
administered without an actual increase in dosing). To consider these different scenarios, the 
following rules for the derivation of actual dose (mg) will be applied:

If actual volume (mL) < planned volume (mL):
o
actual dose (mg) = actual volume (mL)/planned volume (mL) x planned dose (mg)


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
If actual volume (mL) > = planned volume (mL) and no overdose indicated in eCRF:
o
actual dose (mg) = planned dose (mg)

If actual volume (mL) > = planned volume (mL) and overdose indicated in CRF:
o
actual dose (mg) = actual volume (mL)/planned volume (mL) x planned dose (mg)
Table 5: Examples of AZD4573 dose preparations
Dose (mg)
Required 
volume 
of 
study drug (mL)
Required volume of saline 
(mL)
Total dose volume of 
diluted study drug (mL)
1.5
1
60
61
3
2
100
102
6
4
250
254
9
6
250
256
12
8
250
258
Source: AZD4573 handling instructions
RDI (%) = 100 x d/D, where d is the actual cumulative dose delivered up to the actual last day of dosing, and
D is the intended cumulative dose up to the actual last day of dosing; D is the total dose that would be delivered 
if there were no modification to dose or schedule. Note: When accounting for the calculation of intended 
cumulative dose 2 days should be added to the date of last dose to reflect the protocol allowed window for 
dosing.
The calculation of RDI for AZD4573 is illustrated with the following example. Assume a subject
receives final dose of AZD4573 on Study Day 85. This subject was therefore 12.1 weeks (85/7) on 
treatment. The intended number of doses is therefore 13. From the above formula D = 6 + 9 + (12 x 
11) = 147 mg. Assume the actual doses received by the subject is 6, 0, 6, 9, 12, 12, 12, 12, 0 and 12. 
From the above formula, d = 81 mg. RDI for the overall treatment period is therefore 100% x 81/147
= 55.1%. For the RDI in Cycle 1, d = 6 + 6 + 9 + 12 + 12 = 45 (Cycle 1 ends after receiving the 5th
dose of AZD4573), and D = 6 + 9 + (12 x 3) = 51. The RDI in Cycle 1 is therefore 100% x 45/51 = 
88.24%.
The following summaries will be produced:

Summary of Interruptions (including duration of interruptions) and reductions of IP

Summary of RDI

Summary of intended and actual exposure AZD4573
Module 2:
The RDI will not be calculated and not presented for Module 2 subjects. 
4.11.3 Dose limiting toxicities (DLTs) 
Module 1: 


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DLTs contributing to dose setting in Module 1 Part A Cycle 1 will be listed and summarised 
separately from AEs which meet the DLT definition criteria but are presented after the initial DLT 
setting assessment period in Module 1 Part A or in Module 1 Part B (DLT like-events). 
The DLT criteria are defined in Section 15.3 of the CSP.
The number of Module 1 Part A dose-setting subjects evaluable for determination of DLTs during 
the DLT-assessment period and the number of subjects with any DLT will be summarised by dose 
level. For analysis reporting purposes, the DLTs are as approved and documented at the Safety 
Review Committee meetings. Excel spreadsheet created manually from the SRC meeting minutes 
and checked independently by another individual will be shared with the “DLT Evaluability =Y/N”
information. The MTD will be selected from all tried dose levels that have not been previously 
declared to be unsafe with a DU decision according to the mTPI-2 algorithm (see CSP Section 15.2). 
With this constraint, the MTD will be determined as the dose level with the DLT estimate closest to 
the target toxicity level of 30%. The MTD will be determined by isotonic regression analysis applied 
to DLT rates observed in the DLT-assessment period during dose exploration using the mTPI‑2 
method In the case of dose levels with estimated toxicity of equal distance (tied dose levels) from the 
target toxicity of 30%, the following approach is used: 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.
For Module 1 Part B subjects in meeting the same criteria for DLT evaluability that were used for
Module 1 Part A dose setting, the number and percentage with any DLT-like event reported as an 
adverse event, will be summarised.
For pooled RP2D-treated Module 1 Part A and Part B subjects that received 3 AZD4573 doses at 
target level, the number and percentage that experienced at least one DLT-like event reported as an 
adverse event after receiving any further amount of study treatment will be summarised.
Types of DLTs and DLT-like events and numbers of events per subject will also be summarised.
Module 2: 
This section is not applicable to Module 2 subjects. 
4.11.4 Adverse Events
Adverse Events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 24.1 or higher and will be graded according to the National Cancer Institute of 
Common Terminology Criteria for AEs (CTCAE version 5.0).
AEs are defined as treatment emergent (TEAEs) if they onset or worsen (by investigator report of a 
change in intensity/severity), during the treatment emergent phase defined below. Worsening is 
determined by comparison with the pre-treatment severity of the AE recorded closest to the start of 
dosing.


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When assigning AEs to the relevant phase of the study the following rules will apply: 

Pre-treatment phase – All AEs with a start date after signing the informed consent form (ICF), 
prior to the first administration of IP that do not subsequently go on to worsen during the 
treatment emergent phase.

Treatment emergent phase – All AEs starting or worsening (severity) following the first 
administration of IP for the duration of the treatment period, up to and including 30 days after 
the last dose of study treatment as per the study safety follow-up period but prior to subsequent 
cancer therapy. AEs with a missing start time which occur on the same day as first IP 
administration are reported as treatment emergent. Note that the treatment emergent phase 
includes the on treatment and safety follow-up periods.

Off-treatment phase – All AEs starting more than 30 days after last dose of study treatment 
or once subsequent cancer therapy is started, whichever is earlier.
Serious AEs (SAEs)
A SAE is any AE that:

Results in death

Is immediately life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect in offspring of the subject

Is an important medical event that may jeopardize the subject.
AEs of Special Interest (AESIs)
The following are considered to be AESIs for AZD4573:

Tumour lysis syndrome (TLS) (see Section 4.11.12)

Hepatotoxicity (including Potential Hy’s Law (PHL), Drug-induced liver injury (DILI), and 
Bilirubin increase with transaminase increase (ALT or AST or both).

Neutropenia (including Febrile neutropenia, Neutropenic sepsis, and Neutrophil count 
decrease)

Thrombocytopenia, including Platelet count decrease

Myocardial ischaemia

Pyrexia
The following are AESIs for acalabrutinib:

Ventricular arrhythmias (eg, ventricular extrasystoles, ventricular tachycardia, ventricular 
arrhythmia, ventricular fibrillation).
Other significant adverse events (OAE)
The list of AESI is comprehensive and no OAEs are not defined. 


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4.11.5 Deaths
A summary of deaths will be provided with the number and percentage of subjects categorised as:

Related to disease under investigation only

AE outcome=death only

AE with outcome of death only (AE start date falling after 30 day follow up period)

Both related to disease under investigation and with AE outcome = death

Other deaths
A corresponding listing will also be produced.
4.11.6 Clinical Laboratory, Blood Sample
4.11.6.1 Definitions and Derivations
All local laboratory results collected will be listed (refer to Section 17.1.6, 17.1.7 and Section 10.2 of 
the CSP for the list of clinical safety laboratory tests to be performed and the SoA for timing and 
frequency).
Laboratory tests will be grouped according to chemistry, haematology, and coagulation. Listings will 
be provided for all laboratory results. Laboratory parameters will be assessed at baseline as well as 
throughout the study.
For chemistry and haematology parameters, laboratory abnormalities with toxicity grades according 
to the NCI CTCAE version 5.0 will be derived.
Laboratory variables that will be measured are detailed in Table 6.
Table 6: Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Blasts
S-Albumin
S-C Reactive Protein 
B-Blasts/Leukocytes
S-Alkaline Phosphatase 
(ALP)
S-Factor V Leiden
B-Hematocrit
S-Alanine 
Aminotransferase (ALT)
S-Gamma Glutamyl Transferase 
(GGT)
B-Hemoglobin 
S-Aspartate 
Aminotransferase (AST)
S-Glucose
B-Leukocytes (white blood cell count)
S-Bicarbonate
S-Lactate Dehydrogenase (LDH)
B-Lymphocytes (ALC)
S-Direct Bilirubin
S-Magnesium
B-Lymphocytes/Leukocytes
S-Bilirubin (BILI)
S-Phosphate


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B-Platelet
S-Indirect Bilirubin 
S-Potassium
S-Calcium 
S-Protein
Coagulation
S-Cholesterol
S-Sodium
Activated partial thromboplastin time 
(APTT)/Prothrombin time (PT)
S-Creatine Kinase (CK or 
CPK)
S-Triglycerides
Prothrombin international normalized ratio 
(INR)
S-Chloride 
S-Urate
D-dimer (where available at institution)
S-Creatinine
S-Urea Nitrogen 
Fibrinogen
S-Creatinine Clearance 
Urinalysis (dipstick)
U- Erythrocytes/Blood
U-Glucose
U-Protein
U-Ketones
Abbreviations: B=blood; P=plasma; S=serum; U=urinalysis.
All values will be classified as low (below range), normal (within range), or high (above range) based 
on local laboratory reference ranges. Results will be converted to standard units. For assessments 
included in CTCAE version 5.0, the CTCAE grade will be calculated.
Liver Function Parameters
Subjects with elevated post-baseline ALT, AST, or Total Bilirubin will be identified. The number 
and percentages of these subjects will be tabulated.
4.11.6.2 Presentations
All clinical laboratory results will be listed.
For all continuous laboratory assessments, absolute values, change from baseline will be summarised 
using descriptive statistics at each time point by dose level/cohort. Box plots of absolute values and 
change from baseline values for haematology and clinical chemistry parameters will also be 
presented.
For clinical haematology, clinical chemistry and coagulation endpoints, 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. In addition, the 
number of subjects with ≥2 CTCAE grade changes and CTCAE grade changes of 3 or 4 will be 
summarised by actual dose level/cohort for clinical chemistry and haematology parameters.
Liver Function Parameters


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For subjects with “Potential Hy’s law”, the change in the following laboratory parameters from 
baseline to each post-baseline visit will be summarized: ALT, AST, ALP, GLDH, LDH, GGT, and 
INR. Individual subject data for these laboratory parameters will be listed as well.
Plots for both maximum post-baseline ALT and AST versus the maximum post-baseline BILI 
(expressed as multiples of their upper limit of normal [ULN] reference range) will be produced with 
reference lines at 3 x ULN for ALT and AST and 2 x ULN for total bilirubin.
Liver biochemistry test results over time for subjects 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.
4.11.7 Clinical Laboratory, Urinalysis
4.11.7.1 Definitions and Derivations
Urinalysis variables that will be measured are detailed in Table 6.
4.11.7.2 Presentations
Shift tables (“Negative”, “Trace”, “Positive”, “0”, “+”, “++”, “+++”) from baseline to worst on-
treatment value will be produced for urinalysis.
4.11.8 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)

Weight (Kg)

Height (cm)
Change from baseline in vital signs will be calculated for each post-dose visit.
Descriptive statistics for absolute values and changes from baseline will be presented by dose level.
Absolute values and change from baseline blood pressure and pulse rate will be presented in box
plots.
4.11.9 ECGs
The following parameters will be assessed in 12-lead ECGs:

RR-interval (msec)

QRS-interval (msec)

RR-interval (msec)

QT-interval (msec)


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
QTc-interval (msec)

QT-interval corrected using the Fridericia correction formula (QTcF) (msec)

Heart rate (beats per minute [bpm])
From these resting 12-lead ECGs values of the QT and RR intervals, the QTcF will be rederived using 
the following formula:
QTcF = QT/RR^ (1/3) where RR is in seconds
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal’ or ‘Borderline’.
All ECG parameters will be listed by subject including changes from baseline for numeric ECG 
parameters. 
Descriptive statistics for absolute values and changes from baseline will be presented by dose level.
The average of the three individual tracings will be used in summaries and listings. The individual 
tracings will be also displayed in the data listings.
Box plots of absolute values and change from baseline in ECG parameters over time will be presented.
QTcF outliers (defined as values following IP 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

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
The result of echocardiograms at screening and after an abnormal ECG finding (T wave 
inversion/flattening) will be listed and, if appropriate, presented in a summary table. In addition, the 
results of all multi-gated acquisition (MUGA) scans to assess left ventricular ejection fraction (LVEF) 
will be listed. ECG data will be collected by ERT.
4.11.10 Physical Examination
The physical examination will include general appearance of the subject, examination of the skin, 
eyes, ears, nose, throat, respiratory system, cardiovascular system, abdominal cavity. extremities, 
musculoskeletal system, lymphatic system, and neurological. Physical Examination results will be 
listed by subject.
4.11.11 Eastern Cooperative Oncology Group performance status (ECOG PS)
ECOG performance status scores will be assessed at screening and before each dose of AZD4573 
according to ECOG criteria as follows:


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0 = Fully active, able to carry out all pre-disease activities without restrictions
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature eg, light housework, office work
2 = Ambulatory and capable of self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 = Completely disabled, cannot carry on self-care, totally confined to bed or chair
5= Death
The ECOG performance status will be listed and summarised as frequency counts by dose level and 
visit.
4.11.12 B Symptoms
Information on B symptoms (Unintentional Weight Loss within 6 Months, Disease Related 
Intermittent Fevers > 38 C, Drenching Sweats Especially at Night, Significant Fatigue, Worsening of 
B-Symptoms compared to baseline, Worsening of B-Symptoms compared to prior visit, comments) 
will be listed for all subjects and visits.
4.11.13 Tumour lysis syndrome 
Tumour lysis syndrome (TLS) is an important identified risk for AZD4573 and an identified risk for 
acalabrutinib. Subjects will be required to be monitored for TLS for up to 24 hours post dose until 
they have received at least one AZD4573 dose at the target dose level (ie, for at least the first 3
AZD4573 once-weekly doses), and data will be recorded on the TLS Monitoring forms.
During these TLS assessment periods, blood samples will be collected pre-dose and every 4-6 hours 
until 24 hours after infusion, for analysis of potassium, calcium, phosphate, uric acid, creatinine and 
blood urea nitrogen, and subjects will be monitored for clinical signs of TLS (increased creatinine, 
cardiac arrhythmia, seizure). Laboratory values and clinical signs of TLS occurring during the TLS 
assessment periods are recorded and evaluated according to Cairo-Bishop criteria under CSP version 
1 2, 3 and according to Howard Modification of Cairo-Bishop under CSP version 3, 4, and 5.
If laboratory findings met the Cairo-Bishop criteria for laboratory TLS investigators are instructed to 
record an AE of laboratory/biochemical TLS. If a clinical sign of TLS is present for the same 
assessment period as laboratory findings consistent with laboratory TLS, Investigators are instructed 
to only record an AE of clinical TLS. Thus, there are two data sources contributing to the analysis of 
TLS: TLS monitoring data and AE data.
All laboratory TLS data will be summarized and presented by dose level under one overall category 
named “Laboratory TLS confirmed by Cairo-Bishop criteria or Howard Modification of Cairo-
Bishop criteria”.


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The different TLS laboratory subcategories will be presented under those defined Cairo-Bishop 
criteria as are considered the most inclusive categories. For example, “Laboratory TLS criteria met: 
Potassium (>= 6.0 mmol/L or 6 mg/L)” will be counted under the category “Potassium (>= 6.0 
mmol/L or 6 mg/L) or 25% increase from baseline”. 
TLS monitoring data
According to the TLS monitoring schedule in CSP Section 10.2 for Module 1 and Section 19.2 for 
Module 2 which includes multiple scheduled assessment time points after each infusion of study drug, 
subjects could have multiple records of “TLS confirmed? = Yes” per infusion. “TLS confirmed? = 
Yes” means that at least laboratory TLS criteria have been met. TLS monitoring data will be 
summarised per infusion at episode-level (subjects may have a TLS episode after more than one 
infusion) and subject-level. A maximum of one TLS episode per infusion per subject will be counted 
for each infusion. For records of “TLS confirmed? = Yes” and clinical TLS (subjects with data 
supporting a clinical grading entry for one or more of creatinine abnormality, cardiac arrhythmia, 
seizure):

The highest Investigator-assigned clinical Cairo-Bishop grade per infusion and per subject 
will be summarised separately for creatinine abnormality, cardiac arrhythmia, and seizure. 

The overall Cairo-Bishop grade will be derived based on the highest contributing Investigator-
assigned clinical grade (among grades for creatinine abnormality, cardiac arrhythmia, seizure)
for each record of clinical TLS; the highest derived overall Cairo-Bishop grade per infusion 
and per subject will be summarised. 

The number of infusion episodes of TLS per subject will be described categorically and using 
summary statistics. Time to first onset of TLS (hours from start of infusion to first onset of 
TLS) will be described using summary statistics according to the earliest timepoint with “TLS 
confirmed? = Yes” (including subjects without clinical TLS).
Time to first onset of TLS (hours from start of infusion to first onset of TLS) will be described using 
summary statistics according to the earliest timepoint with “TLS confirmed? = Yes” (including 
subjects without clinical TLS).
AE data
Investigators can report AEs at any time during the study period, hence reporting of AEs of TLS is
not restricted to the 24-hour period after each infusion of study treatment during the ramp-up period. 
Accordingly, there may be a discrepancy between the number of subjects with an AE of TLS and the 
number of subjects with a TLS monitoring record of “TLS confirmed? = Yes". As each CTCAE grade 
change will be recorded as a separate AE in this study, subjects may have more than one AE record 
during continuous occurrence of TLS if the severity of TLS changed before resolution. Subject-level 
summaries will present the maximum CTCAE grade for each subject, event level summaries will 
present the maximum CTCAE grade for each continuous occurrence. In addition to presentation by 
MedDRA PT and CTCAE grade within standard AE tables and listings, AEs of TLS will also be 
presented by MedDRA LLT, as this level of the hierarchy allows distinction between clinical and 


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laboratory TLS. The number and percentage of subjects with an AE of LLT clinical TLS, laboratory 
TLS or (unspecified) TLS will be presented by maximum CTCAE grade, and total numbers of AEs. 
Bar charts showing the number of AEs of TLS and the number and percentage of subjects with AEs 
of TLS by week since first AZD4573 administration will be presented. Time to first onset of any AE 
of TLS (days) since first AZD4573 administration will be described using summary statistics.
4.11.14 Other Safety Assessments 
4.11.14.1 Presentations
Serum immunoglobulins (IgA, IgM, IgG) will be listed and summarized descriptively.
4.12 Interim Analyses
No interim analyses are planned for the study due to the decision to permanently halt enrolment. 
4.13 Determination of Sample Size
Refer to Section 18.2 of the CSP for Module 1 and Section 27.2 of the CSP for Module 2.
4.14 Changes or Clarification to Protocol in the Conduct of the Study or Planned Analysis
CSP version 5.0 is describing the entire statistical analysis originally planned for Module 2, however 
due to the limited sample size (ie, 3 subjects treated), Module 2 data will not be presented in summary 
tables and only by-subject listings and figures will be produced.


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5
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 2014
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for 
initial evaluations, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The 
Lugano Classification. J Clin Oncol 2014;32:3059-68.
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


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6
APPENDICES
Module 1 - Part A subjects to be included in Part B analysis
PURPOSE:
This document describes the process for using data from subjects enrolled in Module 1 Part A in
analyses for Module 1 Part B. This document describes:

the process for Cell of Origin (COO) testing, used to identify GCB and non-GCB DLBCL
subjects;

the selection criteria for Part A subjects whose data will be included in the final analysis for
Part B;

the process to document the recycling of Part A subjects data.
PROCESS
1. Cell of Origin (for all part A and part B subjects)
For the purposes of recycling of data from Part A subjects for analysis with Part B subjects data, 
COO data from local assessment will be used.
2. Definition of Part A subjects that will be included in the Module 1 Part B final analysis
Data from Module 1 Part A subjects will be analysed together with data from Part B subjects if the 
Part A subjects fulfil all the conditions below:

Must have received any amount of AZD4573 and acalabrutinib on study;

Must have been enrolled in the 12 mg (RP2D) dose level cohort;

Must have a diagnosis of de novo DLBCL, ie:
o
DLBCL NOS (de novo), or
o
High-Grade B cell Lymphoma (NOS), or
o
High-Grade B cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangements;

Must have measurable disease at baseline (ie be part of the response evaluable set).
3. Documentation of review and confirmation
The Parexel Programming team will programmatically identify Part A subjects whose data can be 
recycled in Part B for final analysis purposes, based on the criteria described in this document. 
Subjects that can be recycled will be marked by population flags in the ADAM and SDTM 
specifications. TFLs will be generated including the correct individuals (including recycled 
subjects) in each cohort; a listing of recycled subjects will also be included in the TFLs.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d8230c00002-sap-ed-5
Document Title:
Statistical Analysis Plan Edition 5
Document ID:
Doc ID-004599196
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
30-Oct-2023 14:53 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD

Prot_006.pdf: 
Clinical Study Protocol - 5.0
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Clinical Study Protocol
Study Intervention
AZD4573
Study Code
D8230C00002
Version
5.0
Date
01 June 2023
A Modular Phase I/II, Open-label, Multicentre Study to Assess 
AZD4573 in Novel Combinations with Anti-cancer Agents in 
Patients with Advanced Haematological Malignancies
Sponsor Name: AstraZeneca AB
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden.
Regulatory Agency Identifier Number(s)
European Clinical Trials Database (EudraCT) number: 2020-001642-18
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4, Version 5
01 June 2023
Amendment 3, Version 4
01 August 2022
Amendment 2, Version 3
21 July 2021
Amendment 1, Version 2
03 July 2020
Version 1
30 April 2020
Amendment 4, 01 June 2023
This amendment is considered substantial based on 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
Since Study D8230C00002 was first opened (in July 2020) significant challenges have occurred with 
recruitment into both Module 1 and Module 2. These challenges precluded completion enrolment 
within the allocated timeframe of January 2023. AstraZeneca has therefore taken the decision to stop 
recruitment into the study. The decision was not prompted by any new or altered safety concern with 
AZD4573 or acalabrutinib and has no impact on the overall risk-benefit assessment for either IMP. 
Based on this decision, the main purpose of this protocol amendment is to add a rationale for the 
proposed reduction in scope of study D8230C00002 and to set out measures to allow participants still 
receiving clinical benefit of the study treatment after data collection for the primary analysis has 
completed to continue study treatment. End of study definitions and scope of data collection are 
updated to describe this scenario
End of study definitions and scope of data collection are updated to describe this scenario. 
See table below for a summary of the main changes. Additionally, typographical errors were corrected,
and minor edits made in the protocol text where needed.
Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-Substantial
4.1: Overall Design
Rationale added as to 
why recruitment into the 
study has permanently 
halted.  
During the study, 
significant 
challenges have 
occurred with 
recruitment into 
Substantial


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Text added to define that 
participants still 
receiving clinical benefit 
of the study treatment 
after data collection for 
the primary analysis may 
continue to receive the 
study treatment. 
Text added as to the 
initially planned interim 
analysis will not be 
performed and that the 
results from the Module 
1 DLBCL cohorts will be 
pooled for the purpose of 
the primary analysis. 
The following text was 
added: “Since Study 
D8230C00002 was first 
opened (in July 2020) 
significant challenges 
have occurred with 
recruitment into both 
Module 1 and Module 2. 
These challenges 
precluded completion 
enrolment within the 
allocated timeframe of 
January 2023. 
AstraZeneca has 
therefore taken the 
decision to stop 
recruitment into the 
study. Based on this 
decision, the main 
purpose of this protocol 
amendment is to add a 
rationale for the 
both Module 1 and 
Module 2, which are 
likely to preclude 
completion of the 
study within the 
previously allocated 
timeframe. 


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proposed reduction in 
scope of study 
D8230C00002 and to set 
out measures to allow 
participants s still 
receiving clinical benefit 
of the study treatment 
after data collection for 
the primary analysis has 
completed to continue 
study treatment. End of 
study definitions and 
scope of data collection 
are updated to describe 
this scenario”
8.2.10: Reporting of 
Serious Adverse 
Events
Text added: “Participants 
continuing study 
treatment after the end of 
data collection for the 
primary analysis will be 
followed for SAEs with 
paper reporting instead 
of eCRF reporting.”
Clarification that no 
eCRF reporting will 
be applicable 
following the end of 
data collection
Non-substantial
13.1: Overall 
Design
Clarification added on 
possible dose escalation 
decisions for Module 1, 
based on existing 
statistical model. (± 
Equivalence Interval 
Margin) added. 
Clarification of how 
the mTPI-2 method 
will be implemented
Non-Substantial
4.5: End of Study 
Definition
13.4: End of Study 
Definition 
The end of study 
definition in the Core 
section of the protocol 
was updated.
The language was
updated to state that the 
Defining end of 
study and allowing 
Module 1 
participants to 
continue receiving 
treatment after the 
data cut-off date, if 
Substantial 


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last visit of the study will 
be the date when the last 
participant permanently 
discontinued treatment 
with all investigational 
products.
The end of study 
definition for participants
enrolled was updated. 
Text was added to 
describe treatment 
continuation, data 
collection and clinical 
database closure due to 
the early permanently 
halted enrolment. 
still receiving 
clinical benefit.
15.6: Definition of 
DLT-evaluable 
Participant, Table 21
Module 1 definition of 
“DLT-evaluable 
participant” clarified 
Clarification per 
memo “Information 
regarding protocol 
inconsistencies” 10 
March 2022
Non-Substantial
6.13: Intervention 
after the end of the 
study
15.13: Intervention 
after the end of the 
study
15.7: Duration of 
therapy
Text was added, allowing 
Module 1 participants to 
continue receiving study 
intervention after the end 
of the study if, in the 
opinion of the 
Investigator, they are still 
receiving clinical benefit 
from treatment.
 
 
 
For ethical reasons, 
participants should 
have the possibility 
to continue 
treatment if 
applicable
The Investigator 
should continue to 
monitor the 
participant for SAEs 
following the end of 
data collection 
 
 
  
Substantial
CCI
CCI


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17.1.9.3: Survival 
Follow-up
“...third party” was 
removed.
"In preparation for an 
analysis, survival calls 
will be made in the week 
following the data-cut-
off for the analysis" was 
added.
The text was updated to 
clarify that the follow-up 
calls/clinic visits for 
survival should occur 
starting 3 months after 
end of
treatment/discontinuation
No third-party will 
be used
Survival calls will 
identify if any 
Module 1 
participants should 
be censored 
following data-cut-
off
Clarification as to 
when the follow-up 
calls will start
Non-substantial
18.3: Populations 
for analyses, Table 
22
“Modified response 
evaluable” changed to 
“Interim response 
evaluable” 
Clarification
Non-Substantial
18.4.5.1: Objective 
Response Rate and 
Proportion of 
Participants with 
Complete Response
Clarifying text was 
added to define OR, 
ORR, and CRR
Clarification 
Non-Substantial
18.4.5.2: Time to 
response
Re-worded to clarify 
definition of TTR
Clarification
Non-Substantial
18.4.5.3: Duration 
of response
Clarification of DoR
Clarification
Non-substantial
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27.4.5.3: Duration 
of response
18.5 Interim 
analyses
Section text deleted and 
“No interim analyses are 
planned for the study due 
to the decision to 
permanently halt 
enrolment" added. 
No interim analyses 
planned for Module 
1, due to early 
primary analysis 
following 
permanently halted 
enrolment
Substantial
26.1.7: Clinical 
Safety Laboratory 
Assessments
Clarification that the 
TLS monitoring applies 
to Period 1 and 2 
Clarification
Non-substantial
26.1.9.3: Survival 
Follow-up
“...third party” was 
removed
No third-party will 
be used
Non-substantial
18.3: Population for 
Analyses, Table 22
27.3: Populations 
for Analyses, Table 
43
“modified response 
evaluable” changed to 
“interim response 
evaluable”
Clarification
Non-Substantial
Throughout 
document
The word “patient” is 
exchanged to 
“participant” 
Align with standard 
wording 
recommended by 
health authorities
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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 2
TABLE OF CONTENTS ...................................................................................................... 8
1
PROTOCOL SUMMARY ................................................................................ 20
1.1
Synopsis ........................................................................................................... 20
1.2
Schema............................................................................................................. 27
1.3
Schedule of Activities ....................................................................................... 28
2
INTRODUCTION - CORE............................................................................... 28
2.1
Study Rationale ................................................................................................ 28
2.2
Background ...................................................................................................... 29
2.2.1
CDK9 and RNA Transcription Elongation ........................................................ 29
2.2.2
CDK9 and Cancer............................................................................................. 30
2.2.3
Targeting CDK9................................................................................................ 31
2.2.4
AZD4573 and CDK9 ........................................................................................ 31
2.2.5
Nonclinical Information and Correlative Studies............................................... 32
2.2.5.1
Primary, Secondary and Safety Pharmacology .................................................. 32
2.2.5.2
Good Laboratory Practice 1-Month Toxicology Studies (Rat and Monkey)....... 34
2.2.6
Clinical Experience with AZD4573................................................................... 35
2.3
Benefit/Risk Assessment................................................................................... 38
2.3.1
Risk Assessment ............................................................................................... 38
2.3.2
Benefit Assessment........................................................................................... 40
2.3.3
Overall Benefit/Risk Conclusion....................................................................... 41
3
OBJECTIVES AND ENDPOINTS – CORE..................................................... 41
4
STUDY DESIGN - CORE................................................................................ 44
4.1
Overall Design.................................................................................................. 44
4.2
Scientific Rationale for Study Design ............................................................... 48
4.3
Regulatory Amendment for Additional Modules ............................................... 49
4.3.1
Europe and Rest of World ................................................................................. 49
4.3.2
United States of America .................................................................................. 49
4.4
Justification for Dose........................................................................................ 50
4.5
End of Study Definition.................................................................................... 50
5
STUDY POPULATION - CORE ...................................................................... 50
5.1
Inclusion Criteria – Core................................................................................... 50
5.2
Exclusion Criteria – Core.................................................................................. 54
5.3
Lifestyle Considerations ................................................................................... 57
5.3.1
Reproduction .................................................................................................... 57
5.4
Screen Failures ................................................................................................. 58


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6
STUDY INTERVENTION - CORE.................................................................. 58
6.1
Study Intervention(s) Administered................................................................... 59
6.1.1
Investigational Products.................................................................................... 59
6.2
Starting Dose, Dose-Escalation Scheme, and Stopping Criteria......................... 60
6.3
Definition of Dose-limiting Toxicity (DLT)....................................................... 60
6.4
Definition of Maximum Tolerated Dose (MTD)................................................ 60
6.5
Definition of Recommended Phase II Dose (RP2D).......................................... 60
6.6
Definition of Evaluable Participant ................................................................... 61
6.7
Duration of Therapy.......................................................................................... 61
6.8
Preparation/Handling/Storage/Accountability of Interventions.......................... 61
6.9
Measures to Minimise Bias: Randomisation and Blinding................................. 62
6.10
Study Intervention Compliance......................................................................... 62
6.11
Prior/Concomitant Therapy............................................................................... 62
6.12
Dose Modification ............................................................................................ 63
6.12.1
Retreatment Criteria.......................................................................................... 64
6.13
Intervention After the End of the Study............................................................. 64
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL - CORE.............................................. 65
7.1
Discontinuation of Study Intervention............................................................... 65
7.1.1
Temporary Discontinuation............................................................................... 66
7.1.2
Rechallenge ...................................................................................................... 66
7.2
Participant Withdrawal from the Study.............................................................. 66
7.3
Procedures for Handling Participants Incorrectly Initiated on AZD4573 or 
Combination Therapy ....................................................................................... 67
7.4
Lost to Follow-up ............................................................................................. 67
8
STUDY ASSESSMENTS AND PROCEDURES - CORE................................. 67
8.1
Safety Assessments........................................................................................... 68
8.2
Adverse Events and Serious Adverse Events..................................................... 68
8.2.1
Time Period and Frequency for Collecting AE and SAE Information................ 68
8.2.2
Follow-up of AEs and SAEs ............................................................................. 69
8.2.3
Causality Collection.......................................................................................... 70
8.2.4
Adverse Events Based on Signs and Symptoms ................................................ 70
8.2.5
Adverse Events Based on Examinations and Tests ............................................ 70
8.2.6
Potential Hy’s Law Cases ................................................................................. 71
8.2.7
Disease Progression.......................................................................................... 71
8.2.8
New Cancers..................................................................................................... 71
8.2.9
Handling of Deaths........................................................................................... 71
8.2.10
Reporting of Serious Adverse Events ................................................................ 72
8.2.11
Adverse Events of Special Interest for AZD4573 .............................................. 73
8.2.12
Pregnancy......................................................................................................... 74


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8.2.12.1
Maternal Exposure............................................................................................ 74
8.2.12.2
Paternal Exposure............................................................................................. 75
8.2.13
Medication Error............................................................................................... 75
8.3
Overdose .......................................................................................................... 75
8.4
Efficacy Assessments........................................................................................ 76
8.5
Human Biological Samples............................................................................... 76
8.5.1
Pharmacokinetics.............................................................................................. 77
8.5.2
Pharmacodynamics........................................................................................... 77
8.6
............................................................. 77
8.7
Optional Genomics Initiative Sample................................................................ 77
8.8
Health Economics OR Medical Resource Utilisation and Health Economics..... 77
9
STATISTICAL CONSIDERATIONS – CORE.................................................. 77
10
PROTOCOL SUMMARY – MODULE 1 ......................................................... 78
10.1
Schema............................................................................................................. 78
10.2
Schedules of Activities – Module 1................................................................... 80
11
INTRODUCTION – MODULE 1................................................................... 101
11.1
Study Rationale – Module 1............................................................................ 101
11.2
Acalabrutinib Background .............................................................................. 102
11.2.1
Clinical Experience with Acalabrutinib........................................................... 103
11.3
Benefit/Risk Assessment – Module 1 .............................................................. 105
11.3.1
Risk Assessment ............................................................................................. 105
11.3.2
Benefit Assessment......................................................................................... 108
11.3.3
Overall Benefit/Risk Conclusion..................................................................... 109
12
OBJECTIVES AND ENDPOINTS – MODULE 1.......................................... 110
13
STUDY DESIGN – MODULE 1 .................................................................... 112
13.1
Overall Design................................................................................................ 112
13.2
Scientific Rationale for Study Design ............................................................. 117
13.2.1
DLBCL Participants........................................................................................ 117
13.2.2
MZL Participants............................................................................................ 118
13.3
Justification for Dose...................................................................................... 119
13.4
End of Study Definition.................................................................................. 121
14
STUDY POPULATION – MODULE 1........................................................... 121
14.1
Inclusion Criteria ............................................................................................ 121
14.2
Exclusion Criteria ........................................................................................... 123
14.3
Lifestyle Considerations ................................................................................. 124
14.3.1
Meals and Dietary Restrictions – Module 1..................................................... 124
14.4
Screen Failures ............................................................................................... 125
15
STUDY INTERVENTION – MODULE 1 ...................................................... 126
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15.1
Study Intervention(s) Administered................................................................. 126
15.1.1
Investigational Products.................................................................................. 126
15.2
Starting Dose, Dose-Escalation Scheme, and Stopping Criteria....................... 128
15.3
Definition of Dose-limiting Toxicity (DLT)..................................................... 130
15.4
Definition of Maximum Tolerated Dose (MTD).............................................. 132
15.5
Definition of Recommended Phase II Dose (RP2D)........................................ 132
15.6
Definition of DLT-evaluable Participant.......................................................... 133
15.7
Duration of Therapy........................................................................................ 133
15.8
Preparation/Handling/Storage/Accountability of Interventions........................ 133
15.9
Measures to Minimise Bias: Randomisation and Blinding............................... 134
15.10
Study Intervention Compliance....................................................................... 134
15.11
Concomitant Therapy...................................................................................... 134
15.11.1
Permitted Concomitant Therapy...................................................................... 135
15.11.2
Prohibited Concomitant Therapy..................................................................... 135
15.11.3
AZD4573 and Concomitant Therapy............................................................... 136
15.11.4
Acalabrutinib and Concomitant Treatments..................................................... 136
15.12
Dose Modification .......................................................................................... 137
15.12.1
Retreatment Criteria........................................................................................ 146
15.13
Intervention After the End of the Study........................................................... 147
16
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL – MODULE 1.................................. 148
16.1
Discontinuation of Study Intervention............................................................. 148
16.1.1
Temporary Discontinuation............................................................................. 148
16.1.2
Rechallenge .................................................................................................... 148
16.2
Participant Withdrawal from the Study............................................................ 148
16.3
Procedures for Handling Participants Incorrectly Initiated on AZD4573 or 
Combination Therapy ..................................................................................... 148
16.4
Lost to Follow-up ........................................................................................... 148
17
STUDY ASSESSMENTS AND PROCEDURES – MODULE 1..................... 149
17.1
Safety Assessments......................................................................................... 149
17.1.1
Enrolment and Screening ................................................................................ 149
17.1.2
Physical Examinations.................................................................................... 150
17.1.3
Vital Signs ...................................................................................................... 150
17.1.4
WHO/ECOG Performance Status ................................................................... 151
17.1.5
B Symptoms ................................................................................................... 152
17.1.6
Clinical Safety Laboratory Assessments.......................................................... 152
17.1.7
Other Safety Assessments ............................................................................... 157
17.1.8
Electrocardiograms (ECGs) ............................................................................ 158
17.1.9
Follow-up ....................................................................................................... 159
17.1.9.1
30-day SFU Visit ............................................................................................ 159
17.1.9.2
Long-term Follow-up Visits ............................................................................ 159


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17.1.9.3
Survival Follow-up ......................................................................................... 159
17.1.10
Prevention and Management of Safety Concerns for AZD4573 in Combination 
with Acalabrutinib .......................................................................................... 160
17.1.10.1
Headache........................................................................................................ 160
17.1.10.2
Diarrhoea........................................................................................................ 160
17.1.10.3
Nausea and Vomiting ...................................................................................... 161
17.1.10.4
Hepatitis B Reactivation ................................................................................. 161
17.1.10.5
Progressive Multifocal Leukoencephalopathy (PML)...................................... 162
17.1.10.6
Haemorrhage .................................................................................................. 162
17.1.10.7
Infections........................................................................................................ 162
17.1.10.8
Cytopenia ....................................................................................................... 163
17.1.10.9
Liver Chemistry Test Abnormalities and the Risk of Liver Injury.................... 163
17.1.10.10 Tumour Lysis Syndrome (TLS)....................................................................... 165
17.1.10.11 Second Primary Malignancies......................................................................... 169
17.1.10.12 Atrial Fibrillation/Flutter and Sinus Tachycardia............................................. 169
17.1.10.13 Infection/Bone Marrow Toxicity with Peripheral Effect / Lymphoid Tissue 
Hypocellularity............................................................................................... 169
17.1.10.14 Pancreatic and Cortical Adrenal Injury (as well as Surveillance for Renal, 
Thymus, and Spleen Toxicity)......................................................................... 170
17.1.10.15 Drug-Drug interactions ................................................................................... 170
17.1.10.16 Myocardial Ischaemia and Heart Rate Increased ............................................. 170
17.1.10.17 Management of Other Events: Infusion Site Reactions.................................... 171
17.2
Adverse Events and Serious Adverse Events................................................... 171
17.2.1
Adverse Events of Special Interest for Acalabrutinib....................................... 171
17.3
Overdose ........................................................................................................ 171
17.4
Efficacy Assessments...................................................................................... 172
17.4.1
Disease Assessment Criteria............................................................................ 172
17.4.2
Disease Assessment Schedule ......................................................................... 176
17.4.3
Bone Marrow Assessments ............................................................................. 177
17.4.4
Tumour Assessment........................................................................................ 178
17.5
Human Biological Samples............................................................................. 180
17.6
Pharmacokinetics............................................................................................ 180
17.6.1
Determination of Drug Concentration ............................................................. 182
17.7
Pharmacodynamics......................................................................................... 182
17.7.1
Collection of Samples (Part A and Part B)....................................................... 182
17.8
Exploratory 
 Samples (Part A and Part B) ................ 184
17.9
Exploratory Whole Blood Analyses Samples .................................................. 185
17.9.1
Whole Blood for Exploratory 
 (Part A 
and B)............................................................................................................. 187
17.9.2
Whole Blood for 
........................................ 187
17.9.3
Whole Blood Samples for 
........................................... 188
17.9.4
Whole Blood Samples for 
 (Part A and B)....................... 189
17.9.5
Whole Blood for 
 Exploratory Analysis (Part B Only).................. 190
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17.9.6
Exploratory Blood 
 Samples................................................................. 190
17.10
........................................................... 191
17.10.1
Collection of Archival Tumour Samples.......................................................... 191
17.10.2
Collection of Tumour Biopsy Samples............................................................ 191
17.10.3
Collection of Bone Marrow............................................................................. 192
17.10.4
Other Study Related 
 Research ....................................................... 193
17.10.4.1
 Sample for 
 Isolation..................................................... 193
17.10.5
Collection of Optional 
 Samples ..................................................... 193
17.10.5.1
Optional Tumour Biopsy at Disease Progression............................................. 193
17.11
Optional Genomics Initiative Sample.............................................................. 193
17.12
Medical Resource Utilisation and Health Economics ...................................... 194
17.13
Important Medical Procedures to be Followed by the Investigator................... 194
17.13.1
Medical Emergencies and Contacts................................................................. 194
18
STATISTICAL CONSIDERATIONS – MODULE 1....................................... 195
18.1
Statistical Hypotheses..................................................................................... 195
18.2
Sample Size Determination............................................................................. 195
18.3
Populations for Analyses................................................................................. 196
18.4
Statistical Analyses ......................................................................................... 197
18.4.1
General Considerations................................................................................... 197
18.4.2
Demographics, Baseline Characteristics, and Study Status.............................. 197
18.4.3
Exposure......................................................................................................... 197
18.4.4
Safety ............................................................................................................. 198
18.4.5
Efficacy .......................................................................................................... 199
18.4.5.1
Objective Response Rate and Proportion of Participants with Complete 
Response ........................................................................................................ 199
18.4.5.2
Time to Response (TTR)................................................................................. 200
18.4.5.3
Duration of Response (DoR)........................................................................... 200
18.4.5.4
Progression-free Survival (PFS)...................................................................... 200
18.4.5.5
Overall Survival (OS) ..................................................................................... 200
18.4.6
Pharmacokinetics............................................................................................ 201
18.5
Interim Analyses............................................................................................. 201
18.6
No interim analyses are planned for the study due to the decision to permanently 
halt enrolment. Safety Review Committee – Module 1.................................... 201
19
PROTOCOL SUMMARY – MODULE 2 ....................................................... 204
19.1
Scheme........................................................................................................... 204
19.2
Schedules of Activities – Module 2................................................................. 206
20
INTRODUCTION – MODULE 2................................................................... 221
20.1
Study Rationale – Module 2............................................................................ 221
20.2
Acalabrutinib Background .............................................................................. 221
20.2.1
Clinical Experience with Acalabrutinib........................................................... 222
20.3
Benefit/Risk Assessment – Module 2 .............................................................. 224
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20.3.1
Risk Assessment ............................................................................................. 224
20.3.2
Benefit Assessment......................................................................................... 228
20.3.3
Overall Benefit/Risk Conclusion..................................................................... 229
21
OBJECTIVES AND ENDPOINTS – MODULE 2.......................................... 230
22
STUDY DESIGN – MODULE 2 .................................................................... 233
22.1
Overall Design................................................................................................ 233
22.2
Scientific Rationale for Study Design ............................................................. 234
23
STUDY POPULATION – MODULE 2........................................................... 237
23.1
Inclusion Criteria ............................................................................................ 237
23.2
Exclusion Criteria ........................................................................................... 238
23.3
Lifestyle Considerations ................................................................................. 239
23.3.1
Meals and Dietary Restrictions – Module 2..................................................... 239
23.4
Screen Failures ............................................................................................... 240
23.5
Justification for Dose...................................................................................... 240
23.6
End of Study Definition.................................................................................. 240
24
STUDY INTERVENTION – MODULE 2 ...................................................... 241
24.1
Study Intervention(s) Administered................................................................. 241
24.1.1
Investigational Products.................................................................................. 241
24.2
Starting Dose, Dose-Escalation Scheme, and Stopping Criteria....................... 243
24.3
Definition of Evaluable Participant ................................................................. 243
24.4
Duration of Therapy........................................................................................ 243
24.5
Preparation/Handling/Storage/Accountability of Interventions........................ 244
24.6
Measures to Minimise Bias: Randomisation and Blinding............................... 245
24.7
Study Intervention Compliance....................................................................... 245
24.8
Concomitant Therapy...................................................................................... 245
24.8.1
Permitted Concomitant Therapy...................................................................... 245
24.8.2
Prohibited Concomitant Therapy..................................................................... 246
24.8.3
AZD4573 and Concomitant Therapy............................................................... 247
24.8.4
Acalabrutinib and Concomitant Treatments..................................................... 247
24.9
Dose Modification .......................................................................................... 248
24.9.1
Retreatment Criteria........................................................................................ 257
24.10
Intervention After the End of the Study........................................................... 258
25
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL – MODULE 2.................................. 259
25.1
Discontinuation of Study Intervention............................................................. 259
25.1.1
Temporary Discontinuation............................................................................. 259
25.1.2
Rechallenge .................................................................................................... 259
25.2
Patient Withdrawal from the Study.................................................................. 259


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25.3
Procedures for Handling Participants Incorrectly Initiated on AZD4573 or 
Combination Therapy ..................................................................................... 259
25.4
Lost to Follow-up ........................................................................................... 259
26
STUDY ASSESSMENTS AND PROCEDURES – MODULE 2..................... 260
26.1
Safety Assessments......................................................................................... 260
26.1.1
Enrolment and Screening ................................................................................ 260
26.1.2
Physical Examinations.................................................................................... 261
26.1.3
Vital Signs ...................................................................................................... 261
26.1.4
Electrocardiograms (ECGs) ............................................................................ 263
26.1.5
WHO/ECOG Performance Status ................................................................... 263
26.1.6
B Symptoms ................................................................................................... 264
26.1.7
Clinical Safety Laboratory Assessments.......................................................... 265
26.1.8
Other Safety Assessments ............................................................................... 270
26.1.9
Follow-up ....................................................................................................... 271
26.1.9.1
30-day SFU Visit ............................................................................................ 271
26.1.9.2
Long-term Follow-up Visits ............................................................................ 271
26.1.9.3
Survival Follow-up ......................................................................................... 272
26.1.10
Prevention and Management of Safety Concerns for AZD4573 in Combination 
with Acalabrutinib .......................................................................................... 272
26.1.10.1
Headache........................................................................................................ 273
26.1.10.2
Diarrhoea........................................................................................................ 273
26.1.10.3
Nausea and Vomiting ...................................................................................... 273
26.1.10.4
Hepatitis B Reactivation ................................................................................. 274
26.1.10.5
Progressive Multifocal Leukoencephalopathy (PML)...................................... 275
26.1.10.6
Haemorrhage .................................................................................................. 275
26.1.10.7
Infections........................................................................................................ 275
26.1.10.8
Cytopenia ....................................................................................................... 276
26.1.10.9
Liver Chemistry Test Abnormalities and the Risk of Liver Injury.................... 276
26.1.10.10 Tumour Lysis Syndrome (TLS)....................................................................... 278
26.1.10.11 Second Primary Malignancies......................................................................... 282
26.1.10.12 Atrial Fibrillation/Flutter and Sinus Tachycardia............................................. 282
26.1.10.13 Infection/Bone Marrow Toxicity with Peripheral Effect / Lymphoid Tissue 
Hypocellularity............................................................................................... 282
26.1.10.14 Pancreatic and Cortical Adrenal Injury (as well as Surveillance for Renal, 
Thymus, and Spleen Toxicity)......................................................................... 283
26.1.10.15 Drug-Drug interactions ................................................................................... 283
26.1.10.16 Myocardial Ischaemia and Heart Rate Increased ............................................. 283
26.1.10.17 Management of Other Events: Infusion Site Reactions.................................... 284
26.2
Adverse Events and Serious Adverse Events................................................... 284
26.2.1
Adverse Events of Special Interest for Acalabrutinib....................................... 284
26.3
Overdose ........................................................................................................ 284
26.4
Efficacy Assessments...................................................................................... 284
26.4.1
Disease Assessment Criteria............................................................................ 285
26.4.2
Disease Assessment Schedule ......................................................................... 289


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26.4.3
Bone Marrow Assessments ............................................................................. 291
26.4.4
Tumour Assessment........................................................................................ 292
26.5
Human Biological Samples............................................................................. 294
26.6
Pharmacokinetics............................................................................................ 294
26.6.1
Determination of Drug Concentration ............................................................. 295
26.7
Pharmacodynamics......................................................................................... 296
26.7.1
Collection of Samples..................................................................................... 296
26.8
Exploratory 
 Samples............................................... 297
26.9
Exploratory Whole Blood Analyses Samples .................................................. 298
26.9.1
Whole Blood for Exploratory 
............. 301
26.9.2
Whole Blood for 
Analysis............................................................... 301
26.9.3
Whole Blood Samples for 
........................................... 302
26.9.4
Whole Blood Samples for 
.............................................. 303
26.9.5
Whole Blood for 
 Exploratory Analysis........................................ 303
26.9.6
Exploratory Blood 
 Samples................................................................. 304
26.10
........................................................... 305
26.10.1
Collection of Archival Tumour Samples.......................................................... 305
26.10.2
Collection of Tumour Biopsy Samples............................................................ 306
26.10.3
Collection of Bone Marrow............................................................................. 307
26.10.4
Other Study Related 
 Research ....................................................... 307
26.10.4.1
 Sample for 
 Isolation..................................................... 307
26.10.5
Collection of Optional 
 Samples ..................................................... 307
26.10.5.1
Optional Tumour Biopsy at Disease Progression............................................. 307
26.11
Optional Genomics Initiative Sample.............................................................. 307
26.12
Medical Resource Utilisation and Health Economics ...................................... 308
26.13
Important Medical Procedures to be Followed by the Investigator................... 308
26.13.1
Medical Emergencies and Contacts................................................................. 308
27
STATISTICAL CONSIDERATIONS – MODULE 2....................................... 309
27.1
Statistical Hypotheses..................................................................................... 309
27.2
Sample Size Determination............................................................................. 309
27.3
Populations for Analyses................................................................................. 310
27.4
Statistical Analyses ......................................................................................... 311
27.4.1
General Considerations................................................................................... 311
27.4.2
Demographics, Baseline Characteristics, and Study Status.............................. 311
27.4.3
Exposure......................................................................................................... 312
27.4.4
Safety ............................................................................................................. 312
27.4.5
Efficacy .......................................................................................................... 313
27.4.5.1
Objective Response Rate and Proportion of Participants with Complete 
Response ........................................................................................................ 313
27.4.5.2
Time to Response (TTR)................................................................................. 314
27.4.5.3
Duration of Response (DoR)........................................................................... 314
27.4.5.4
Progression-Free Survival (PFS)..................................................................... 314
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27.4.5.5
Overall Survival (OS) ..................................................................................... 314
27.4.6
Pharmacokinetics............................................................................................ 315
27.5
Safety Review Committee – Module 2............................................................ 315
28
REFERENCES............................................................................................... 317
29
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 325
LIST OF FIGURES
Figure 1
CDK9 and RNA Transcription................................................................. 30
Figure 2
Schematic of Study D8230C00001 .......................................................... 36
Figure 3
Modular Protocol Design......................................................................... 46
Figure 4
Module 1 Overall Study Design for AZD4573 in Combination with 
Acalabrutinib in Participants with Relapsed or Refractory DLBCL or 
Relapsed or Refractory MZL ................................................................... 78
Figure 5
Module 1 Part A (Dose Setting) Study Design ......................................... 79
Figure 6
Overall Study Design for AZD4573 Monotherapy Window Study 
Followed by AZD4573 Plus Acalabrutinib in Participants with Relapsed 
or Refractory Mantle Cell Lymphoma – Module 2, Part A..................... 205
LIST OF TABLES
Table 1
Preliminary Efficacy Data – Best Overall Response Rate by Cohort 
(Study D8230C00001)............................................................................. 36
Table 2
Criteria for Adequate Organ Function...................................................... 51
Table 3
Highly-Effective Methods of Contraception............................................. 58
Table 4
Schedule of Activities: Module 1 (AZD4573 with Acalabrutinib) Part A 
– Dose Setting Cohorts ............................................................................ 80
Table 5
Schedule of Activities: Module 1 (AZD4573 with Acalabrutinib) Part B 
– Expansion............................................................................................. 91
Table 6
Risk Assessment.................................................................................... 106
Table 7
Objectives and Endpoints – Module 1.................................................... 110
Table 8
Dosing Schedule – Module 1 ................................................................. 114
Table 9
Criteria for Adequate Haematological Function ..................................... 123
Table 10
Investigational Products......................................................................... 127


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Table 11
Decision Rules Based on mTPI-2 for Dose Escalation ........................... 128
Table 12
Acalabrutinib Dose Reduction Options .................................................. 137
Table 13
Recommended Dose Modifications for AZD4573 and Acalabrutinib..... 138
Table 14
Recommended Dose Modifications for AZD4573 and Acalabrutinib for 
Abnormal Liver Chemistry Results........................................................ 143
Table 15
ECOG Performance Status Scale ........................................................... 152
Table 16
Mandatory TLS Prophylaxis Guidance (in Addition to Institutional 
Guidance).............................................................................................. 167
Table 17
Lugano Modification of Ann Arbor Staging System (for Primary Nodal 
Lymphomas).......................................................................................... 172
Table 18
The Lugano Response Criteria for Non-Hodgkin’s Lymphoma.............. 173
Table 19
Radiologic Scans and PET Scans for Tumour Assessments.................... 176
Table 20
 Sampling Schedule (All Patients) .................. 184
Table 21
Exploratory Whole Blood Analyses Samples (All Patients) - MODULE 
1 ............................................................................................................ 186
Table 22
Analysis Sets ......................................................................................... 196
Table 23
Schedule of Activities: (AZD4573 Monotherapy) Module 2, Part A, 
Period 1................................................................................................. 206
Table 24
Schedule of Activities: (AZD4573 + Acalabrutinib) – Module 2, Part A, 
Period 2................................................................................................. 214
Table 25
Risk Assessment – AZD4573 Monotherapy........................................... 225
Table 26
Objectives and Endpoints – Module 2.................................................... 230
Table 27
Criteria for Adequate Haematological Function ..................................... 238
Table 28
Investigational Products......................................................................... 241
Table 29
Part A - Duration of AZD4573 Monotherapy......................................... 244
Table 30
Acalabrutinib Dose Reduction Options .................................................. 248
Table 31
Recommended Dose Modifications for AZD4573 and Acalabrutinib..... 250
Table 32
Recommended Dose Modifications for AZD4573 and Acalabrutinib for 
Abnormal Liver Chemistry Results........................................................ 254
Table 33
ECOG Performance Status Scale ........................................................... 264
Table 34
Mandatory TLS Prophylaxis Guidance (in Addition to Institutional 
Guidance).............................................................................................. 279
Table 35
Lugano Modification of Ann Arbor Staging System (for Primary Nodal 
Lymphomas).......................................................................................... 285
Table 36
The Lugano Response Criteria for Non-Hodgkin’s Lymphoma.............. 286
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Table 37
Radiologic Scans and PET Scans for Tumour Assessments During 
AZD4573 Monotherapy (Period 1) ........................................................ 289
Table 38
Radiologic Scans and PET Scans for Tumour Assessments During 
AZD4573 + Acalabrutinib Combination Therapy (Period 2).................. 290
Table 39
 Sampling Schedule (All Participants) ............ 297
Table 40
Exploratory Whole Blood Analyses Samples (All Participants) -
MODULE 2 Period 1............................................................................. 299
Table 41
Exploratory Whole Blood Analyses Samples (All Participants) -
MODULE 2 Period 2............................................................................. 300
Table 42
Probability of True ORR Being Greater Than 10% or 30% for Different 
Scenarios of Responses at the End of Period 1 and Period 2 of Part A.... 309
Table 43
Analysis Sets -Module 2 ........................................................................ 311
Cairo-Bishop Definition of Laboratory Tumour Lysis Syndrome (Howard Modification) . 355
Cairo-Bishop Clinical Tumour Lysis Syndrome Grading Criteria...................................... 355
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 326
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 336
Appendix C
Handling of Human Biological Samples ................................................ 341
Appendix D
Optional Genomics Initiative Saliva Sample .......................................... 343
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 347
Appendix F
Cairo-Bishop Tumour Lysis Syndrome Definition and Grading Criteria 
(Howard Modification) .......................................................................... 355
Appendix G
Strong Inhibitors and Inducers of CYP3A.............................................. 357
Appendix H
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 359
Appendix I
References............................................................................................. 362
Appendix J
Abbreviations ........................................................................................ 367
Appendix K
Protocol Amendment History................................................................. 373
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Modular Phase I/II, Open-label, Multicentre Study to Assess AZD4573 in 
Novel Combinations with Anti-cancer Agents in Patients with Advanced Haematological 
Malignancies
Short Title: AZD4573 in Novel Combinations with Anti-cancer Agents in Patients with 
Advanced Haematological Malignancies
Rationale: AZD4573 (formerly known as AZ13810325) is a potent and selective inhibitor of 
cyclin-dependent kinase 9 (CDK9) with nanomolar potency against the enzyme (half maximal 
inhibitory concentration [IC50 < 4 nM]) and excellent selectivity over other CDK family 
members. AZD4573 decreases pSer2RNAP2 levels [the phosphorylation levels of Ser2 found 
in the carboxyl-terminus domain (CTD) of RNA polymerase II (RNAP2)]. This decrease in 
pSer2RNAP2 is linked to preferential reduction of labile proteins like the B-cell lymphoma 2 
(BCL2) family anti-apoptotics Mcl-1 and Bfl-1 as well as other well-known oncoproteins like 
myelocytomatosis (MYC), which leads to rapid induction of apoptosis in a broad range of 
human cancer cell lines derived from haematological malignancies. AZD4573 demonstrates 
significant anti-tumour activity in vivo associated with transient CDK9 inhibition across a 
range of tumour xenograft models as a single agent when dosed intermittently.
AZD4573 may therefore have the potential to provide clinical benefit in terms of anti-tumour 
activity in participants with selected haematological malignancies who have relapsed after, or 
are refractory to prior standard therapy, and for whom there is no other standard therapy 
available. AZD4573 is a novel targeted agent that has shown activity across a range of 
haematological malignancy models and has also demonstrated improved depth and duration of 
response (DoR) when combined with a number of standard-of-care (SoC) or other targeted 
agents in vivo.
The mechanism of action and in vivo data in nonclinical models suggest the potential to 
combine AZD4573 with a number of other anti-cancer treatments, resulting in either 
synergistic or additive activity. This study is modular in design, allowing evaluation of the 
safety, efficacy, and tolerability of AZD4573 in novel combinations with other anti-cancer 
agents. Further modules will be added via protocol amendment. Study information applicable 
to all participants in this study will be described in the core section of this protocol; the 
rationale for each combination and treatment arm, and specific study information and 
assessments will be described in each separate module.


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There are two parts to each combination module of this study:

Part A: Phase I dose setting (dose confirmation in Module 2) to assess safety and 
tolerability and determine/confirm dose(s) and schedule(s) of each combination treatment 
to be evaluated in Part B.

Part B: Phase II cohort expansions in select participant groups to assess preliminary 
anti-tumour efficacy of each combination treatment.
Initiation of Part B for each module will depend on the evaluation of safety outcomes in 
Part A. The addition of new modules will depend on evaluation of preclinical data showing a 
synergistic or additive effect of AD4573 in combination with other anti-cancer agents in the 
relevant disease model.
This protocol refers to the following modules and study drugs:
AZD4573 Combination Therapy with Acalabrutinib - Modules 1 and 2
Acalabrutinib is a selective, irreversible small molecule Bruton’s tyrosine kinase (BTK) 
inhibitor. In B cells, BTK signaling results in activation of pathways necessary for B-cell 
proliferation, trafficking, chemotaxis, and adhesion. Acalabrutinib and its major metabolite 
ACP-5862 inactivate BTK by forming a covalent bond with a cysteine residue in the kinase 
active site. This leads to inhibition of signaling through the B-cell receptor (BCR) in sensitive 
cells. In nonclinical and clinical studies, acalabrutinib inhibited BTK-mediated activation of 
downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation 
and survival.
Acalabrutinib is also known as ACP-196 and Calquence®. Calquence is approved in the 
United States and is either approved or under regulatory assessment in other countries as:

Monotherapy for the treatment of adult patients with mantle cell lymphoma (MCL) who 
have received at least one prior therapy.

Monotherapy and in combination with obinutuzumab for the treatment of adult patients 
with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL).
Module 1: AZD4573 + acalabrutinib in participants with relapsed or refractory diffuse 
large B-cell lymphoma (DLBCL) or relapsed or refractory marginal zone lymphoma 
(MZL).
Data with AZD4573 in combination with acalabrutinib in an activated B-cell (ABC) DLBCL 
xenograft model have shown an increase in both the magnitude and duration of anti-tumour 


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response compared with either single agent alone. In addition, given acalabrutinib’s 
previously demonstrated activity in B-cell malignancies, its initial demonstration of activity in 
the difficult-to-treat population of relapsed/refractory (r/r) DLBCL as monotherapy, and 
mechanism of action (non-overlapping with CDK9 inhibitors), combination therapy with 
acalabrutinib and AZD4573 may reasonably be expected to yield greater clinical benefit than 
with either agent alone.
The first generation BTK inhibitor ibrutinib is Food and Drug Administration 
(FDA)-approved for treatment of patients with MZL requiring systemic therapy who have 
received at least one prior anti-CD20-based therapy. However, there remains an unmet need 
for treatment of patients with advanced MZL.
AZD4573 decreases pSer2RNAP2 levels linked to reduction of Mcl-1, Bfl-1 and Myc proteins 
and is associated with rapid and preferential induction of apoptosis in a broad range of human 
cancer cell lines derived from patients with haematological malignancies. Mcl-1 expression 
has been evaluated in human B-cell lymphomas, including MZL (Cho-Vega et al 2004). Mcl-1 
was expressed across different subtypes of MZL: in 4 of 5 (80%) nodal and splenic marginal 
zone B-cell lymphoma, and 4 of 11 (36%) extranodal marginal zone B-cell lymphoma of 
mucosa-associated lymphoid tissue (MALT) type. Given the demonstrated activity of BTK 
inhibitors in MZL (Lue et al 2020), their relatively well-tolerated safety profile, and a 
mechanism of action that is non-overlapping with CDK9 inhibitors, it is hypothesised that 
combination therapy with AZD4573 and acalabrutinib may yield greater clinical benefit than 
with either agent alone in patients with MZL. 
Part A of Module 1 will enrol participants with r/r diffuse DLBCL or r/r MZL who have failed 
prior therapy(ies), are not eligible for curative treatment options, and for whom there is no 
standard therapy available.
In Part B, separate expansion cohorts for DLBCL germinal centre B-cell (GCB) and non-GCB 
subtypes will be opened at the recommended Phase II dose (RP2D). A further expansion in 
MZL participants may be opened by a protocol amendment, based on emerging clinical data.
Module 2: AZD4573 monotherapy window followed by AZD4573 + acalabrutinib in 
participants with relapsed or refractory MCL.
Acalabrutinib, a potent and selective BTK inhibitor, is approved by the FDA for the treatment 
of adults with MCL who have received at least one prior therapy. In a Phase II study of 
acalabrutinib involving 124 participants with relapsed or refractory (r/r) MCL, 81% of 
participants had a complete response (CR 40%) or partial response (PR 41%) after a median 
of 15.2 months of follow-up. Kaplan-Meier (KM) estimates of median Duration of Response 
(DoR), progression-free survival (PFS) and overall- survival (OS) were not reached 


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(Wang et al 2018). At long-term follow-up after a median of 38.1 months, the median DoR 
was 28.6 months (95% confidence interval (CI) 17.5-39.1 months] and median PFS was 22.0 
months (16.6-33.3 months) (Wang et al 2020).
Part A of Module 2 is a window study comprising 2 cycles (8 weeks) of AZD4573 
monotherapy (Period 1) followed by AZD4573 + acalabrutinib combination treatment 
(Period 2). It will enrol participants with r/r MCL who have failed at least one line of prior 
therapy, are not eligible for curative treatment options. AZD4573 will be administered as 
monotherapy (at the R2PD from the ongoing FTIH study [D8230C00001] in DLBCL) and in 
combination with acalabrutinib 100 mg twice daily. The dose of AZD4573 in combination 
with acalabrutinib will be the RP2D determined in Module 1 Part A.
The study design of Part B of Module 2 will be determined from the data emerging from 
Part A. Specifics of Part B will be defined in a future protocol amendment.
Additional modules and combinations of AZD4573 with other anti-cancer agents may be 
added in the future by amendment.
Objectives and Endpoints Applicable to all Modules
Table S1
Objectives and Endpoints
Objectives
Endpoints
Primary
Part A

Assess the safety and tolerability, describe the 
DLTs, and identify the MTD and/or RP2D of 
AZD4573 when administered intravenously to 
participants with advanced relapsed/refractory 
haematological malignancies, in novel 
combinations with other anti-cancer agentsa

Adverse events, DLTs, laboratory data, 
vital signs, and ECG changes
Part B

Assess the efficacy of AZD4573 in novel 
combinations with other anti-cancer agents in 
participants with relapsed/refractory 
haematological malignancies

Refer to Modules for endpoints
Secondary
Part A and B

Assess the plasma/serum PK of AZD4573 and 
other anti-cancer agents when given in 
combination

Plasma concentrations and derived PK 
parameters for AZD4573 summarised 


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Objectives
Endpoints
by cohort and dose level for the PK 
analysis set

Plasma/serum concentrations and 
derived PK parameters for other anti-
cancer agents summarised by cohort 
and dose level for the PK analysis set
Part B

Further assess efficacy of AZD4573 in novel 
combinations with other anti-cancer agents

Refer to Modules for endpoints

Assess the safety and tolerability of the RP2D of 
AZD4573 in novel combinations with other anti-
cancer agents

Adverse events, laboratory data, vital 
signs, and ECG changes
a
If the MTD and RP2D have already been set in another disease population, the dose setting phase can be a 
dose-confirmation phase.
Abbreviations: DLT = dose-limiting toxicity; ECG = electrocardiogram; MTD = maximum tolerated dose; 
PK = pharmacokinetics; RP2D = recommended Phase II dose.
 Refer to the individual study 
modules of the protocol for detailed objectives and endpoints.
Overall Design
This is a modular, multicentre, open-label, non-randomised, Phase I/II, dose-setting and 
expansion study including an intra-patient ramp up, designed to investigate the safety, 
tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of AZD4573 
in novel combinations with other anti-cancer agents in participants with select r/r 
haematological malignancies.
This is a non-randomised study. Each potential participant approved for screening is assigned 
a unique participant enrolment number. If a participant withdraws from the study, then the 
enrolment number cannot be reused.
A study-specific Safety Review Committee (SRC), in accordance with its charter, will be 
responsible for providing ongoing safety surveillance of the study, with regularly scheduled 
reviews of safety, PK, and other relevant data.
Part A of each module will identify the maximum tolerated dose (MTD) and/or RP2D of 
AZD4573 in combination with other anti-cancer agents. If the MTD and RP2D have been set 
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in a given disease population, the dose setting phase can be a dose confirmation phase. In 
Module 1, the initial target dose of AZD4573 selected for this study in combination with other 
anti-cancer agents will be attained by an intra-patient ramp up during the first cycle of 
treatment. A recommendation about the dose level for each next cohort of evaluable 
participants will be made by the SRC, guided by decision rules provided in study modules. 
For example, in Module 1 the decision rules are based on a modified toxicity probability 
interval (mTPI-2) design with a 30% target dose-limiting toxicity (DLT) rate (± 5%) for MTD: 
dose escalation, stay at the current dose, de-escalation, or de-escalation and current dose is 
unsafe so will never be used again due to unacceptable toxicity.
In Part B (expansion) of each module, separate expansion cohorts for participant subgroups 
will be opened in order to further assess safety and tolerability, and explore anti-tumour 
activity of particular drug combinations.
Module 1
Module 1, Part A will enrol ‘all-comer’ participants with r/r large B-cell lymphoma including 
subtypes such as DLBCL not otherwise specified [NOS], high-grade B-cell lymphoma 
[HGBCL], primary mediastinal large B-cell lymphoma [PMBCL], or large B-cell lymphoma 
transformed from indolent B-cell lymphomas (including but not limited to Richter Syndrome, 
transformed Follicular Lymphoma, transformed MZL), or r/r MZL, who have failed prior 
therapy(ies), are not eligible for curative treatment options, and for whom there is no standard 
therapy available. A 5-week DLT-assessment period will incorporate the whole of Cycle 1, 
including the dose ramp up and the first 3 weeks at the target dose.
Dosing will be staggered by at least one week between the first and the second participant 
dosed in each new dose level cohort. Subsequent participants dosed will be staggered by a 
minimum of 3 days until a decision is made regarding dose escalation or de-escalation.
Module 1, Part B will enrol only participants with r/r de novo DLBCL and will focus on 
evaluating the preliminary efficacy of combination therapy in GCB and non-GCB subtypes in 
two separate expansion cohorts.
Module 1 will enrol participants at approximately 30 sites in approximately 10 countries.
Module 2
Module 2, Part A will enrol participants with r/r MCL who have failed at least one line of 
prior therapy.
Part A will have 2 dosing periods. Period 1 will explore once-weekly intravenous (IV) 
administration of AZD4573 12 mg monotherapy. Period 1 will confirm in MCL the AZD4573 
monotherapy RP2D dose that was established in DLBCL in the first-time-in-human (FTIH) 


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study (D8230C00001), as the dose setting in the FTIH study did not include participants with 
MCL. In Period 1, participants will receive AZD4573 6 mg at Cycle 1 Week 1 and AZD4573 
9 mg at Cycle1 Week 2, then AZD4573 12 mg weekly thereafter. Period 2 will assess the 
safety and tolerability of AZD4573 administered in combination with oral acalabrutinib.
Specifics of Part B study design will be defined in a future protocol amendment.
Disclosure Statement: This is a non-randomised, open-label, sequential, dose setting and 
expansion treatment study with no masking.
Number of Participants:
In Module 1, depending on dose escalation/de-escalation and enrolment in the expansion 
groups, up to a maximum of 105 participants will be treated with AZD4573 + acalabrutinib.
In Module 1 Part A (dose setting), 3 to 9 evaluable participants may be treated in each of up to 
3 dose levels using an mTPI-2 design permitting up to a maximum of 24 DLT-evaluable 
participants for dose setting (ie, a maximum of 9 evaluable participants at each of two dose 
levels and 6 evaluable participants at the third dose level). In addition, any safe dose level may 
be backfilled to include up to approximately 21 evaluable participants to collect additional 
tolerability, PK
 The maximum number of evaluable participants in 
Part A is therefore 63. In Part B (expansion), separate RP2D expansion cohorts will be opened 
for GCB and non-GCB DLBCL subtypes. For primary analyses, a total of approximately 
21 RP2D-treated response-evaluable participants of GCB subtype and approximately 
21 RP2D-treated response-evaluable participants of non-GCB subtype will be incorporated, 
including participants from Part A and Part B. The total number of evaluable participants 
treated in Part B will be up to approximately 42.
In Module 2, approximately12 participants in Part A will receive monotherapy with AZD4573 
(with intra-patient ramp up), followed by administration of AZD4573 in combination with 
acalabrutinib. The study design of Part B of this module, including number of participants, 
will be determined from the data emerging from Part A.
Intervention Groups and Duration:
Duration of therapy will be defined in specific modules.
In Module 1 (AZD4573 + acalabrutinib combination therapy), treatment with AZD4573 and 
acalabrutinib, in Part A and Part B, may be continued until disease progression, an 
unacceptable drug-related toxicity occurs, or the participant withdraws or is withdrawn from 
the study as defined in the protocol.
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In Part A (dose setting), this study module will initially explore once-weekly intravenous (IV) 
administration of AZD4573 at up to 3 target dose levels in combination with oral acalabrutinib 
100 mg twice daily and will enrol all-comer participants with DLBCL or MZL.
In Part B (expansion), separate expansion cohorts for GCB and non-GCB DLBCL subtypes 
will be opened at the RP2D.
For both Part A and Part B of Module 1, Cycle 1 consists of 5 weeks (DLT-assessment period 
in Part A), including an intra-patient dose ramp up. Subsequent cycles are 21 days (3 weeks) 
with once-weekly dosing of AZD4573 in combination with acalabrutinib 100 mg twice daily.
Other dosing schedules and ramp-up periods may be explored by protocol amendment under 
advisement of the SRC.
All participants will be followed for survival until death, loss to follow-up, the Sponsor closes 
study or withdrawal of consent, whichever occurs first.
In Module 2, participants with r/r MCL will be administered AZD4573 as monotherapy and in 
combination with acalabrutinib 100 mg twice daily.
Part A will have 2 dosing periods. Period 1 will explore once-weekly IV administration of 
AZD4573 12 mg monotherapy (with intra-patient ramp up) in 2 cycles. The AZD4573 12 mg 
dose to be administered in Period 1, Cycles 1 and 2, is the established RP2D in DLBCL 
determined in the FTIH study (Study D8230C00001).
Period 2 will assess the safety and tolerability of combination therapy of AZD4573 with 
acalabrutinib 100 mg twice daily. The dose of AZD4573 in combination with acalabrutinib 
will be the RP2D determined in Module 1 Part A. Treatment with AZD4573 combination 
therapy may be continued until disease progression, an unacceptable drug-related toxicity 
occurs, or the participant withdraws or is withdrawn from the study as defined in the protocol.
All participants will be followed for survival until death, loss to follow-up, the Sponsor closes 
the study, or withdrawal of consent, whichever occurs first.
Data Monitoring Committee: No
Statistical Methods: Refer to the individual study modules for the statistical 
considerations in this study.
1.2
Schema
Refer to individual study modules for study schema.


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1.3
Schedule of Activities
Refer to individual study modules for schedule of activities (SoA).
2
INTRODUCTION - CORE
2.1
Study Rationale
This is a modular, Phase I/II, open-label, multicentre study of AZD4573 administered 
intravenously in novel combinations with other anti-cancer agents, to participants with 
advanced haematological malignancies.
The mechanism of action of AZD4573 and in vivo data in nonclinical models suggest the 
potential to combine it with a number of other anti-cancer treatments, resulting in either 
synergistic or additive activity (see Section 4.1). The modular study design allows an 
investigation of optimal combination doses of AZD4573 with other anti-cancer treatments.
The study will consist of one or more modules, each evaluating the safety, tolerability, and 
efficacy of AZD4573 in combination with one or more other anti-cancer agents. Further 
modules will be added via protocol amendment. Study information applicable to all
participants in this study will be described in the core protocol; each specific study treatment 
will be described in a separate module.
There are two parts to each combination module of this study:

Part A: Phase I dose setting to assess safety and tolerability and determine or confirm 
dose(s) and schedule(s) of each combination treatment to be evaluated in Part B.

Part B: Phase II cohort expansions in select participant groups to assess preliminary 
anti-tumour efficacy of each combination treatment.
Initiation of Part B for each module will depend on the evaluation of safety outcomes in 
Part A. The addition of new modules will depend on evaluation of preclinical data showing a 
synergistic or additive effect of AD4573 in combination with other anti-cancer agents in the 
relevant disease model.
Additional modules and combinations of AZD4573 with other anti-cancer agents may be 
added in the future via protocol amendment (see Section 4.3).
The results from this study will form the basis for decisions for future studies.


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2.2
Background
Background information for AZD4573 is included in this section. Refer to individual study 
modules for background information on the other anti-cancer agents being used in 
combination with AZD4573.
2.2.1
CDK9 and RNA Transcription Elongation
Cyclin-dependent kinases represent a family of closely related serine/threonine kinases that 
bind their cognate regulatory subunits, known as cyclins, to form active heterodimeric 
complexes. Several cyclin-dependent kinase (CDK)/cyclin complexes play crucial roles in 
regulating cell cycle progression (CDK1, 2, 4, 6), however, more recently they have also been 
implicated in transcription and mRNA processing (CDK7, 8, 9, 12, 13) (Lue et al 2020, 
Lim and Kaldis 2013, Malumbres 2014).
Regulation of transcription is a complex process governed in part through activity of CDK9 
(Bywater et al 2013, Khoury et al 2003, Krystof et al 2012, Morales and Giordano 2016). 
Following successful transcription initiation, RNAP2 pauses downstream of the transcription 
start site, which serves as a checkpoint and allows for the rapid, synchronous activation of 
genes and integration of multiple regulatory signals before proper elongation can proceed 
(Gilchrist et al 2010, Adelman and Lis 2012). To release RNAP2 from this pause and permit 
subsequent elongation, multiple CDK9-mediated phosphorylation events are required. CDK9 
forms the catalytic unit of the positive transcription elongation factor b (P-TEFb) 
(Bywater et al 2013). P-TEFb phosphorylates the elongation repressive complex made up of 
5,6-dichloro-1-β-D-ribofuranosylbenzimidazole-sensitivity-inducing factor (DSIF) and the 
negative elongation factor (NELF) resulting in the dissociation of NELF from RNAP2 and 
conversion of DSIF to a positive elongation factor. P-TEFb also phosphorylates the carboxyl-
terminus domain (CTD) of RNAP2, which is comprised of 52 heptapeptide repeats 
(YSPTSPS), at the Ser2 position in the final step before elongation can proceed 
(Sanso and Fisher 2013).


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Figure 1
CDK9 and RNA Transcription
2.2.2
CDK9 and Cancer
As an integral node of the transcription regulatory network, CDK9 represents a potential 
target for cancer therapy. Short-term inhibition of CDK9 results in transient transcriptional 
repression and rapid downregulation of genes with short-lived mRNAs and labile proteins 
(Boiko et al 2020). This provides therefore a therapeutic opportunity to treat tumours 
preferentially dependent on target key driver oncogenes fitting that profile without having 
broad toxicity related to general transcriptional repression. Two such genes are MCL-1 and 
MYC (Yang et al 1996, Stewart et al 2010, Hann and Eisenman 1984). MCL-1 is an 
anti-apoptotic BCL2 family member, and its amplification and overexpression have been 
linked to increased survival of and chemotherapy resistance in various cancers 
(Beroukhim et al 2010, Baiocchi et al 2010, Balko et al 2014, Gomez-Bougie et al 2007, 
Glaser et al 2012). MYC is a proto-oncogenic transcription factor that coordinates diverse 
transcription programs and is overexpressed through amplification or genomic rearrangement 
in multiple indications (Beroukhim et al 2010, Ciriello et al 2013). Given the pivotal role 
played by MCL-1 and MYC in tumour cell growth and survival and tumour maintenance, 


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depletion of these oncoproteins in specific tumour contexts results in rapid cell death and 
tumour regressions (Glaser et al 2012, Silkenstedt et al 2021, Soucek et al 2013). CDK9 
therefore represents an intriguing target to indirectly and transiently modulate these 
oncoproteins through transcription regulation to drive oncogene-addicted tumour cells toward 
cell death while sparing normal cells and tissues not dependent on these and other short half-
life pro-tumour survival proteins.
2.2.3
Targeting CDK9
Several multi-CDK inhibitors have been progressed in clinical trials, including dinaciclib, 
which has CDK9 activity that reduced levels of MCL-1 in r/r CLL patients and demonstrated 
clinical activity attributed to CDK9 inhibition (Noy et al 2017, Parry et al 2010, Flynn et al 
2015, Kumar et al 2015, Gojo et al 2013, Varadarajan et al 2015, Rahaman et al 2016). 
However, a more potent and selective CDK9 inhibitor, along with the appropriate PK for 
tuneable target engagement and an optimal dose/schedule leading to improved efficacy and/or 
therapeutic index is warranted.
2.2.4
AZD4573 and CDK9
AZD4573 (formerly known as AZ13810325) is a potent and selective inhibitor of CDK9 with 
nanomolar potency against the enzyme (IC50 < 4 nM) and excellent selectivity over other 
CDK family members. AZD4573 decreases pSer2RNAP2 levels. This decrease in 
pSer2RNAP2 is linked to preferential reduction of labile proteins like the BCL2 family 
anti-apoptotics Mcl-1 and Bfl-1 as well as other well-known oncoproteins like MYC, which 
leads to rapid induction of apoptosis in a broad range of human cancer cell lines derived from 
haematological malignancies (Cidado et al 2020, Boiko et al 2020).
AZD4573 demonstrates significant anti-tumour activity in vivo associated with transient 
CDK9 inhibition across a range of tumour xenograft models as a single agent when dosed 
intermittently. For example, durable tumour regressions can be achieved in the MV-4-11 acute 
myeloid leukaemia (AML) model with AZD4573 dosed on Day 1 and Day 2 weekly with 6 to 
8 hours pSer2RNAP2 suppression on each day. Similar regressions are observed in the 
DLBCL tumour xenograft model, OCI-LY10, using both the aforementioned bi-weekly 
schedule as well as a once-weekly regimen, although responses are not as durable for the 
latter. AZD4573 also demonstrates improved depth and DoR when combined with a number 
of SoC or other targeted agents in vivo. For example, a combination of AZD4573 with 
rituximab in SUDHL-4 or with acalabrutinib in the OCI-LY10 model leads to significantly 
improved DoR post-completion of dosing as compared to each drug alone.


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2.2.5
Nonclinical Information and Correlative Studies
2.2.5.1
Primary, Secondary and Safety Pharmacology
This section summarises the nonclinical primary, secondary, and safety pharmacology of 
AZD4573. The key findings are summarised below:

AZD4573 is a potent inhibitor of CDK9 as measured in enzyme assays (IC50 < 4.0 nM), 
with > 5.8-fold selectivity for CDK9 over other CDKs and > 47.0-fold over other kinases. 
The mode of inhibition of AZD4573 was determined to be consistent with an adenosine 
triphosphate competitive inhibitor with rapid association (fast on) and fast intermediate 
dissociation kinetics.

AZD4573 induced time- and dose-dependent reduction in phosphorylation of the CDK9 
substrate RNAP2 at serine 2 in cells with an IC50 of 13.4 nM with selectivity over other 
CDK substrates. Loss of pSer2RNAP2 levels was associated with loss of Mcl-1 and MYC 
mRNA and MCL-1 and c-Myc protein levels (but not BCL2 and B-cell lymphoma 
extra-large [BCL-XL]) and subsequent caspase activation in MCL-1-dependent MV-4-11 
cells within 6 hours. Six to 8 hours treatment was sufficient to induce maximal caspase 
activation and loss of cell viability in this cell line.

AZD4573 rapidly induced dose-dependent apoptosis and loss of viability in a broad range 
of human cancer cell lines in vitro, particularly subtypes of AML, multiple myeloma 
(MM) and non-Hodgkin lymphoma (NHL) cell lines.

AZD4573 demonstrated time- and dose-dependent transient modulation of pSer2RNAP2 
and Mcl-1 and c-Myc protein levels leading to rapid induction of apoptosis in vivo that 
correlated with anti-tumour response in the MV-4-11 xenograft model. Almost complete 
regressions were observed in multiple studies when AZD4573 was dosed at 15 mg/kg 
twice daily with a 2-hour split dose on Day 1 and Day 2 every 7 days. Additionally, 
AZD4573 dosed once weekly in the OCI-LY10 xenograft model resulted in regressions 
although the DoR was shorter compared to the twice daily schedule. Consistent with in 
vitro data, AZD4573 also demonstrated anti-tumour activity as monotherapy with 
intermittent dosing in multiple additional human xenograft cancer models in vivo. 
Significant anti-tumour activity or regressions were observed in several models of AML, 
NHL and MM when dosed at 15 mg/kg twice daily on Day 1 and Day 2 every 7 days. 
Doses were well tolerated and without significant body weight loss.
AZD4573 also demonstrated good ability to combine with multiple agents in vivo improving 
efficacy. Combination of AZD4573 with Cytarabine prolonged durability of response in an 
AML xenograft model. Combination of AZD4573 with the BTK inhibitor acalabrutinib also 
resulted in more durable responses in an ABC DLBCL xenograft model using either the 
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causes an increase of certain BCL2 family pro-apoptotic proteins, like Bim (Deng 2017a, 
Deng et al 2017b, Sasi et al 2019), pushing the cancer cells closer to their apoptotic threshold, 
a mechanism known as ‘apoptotic priming’ (NCCN 2021, Ni Chonghaile et al 2011).
With the addition of AZD4573 following a short lead-in of acalabrutinib, both the magnitude 
and duration of anti-tumour response is increased compared to either monotherapy as 
evidenced by more rapid and robust cleavage of caspase-3 and delayed time to tumour 
regrowth following treatment cessation (Patent WO2019/058348; data on file, Astra Zeneca). 
Combination of AZD4573 with the anti-CD20 monoclonal antibody rituximab, a rituximab 
and chemotherapy combination therapy (RCHOP) or the BCL2 inhibitor venetoclax improved 
anti-tumour activity leading to complete regressions and highly durable responses in a GCB 
DLBCL model. Prolonged DoR to AZD4573 while still on treatment was observed in a MM 
model when combined with bortezomib. All combinations were well tolerated.

In a secondary pharmacodynamic screen of 189 molecular targets, AZD4573 had activity 
(a defined IC50 value) against 10 targets within 100-fold of the CDK9 cell-based IC50. 
When tested in the same panel, two pharmacologically active metabolites, AZ13830647 
and AZ13848532, had a profile qualitatively similar to that of AZD4573, but with lower 
absolute potencies across the targets.

AZD4573, AZ13830647 and AZ13848532 showed no activity (a defined IC50 value) in a 
panel of cardiac ion channels (including human Ether-à-go-go-Related Gene [hERG])
when tested up to 33 μM.

In an anaesthetised rat study, a 1-hour IV infusion of 6.0 and 18.0 mg/kg AZD4573 was 
associated with a dose-dependent increase in heart rate (up to 27%). Concomitant with the 
increase in heart rate, a small transient decrease in the QA interval of up to 16% 
(indicating an increase in left ventricular contractility) was observed at 18.0 mg/kg. 
Recovery during the washout period was evident for both parameters affected. The lowest 
effect level for effects on the rat cardiovascular system was an AZD4573 free plasma 
concentration of 1250.0 nM at the end of the 6.0 mg/kg infusion.

In a cynomolgus monkey telemetry study, a 2-hour IV infusion of AZD4573 had no 
effects on the cardiovascular system when tested up to the MTD of 1.25 mg/kg previously 
determined in a toxicology study (AZD4573 free plasma concentration at the end of the 
infusion of 75.0 nM).

A 2-hour IV infusion of AZD4573 had no effects on the nervous or respiratory systems in 
rats, when tested in modified Irwin and whole-body plethysmography studies, up to 
10.0 mg/kg (AZD4573 plasma free maximum concentration [Cmax] of 445.0 nM, inferred 
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The results from these pharmacological studies support the use of AZD4573 in the proposed 
clinical trial.
2.2.5.2
Good Laboratory Practice 1-Month Toxicology Studies (Rat and Monkey)
The toxicology of AZD4573 has been evaluated in repeat dose cycle IV infusion studies of up 
to 1-month duration in rats and cynomolgus monkeys. A non-Good Laboratory Practice (GLP) 
in vitro genotoxicity study was also conducted.
Key findings from these studies are summarised below:

Dose-related decreases in peripheral white blood cell parameters, particularly neutrophils 
or lymphocytes, were noted in the rat and cynomolgus monkey following repeated dose 
cycle administration of AZD4573. The DLT in the rat was severe neutropenia with 
resulting disseminated bacterial colonies in several tissues. These white blood cell 
decreases were related to the primary pharmacological action of AZD4573 and showed 
evidence of partial recovery between dose cycles and at the end of the 16-day recovery 
period.

The principal histopathological finding in the 1-month repeat dose cycle toxicology 
studies was dose-dependent decreased cellularity of lymphoid tissues and bone marrow, 
which are consistent with the primary pharmacological action of AZD4573. Decreased 
cellularity was seen in the thymus, spleen, and lymph nodes of rats and cynomolgus 
monkeys, and in the bone marrow and Peyer’s patch of rats only. Reversibility of the 
bone marrow findings was seen at the end of the 16-day recovery period, but mild 
decreases in lymphoid tissue cellularity were still present in both species at the end of the 
recovery period.

Repeated dosing of AZD4573 to the cynomolgus monkey was associated with 
dose-limiting emesis and diarrhoea at 1.0 mg/kg and above. No test article-related 
histopathological changes were seen in the gastrointestinal tract in the monkey dose range 
finding and 1-month studies.

Exocrine pancreatic acinar cell atrophy and/or vacuolation were seen at ≥0.5 mg/kg in 
the cynomolgus monkey 1-month toxicology study. In the rat, repeat dosing of AZD4573 
showed vascular fibrinoid necrosis, interstitial oedema, fibrino-haemorrhagic 
inflammation or acinar cell apoptosis in the pancreas at ≥8.0 mg/kg. Transient increases 
in amylase and lipase correlated with the observed histopathological changes. 
Reversibility was noted at the end of the 16-day recovery period in the rat, but mild acinar 
cell atrophy was still present in the monkey.
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
Mucosal or villous atrophy with mucosal oedema were observed in the small and large 
intestine at ≥6.0 mg/kg in the 1-month rat toxicology study. Reversibility of the intestinal 
findings was noted at the end of the 16-day recovery period.

Cortical necrosis of the adrenal glands was observed in the rat at ≥6.0 mg/kg following 
repeated dosing in the 1-month toxicology study and showed reversibility at the end of 
the 16-day recovery period.

Femoro-tibial epiphyseal growth plate dysplasia was present in cynomolgus monkeys at 
≥0.5 mg/kg in the 1-month repeat dose toxicology study and showed reversibility at the 
end of the 16-day recovery period.

Histopathological findings were noted in the kidneys of rats (tubular necrosis and 
dilatation) at a non-tolerated dose of 12.0 mg/kg and in the monkey (tubular basophilia 
and dilatation) at 1.0 mg/kg and above in the dose range finding studies. There were no 
test article-related histopathological changes in the kidneys of rats or monkeys in the 
1-month toxicology studies following dosing up to 8.0 mg/kg or 1.25/1.0 mg/kg, 
respectively.

Dosing procedure-related haemorrhage, erosion, ulceration or mixed cell infiltration were 
evident at the rat administration and monkey extravascular tolerance sites on the 
one-month toxicology studies. Reversibility of the extravascular tolerance site findings 
were seen at the end of the 16-day recovery period, but the rat administration site changes 
were still present.

AZD4573 was non-mutagenic in a non-GLP Ames test.

AZD4573 showed no evidence of phototoxic potential in a Balb/c 3T3 mouse fibroblast 
assay when conducted in the presence and absence of ultraviolet light.
The results from these toxicology studies support clinical trials with AZD4573 in patients with 
advanced cancer.
2.2.6
Clinical Experience with AZD4573
A FTIH, multicentre, Phase I dose-escalation study (D8230C00001) including an intra-patient 
ramp up is currently being conducted with AZD4573 monotherapy in participants with r/r 
haematological malignancies. Two parallel arms of the study (A and B) are composed of 
separate cohorts of participants at different target dose levels (9, 12, and 18 mg). Arm A
includes participants with r/r haematological malignancies (all comers, excluding AML, acute 
lymphocytic leukaemia [ALL], high risk myelodysplastic syndromes [MDS], chronic 
myelomonocytic leukaemia [CMML], CLL, and Richter’s syndrome). Arm B includes 
participants with r/r haematological malignancies, including but not limited to AML, ALL, 
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high-risk MDS, CMML, CLL, and Richter’s syndrome. 
 
summarises in greater detail the results from the first 38 participants (number of participants: 
Cohort 1 Arm A = 9, Cohort 1 Arm B = 5, Cohort 2 Arm A = 11, Cohort 2 Arm B = 8, Cohort 
3 Arm A = 1, Cohort 3 Arm B = 4) treated at 18 mg and 12 mg target doses. A diagram of the 
previous and now ongoing cohorts treated is presented in Figure 2.
Figure 2
Schematic of Study D8230C00001
 
 
Abbreviation: QW = once weekly.
With respect to safety, 35 of 38 participants (92.1%) had ≥1 Common Terminology Criteria 
for Adverse Events (CTCAE) treatment-emergent adverse event (TEAE) of Grade ≥3. The 
most frequently reported CTCAE Grade 3/4 TEAEs (≥20% of participants overall) were: 
tumour lysis syndrome (TLS; 16 participants, 42.1%); neutropenia (14 participants, 36.8%); 
anaemia (9 participants, 23.7%).
The most common TEAEs identified as DLTs in 9 participants included TLS (3 participants), 
thrombocytopenia (1), transaminase or gamma-glutamyl transferase (GGT) elevations (4) and 
hypotension (1). The last event was regarded as potentially related to inadequate hydration 
during TLS prophylaxis.
Preliminary efficacy data from the first 30 participants is summarised in Table 1.
Table 1
Preliminary Efficacy Data – Best Overall Response Rate by Cohort 
(Study D8230C00001)
Cohort 1
(AZD4573 18 mg)
n (%)
Cohort 2
(AZD4573 12 mg)
n (%)
Cohort 3
(AZD4573 9 mg)
n (%)
Total
(N=30)
n (%)
Arm A
(N = 9)
Arm B
(N = 5)
Arm A
(N = 11)
Arm B
(N = 8)
Arm A
(N = 1)
Arm B
(N = 4)
Best overall 
response
CR
1 (11.1)
0
0
0
0
0
1 (2.6)
PR
0
0
1 (9.1)
0
0
0
1 (2.6)
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Cohort 1
(AZD4573 18 mg)
n (%)
Cohort 2
(AZD4573 12 mg)
n (%)
Cohort 3
(AZD4573 9 mg)
n (%)
Total
(N=30)
n (%)
Arm A
(N = 9)
Arm B
(N = 5)
Arm A
(N = 11)
Arm B
(N = 8)
Arm A
(N = 1)
Arm B
(N = 4)
SD
3 (33.3)
1 (20.0)
3 (27.3)
1 (12.5)
0
0
8 (21.1)
PD
4 (44.4)
1 (20.0)
4 (36.4)
4 (50.0)
0
1 (25.0)
14 (36.8)
NA/Unknown
1 (11.1)
3 (60.0)
3 (27.3)
3 (37.5)
1 (100)
2 (50.0)
13 (34.2)
Objective 
response rate
1 (11.1)
0
1 (9.1)
0
0
1 (25.0)
3 (7.9)
95% CI
(0.3, 48.3)
(0, 52.2)
(0.2, 41.3)
(0, 36.9)
(0, 97.5)
(0.6, 80.6)
(1.7, 21.41)
Response assessments are per Investigator by standardised response criteria for the applicable indication (eg, Cheson criteria 
for DLBCL, Döhner criteria for AML).
Abbreviations: AML = acute myeloid leukaemia; CI = confidence interval; CR = complete response; DLBCL = diffuse large 
B-cell lymphoma; NA = not available; PD = progressive disease; PR = partial response; SD = stable disease.
Overall, best overall responses (based on disease assessments at the protocol-defined 2 month 
assessment time point) included one with CR, one with PR, 8 with stable disease (SD), and 12 
with progressive disease (PD):

Of the participants with DLBCL (n = 17), there was one with CR, one with PR, 4 with 
SD, 7 with PD, and 4 with unknown response. Among these, one with SD and one with a 
CR experienced CTCAE Grade3 TLS. Responses were observed in participants whose 
tumour cell of origin was GCB and non-GCB.
In addition, signs of clinical activity were observed in participants with DLBCL and CLL as 
short, repeated tumour size reductions after each AZD4573 administration of up to 49% of the 
tumour volume, but with tumour regrowth during off-treatment periods. This pattern was 
observed over a range of dose levels and points to the need for combination therapies directed 
to sustaining the potential clinical benefit with AZD4573 treatment.
Evidence of clinical activity was also observed in participants with other haematological 
malignancies, including CLL, AML, and MM. For example, one participant with MM 
previously treated with two lines of therapy, exhibited SD and remained on AZD4573 
treatment for 30 months, whereafter the participant went on to radiotherapy to treat a 
remaining plasmacytoma. Overall, among the first 38 participants with mixed haematological 
malignancies treated, 16 (42.1%) exhibited laboratory evidence of TLS. These data suggest 
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that efficacy and manageable safety may be achievable not just in DLBCL, but also in a range 
of other haematological diseases.
 
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD4573 may be found in 
Refer to individual study modules for the benefit/risk assessment of other anti-cancer agents in 
combination with AZD4573.
2.3.1
Risk Assessment
Based on nonclinical toxicology findings and clinical experience to date, including experience 
from other medicinal products in the same class, the following have been assessed as risks for 
AZD4573:
Important identified risks:

Tumour lysis syndrome

Transaminases increase

Bilirubin increase with transaminase (alanine aminotransferase [ALT] or aspartate 
aminotransferase [AST], or both ALT and AST) increase

Diarrhoea

Nausea

Vomiting

Neutropenia (includes neutrophil count decreased)

Febrile neutropenia
Important potential risks:

Gastrointestinal toxicity

Infection/Bone marrow toxicity with peripheral effect/lymphoid tissue hypocellularity

Liver injury

Neutropenic sepsis
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Potential risks for AZD4573 include:

Pancreatic injury 

Cortical adrenal injury 

Drug-drug interactions

Myocardial ischaemia

Heart rate increase
For a complete characterisation for each risk please refer to 
 
In general, the protocol includes frequent monitoring of blood counts and clinical chemistry, 
along with additional safety monitoring. A urine dipstick test will also be performed, where a 
positive test will trigger urine microanalysis to exclude casts (red cell and protein casts). For a 
summary of management for each risk please refer to the individual study modules. Dose 
modifications for management of AZD4573 toxicities are also provided in the individual study 
module.
In addition to these risks, Embryo-foetal and Reproductive toxicity is Missing information in 
relation to AZD4573.
No reproductive toxicology nor teratogenic studies have been conducted with AZD4573 to 
date, and it is unknown whether the drug is excreted in human milk. Therefore, women of 
childbearing potential and men should agree to use highly-effective contraception as specified 
in Section 5.3, and women who are breastfeeding are excluded from the study. Women and 
men should be fully informed of the lack of reproductive toxicity testing, and women must 
have a negative serum pregnancy test at Screening, and a negative serum or urine pregnancy 
before receiving investigational product (IP).
AstraZeneca has procedures in place to ensure that new or emerging, important clinical safety 
findings are handled in accordance with a globally consistent process. This guarantees that 
AstraZeneca’s safety reporting obligations to Regulatory Authorities, investigators, and Ethics 
Committees are met and optimal risk management of participants is maintained. These 
procedures have been developed to be consistent with ‘International Council for 
Harmonisation (ICH) E2A Clinical Safety Data Management: Definitions and standards for 
reporting,’ which provides guidance to support that suspected unexpected serious adverse 
reaction (SUSAR) information must be provided as early as possible, but no later than 15 days 
after the Sponsor becomes aware that the case meets the minimum criteria for expedited 
reporting.
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Clinical safety findings may arise during or after a participant has completed the study, 
including but not limited to individual case reports. Important new clinical safety findings are 
those findings that might adversely influence the benefit/risk assessment of a medicinal 
product. Upon review of a specific clinical safety finding, AstraZeneca may make a decision 
to communicate the analysis of a safety finding in an expedited manner, so that investigators 
can appropriately manage participants accordingly and ensure that there remains a positive 
risk-benefit analysis.
The majority of adverse events (AEs) observed with the clinical use of AZD4573 to date have 
been gastrointestinal (nausea, vomiting, and diarrhoea), haematological (neutropenia, febrile 
neutropenia, and thrombocytopenia), hepatic (transaminase increase with or without 
concomitant bilirubin increase), and TLS. These events have been manageable with 
appropriate prophylaxis and treatment, and by dose modification.
During the 3-week dose ramp up in the FTIH study (D8230C00001) in DLBCL participants, 
one event of clinical TLS was seen. The abnormal TLS laboratory results were detected at 6 
hours after the start of the infusion. Based on these data, if, in the current study, a participant 
has no signs of laboratory or clinical TLS at the 6-hour TLS monitoring assessment, the 
participant may leave the clinic after the collection of other laboratory samples, as per the 
SoA, at 7 hours after the start of the infusion and managed as an outpatient, at the discretion of 
the Investigator. These participants must return to the clinic the next morning to complete the 
24 hour TLS monitoring period as per the SoA (Cycle 1 Weeks 1-3). Participants showing 
signs of laboratory or clinical TLS at 6 hours after the start of the infusion must be admitted 
for in-patient TLS monitoring for a minimum of 24 hours after the start of the infusion and 
monitored every 4 to 6 hours during this time (or more frequently if clinically indicated). Sites 
retain the option to hospitalise participants based on clinical judgement, despite normal TLS 
laboratory results 6 hours after the start of the infusion.
Regarding the hepatic toxicity events encountered to date with AZD4573, it has been observed 
that while the biochemical changes of increased transaminase with concomitant elevation in 
bilirubin seen in some participants could be classified as Hy’s Law by its strict definition, they 
do not follow a pattern that is consistent with true Hy’s Law predictive of hepatic injury. The 
events are rapidly resolved and to date have not led to any clinical sequelae or lasting hepatic 
injury. Repeated dosing with AZD4573 following these events has demonstrated that there is 
no consistent pattern of recurrence and no consistent increase in severity of the events if they 
do recur.
2.3.2 Benefit Assessment
AZD4573 may have the potential to provide clinical benefit in terms of anti-tumour activity, 
as monotherapy and in combination with other anti-cancer treatments, in patients with a 


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variety of r/r haematological malignancies who have exhausted, or cannot tolerate, SoC 
options.
Preliminary anti-tumour activity has been observed with AZD4573 as monotherapy in 
participants with r/r haematological malignancies in the ongoing Phase I, FTIH, dose-
escalation study (D8230C00001; see Section 2.2.6). Best overall responses included one CR, 
one PR, and 4 SD in participants with DLBCL and evidence of clinical activity was observed 
in participants with other haematological malignancies, such as CLL, AML, and MM.
Please refer to the individual study modules for the benefit/risk assessments for each 
combination treatment.
2.3.3 Overall Benefit/Risk Conclusion
Considering the measures in place to minimise risks with AZD4573 in participants of this 
Phase I/II study (including safety monitoring and dose modification criteria specified in the 
protocol for cases of transaminase ± bilirubin increase) and the observed clinical responses 
and SD in a r/r participant population with AZD4573 monotherapy, the Sponsor believes the 
anticipated benefits that may be afforded to participants with r/r haematological malignancies 
currently outweigh the identified and potential risks associated with AZD4573.
As outlined in Section 2.2.6, AZD4573 has shown activity in the ongoing FTIH study 
(D8230C00001). The results of nonclinical studies with AZD4573 in combination with other 
anti-cancer agents demonstrate an increase in both the magnitude and duration of anti-tumour 
response compared with single agents alone (Section 2.2.5.1). Therefore, therapy with 
AZD4573 in combination with other anti-cancer agents may reasonably be expected to yield 
greater clinical benefit than with AZD4573 alone.
Please refer to the individual study modules for the benefit/risk assessments for each 
combination treatment.
Please refer to Appendix A 11 for the benefit/risk assessment pertaining to the conduct of this 
study during the COVID-19 pandemic.
3
OBJECTIVES AND ENDPOINTS – CORE
Refer to the individual study modules of the protocol for detailed objectives and endpoints.
Objectives
Endpoints
Primary
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Objectives
Endpoints

Assess the safety and tolerability, describe 
the DLTs, and identify the MTD and/or 
RP2D of AZD4573 when administered 
intravenously to participants with advanced 
relapsed/refractory haematological 
malignancies, in novel combinations with 
other anti-cancer agentsa

Adverse events, laboratory data, vital signs, 
and ECG changes
Part B

Assess the efficacy of AZD4573 in novel 
combinations with other anti-cancer agents
in participants with relapsed/refractory 
haematological malignancies

Refer to Modules for endpoints
Secondary
Part A and B

Assess the plasma/serum PK of AZD4573 
and other anti-cancer agents when given in 
combination

Plasma concentrations and derived PK 
parameters for AZD4573 summarised by 
cohort and dose level for the PK analysis 
set

Plasma/serum concentrations and derived 
PK parameters for other anti-cancer agents 
summarised by cohort and dose level for 
the PK analysis set
Part B

Further assess efficacy of AZD4573 in 
novel combinations with other anti-cancer 
agents

Refer to Modules for endpoints

Assess the safety and tolerability of the 
RP2D of AZD4573 in novel combinations 
with other anti-cancer agents

Adverse events, laboratory data, vital signs, 
and ECG changes
Exploratory
Part A

Assess the efficacy of AZD4573 in novel 
combinations with other anti-cancer agents 
in participants with relapsed refractory 
haematological malignancies

Refer to Modules for endpoints


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Objectives
Endpoints
Part A and B

Assess the PD of AZD4573
 
 


Assess
 
 

 
 
 
 
 

To 
 
 
 
 

 
 
a
If the MTD and RP2D have been set in a given disease population, the dose setting phase can be a 
dose confirmation phase.
Abbreviations: DLT = dose-limiting toxicity; ECG = electrocardiogram; MTD = maximum tolerated dose; 
PK = pharmacokinetics; RP2D = recommended Phase II dose.
 
 
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4
STUDY DESIGN - CORE
4.1
Overall Design
In accordance with AstraZeneca standard procedures this clinical study protocol (CSP) has 
been subject to a full peer review.
This is a modular, multicentre, open-label, non-randomised, Phase I/II, dose setting and 
expansion study including an intra-patient dose ramp up.
AZD4573 will be administered intravenously in novel combinations with anti-cancer agents, 
to participants with r/r haematological malignancies.
Module 1 comprises AZD4573 combined with acalabrutinib in participants with r/r DLBCL or 
r/r MZL.
Module 2 Part A is a window study comprising AZD4573 monotherapy followed by 
AZD4573 + acalabrutinib combination treatment in participants with r/r MCL.
Inclusion of further modules via protocol amendments will be based on emerging preclinical 
data (eg, showing a synergistic or additive effect of AZD4573 with the proposed anti-cancer 
therapy) and emerging safety and tolerability data from previous modules.
Other modules studying AZD4573 in combination with other anti-cancer therapies for 
treatment of advanced haematological malignancies may include, but are not restricted to:

Combination of AZD4573 with acalabrutinib and rituximab

Combination of AZD4573 with venetoclax

Combination of AZD4573 with bendamustine and rituximab

Combination of AZD4573 with gemcitabine and oxaliplatin

Combination of AZD4573 with azacytidine
A study-specific SRC (including at a minimum the Sponsor Medical Monitor and participating 
investigators who have enrolled participants), in accordance with its charter, will be 
responsible for providing ongoing safety surveillance of the study, with regularly scheduled 
reviews of safety, PK, and other relevant data. This committee will be responsible for making 
recommendations for dose escalation or dose de-escalation decisions, including 
recommendations on opening cohorts for backfill, as well as making recommendations 
regarding further conduct of the study. This committee may also meet to review data at other 
time points (eg, in response to AEs assessed as medically relevant by the Medical Monitor). 
The SRC will review available clinical and laboratory safety data and other relevant data prior 


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to making recommendations. All SRC recommendations will be documented and shared in 
writing with all participating sites in accordance with its charter.
The initial dosing schedule of AZD4573 in each module may be subsequently changed 
between participant cohorts, in response to emerging safety, PK, and PD findings.
The structure of the study protocol is illustrated in Figure 3, where the protocol core contains 
elements common to all modules and then one or more modules containing the specific details 
relevant to that module.
Assignment of participants to receive study treatment in a given study module will be based 
on meeting inclusion/exclusion criteria and available slots. Guidelines for participant 
allocation when multiple study cohorts are open will be provided separately in the Patient 
Enrolment Guidelines. There are no control groups, other than historical data, in any of the 
study cohorts.
Since Study D8230C00002 was first opened (in July 2020) significant challenges have 
occurred with recruitment into both Module 1 and Module 2. These challenges precluded 
completion enrolment within the allocated time frame of January 2023. AstraZeneca has 
therefore taken the decision to stop recruitment into the study. Based on this decision, the 
main purpose of this protocol amendment is to add a rationale for the proposed reduction in 
scope of study D8230C00002 and to set out measures to allow patients still receiving clinical 
benefit of the study treatment after data collection for the primary analysis has completed to 
continue study treatment. End of study definitions and scope of data collection are updated to 
describe this scenario


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Figure 3
Modular Protocol Design
The population of participants to be included in Part A of each module will be defined in the 
respective module.
Part A of each module will identify the MTD and/or RP2D of AZD4573 in combination with 
other anti-cancer agents. The initial target dose of AZD4573 selected for this study in 
combination with other anti-cancer agents will be attained by an intra-patient ramp up during 
the first cycle of treatment. If the MTD and RP2D have already been set in another disease 
population, the dose setting phase can be a dose confirmation phase.
During dose setting, a recommendation about the dose level for each next cohort of evaluable 
participants will be made by the SRC, guided by decision rules provided in study modules. In 
Module 1, the decision rules are based on a modified toxicity probability interval (mTPI-2) 
design (Guo et al 2017) with a 30% target DLT rate (± 5%) for MTD: dose escalation, stay at 
the current dose, de-escalation, or de-escalation and current dose is unsafe so will never be 
used again due to unacceptable toxicity.


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Part B cohort expansions of specific participant groups will be defined in the respective 
modules.
After determining the RP2D in Part A (dose setting), separate expansion cohorts for 
participant subgroups may be opened in Part B in order to further assess safety and tolerability 
and explore anti-tumour activity of particular drug combinations.
Cycle 1 may also include the intra-patient ramp-up. Participants in relevant subgroups who are 
treated at the RP2D dose level in Part A will contribute to primary analyses along with 
participants from Part B.
During the 3-week dose ramp-up in the FTIH study (D8230C00001) in DLBCL participants, 
one event of clinical TLS was seen. The abnormal TLS laboratory results were detected at 6 
hours after the start of the infusion. Based on these data, if, in the current study, a participant 
has no signs of laboratory TLS or clinical TLS at the 6-hour TLS monitoring assessment, the 
participant may leave the clinic after the collection of other laboratory samples, as per the 
SoA, at 7 hours after the start of the infusion and managed as an outpatient, at the discretion of 
the Investigator. These participants are not required to be hospitalised overnight, and must 
return to the clinic the next morning to complete the 24-hour TLS monitoring period as per 
SoA (Cycle 1 Weeks 1-3).
During the intra-patient ramp-up phase (Cycle 1, Week 1-Week 3), overnight hospitalisation is 
required for participants showing signs of laboratory or clinical TLS at 6 hours after the start 
of the infusion must be admitted for in-patient TLS monitoring for a minimum of 24 hours 
after the start of the infusion and monitored every 4 to 6 hours during this time (or more 
frequently if clinically indicated). Sites retain the option to hospitalise participants based on 
clinical judgement, despite normal TLS laboratory results 6 hours after the start of the 
infusion.
Admission for further AZD4573 administrations is strongly recommended for participants 
who have experienced TLS events during the ramp-up phase. Participants who have 
previously experienced TLS should be admitted the night before each AZD4573 dose for TLS 
prophylaxis. Please refer to each study module for prophylaxis and management of TLS.
All participants will have haematology, chemistry, and urinalysis safety panels performed at 
Screening. Once dosing commences, all participants will be evaluated for safety, including 
clinical chemistry and haematology. If clinically indicated, additional clinical laboratory tests 
and evaluations are to be performed by the Investigator (eg, additional haematology/clinical 
chemistry panels, TLS parameters, liver enzyme tests); these need to be entered into the 
electronic case report form (eCRF).


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4.2
Scientific Rationale for Study Design
This is a modular Phase I/II study evaluating the safety, tolerability, and clinical efficacy of 
AZD4573 in novel combinations with other anti-cancer agents in participants with r/r 
haematological malignancies who have failed prior standard therapy(ies) and for whom no 
other standard therapy is available.
Refer to individual modules for the rationale for the study design for each specific 
combination of AZD4573 with other anti-cancer agents.
Preliminary anti-tumour activity has been observed with AZD4573 as monotherapy in 
participants with r/r haematological malignancies in the ongoing Phase I, FTIH, dose-
escalation study (D8230C00001; see Section 2.2.6). In addition, data with AZD4573 in 
combination with various other anti-cancer agents in nonclinical models have shown an 
increase in both the magnitude and duration of anti-tumour response compared with the single 
agents alone (see Section 2.2.5.1). This study is, therefore, modular in design, allowing 
evaluation of the safety, tolerability, PK, pharmacodynamics, and preliminary activity of 
AZD4573 in combination with different anti-cancer agents in participants with select r/r 
haematological malignancies.
This study will characterise the PK of AZD4573 and other anti-cancer agents when given in 
combination and explore 
 by assessing 
pharmacodynamic/exploratory 
, and 
 
 The results from this study will form the basis for decisions for future clinical studies.
 
 
 
 
 
 
 
 
 
 
 
 
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In conclusion, based on the data available to support preclinical activity of AZD4573 across a 
range of in vitro/in vivo models originating from cells from patients with haematological 
malignancies, coupled with clinical activity observed with other CDK9 inhibitors and 
preliminary safety and efficacy data available from the first 38 participants dosed with 
AZD4573 in the FTIH study (D8230C00001), it is felt that further investigation of AZD4573 
is warranted given the high unmet need for treatment in the patient population chosen for this 
study.
4.3
Regulatory Amendment for Additional Modules
To support amendment of the protocol for additional modules, AstraZeneca will provide a 
summary of all nonclinical and clinical data to support the proposed new combination and 
dosing schedule; this will include updating the following:

Study objectives

Background information providing rationale for the proposed patient population(s) and 
the proposed treatment plan(s)

Study eligibility criteria

A detailed description of the proposed study treatment plans

A revised schedule of participant assessments

A summary of safety data from the completed or ongoing cohort(s)/modules(s) and the 
proposed toxicity management plans for the proposed new combination

A description of any dose modifications and the data (clinical safety information, clinical 
PK data, and nonclinical data) that support the safety of the proposed dose modifications 
for the regimen in question

A clearly stated sample size and justification for the proposed sample size based on the 
objectives for that specific cohort/module

A detailed description of the method and performance characteristics of any test that will 
be used to identify the participant population to be enrolled in the cohort/module, if the 
population will be selected based on a diagnostic assay
4.3.1
Europe and Rest of World
AstraZeneca will provide a substantial amendment for review and approval.
4.3.2
United States of America
AstraZeneca will provide an amendment to the FDA 60 days in advance of planned enrolment 
into a new Module for any combination involving a drug for which the RP2D has not been 
determined for the proposed dosage regimen to be employed, or at least 30 days in advance of 


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a planned enrolment into a Module for drugs where the RP2D has been determined for the 
proposed dosage regimen to be employed.
4.4
Justification for Dose
Refer to individual modules for dose justification.
4.5
End of Study Definition
The end of module is defined as the last scheduled visit or contact of the last participant 
enrolled in the module. 
The overall end of the study is defined as the date of the last visit of the last participant. In the 
event any participant remains on treatment following the end of the data collection for the 
primary analysis, the last visit of the study will be the date when the last participant
permanently discontinued treatment with all investigational products. However, the database 
will be closed following end of data collection, and participants remaining on treatment will 
only be followed for SAEs. In all other aspects, the participant will receive SoC as per local 
practice.
Individual participants will normally be considered to have completed the study if they have 
had a 30-Day Safety Follow-up visit performed, or if the treating site has confirmed the SFU 
visit will not be performed.  For participants continuing treatment after the data cut-off for the 
primary analysis the last visit of the study will be the date when the last participant
permanently discontinued treatment with all investigational products. 
Details of planned data analyses are provided in each of the study modules. The results from 
each module will be reported to Regulatory Authorities within one year of the end of the 
module.
Details on dissemination of clinical data are contained in Appendix A 6.
5
STUDY POPULATION - CORE
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria – Core
NOTE: This study will be enrolling participants with haematological malignancies.
Each participant should meet all of the inclusion criteria and none of the exclusion criteria for 
this study in order to be assigned to a study cohort. Under no circumstances can there be 


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exceptions to this rule. Participants who do not meet the entry requirements are screen 
failures, refer to Section 5.4.
Participants must meet the inclusion and exclusion criteria of both the core and the module 
protocol. Where there are differences in stringency or cut-off values, the specific module takes 
precedence. For example, if haematological medication parameters are stricter in the module 
than in the core, the Investigator should adhere to the module criteria.
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
Provision of signed and dated, written informed consent prior to any mandatory study-specific 
procedures, sampling, and analyses. Participants are also required to consent to the provision 
of any archival tumour biopsies, where applicable. For participants who consent, provision of 
signed and dated written genetic informed consent prior to collection of samples for genetic 
analysis.
Age
1
Participant must be ≥18 years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2
Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
3
Must have received at least one prior line of therapy for the treatment of current disease 
and a clinical study is the best option for next treatment based on prior response and/or 
tolerability.
4
Documented active disease requiring treatment that is r/r defined as:

Recurrence of disease after response to at least one prior line(s) of therapy
or

Progressive disease after completion of or on the treatment regimen preceding entry 
into the study or

Disease that did not achieve an objective response (overall response of CR or PR).
5
Adequate haematological function (as defined in individual modules).
6
Adequate organ function at Screening as defined below in Table 2:
Table 2
Criteria for Adequate Organ Function
Category
Parameter
Value


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Hepatic
Bilirubin
≤ 1.5 × ULN in the absence Gilbert’s syndromea
≤3.0 × ULN if the participant has Gilbert’s 
syndromea
Alanine transaminase and aspartate 
transaminase
< 3.0 × ULN
Renal
Calculated creatinine clearance by 
Cockcroft Gault equation [(140-Age) 
• Mass (kg)/(72 • creatinine mg/dL) • 
multiply by 0.85 if female])
≥ 60 mL/minute
Coagulation
INR
< 1.5 × ULN
Pancreatic
Lipase
≤ 3.0 × ULN and no ongoing pancreatitis
Amylase
≤ 3.0 × ULN and no ongoing pancreatitis
Cardiac
LVEF as assessed by 
echocardiography MUGAb
≥ 40.0%
a
Gilbert’s syndrome = ratio between total and direct bilirubin > 5.
b
Appropriate correction to be used, if a MUGA is performed.
Abbreviations: INR = International Normalised Ratio; LVEF = left ventricular ejection fraction; 
MUGA = multigated acquisition scan; ULN = upper limit of normal.
7
Uric acid level < upper limit of normal (ULN). If hyperuricaemia is present at Screening, 
SoC therapy for hyperuricaemia should be administered (including IV fluid and 
rasburicase or allopurinol) to reduce the uric acid levels to < ULN before the start of 
study intervention.
8
Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing capsules intact without difficulty, receiving IV 
administration of study drug and being admitted, when required, for up to 24 hours during 
study drug administration.
Sex
9
Male or female.
Reproduction
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. Male participants must be 
willing to use barrier contraception (ie, condoms) and female partners should use 
highly-effective methods of contraception for the duration of the study and for a washout 
period of 4 months for men and 7 months for women after discontinuing AZD4573.


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A more detailed description of the required lifestyle restrictions relating to reproduction is 
provided in Section 5.3.1.
10 Negative pregnancy test (serum) at Screening for female participants of childbearing 
potential.
11 Female participants should not be breastfeeding.
12 Female participants must be one year post-menopausal, surgically sterile, or using one 
highly-effective form of birth control (the participant should have been stable on their 
chosen method of birth control for a minimum of 3 months before entering the study and 
continue to 7 months after the last dose).
A more detailed description of the required lifestyle restrictions relating to reproduction is 
provided in Section 5.3.1.
Genomics Initiative Research Study (Optional):
For inclusion in the optional Genomics Initiative component of the study, participants must 
fulfil the following additional criteria:
1
Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of saliva samples for optional genetic research that supports 
Genomics Initiative. If a participant declines to participate in the genetic component of 
the study, there will be no penalty or loss of benefit to the participant. The participant will 
not be excluded from other aspects of the study described in this protocol, so long as they 
consented to the main study.
Tumour Biopsy At Disease Progression (Optional):
For inclusion in the optional tumour biopsy component of the study, participants must fulfil 
the following additional criteria:
1
Provision of signed, written, and dated informed consent for tumour biopsy at disease 
progression. If a participant declines to participate in the tumour biopsy component of the 
study, there will be no penalty or loss of benefit to the participant. The participant will not 
be excluded from other aspects of the study described in this protocol, so long as they 
consented to the main study.
2
Having an accessible tumour/lymphadenopathy and a stable clinical condition that will 
allow the participant to tolerate the procedure, if deemed safe and feasible by the 
Investigator.
Refer to the individual modules for additional module-specific inclusion criteria.


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5.2
Exclusion Criteria – Core
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Participants with non-secretory myeloma.
2
With the exception of alopecia, any unresolved non-haematological toxicities from prior 
therapy greater than CTCAE Grade 1 at the time of starting study treatment.
3
Presence of, or history of, central nervous system (CNS) lymphoma, leptomeningeal 
disease, or spinal cord compression.
4
History of prior non-haematological malignancy except for the following:
(a) Malignancy treated with curative intent and with no evidence of active disease 
present for more than one year before Screening and felt to be at low risk for 
recurrence by treating physician.
(b) Adequately treated lentigo maligna melanoma without current evidence of disease or 
adequately controlled non-melanomatous skin cancer.
(c) Adequately treated carcinoma in situ without current evidence of disease.
5
As judged by the Investigator, any evidence of severe or uncontrolled systemic disease 
(eg, severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal 
lung disease]), or current unstable or uncompensated respiratory or cardiac conditions, or 
uncontrolled hypertension, history of, or active, bleeding diatheses (eg, haemophilia or 
von Willebrand disease) or uncontrolled active systemic fungal, bacterial, viral, or other 
infection (defined as exhibiting ongoing signs/symptoms related to the infection and 
without improvement, despite appropriate antibiotics or other treatment), or IV 
anti-infective treatment within two weeks before first dose of study drug.
6
Known history of infection with human immunodeficiency virus (HIV).
7
Serologic status reflecting active hepatitis B or C infection:
(a) Participants who are hepatitis B core antibody (anti-HBc) positive and who are 
surface antigen negative will need to have a negative polymerase chain reaction 
(PCR) result before enrolment. Those who are hepatitis B surface antigen positive or 
hepatitis B PCR positive will be excluded.
(b) Participants who are hepatitis C antibody positive will need to have a negative PCR 
result before enrolment. Those who are hepatitis C PCR positive will be excluded.
8
Any of the following cardiac criteria:
(a) Resting QT interval corrected using Fridericia’s formula (QTcF) ≥470 msec 
obtained from a single ECG.


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(b) Any clinically important abnormalities in rhythm (except for participants with a 
pacemaker in place), conduction or morphology of resting ECG (eg, complete left 
bundle branch block, third degree heart block).
(c) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, congenital long QT syndrome, family history of long QT 
syndrome or unexplained sudden death under 40 years of age. Concomitant 
medications known to prolong QTc should be used with caution and cannot be used 
starting with the first dose of study drug and through the DLT-assessment period 
(Part A) or during the scheduled ECG assessments.
9
History of severe allergic or anaphylactic reactions to BH3 mimetics or history of 
hypersensitivity to active or inactive excipients of study treatment.
10 Documented confirmation and ongoing treatment of adrenal gland insufficiency or 
pancreatitis.
11 Undergone any of the following procedures or experienced any of the following 
conditions within 6 months prior to first dose:
(a) coronary artery bypass graft
(b) angioplasty
(c) vascular stent:
(i)
A participant who has had a cardiac stent or arterial stent implanted within 
6 months prior to first dose, is not eligible for the study.
(ii) A participant who has had a venous stent implanted within 6 months prior to first 
dose, is eligible for the study.
(d) myocardial infarction
(e) angina pectoris
(f) congestive heart failure (New York Heart Association Class ≥2)
(g) ventricular arrhythmias requiring continuous therapy
(h) atrial fibrillation, which is judged as uncontrolled by the treating physician
(i)
haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other 
CNS bleeding
Prior/Concomitant Therapy
12 Treatment with any of the following:
(a) Received cytotoxic chemotherapy within 21 days (or 42 days for nitrosoureas or 
mitomycin C).
(b) Received radiotherapy within 14 days.


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(c) Received major surgery (as defined by the Investigator), or immunotherapy 
(specifically immune checkpoint inhibitors) within 28 days.
(d) Received adoptive cellular therapy such as autologous or donor natural killer (NK) 
cell or T lymphocyte infusions [eg, CAR-T cells]) within 60 days.
(e) Received an investigational drug within 14 days of the first scheduled dose or not 
recovered from associated toxicities.
(f) Participants who have previously received an autologous stem cell transplantation 
(SCT) are excluded if less than 90 days have elapsed from the time of transplant or 
the participant has not recovered from transplant-associated toxicities prior to the first 
scheduled dose.
(g) Participants with a history of allogeneic SCT are excluded, UNLESS the following 
eligibility criteria are met: transplant was > 180 days prior to the first scheduled dose 
AND participant must not have taken immunosuppressive medications associated 
with the transplant for at least 1 month prior to first scheduled dose.
13 Requires ongoing immunosuppressive therapy, including systemic (eg, intravenous or 
oral) corticosteroids for treatment of lymphoid cancer or other conditions. Note: 
Participants may use topical or inhaled corticosteroids or low-dose steroids (≤ 10 mg of 
prednisone or equivalent per day) as therapy for comorbid conditions. Short courses of 
steroids before study entry are allowed. During study participation, participants may also 
receive systemic corticosteroids as needed for treatment-emergent comorbid conditions.
14 Receipt of live, attenuated vaccine within 28 days before the first dose of study 
treatment(s).
Other Exclusions
15 Judgement by the Investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.
In addition, the following is considered a criterion for exclusion from the optional genetic 
research:

Previous allogeneic bone marrow transplant
Refer to the individual modules for additional module-specific exclusion criteria.


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5.3
Lifestyle Considerations
Refer to the individual modules for any possible lifestyle restrictions in addition to those listed 
below.
5.3.1
Reproduction
The following restrictions apply while the participant is receiving AZD4573 and for the 
specified times before and after:

Female participants must be one year post-menopausal, surgically sterile, or using one 
highly-effective form of birth control (a highly-effective method of contraception is 
defined as one that can achieve a failure rate of less than 1% per year when used 
consistently and correctly). Women of childbearing potential should use highly-effective 
methods of contraception (see Table 3). They should have been stable on their chosen 
method of birth control for a minimum of 3 months before entering the study until 
7 months after discontinuing AZD4573.

Female participants must not donate, or retrieve for their own use, ova from the time of 
start of dosing and throughout the study treatment period, and for at least 7 months after 
the final study drug administration.
Note: True abstinence can only be used as the sole method of contraception if it is consistently 
employed as the participant’s preferred and usual lifestyle, and if considered acceptable by 
local regulatory agencies and IRB/Independent Ethics Committees (IEC). Periodic abstinence 
(eg, calendar, ovulation, sympto-thermal, and post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.

Male participants should be asked to avoid unprotected sex (ie, always use a condom) 
with women of childbearing potential during the study and for a washout period of 
4 months after discontinuing AZD4573. Female partners of male participants should use 
highly-effective methods of contraception for the duration of the study and for a washout
period of 4 months after their partner discontinues AZD4573. Male participants should 
refrain from donating sperm from the start of dosing until 4 months after discontinuing 
AZD4573. If male participants wish to father children, they should be advised to arrange 
for freezing of sperm samples before the start of receiving AZD4573.


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Table 3
Highly-Effective Methods of Contraception
Barrier/Intrauterine methods
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system (eg, Mirena®)a
Hormonal methods
•
Implantsb: Etonogestrel-releasing implants (eg, Implanon® 
or Norplant®)
•
Intravaginal Devicesb: Ethinyl oestradiol/etonogestrel-
releasing intravaginal devices (eg, NuvaRing®)
•
Injectionb: Medroxyprogesterone injection: 
eg, Depo-Provera®
•
Combined Pill: Normal and low-dose combined oral 
contraceptive pill
•
Patchb : Norelgestromin/ethinyl oestradiol-releasing 
transdermal system (eg, Ortho Evra®)
•
Minipillb: Progesterone based oral contraceptive pill using 
desogestrel. Cerazette® is currently the only highly-effective 
progesterone-based pill
a
This is also considered a hormonal method
b
Not approved for use in Japan
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from Regulatory Authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned the same participant enrolment 
number as for the initial screening. The Investigator should confirm this with the designated 
study physician.
6
STUDY INTERVENTION - CORE
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Please refer to the following modules outlining the specific treatment details:

Module 1: AZD4573 + acalabrutinib in participants with r/r DLBCL or r/r MZL.


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
Module 2: AZD4573 monotherapy followed by AZD4573 + acalabrutinib in participants 
with r/r MCL.
Additional modules and combinations of AZD4573 with other anti-cancer agents may be 
added in the future by amendment.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
AZD4573 will be administered as an absolute (flat) dose, 2-hour (± 15 minutes) IV infusion 
once weekly, at least 5 days apart, in combination with other anti-cancer agents (initial 
frequencies, schedules, and sequencing of AZD4573 dosing with respect to the combination 
agent(s) will be defined in their respective module; alternate frequencies, schedules, and 
sequences may be instigated in response to emerging safety, tolerability, or PK data via a 
protocol amendment).
For all participants, results of safety laboratory testing (haematology and clinical 
chemistry at a minimum) must be available prior to dosing and must be reviewed by the 
Investigator prior to each administration of AZD4573.
Liver chemistry tests: For any participant on study who experiences elevated ALT /AST 
≥ 3 × ULN and/or elevated total bilirubin ≥ 2 × ULN: repeated liver chemistry tests (INR, 
fibrinogen, D-dimer [where available at institution], alkaline phosphatase (ALP), ALT, AST, 
glutamic dehydrogenase (GLDH), creatinine phosphokinase (CPK), total bilirubin, direct 
bilirubin, indirect bilirubin) are required at 48 hours (-2/+12 hours) and 96 hours (- 2/+12 
hours) after the start of the infusion and until resolution of the event. However, in case the 
event is not resolved within 96 hours the medical monitor should be contacted. If GLDH 
cannot be performed locally, LDH will be analysed locally and a serum sample must be 
collected for central retrospective GLDH analysis. Refer to the Laboratory Manual for details.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets 
potential Hy’s Law (PHL) criteria at any point during the study. The Investigator participates, 
together with the Sponsor, in review and assessment of these cases. Hy’s Law (HL) criteria 
are met if there is no alternative explanation for the elevations in transaminases and total 
bilirubin levels.
If an unscheduled ECG is done at any time: troponin and an electrolyte panel* must be done 
to coincide with the ECG testing.
* can include: sodium, calcium, potassium, chloride, phosphate, magnesium.


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If a participant is assessed as meeting PHL criteria, please refer to Appendix E.
In case of any unacceptable deterioration in laboratory values, not fulfilling eligibility 
criteria, and deemed as clinically significant by the Investigator, the Medical Monitor 
must be contacted to discuss whether AZD4573 dosing can be continued.
AZD4573 will be supplied by the Sponsor.
 
 
Please refer to the individual study modules for the method of supply of combination agents.
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines by AstraZeneca Research & Development supply chain. The labels will fulfil Good 
Manufacturing Practice Annex 13 requirements for labelling. Label text will be translated into 
local language.
All IPs should be kept in a secure place under appropriate storage conditions. The appropriate 
storage conditions for AZD4573 and combination agents will be defined on the product label.
6.2
Starting Dose, Dose-Escalation Scheme, and Stopping Criteria
Refer to each protocol module for further details of the dose-escalation-decision rules and 
information for the combination agents used.
A study-specific SRC, in accordance with its charter, will be responsible for making 
recommendations for dose escalation or dose de-escalation decisions, including decisions on 
opening cohorts for backfill, as well as making recommendations regarding further conduct of 
the study. The SRC will review available clinical and laboratory safety data and other relevant 
data prior to making recommendations.
6.3
Definition of Dose-limiting Toxicity (DLT)
DLTs will be defined in individual study modules.
6.4
Definition of Maximum Tolerated Dose (MTD)
MTDs will be defined in individual study modules.
6.5
Definition of Recommended Phase II Dose (RP2D)
The RP2D will be defined in individual study modules.
CCI


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6.6
Definition of Evaluable Participant
Evaluable participants will be defined in individual study modules.
6.7
Duration of Therapy
Duration of therapy will be defined in individual study modules.
6.8
Preparation/Handling/Storage/Accountability of Interventions
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention and only authorised site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labelled storage conditions with access limited to the Investigator and authorised site 
staff.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
 
AZD4573 should only be used as directed in this protocol and as detailed in a separate 
Handling Instructions document for AZD4573. Details of treatment with AZD4573 for each 
participant will be recorded in the eCRF. 
 
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.
CCI
CCI


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6.9
Measures to Minimise Bias: Randomisation and Blinding
This is a non-randomised study. Each potential participant approved for screening is assigned 
a unique participant enrolment number. If a participant withdraws from the study, then the 
enrolment number cannot be reused.
6.10
Study Intervention Compliance
Refer to individual study modules for study intervention compliance.
6.11
Prior/Concomitant Therapy
Information on any treatment received in the 30 days before starting IP and all concomitant 
treatments given during the study, with reasons for the treatment, will be recorded in the 
eCRF. If medically feasible, participants taking regular medication should be maintained on it 
throughout the study period.
Any prophylactic treatment given as part of the study is to be recorded in the eCRF as 
concomitant therapy.
AZD4573 and concomitant treatments are described below, refer to individual study modules 
for other study interventions.
AZD4573 and concomitant treatments
Given the proposed clinical dosing regimen of AZD4573, a short IV infusion over 2 hours 
(once weekly), and the observed short half-life of approximately 4 to 7 hours, the risk of 
clinically meaningful drug interactions with AZD4573 is considered to be low.
In vitro studies suggest AZD4573 could reversibly inhibit cytochrome P450 (CYP)3A4/5, 
CYP2C8, CYP2C9, CYP2C19, organic anion transporting polypeptide (OATP)1B1, 
OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2 and 
multi-antimicrobial extrusion protein (MATE). However, clinical studies have not yet been 
performed to assess drug-drug interaction. Based on the static model recommended 
(FDA 2017), exposure increase of CYP3A-sensitive substrates caused by AZD4573 will be 
1.06, making it a weak inhibitor.
AZD4573 is not a strong inducer of CYP1A2, CYP2B6, or CYP3A, based on in vitro studies.
If potent CYP3A4 inhibitors are administered, it is recommended to avoid administering them 
on the same day as AZD4573 administration where possible. Alternatively, such inhibitors 
could be administered 8 to 12 hours after the completion of the AZD4573 infusion, if deemed 
clinically warranted in the opinion of the Investigator.


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It is recommended that treatment with strong CYP3A4 inducers is avoided, unless it is 
deemed clinically warranted in the opinion of the Investigator.
Concomitant drugs that have the potential to prolong QTc, should not be used around the time 
of the scheduled ECG assessments during this study.
Concomitant use of paracetamol is permitted but is limited to a maximum dose of 4 grams per 
day. Other anti-cancer agents, investigational agents (other than co-administered agents 
described in the study module), or radiotherapy should not be given while the participant is 
taking AZD4573, although radiation for palliation at focal sites is permitted after discussion 
with the Medical Monitor.
After the start of study intervention, blood and platelet transfusions are allowed as clinically 
indicated at any time during the study and can be given as per local institutional guidelines.
Supportive care (eg, recombinant growth factor support), and other medications that are 
considered necessary for the participant’s wellbeing (eg, bisphosphonates), may be given at 
the discretion of the Investigator and in accordance with local institutional guidelines.
At study entry, participants may be using topical or inhaled corticosteroids or low-dose 
steroids (≤10 mg of prednisone or equivalent per day) as therapy for comorbid conditions, but 
use of corticosteroids as therapy for lymphoid cancer is not permitted. Doses of systemic 
corticosteroid > 10 mg/day may be used during the study if clinically indicated (eg, for 
treatment of an AE/SAE), but the dose must be tapered back down to no greater than 
10 mg/day upon resolution of the event, to avoid chronic use.
AstraZeneca recommends administering non-live inactivated vaccines 72 hours prior to 
administration of the first dose of any IP to avoid biases in the interpretation of safety data due 
to the potential overlap of vaccine-related AEs with IP AEs.
6.12
Dose Modification
If, in the opinion of the Investigator, a participant experiences a clinically significant and/or 
unacceptable adverse reaction, including a DLT not attributable to the disease or 
disease-related processes under investigation, but is considered to be possibly related to 
AZD4573 by the Investigator, then the dose may be temporarily or permanently halted or 
reduced.
Supportive therapy will be administered as required. Relevant reporting and discussion with 
the Medical Monitor will take place before resumption of dosing.
Events meeting the definition of a DLT as defined in the specific study modules must be 


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reported accordingly. Refer to specific study modules for dose modifications.
6.12.1
Retreatment Criteria
Retreatment is defined as the first dose of study drug after a period of intentional pause in 
study drug treatment (other than missed doses, eg, study treatment put on hold until resolution 
of COVID-19). Refer to specific study modules for retreatment criteria.
6.13
Intervention After the End of the Study
After the data cut-off for the primary analysis, the clinical study database will be closed to the 
entry of new data. However, patients still receiving AZD4573 at that time will be able to 
continue receiving study treatment (in accordance with guidance in this protocol and the IB)
if, in the opinion of the Investigator, they are still deriving clinical benefit.


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7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL - CORE
7.1
Discontinuation of Study Intervention
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
Participants must be discontinued from study intervention in the following situations:

Participant decision. The participant is at any time free to withdraw his/her participation 
in the study, without prejudice

Withdrawal of consent from the study

Withdrawal of consent from further treatment with IP

Investigator decision

Any AE that meets criteria for discontinuation of IP as defined in Section 8.2

Initiation of alternative anti-cancer therapy including another investigational agent

Investigator determination that the participant is no longer benefiting from the treatment 
regimen

Severe noncompliance to this protocol as judged by the Investigator and/or AstraZeneca

Confirmed disease progression

Participant is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing treatment with IP might constitute a safety risk 
(Section 7.3)

A female participant becomes pregnant
Participants that are withdrawn from the study but are evaluable per the definition in each 
module will not be replaced. Any participant that is withdrawn and is not evaluable may be 
replaced to ensure a minimum number of evaluable participants.
Participants may withdraw from any aspect of the voluntary exploratory research at any time, 
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. The medical care that a participant may 
receive after the study has ended may involve a different drug or treatment, which the 
hospital, together with the Investigator considers to be the most suitable alternative. The 
Investigator will be responsible for making arrangements for the continuation of a 
participant’s medical care after participation in this study has ended.


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7.1.1
Temporary Discontinuation
Applicable criteria and procedures for restarting study intervention will be defined in 
individual study modules.
7.1.2
Rechallenge
Applicable rechallenge procedures will be defined in individual study modules.
7.2
Participant Withdrawal from the Study
All participants will be followed for survival until death, loss to follow-up, AstraZeneca closes 
the study, or withdrawal of consent, whichever occurs first.

A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioural, 
compliance, or administrative reasons.

A participant who considers withdrawing from the study must be informed by the 
Investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).

At the time of withdrawal from the study, if possible, the 30-day Safety Follow-Up (SFU) 
visit should be conducted, as shown in the SoA. See the SoA for data to be collected at 
the time of study withdrawal and follow-up and for any further evaluations that need to be 
completed.

The participant will discontinue the study intervention and be withdrawn from the 
study at that time.

If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation. The 
Investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.


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In addition, participants may be withdrawn from the study in the event that the Sponsor 
terminates this study (see Appendix A 9).
7.3
Procedures for Handling Participants Incorrectly Initiated on 
AZD4573 or Combination Therapy
Any participants determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing treatment with IP might constitute a safety risk.
Where participants that do not meet the inclusion criteria are enrolled in error or incorrectly 
started on treatment with AZD4573 or combination therapy, or where participants 
subsequently fail to meet the study criteria after initiation of treatment, the Investigator should 
inform the Medical Monitor immediately. The Medical Monitor is to ensure all such contacts 
are appropriately documented.
7.4
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix A 9.
8
STUDY ASSESSMENTS AND PROCEDURES - CORE

Study procedures and their timing for each module are summarised in the SoA for that 
module. Protocol waivers or exemptions are not allowed.


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
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study requirements, including those specified in the SoA, is essential 
and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the informed consent form (ICF) may be utilised 
for screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA.

Refer to the specific study modules for the maximum amount of blood collected from 
each participant over the duration of the study.
8.1
Safety Assessments
Refer to the specific study modules for the safety assessments in this study.
8.2
Adverse Events and Serious Adverse Events
The principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B 1 and Appendix B 2.
An AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorised representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.2.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events and SAEs will be collected and recorded from the time of signing of the ICF
throughout the treatment period and including the follow-up period, 30 days after the last dose 
of study intervention.
If the Investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the SFU period in a participant 


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treated by him or her, the Investigator shall, without undue delay, report the SAE to the 
Sponsor.
8.2.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF. 
AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the IP(s) (yes or no)

Action taken with regard to IP(s)

Outcome

Information regarding DLTs
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication

Detailed information on the event (symptoms and signs, work-up done)


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8.2.3
Causality Collection
The Investigator should assess causal relationship between IP 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 IP?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B 3 to the CSP.
8.2.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.2.5
Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests and vital signs will be summarised in the 
CSR.
Deterioration as compared to baseline in protocol-mandated parameters should therefore only 
be reported as AEs if they fulfil any of the SAE criteria, are the reason for discontinuation of 
treatment with the IP or are considered to be clinically relevant as judged by the Investigator 
(which may include but not be limited to consideration as to whether treatment or non-planned 
visits were required or other action was taken with the study treatment [eg, dose adjustment or 
drug interruption]).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).
Deterioration of a laboratory value that is unequivocally due to disease progression should not 
be reported as an AE.


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Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
In case TLS is observed at any time during the study, this should be reported as an AE and on 
the AE page of the eCRF (in addition to the completion of applicable TLS monitoring forms), 
the TLS should be graded according to CTCAE on the AE page.
8.2.6
Potential Hy’s Law Cases
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN 
must be reported as SAEs due to medical significance. Please refer to Appendix E for 
further instruction on cases of increases in liver biochemistry and evaluation of HL. Please 
also refer to specific dose modification guidance contained in each module for use in events of 
PHL. Discussions regarding study drug discontinuation (eg, with the Medical Monitor) due to 
increased liver transaminases and/or bilirubin increases should be documented.
8.2.7
Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the IP is being studied. It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease. The development of new, 
or progression of existing metastasis, to the primary cancer under study should be considered 
as disease progression and not an AE. Events, which are unequivocally due to disease 
progression, should not be reported as an AE during the study. Death clearly resulting from 
disease progression should not be reported as an SAE.
8.2.8
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the seriousness criteria. New cancers are those that are not the primary reason for the 
administration of the study treatments and have been identified after the participant’s 
inclusion in this study. They do not include metastases of the original cancer.
8.2.9
Handling of Deaths
All deaths that occur during the treatment period including SFU period should be reported as 
follows:

Death that is unequivocally due to disease progression should be communicated to the 
study monitor/medical monitor as soon as possible and be documented in the relevant 
eCRF module, but it should not be reported as an SAE during the study.


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
Where death is not clearly due to the progression of the disease under study, the AE 
causing the death should be reported to the study monitor as an SAE within 24 hours. The 
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. Autopsy report should be requested if available.

Deaths with an unknown cause should always be reported as an SAE, but every effort 
should be made to establish a cause of death. A post-mortem may be helpful for the 
cause-of-death assessment and, if performed, a copy of the post-mortem results (with 
translation of important parts into English) should be reported in an expedited fashion to 
an AstraZeneca representative within the usual timeframes.

Deaths that occur after the treatment period during the survival follow-up period should 
be reported on the survival log on the eCRF.
8.2.10
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF.
Participants continuing study treatment after the end of data collection for the primary analysis 
will be followed for SAEs with paper reporting instead of eCRF reporting. 
If any SAE occurs in the course of the study, then 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 is 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 eCRF system, an 
automated email alert will be sent to the designated AstraZeneca representative.
If the electronic data capture (EDC) system is not available, then the Investigator or other 
study-site staff will report a SAE to the appropriate AstraZeneca representative by telephone.


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The AstraZeneca representative will advise the Investigator/study-site staff how to proceed.
 
Participants will be required to be monitored for TLS for up to 24 hours post dose until they 
have received at least one AZD4573 dose at the target dose level (ie, for at least the first 3 
AZD4573 once-weekly doses). If a participant has no signs of laboratory TLS at the 6-hour 
TLS monitoring assessment, the participant may leave the clinic after the collection of other 
laboratory samples, as per the SoA, at 7 hours after the start of the infusion and managed as an 
outpatient, at the discretion of the Investigator. These participants must return to the clinic the 
next morning to complete the 24-hour TLS monitoring period as per the SoA (Cycle 1 Weeks 
1-3). Participants with TLS at the 6-hour TLS monitoring assessment must be admitted for in-
patient TLS monitoring for a minimum of 24 hours after the start of the infusion and 
monitored every 4 to 6 hours during this time (or more frequently if clinically indicated).
Sites retain the option to hospitalise participants based on clinical judgement, despite normal 
TLS laboratory results 6 hours after the start of the infusion. Admitting the participant for 
subsequent dose administrations will be done at Investigator discretion.
Any hospitalisation due to occurrence of an AE must be reported as an SAE, per definition. 
However, if hospitalisation is purely for the purposes of extended observation then this does 
not qualify as an SAE and does not need to be reported.
8.2.11
Adverse Events of Special Interest for AZD4573
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 IP 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 including detailed information 
(signs and symptoms, work-up done, and results), allows ongoing surveillance of these events 
in order to further characterise and understand them in relation to the use of the IP. All AESIs 
should be recorded in the eCRF as soon as possible, and 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.
The following are considered to be AESIs for AZD4573:
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
Tumour lysis syndrome

Hepatotoxicity (including PHL, drug-induced liver injury (DILI), and bilirubin increase 
with transaminase (ALT or AST or both ALT and AST) increase

Neutropenia (including Febrile neutropenia, Neutropenic sepsis, and Neutrophil count 
decrease

Thrombocytopenia, including Platelet count decrease

Myocardial ischaemia

Pyrexia
8.2.12
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca, except when 
the pregnancy is discovered before the participant has received AZD4573.
If a pregnancy is reported, the Investigator should inform AstraZeneca within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.2.12.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under 
study may have interfered with the effectiveness of a contraceptive medication.
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 
participant was discontinued from the study.
If any pregnancy occurs in a female participant during exposure to IP or in the 7 months after 
discontinuing the IP, then the Investigator 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 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 


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or 5 calendar days for SAEs (see Section 8.2.10) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.
8.2.12.2
Paternal Exposure 
Pregnancy of a participant’s partner is not considered to be an AE. However, any conception 
occurring from the date of dosing until 4 months after discontinuation of dosing should be 
reported to AstraZeneca and followed up for its outcome.
If a pregnancy occurs in a participant’s partner within the timeframe specified above, then 
investigators or other site personnel will inform the appropriate Sponsor representative 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The same timelines apply when outcome information is available. Detailed instructions on 
reporting pregnancies are provided in the Investigator manual separate from this protocol.
8.2.13
Medication Error
If a medication error occurs in the course of the study, then the Investigator 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 
relevant information is completed within one (Initial Fatal/Life-Threatening or Follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.2.10) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Appendix B 4.
8.3
Overdose
For this study, any dose of study intervention greater than the dose that was intended to be 
given will be considered an overdose.
All overdoses should be recorded as follows:

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.


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
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, the Investigator 
or other site personnel will inform appropriate AstraZeneca representatives 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 
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 8.2.10) and within 30 
days for all other overdoses.
For AZD4573, no data on overdosing are available. There is no known antidote for AZD4573. 
Investigators should be advised that any participant who receives a higher dose than that 
intended should be monitored closely, managed with appropriate supportive care under local 
institutional guidelines and followed up expectantly.
Refer to individual study modules for overdose information on the other anti-cancer agents 
being used in combination with AZD4573.
8.4
Efficacy Assessments
Refer to the individual study modules for the efficacy assessments in this study.
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 Sample see Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated.

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.
Details of sample collection, processing, shipping and storage of samples for exploratory 
research will be described in the Laboratory Manual. Each sample for exploratory research 
will be identified with the study number and participant enrolment number.


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The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples may be stored for a maximum of 
15 years or as per local regulations from the date of the last participant’s last visit, after which 
they will be destroyed. DNA is a finite resource that may be used up during analyses. The 
results of any further analyses will be reported either in the CSR itself or as an addendum, or 
separately in a scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.5.1
Pharmacokinetics
Refer to the individual study modules for the assessments of PK in this study.
8.5.2
Pharmacodynamics
Refer to the individual study modules for the assessments of pharmacodynamics in this study.
8.6
Refer to the individual study modules for the assessments 
 in this study.
8.7
Optional Genomics Initiative Sample
Refer to the individual study modules for information on the optional collection of samples for 
genetic research in this study.
8.8
Health Economics OR Medical Resource Utilisation and Health 
Economics
Health Economics/Medical Resource Utilisation and Health Economics parameters are not 
evaluated in this study.
9
STATISTICAL CONSIDERATIONS – CORE
Refer to the individual study modules for the statistical considerations in this study.
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MODULE 1: AZD4573 PLUS ACALABRUTINIB IN PARTICIPANTS 
WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL 
LYMPHOMA (DLBCL) OR RELAPSED OR REFRACTORY 
MARGINAL ZONE LYMPHOMA (MZL)
10
PROTOCOL SUMMARY – MODULE 1
10.1
Schema
Figure 4
Module 1 Overall Study Design for AZD4573 in Combination with 
Acalabrutinib in Participants with Relapsed or Refractory DLBCL or 
Relapsed or Refractory MZL
Note: Part A includes ‘All-comer’ participants with relapsed or refractory large B-cell lymphoma including 
subtypes such as DLBCL NOS, HGBCL, PMBCL, or large B-cell lymphoma transformed from indolent B-cell 
lymphomas (including Richter Syndrome, transformed Follicular Lymphoma, transformed marginal zone 
lymphoma) or participants with r/r MZL. Part B only includes participants with de novo DLBCL (GCB or 
non-GCB).
Abbreviations: AE = adverse event; DLBCL = diffuse large B-cell lymphoma; DoR = duration of response; 
EOP2a = end of Phase IIA; GCB = germinal centre B-cell; HGBCL = high-grade B-cell lymphoma; IA = interim 
analysis; MZL = marginal zone lymphoma; NOS = not otherwise specified; ORR = objective response rate; 
PFS = progression-free survival; PMBCL = primary mediastinal B-cell lymphoma; r/r = relapsed/refractory; 
RP2D = recommended Phase II dose.
AZD4573+Acala 
Dose-setting in r/r 
DLBCL and MZL 
all-comers N=up to 
24 participants to 
establish RP2D. 
(Additional 
participants, up to a 
total of approximately 
21 treated per safe 
dose regimen, may be 
enrolled in back-filling)
GCB @ RP2D: Expansion to N=21*   
(IA at n=10*)
EOP2a 
(N=21)
IA = Interim analysis; ORR and tolerability (no 
pause to accrual).
EOP2a = End of Phase 2a analysis; ORR, 
DoR/PFS and AE discontinuation rate.
Note: For each subtype the timing 
of interim and EOP2a analyses are 
independent of when the other 
subtype cohort reaches its analysis 
time-point.
PART A
PART B
* Including relevant subtype patients from Part A
Non-GCB @ RP2D: Expansion to 
N=21* (IA at n=10*)
EOP2a 
(N=21)


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Figure 5
Module 1 Part A (Dose Setting) Study Design
Dosing will be staggered by at least one week between the first and the second participant dosed in each new 
dose level cohort. Subsequent participants dosed will be staggered by a minimum of 3 days until a decision is 
made regarding dose escalation or de-escalation.
After completion of the 5-week DLT-assessment period, treatment with AZD4573 and acalabrutinib may be 
continued until disease progression, an unacceptable drug-related toxicity occurs as defined in the protocol, or 
the participant withdraws or is withdrawn from the study for other reasons.
Abbreviations: BID = twice daily; DLT = dose-limiting toxicity; mTPI = modified toxicity probability interval.


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10.2
Schedules of Activities – Module 1
Table 4
Schedule of Activities: Module 1 (AZD4573 with Acalabrutinib) Part A – Dose Setting Cohorts
Assessment
Screena
Cycle 1,
Weeks 1-5
(includes 
intra-
patient
Dose ramp 
up)
Cycles 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle = 
21 days)ll
Disease 
Assessmentb/
End of 
Treatmentmm
30-Day SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Informed consentd
X
Section 
17.1.1
Inclusion/exclusion
X
Section 
17.1.1
Medical history and 
demographics
X
Section 
17.1.1
Physical examinationf
X
X
X
X
X
X
X
Section 
17.1.2
ECOG performance 
status
X
X
X
X
X
X
X
Section 
17.1.4
Archival tumour 
sample or new biopsy
X
Section 
17.10.1
17.1.10.2


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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes 
intra-
patient
Dose ramp 
up)
Cycles 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle = 
21 days)ll
Disease 
Assessmentb/
End of 
Treatmentmm
30-Day SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Vital signse
X
X
X
X
X
X (each 
infusion)
X
Section 
17.1.3
Weightf
X
X
X
X
X
Section 
17.1.3
B symptoms
X
X
X
X
X
X
X
Section 
17.1.5
12-lead ECGg
X
X
X
X
X
Section 
17.1.8
CMV immunoglobulin 
M [IgM] and PCRh
X
Section 14.2, 
17.1.6
Cardiac troponini
X
X
X
X
X
Section 
17.1.6
T4, Cortisol, ACTH 
and TSHj
X
X 
(Cycle 
2 only)
X
Section 
17.1.6
ECHO/MUGAk
X
As clinically indicatedk
Xk
Section 
17.1.7


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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes 
intra-
patient
Dose ramp 
up)
Cycles 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle = 
21 days)ll
Disease 
Assessmentb/
End of 
Treatmentmm
30-Day SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Haematologyl
X
X
X
X
X
Xl (each 
infusion)
X
Section 
17.1.6
Coagulationm
X
X
X
X
X
Xm
X
Section 
17.1.6
Clinical chemistryn
X
X
X
X
X
Xn (each 
infusion)
X
Section 
17.1.6
TLS monitoringo
Weeks 1-3
Section 
17.1.10.10
Urinalysisp
X
X
X
X
X
X
X
Section 
17.1.6
Pregnancy testing 
(women of 
childbearing 
potential)q
X
(Serum)
Week 1 
(predose)
Once every 21 days (±7 days)
X
Section
17.1.6
Lipase/amylaser
X
X
X
X
X
X
X
Section 
17.1.6


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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes 
intra-
patient
Dose ramp 
up)
Cycles 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle = 
21 days)ll
Disease 
Assessmentb/
End of 
Treatmentmm
30-Day SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Hepatitis serologys
X
See footnote for schedule
Section 
17.1.6 and
Section 
17.1.10.4
CD4, CD8, CD19, 
CD16/NK cell countt
X
See footnote for schedule
X
Section 
17.1.7
Serum 
immunoglobulins 
(IgA, IgM, IgG)t
X
See footnote for schedule
X
Section 
17.1.7
Concomitant 
medication
X
X
X
X
X
X (each 
infusion)
X 
X
X
Section 
15.11
Adverse event 
evaluation
X
X
X
X
X
X (each 
infusion)
X
X
X
Section 8.2
AZD4573/ 
acalabrutinib plasma 
PKu
Weeks 1-3
Cycle 2
Section 17.6


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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes 
intra-
patient
Dose ramp 
up)
Cycles 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle = 
21 days)ll
Disease 
Assessmentb/
End of 
Treatmentmm
30-Day SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Pharmacodynamic 
samples (blood) for 
AZD4573v
Weeks 1-3v
Section 17.7
Pharmacodynamic 
samples (blood) for 
acalabrutinibw
Week 1 and 
Week 4w
Section 17.7
 
X
Weeks 1-3
Section 17.8
Whole blood for 
exploratory 
 
X
Weeks 1, 3, 
and 5
Cycles 
2, 3, 5, 
6, and 7
Cycle 
2
X
(X)
Section 
17.9.1
Whole Blood for 
X
Weeks 1, 3 
and 5
Cycles 
2, 3, 5, 
6, and 7
Cycle 
2
X
(X)
Section 
17.9.2
Whole Blood Samples 
for
 
X
Weeks 1 and 
3
Cycles 
2, 3, 5, 
and 7
Cycle 
2
X
(X)
Section 
17.9.3
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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes 
intra-
patient
Dose ramp 
up)
Cycles 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle = 
21 days)ll
Disease 
Assessmentb/
End of 
Treatmentmm
30-Day SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Whole blood samples 
for 
  
X
Weeks 1 and 
3
Cycle 2
Cycle 
2
X
(X)
Section 
17.9.4
Exploratory blood 
X
Weeks 1-3
Cycles 
2, 3, 5, 
and 7
X
(X)
Section 
17.9.6
 sample for 
 
isolationdd
(X)
Week 1 
(predose)
Section 
17.10.4.1
Genomics Initiative 
saliva sample 
(optional)ee
(X)
Week 1 
(predose)
X
(X)
(X)
(X)
(X)
(X)
(X)
Section 
17.11
Tumour biopsy sample 
(optional)ff
At disease 
progression
(X)ff
Section 
17.10.5.1
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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes 
intra-
patient
Dose ramp 
up)
Cycles 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle = 
21 days)ll
Disease 
Assessmentb/
End of 
Treatmentmm
30-Day SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Bone marrow biopsy 
& aspirategg
X
As clinically 
indicated and 
to confirm 
CR
Section 
17.4.3 and 
Section 
17.10.3
Disease assessmentb
and radiologic scanshh
X
See Table 19 for schedule
X
Section 
17.4.2
Acalabrutinib oral, 
BIDii
Twice daily (from Cycle 1, Week 1 to end of treatment)
Section 15.1
AZD4573 
intravenousjj
Once weekly (from Cycle 1, Week 1 to end of 
treatment)nn
Section 15.1
Acalabrutinib drug 
accountabilitykk
X
X
X
X
X
Section 15.8
Disease progression 
follow-up (SoC)
X
Section 
17.1.9.2
Survival Follow-up
X
Section 
17.1.9.3


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a
Screening tests should be performed within 30 days before the first administration of study drug, unless otherwise indicated.
b
Disease assessments will be done by the Investigator using the Lugano Response Criteria for Non-Hodgkin’s Lymphoma (Cheson et al 2014). Additional disease assessments 
may be performed as clinically indicated.
c
The SFU visit will be performed 30 days (±7 days) after the last dose of all study drug. Tumour assessments will be repeated at this visit if they have not been performed 
within 9 weeks if the participant discontinued before or during Week 26, or 12 weeks if the participant discontinued after Week 26.
d
Informed consent must be obtained ≤30 days before the first dose of study drug and must be obtained before any protocol-defined screening procedures are done.
e
Vital signs (blood pressure, pulse rate, temperature) will be assessed after the participant has rested for at least 10 mins. Blood pressure and pulse rate will be measured at 
Screening, and on Day 1 of Cycle 1, Weeks 1-3 at the following timepoints: predose (within 2 h prior to infusion), 1 h after the start of the infusion (± 10 mins), at end of 
infusion (up to 10 mins post dose) and then 4 h (± 30 mins) and 6 h (± 30 mins) after start of infusion, from Cycle 1 Week 4  onwards, at predose (up to 30 mins prior to 
infusion), at the end of infusion (up to 30 mins post dose), and at the 30-day SFU. Temperature to be taken pre-infusion (up to 2 h prior to all infusions).
f
As the study is intended to recruit adults, height should only be measured at Screening. Weight to be measured at Screening, prior to infusions on Day 1 of each cycle, and at 
the 30-day SFU visit.
g
Participants should be in semi-supine position and resting for ≥ 10 mins before the ECGs. Single ECGs for local and central analysis are required at Screening and at the 
following timepoints: for Cycle 1, Weeks 1-5 and Cycle 2 Day 1 predose (at the day of infusion prior to infusion) and within 30 mins of the end of infusion; for Cycles 3+ on 
Day 1 within 30 mins after the end of infusion, and at the 30-day SFU visit. 
h
All subjects will have CMV testing at Screening including serology testing for CMV immunoglobulin (Ig)G and CMV IgM and CMV DNA PCR testing
i
Cardiac troponin measurements are required at the following timepoints: Screening, Cycle 1, Weeks 1-5, predose (within 72 hours prior to infusion) and at 24 h after the start 
of the infusion, and Cycles 2+ on Day 1 of each cycle, predose (within 72 hours prior to infusion), and at the 30-day SFU visit. Note: either a troponin I or troponin T assay 
can be used per SoC at the respective hospital. If the hospital has both a SoC troponin I and troponin T assay available, the investigator shall use only one consistently for the 
duration of the study.
j
T4, cortisol, ACTH, and TSH to be taken at Screening, predose (within 72 hours prior to infusion) on Cycle 2, Day 1, and at the 30-day SFU.
k
ECHO should be done at Screening and within 14 days after an abnormal ECG finding (eg, T-wave inversion/flattening) or as soon as possible when clinically indicated. If 
an ECHO cannot be taken, a MUGA scan to assess LVEF will be done. In case of any T-wave abnormality, the ECHO (or MUGA) should be repeated at the 30-day 
follow-up visit to address the question of recovery, during the off-treatment period.
l
Haematology testing should be measured at Screening, Cycles 1, 2, and 3 predose (within 72 h prior to infusion) and 24 h after the start of the infusion. From Cycle 4 
onwards, haematology testing should be predose (within 72 h prior to infusion) and (if clinically indicated) 24 h after the start of the infusion. A sample will also be drawn at 
the 30-day SFU. The Investigator may take additional, unscheduled samples throughout the study if deemed clinically warranted and these need to be entered into the eCRF. 
Haematology tests do not need to be repeated before first dose if the first-dose visit is within 3 days of the Screening sample.
m
Coagulation testing should be measured at Screening, Cycles 1, 2, and 3 predose (within 72 h prior to infusion) and 24 h post-infusion of AZD4573. For Cycles 4-8, predose 
(within 72 h of the infusion); the 24-h sample can be omitted unless clinically indicated. For Cycles 9+, on Day 1 of each cycle, an AZD4573 pre-infusion sample will be 
drawn within 72 h prior to infusion. A sample will also be drawn at the 30-day SFU. The Investigator may take additional, unscheduled samples throughout the study if 
deemed clinically warranted and these need to be entered into the eCRF. 


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n
Clinical chemistry should be measured at Screening, Cycles 1, 2, and 3 predose (within 72 h prior to infusion), and 24 h post-infusion of AZD4573. From Cycle 4 onwards, 
clinical chemistry testing should be measured predose (within 72 h prior to infusion) and (if clinically indicated) 24 h after the start of the infusion. A sample will also be 
drawn at the 30-day SFU. The investigator may take additional, unscheduled samples throughout the study if deemed clinically warranted and these need to be entered into 
the eCRF. Clinical chemistry tests do not need to be repeated before first dose if the first-dose visit is within 3 days of the Screening sample.
In addition, GLDH and CPK will be measured at Screening for all participants. If GLDH cannot be performed locally, LDH will be analysed locally and a serum sample 
must be collected for central retrospective GLDH analysis, which will be performed as applicable. Refer to the Laboratory Manual for details.
If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, potassium) and troponin must be done to coincide with the ECG testing.
o
All participants will receive TLS prophylaxis during the intra-patient ramp up and be monitored for TLS during the first 24 hours post start of dose; this requirement will 
continue until they have received at least one AZD4573 dose at the target dose level (i.e., for at least the first 3 AZD4573 once-weekly doses). TLS monitoring will be 
performed at the following timepoints: predose AZD4573, 6 h after the start of the infusion, and 24 h (± 1 h) after the start of the infusion. Participants showing signs of 
clinical or laboratory TLS at 6 h after start of infusion must be admitted for in-patient TLS monitoring for a minimum of 24 h after the start of the infusion and monitored 
every 4 to 6 h during this time (or more frequently if clinically indicated). For each TLS monitoring timepoint, a TLS Monitoring page in the eCRF is to be filled out. Fluid 
balance must be monitored according to local institutional standards.
p
Urine samples will be collected at the following timepoints: Screening, Cycles 1-8, predose AZD4573 (within 72 hours prior to infusion) and within approximately 2 hours 
after the end of infusion, Cycles 9+ on Day 1 of each cycle, predose AZD4573 and within approximately 2 hours after the end of infusion, and at the 30-day SFU.
q
Pregnancy test to be performed at Screening (serum) and predose (serum or urine) on Cycle 1, Week 1, then once every 21 days (± 7 days) prior to initiating a new cycle 
and at the 30-day SFU visit. Additional testing may be performed at Investigator discretion (eg, in the event of suspected contraception failure).
r
Lipase and amylase should be evaluated at Screening, Cycles 1-8 predose AZD4573 (within 72 hours prior to infusion), Cycles 9+, predose AZD4573 (within 72 hours prior 
to infusion) on Day 1 of each cycle, and at the 30-day SFU visit.
s
In addition to hepatitis serology as specified, participants who are anti-HBc positive, or have a known history of HBV infection, should be monitored every 3 months with a 
quantitative PCR test for HBV DNA. In addition, any participants testing positive for any hepatitis serology must have PCR testing for verification purposes.
t
CD4, CD8, CD19, CD16/NK and serum immunoglobulins (IgA, IgM, IgG) will be drawn at Screening, Day 1 (predose) of Cycles 2, 4, 7, 9, 13, 16, 19 and every 6 months 
thereafter (predose), and at the 30-day SFU.
u
Plasma samples for PK analysis will be taken at the following time points: For Cycle 1, of Weeks 1-3 and Cycle 2, Day 1: predose (up to 2 h prior to AZD4573 and 
acalabrutinib administration) and 1 h (± 15 mins), 2 h (± 15 mins), 4 h (± 30 mins), 7 h (± 1 h), and 24 h (± 1 h) (ie, Day 2 of dosing, prior to acalabrutinib dosing) after the 
start of the infusion.
v
Pharmacodynamic evaluations for AZD4573 blood samples will be collected at Cycle 1, Weeks 1 and 2 at predose (up to 2 h prior to dosing of either agent) and 2 h (± 15 
mins), 4 h (± 30 mins), and 24 h (± 2 h) (ie, Day 2, but before acalabrutinib dosing) after the start of the infusion. Cycle 1 Week 3, predose (up to 2h prior to dosing), 2 h (± 
15 mins), 4 h (± 30 mins),7 h (± 1 h), and 24 h (± 2 h) (ie, Day 2, but before acalabrutinib dosing) after the start of the infusion.
w
Pharmacodynamic evaluations for acalabrutinib: blood samples (whole blood) are to be taken predose on Cycle 1, Week 1, (up to 2 h prior to dosing of either agent), and on 
Cycle 1, Week 4 (up to 2 h prior to dosing of either agent).
x
 Samples will be taken for all participants at Screening and Cycle 1, Weeks 1-3: predose (up to 2 h prior to dosing) and 4 h (± 30 mins), 7 h (± 1 h), 
and 24 h (± 1 h) after start of infusion. If the participant has
 at 
24 h after start of infusion, samples will be drawn at 48 h (-2 h/+12 h prior to infusion), 96 h (- 2 h/+12 h prior to infusion), predose-the-following infusion (within 4 h prior 
to infusion), and at each point chemistry panel testing is being performed. 
 with subsequent dosing with AZD4573, 
 
sampling should be performed the same as for Cycle 1, Weeks 1-3. 
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y
Whole blood for exploratory 
samples will be collected at Screening, Cycle 1, Weeks 1, 3, and 5 predose (within 2 h prior to dosing), 
Cycle 2, Days 1 and 15 predose (within 2 h prior to dosing), Day 1 of Cycles 3, 5, 6 and 7 predose (within 2 h prior to dosing), and at every scheduled or unscheduled tumour 
assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken at End of Treatment, a sample should be 
obtained at the 30-day SFU.
z
Whole Blood for 
 will be collected at Screening, Cycle 1, Weeks 1, 3, 
and 5 predose (within 2 h prior to dosing), Cycle 2, Days 1 and 15, predose (within 2 h prior to dosing), and on Day 1 of Cycles 3, 5, 6, and 7 predose (within 2 h prior to 
dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a 
sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
aa
Whole blood samples for 
 will be collected at Screening, Cycle 1, Weeks 1 and 3 predose (within 2 h prior to dosing), Cycle 2, Days 1 and 15, predose 
(within 2 h prior to dosing), Day 1 of Cycles 3, 5, and 7 predose (within 2 h prior to dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of 
infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
bb
Whole blood samples for 
will be collected at Screening, Cycle 1, Weeks 1 and 3 predose (within 2 h prior to dosing), Cycle 2, Days 1 and 15 predose 
(within 2 h prior to dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of 
treatment. If a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
cc
Exploratory blood 
 Whole blood samples will be collected at Screening and Cycle 1 Weeks 1-3 at predose (within 2 h prior to dosing of either agent), 2 h 
(± 15 mins) and 24 h (± 2 h) after the start of the infusion (and prior to acalabrutinib dosing), and on Day 1 of Cycles 2, 3, 5, and 7 predose (within 2 h prior to dosing), and at 
every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken 
at End of Treatment, a sample should be obtained at the 30-day SFU.
dd
 sample for 
 isolation will be collected at Cycle 1, Week 1 predose.
ee
An optional saliva sample for genomics initiative research will be taken from consenting participants prior to the first dose of IP. If for any reason the sample is not taken 
before dosing it may be taken at any visit until the last study visit. Only one sample should be collected per participant for genetics during the study.
ff
A biopsy will be taken at disease progression for participants who consent. The disease progression sample may be taken at the SFU visit if not collected previously.
gg
Bone marrow biopsy and aspirate: 
 
hh
See Table 19 for schedule of disease assessments, including mandatory PET assessments. Disease assessments will be done by the Investigator using the Lugano Response 
Criteria for Non-Hodgkin’s Lymphoma (Cheson et al 2014). Additional disease assessments may be performed as clinically indicated.
ii
Acalabrutinib 100 mg oral capsule to be given twice per day.
jj
AZD4573 is to be administered as an absolute (flat) dose, 2-h (± 15 mins) IV infusion on a once-weekly schedule.
kk
Participant-reported drug administration for acalabrutinib needs to be done on every AZD4573 dosing day, ideally prior to dosing (± 24 h) and is also to be done after the 
last acalabrutinib capsule is taken and the leftover capsules returned to site. Drug accountability for acalabrutinib will occur every 2 weeks, (on an AZD4573 dosing day, 
ideally prior to dosing [± 24 h]).
ll
If a participant is attending Cycle 9+ visits according to a modified schedule, in which AZD4573 is not infused and assessments are not performed every week, the Day 1 
assessments should be performed at least once per cycle.
mm
The End of Treatment visit is the last visit attended by the participant prior to the 30-Day SFU on the study. At this visit, the participant does not receive IMP and should 
undergo the applicable assessments associated with the Cycle and visit they have reached, plus those shown in the “Disease Assessment/End of Treatment” column of the 
SoA.
nn
AZD4573 should be administered at least 5 days apart.
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Abbreviations: ACTH = adrenocorticotropic hormone; BID = twice daily; CMV = cytomegalovirus; CPK = cyclin-dependent kinase; CSP = clinical study protocol; 
ECG = electrocardiogram; eCRF = electronic case report form; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; GLDH = glutamic dehydrogenase; 
Ig = immunoglobulin; 
 LDH = lactate dehydrogenase; LTFU = long-term follow-up; 
; MUGA = multigated 
acquisition; 
; PCR = polymerase chain reaction; PK = pharmacokinetics; SFU = safety follow-up; SoC = standard of care; 
T4 = thyroxine; TLS = tumour lysis syndrome; TSH = thyroid-stimulating hormone.
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Table 5
Schedule of Activities: Module 1 (AZD4573 with Acalabrutinib) Part B – Expansion
Assessment
Screena
Cycle 1,
Weeks 1-5
(includes intra-
patient dose 
ramp up)
Cycle 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle=21 
days)mm
Disease 
assessmentb/
End of 
Treatmentnn
30-Day 
SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Informed consentd
X
Section 
17.1.1
Inclusion/exclusion
X
Section 
17.1.1
Medical history and 
demographics
X
Section 
17.1.1
Physical examinationf
X
X
X
X
X
X
X
Section 
17.1.2
ECOG performance 
status
X
X
X
X
X
X
X
Section 
17.1.4
Tumour biopsy sample 
(mandatory)
X
Section 
17.10.2
Vital signse
X
X
X
X
X
X (each 
infusion)
X
Section 
17.1.3
Weightf
X
X
X
X
X
Section 
17.1.3
B symptoms
X
X
X
X
X
X
X
Section 
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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes intra-
patient dose 
ramp up)
Cycle 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle=21 
days)mm
Disease 
assessmentb/
End of 
Treatmentnn
30-Day 
SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
12-lead ECGg
X
X
X
X
X
Section 
17.1.8
CMV immunoglobulin 
M [IgM] and PCRh
X
Section 14.2, 
17.1.6
Cardiac troponini
X
X
X
X
X
Section 
17.1.6
T4, cortisol, ACTH, 
and TSHj
X
X 
(Cycle 
2 
only)
X
Section 
17.1.6
ECHO/MUGAk
X
As clinically indicated
Xk
Section 
17.1.7
Haematologyl
X
X
X
X
X
Xl (each 
infusions)
X
Section 
17.1.6
Coagulationm
X
X
X
X
X
Xm
X
Section 
17.1.6
Clinical chemistryn
X
X
X
X
X
Xn (each 
infusion)
X
Section 
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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes intra-
patient dose 
ramp up)
Cycle 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle=21 
days)mm
Disease 
assessmentb/
End of 
Treatmentnn
30-Day 
SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
TLS monitoringo
Weeks 1-3
Section 
17.1.6
Urinalysisp
X
X
X
X
X
X
X
Section 
17.1.6
Pregnancy testing 
(women of 
childbearing 
potential)q
X
(Serum)
Week 1 
(predose)
Once every 21 days (±7 days)
X
Section 
17.1.6
Lipase/amylaser
X
X
X
X
X
X
X
Section 
17.1.6
Hepatitis serologys
X
See footnote for schedule
Section 
17.1.6 and 
Section 
17.1.10.4
CD4, CD8, CD19, 
CD16/NK cell countt
X
See footnote for schedule
X
Section 
17.1.7
Serum 
immunoglobulins 
(IgA, IgM, IgG)t
X
See footnote for schedule
X
Section 
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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes intra-
patient dose 
ramp up)
Cycle 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle=21 
days)mm
Disease 
assessmentb/
End of 
Treatmentnn
30-Day 
SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Concomitant 
medication
X
X
X
X
X
X (each 
infusion)
X
X
X
Section 
15.11
Adverse event 
evaluation
X
X
X
X
X
X (each 
infusion)
X
X
X
Section 8.2
AZD4573/ 
acalabrutinib plasma 
PKu
Weeks 1-3
Cycle 
2
Section 17.6
Pharmacodynamic 
samples (blood) for 
AZD4573v
Weeks 1-3v
Section 17.7
Pharmacodynamic 
samples (blood) for 
acalabrutinibw
Weeks 1 and 4, 
(predose)
Section 17.7
 
X
Weeks 1-3
Section 17.8
Whole blood for 
exploratory 
 
b
X
Weeks 1, 3, and 
5
Cycles 
2, 3, 5, 
6, and 
7
Cycle 
2
X
(X)
Section 
17.9.1
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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes intra-
patient dose 
ramp up)
Cycle 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle=21 
days)mm
Disease 
assessmentb/
End of 
Treatmentnn
30-Day 
SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Whole Blood for 
z
X
Weeks 1, 3, and 
5
Cycles 
2, 3, 5, 
6, and 
7
Cycle 
2
X
(X)
Section 
17.9.2
Whole blood samples 
for 
 
c
X
Weeks 1 and 3
Cycles 
2, 3, 5, 
and 7
Cycle 
2
X
(X)
Section 
17.9.3
Whole blood samples 
for 
dd
X
Weeks 1 and 3
Cycle 
2
Cycle 
2
X
(X)
Section 
17.9.4
Whole blood for 
 
exploratory analysisee
X
Week 1
Cycles 
2, 3, 5, 
and 7
X
(X)
Section 
17.9.5
Exploratory blood 
X
Weeks 1-3
Cycles 
2, 3, 5, 
and 7
X
(X)
Section 
17.9.6
 sample for 
 
isolationaa
(X)
Week 1 
(predose)
Section 
17.10.4.1
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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes intra-
patient dose 
ramp up)
Cycle 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle=21 
days)mm
Disease 
assessmentb/
End of 
Treatmentnn
30-Day 
SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Genomics Initiative
saliva sample
(optional)ff
(X)
Week 1 
(predose)
(X)
(X)
(X)
(X)
(X)
(X)
Section 
17.11
Bone marrow biopsy 
& aspiratehh
X
As clinically 
indicated and 
to confirm CR
Section 
17.4.3 and 
Section 
17.10.3
Tumour biopsy sample 
(optional)gg
At disease 
progression
(X)gg
Section 
17.10.5.1
Disease assessmentb
and radiologic scansii
X
See Table 19 for schedule
X
Section 
17.4.2
Acalabrutinib oral, 
BIDjj
Twice daily (from Cycle 1 Week 1 to end of treatment)
Section 15.1
AZD4573 
intravenouskk
Once weekly (from Cycle 1, Week 1 to end of treatment)oo
Section 15.1
Acalabrutinib drug 
accountabilityll
X
X
X
X
X
Section 15.8
Disease progression 
follow-up (SoC)
X
Section 
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Assessment
Screena
Cycle 1,
Weeks 1-5
(includes intra-
patient dose 
ramp up)
Cycle 2-8
(Cycle=21 Days)
Cycles 9+ 
(Cycle=21 
days)mm
Disease 
assessmentb/
End of 
Treatmentnn
30-Day 
SFUc
LTFU
Details in 
CSP Section
Cycle 1
Weeks 1-5,
Day 1 Visits
Days
Day
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Survival follow-up
X
Section 
17.1.9.3
a
Screening tests should be performed within 30 days before the first administration of study drug, unless otherwise indicated.
b
Disease assessments will be done by the Investigator using the Lugano Response Criteria for Non-Hodgkin’s Lymphoma (Cheson et al 2014). Additional disease assessments 
may be performed as clinically indicated.
c
The SFU visit will be performed 30 days (±7 days) after the last dose of all study drug. Tumour assessments will be repeated at this visit if they have not been performed 
within 9 weeks if the participant discontinued before or during Week 26, or 12 weeks if the participant discontinued after Week 26.
d
Informed consent must be obtained ≤30 days before the first dose of study drug and must be obtained before any protocol-defined screening procedures are done.
e
Vital signs (blood pressure, pulse rate, temperature) will be assessed after the participant has rested for at least 10 mins. Blood pressure and pulse rate will be measured at 
Screening, and on Day 1 of Cycle 1, Weeks 1-3 at the following timepoints: predose (up to 2 h prior to infusion), 1 h after the start of the infusion (± 10 mins), at end of 
infusion (up to 10 mins post dose) and then 4 h (± 30 mins) and 6 h (± 30 mins) after start of infusion, from Cycle 1 Week 4 onwards, at predose (up to 30 mins prior to 
infusion), at the end of infusion (up to 30 mins post dose), and at the 30-day SFU. Temperature to be taken pre-infusion (up to 2 h prior to all infusions).
f
As the study is intended to recruit adults, height should only be measured at Screening. Weight to be measured at Screening, prior to infusion on Day 1 of each cycle, and at 
the 30-day SFU visit.
g
Participants should be in semi-supine position and resting for ≥ 10 mins before the ECGs. Single ECGs for local and central analysis are required at Screening and at the 
following timepoints: for Cycle 1, Weeks 1-5 and Cycle 2 Day 1 predose (at the day of infusion  prior to infusion) and within 30 mins of the end of infusion; for Cycles 3+ 
on Day 1 within 30 mins after the end of infusion, and at the 30-day SFU visit. 
h
All subjects will have CMV testing at Screening including serology testing for CMV immunoglobulin (Ig)G and CMV IgM and CMV DNA PCR testing
i
Cardiac troponin measurements are required at the following timepoints: Screening, Cycle 1, Weeks 1-5, predose (within 72 hours prior to infusion) and at 24 h after the start 
of the infusion, and Cycles 2+ on Day 1 of each cycle, predose (within 72 hours prior to infusion), and at the 30-day SFU visit. Note: either a troponin I or troponin T assay 
can be used per SoC at the respective hospital. If the hospital has both a SoC troponin I and troponin T assay available, the investigator shall use only one consistently for the 
duration of the study.
j
T4, cortisol, ACTH, and TSH to be taken at Screening, predose (within 72 hours prior to infusion) on Cycle 2, Day 1, and at the 30-day SFU.


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ECHO should be done at Screening and within 14 days after an abnormal ECG finding (eg, T-wave inversion/flattening) or as soon as possible when clinically indicated. If 
an ECHO cannot be taken, a MUGA scan to assess LVEF will be done. In case of any T-wave abnormality, the ECHO (or MUGA) should be repeated at the 30-day 
follow-up visit to address the question of recovery, during the off-treatment period.
l
Haematology testing should be measured at Screening, Cycles 1, 2, and 3 predose (within 72 h prior to infusion) and 24 h after the start of the infusion. From Cycle 4 
onwards, haematology testing should be predose (within 72 h prior to infusion) and (if clinically indicated) 24 h after the start of the infusion.  A sample will also be drawn at 
the 30-day SFU. The Investigator may take additional, unscheduled samples throughout the study if deemed clinically warranted and these need to be entered into the eCRF. 
Haematology tests do not need to be repeated before first dose if the first-dose visit is within 3 days of the Screening sample.
m
Coagulation testing should be measured at Screening, Cycles 1, 2, and 3 predose (within 72 h prior to infusion) and 24 h post-infusion of AZD4573. For Cycles 4-8, predose 
(within 72 h prior to infusion); the 24-h sample can be omitted unless clinically indicated. For Cycles 9+, on Day 1 of each cycle, an AZD4573 pre-infusion sample will be 
drawn within 72 h prior to infusion. A sample will also be drawn at the 30-day SFU. The Investigator may take additional, unscheduled samples throughout the study if 
deemed clinically warranted and these need to be entered into the eCRF. 
n
Clinical chemistry should be measured at Screening, Cycles 1, 2, and 3 predose (within 72 h prior to infusion), and 24 h post-infusion of AZD4573. From Cycle 4 onwards, 
clinical chemistry testing should be measured predose (within 72 h prior to infusion) and (if clinically indicated) 24 h after the start of the infusion. A sample will also be 
drawn at the 30-day SFU. The investigator may take additional, unscheduled samples throughout the study if deemed clinically warranted and these need to be entered into 
the eCRF. Clinical chemistry tests do not need to be repeated before first dose if the first-dose visit is within 3 days of the Screening sample.
In addition, GLDH and CPK will be measured at Screening for all participants. If GLDH cannot be performed locally, LDH will be analysed locally and a serum sample 
must be collected for central retrospective GLDH analysis, which will be performed as applicable. Refer to the Laboratory Manual for details.
If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, potassium) and troponin must be done to coincide with the ECG testing. 
o
All participants will receive TLS prophylaxis during the intra-patient ramp up and be monitored for TLS during the first 24 hours post start of dose; this requirement will 
continue until they have received at least one AZD4573 dose at the target dose level (i.e., for at least the first 3 AZD4573 once-weekly doses). TLS monitoring will be 
performed at the following timepoints:  predose AZD4573, 6 h after the start of the infusion, and 24 h (± 1 h) after the start of the infusion. Participants showing signs of 
clinical or laboratory TLS at 6 h after start of infusion must be admitted for in-patient TLS monitoring for a minimum of 24 h after the start of the infusion and monitored 
every 4 to 6 h during this time (or more frequently if clinically indicated). For each TLS monitoring timepoint, a TLS Monitoring page in the eCRF is to be filled out. Fluid 
balance must be monitored according to local institutional standards.
p
Urine samples will be collected at the following timepoints: Screening, Cycles 1-8, predose AZD4573 (within 72 hours prior to infusion) and within approximately 2 hours 
after the end of infusion, Cycles 9+ on Day 1 of each cycle, predose AZD4573 and within approximately 2 hours after the end of infusion, and at the 30-day SFU.
q
Pregnancy test to be performed at Screening (serum) and predose (serum or urine) on Cycle 1, Week 1, then once every 21 days (± 7 days) prior to initiating a new cycle 
and at the 30-day SFU visit. Additional testing may be performed at Investigator discretion (eg, in the event of suspected contraception failure).
r
Lipase and amylase should be evaluated at Screening, Cycles 1-8 predose AZD4573 (within 72 hours prior to infusion), Cycles 9+, predose AZD4573 (within 72 hours prior 
to infusion) on Day 1 of each cycle, and at the 30-day SFU visit.
s
In addition to hepatitis serology as specified, participants who are anti-HBc positive, or have a known history of HBV infection, should be monitored every 3 months with a 
quantitative PCR test for HBV DNA. In addition, any participants testing positive for any hepatitis serology must have PCR testing for verification purposes.
t
CD4, CD8, CD19, CD16/NK and serum immunoglobulins (IgA, IgM, IgG) will be drawn at Screening, Day 1 (predose) of Cycles 2, 4, 7, 9, 13, 16, 19 and every 6 months 
thereafter (predose), and at the 30-day SFU.
u
Plasma samples for PK analysis will be taken at the following time points: For Cycle 1, of Weeks 1-3 and Cycle 2, Day 1: predose (up to 2 h prior to AZD4573 and 
acalabrutinib administration), 2 h (± 15 mins), and 4 h (± 30 mins) after the start of the infusion.
v
Pharmacodynamic evaluations for AZD4573 blood samples will be collected at Cycle 1, Weeks 1-3 predose (up to 2 h prior to dosing of either agent) and 2 h (± 15 mins), 4 
h (± 30 mins), 7 h (± 1 h), and 24 h (± 2 h) (ie, Day 2, but before acalabrutinib dosing) after the start of the infusion.


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w
Pharmacodynamic evaluations for acalabrutinib: blood samples (whole blood) are to be taken predose on Cycle 1, Week 1, (up to 2 h prior to dosing of either agent), and on 
Cycle 1, Week 4 (up to 2 h prior to dosing of either agent).
x
 Samples will be taken for all participants at Screening and Cycle 1, Weeks 1-3: predose (within 2 h prior to dosing) and 4 h (± 30 mins), 7 h 
(± 1 h), and 24 h (± 1 h) after start of infusion. If the participant has 
 
 at 24 h after start of infusion, samples will be drawn at 48 h (-2 h/+12 h prior to infusion), 96 h (- 2 h/+12 h prior to infusion), predose-the-following infusion (within 
4 h prior to infusion), and at each point chemistry panel testing is being performed. For any 
 with subsequent dosing with AZD4573, 
 
sampling should be performed the same as for Cycle 1, Weeks 1-3. 
y
Exploratory blood 
 Whole blood samples will be collected at Screening and Cycle 1 Weeks 1-3 at predose (within 2 h prior to dosing of either agent), 2 h 
(± 15 mins) and 24 h (± 2 h) after the start of the infusion (and prior to acalabrutinib dosing), and on Day 1 of Cycles 2, 3, 5 and 7 predose (within 2 h prior to dosing), and at 
every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken 
at End of Treatment, a sample should be obtained at the 30-day SFU.
z
Whole Blood for 
 will be collected at Screening, Cycle 1, Weeks 1, 3, 
and 5 predose (within 2 h prior to dosing), Cycle 2, Days 1 and 15, predose (within 2 h prior to dosing), and on Day 1 of Cycles 3, 5, 6, and 7 predose (within 2 h prior to 
dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a 
sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
aa
sample for 
 isolation will be collected at Cycle 1, Week 1 predose.
bb
Whole blood for exploratory 
 will be collected at Screening, Cycle 1, Weeks 1, 3, and 5 predose (within 2 h prior to dosing), 
Cycle 2, Days 1 and 15 predose (within 2 h prior to dosing), Day 1 of Cycles 3, 5, 6 and 7 predose (within 2 h prior to dosing), and at every scheduled or unscheduled tumour 
assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken at End of Treatment, a sample should be 
obtained at the 30-day SFU.
cc
Whole blood samples for 
 will be collected at Screening, Cycle 1, Week 1 predose (within 2 h prior to dosing), Cycle 1, Week 3, predose (within 2 h 
prior to dosing) and 24 h (± 2 hours), Cycle 2, Days 1 and 15, predose (within 2 h prior to dosing), Day 1 of Cycles 3, 5, and 7 predose (within 2 h prior to dosing), and at 
every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken 
at End of Treatment, a sample should be obtained at the 30-day SFU.
dd
Whole blood samples for 
 will be collected at Screening, Cycle 1, Week 1 predose (within 2 h prior to dosing), Cycle 1, Week 3, predose (within 2 h 
prior to dosing), Cycle 2, Days 1 and 15 predose (within 2 h prior to dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of infusion, 
collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
ee
Whole blood for 
 exploratory analysis samples will be collected at Screening, Cycle 1, Week 1 predose (within 2 h prior to dosing), Day 1 of Cycles 2, 3, 5, and 
7 predose (within 2 h prior to dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease 
progression/end of treatment. If a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
ff
An optional saliva sample for genomics initiative research will be taken from consenting participants prior to the first dose of IP. If for any reason the sample is not taken 
before dosing it may be taken at any visit until the last study visit. Only one sample should be collected per participant for genetics during the study.
gg
A biopsy will be taken at disease progression for participants who consent. The disease progression sample may be taken at the SFU visit if not collected previously.
hh
Bone marrow biopsy and aspirate: 
 
ii
See Table 19 for schedule of disease assessments, including mandatory PET assessments. Disease assessments will be done by the Investigator using the Lugano Response
Criteria for Non-Hodgkin’s Lymphoma (Cheson et al 2014). Additional disease assessments may be performed as clinically indicated.
jj
Acalabrutinib 100 mg oral capsule to be given twice per day.
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kk
AZD4573 is to be administered as an absolute (flat) dose, 2-h (± 15 mins) IV infusion on a once-weekly schedule. 
ll
Participant-reported drug administration for acalabrutinib needs to be done on every AZD4573 dosing day, ideally prior to dosing (± 24 h) and is also to be done after the 
last acalabrutinib capsule is taken and the leftover capsules returned to site. Drug accountability for acalabrutinib will occur every 2 weeks, (on an AZD4573 dosing day, 
ideally prior to dosing [± 24 h]).
mm
If a participant is attending Cycle 9+ visits according to a modified schedule, in which AZD4573 is not infused and assessments are not performed every week, the Day 1 
assessments should be performed at least once per cycle.
nn
The End of Treatment visits is the last visit attended by the participant prior to the 30-Day SFU on the study. At this visit, the participant does not receive IMP and should 
undergo the applicable assessments associated with the Cycle and visit they have reached, plus those shown in the “Disease Assessment/End of Treatment” column of the 
SoA.
oo
AZD4573 should be administered at least 5 days apart.
Abbreviations: ACTH = adrenocorticotropic hormone; BID = twice daily; CMV = cytomegalovirus; CPK = cyclin-dependent kinase; CSP = clinical study protocol; 
ECG = electrocardiogram; eCRF = electronic case report form; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; GLDH = glutamic dehydrogenase; 
Ig = immunoglobulin; 
 LDH = lactate dehydrogenase; LTFU = long-term follow-up; 
; MUGA = multigated 
acquisition; 
; PCR = polymerase chain reaction; PK = pharmacokinetics; SFU = safety follow-up; SoC = standard of care; 
T4 = thyroxine; TLS = tumour lysis syndrome; TSH = thyroid-stimulating hormone.
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11
INTRODUCTION – MODULE 1
11.1
Study Rationale – Module 1
DLBCL
Preliminary anti-tumour activity has been observed with AZD4573 as monotherapy in 
participants with relapsed or refractory (r/r) haematological malignancies in the ongoing 
Phase I, FTIH, dose-escalation study (D8230C00001; see Section 2.2.6), in which best overall 
responses included one with CR, one with PR, and 4 with SD in participants with DLBCL. In 
addition, signs of clinical activity were observed in DLBCL and CLL participants as short, 
repeated tumour size reductions after each AZD4573 administration of up to 49% of the 
tumour volume, but with tumour regrowth during off-treatment periods. This pattern was 
observed over a range of dose levels and points to the need for combination therapies directed 
to sustaining the potential clinical benefit with AZD4573 treatment. Data with AZD4573 in 
combination with acalabrutinib in an activated B-cell (ABC) DLBCL xenograft model have 
shown an increase in both the magnitude and duration of anti-tumour response compared with 
either single agent alone (see Section 2.2.5.1). Inhibition of the BTK pathway with 
acalabrutinib causes an increase of certain BCL2 family pro-apoptotic proteins, like Bim, 
(Deng 2017a, Deng et al 2017b, Sasi et al 2019) pushing the cancer cells closer to their 
apoptotic threshold, a mechanism known as ‘apoptotic priming’ (NCCN 2021, 
Ni Chonghaile et al 2011). With the addition of AZD4573 following a short lead-in of 
acalabrutinib, both the magnitude and duration of anti-tumour response is increased compared 
to either monotherapy as evidenced- by more rapid and robust cleavage of caspase-3 and 
delayed time to tumour regrowth following treatment cessation (Patent WO2019/058348; data 
on file).
Given acalabrutinib’s previously demonstrated activity in B-cell malignancies, its initial 
demonstration of clinical activity in the difficult-to-treat population of r/r DLBCL as 
monotherapy, and mechanism of action (non-overlapping with CDK9 inhibitors), combination 
therapy with acalabrutinib and AZD4573 may reasonably be expected to yield greater clinical 
benefit than with either agent alone.
MZL
Marginal zone lymphoma (MZL) is a rare form of NHL with an indolent course requiring 
intermittent treatment and surveillance. While localised disease may be treated curatively, 
treatment for advanced MZL includes anti-CD20 therapy, chemotherapy, or 
chemoimmunotherapy, however, most patients relapse after first-line treatment
(Denlinger et al 2018; Zucca et al 2020). While lenalidomide, in combination with rituximab, 
and the first generation BTK inhibitor ibrutinib as monotherapy are approved in the United 


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States for treatment of patients with previously treated MZL (ibrutinib as an accelerated 
approval for treatment of patients with MZL requiring systemic therapy and who have 
received at least one prior anti-CD20-based therapy), there remains an unmet need for 
treatment of patients with advanced MZL. Both National Comprehensive Cancer Network 
(NCCN) and ESMO guidelines recommend enrolment of patients with advanced disease into 
clinical trials (NCCN 2021, Zucca et al 2020).
Expression of the anti-apoptotic MCL-1 has been evaluated in human B-cell lymphomas, 
including MZL (Cho-Vega et al 2004). MCL-1 was expressed across different subtypes of 
MZL: in 4 of 5 (80%) nodal and splenic marginal zone B-cell lymphoma, and 4 of 11 (36%) 
extranodal marginal zone B-cell lymphoma of MALT type.
Preliminary data from the ongoing Phase IB/II clinical study evaluating acalabrutinib as 
monotherapy in 40 participants with r/r MZL (Study ACE-LY-003) indicate an objective 
response rate (ORR) of 53.85% (11.54% CR, 42.31% PR) (data on file, AstraZeneca). These 
findings are similar to those reported in the Phase II open-label study which supported 
accelerated FDA approval of ibrutinib in participants with MZL: among 60 evaluable with a 
median of 2 prior treatments (range 1-9), the ORR was 48% (3% CR, 45% PR) 
(Noy et al 2017).
Given the demonstrated activity of BTK inhibitors in MZL (Lue et al 2020), their relatively 
well-tolerated safety profile, and a mechanism of action that is non-overlapping with CDK9 
inhibitors, it is hypothesised that combination therapy with AZD4573 and acalabrutinib may 
yield greater clinical benefit than with either agent alone in patients with MZL.
In Part A, this module will initially explore once-weekly administration of AZD4573 in 
combination with oral acalabrutinib 100 mg twice daily and will enrol participants with 
r/r DLBCL or r/r MZL who have failed prior therapy(ies), are not eligible for curative 
treatment options, and for whom there is no standard therapy available.
In Part B, separate expansion cohorts for DLBCL GCB and non-GCB subtypes will be opened 
at the RP2D. For both Part A and Part B, diagnosis must be confirmed by biopsy and cell of 
origin subtype characterised locally prior to enrolment. Tumour tissue must also be available 
for sending to AstraZeneca for central cell of origin testing (archival tissue or fresh biopsy, 
depending on the study part). A participant will be enrolled based on a prior pathology report.
A further expansion in MZL participants may be opened by a protocol amendment, based on 
emerging clinical data.
11.2
Acalabrutinib Background
For background information on AZD4573, please refer to Section 2.2.


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Acalabrutinib is also known as ACP-196 and Calquence®. Calquence is approved in the 
United States and is either approved or under regulatory assessment in other countries as:

Monotherapy for the treatment of adult patients with MCL who have received at least one 
prior therapy. 

Monotherapy and in combination with obinutuzumab for the treatment of adult patients 
with CLL or SLL.
Acalabrutinib is a selective, irreversible small molecule BTK inhibitor. In B cells, BTK 
signaling results in activation of pathways necessary for B-cell proliferation, trafficking, 
chemotaxis, and adhesion. Acalabrutinib and its major metabolite ACP-5862 inactivate BTK 
by forming a covalent bond with a cysteine residue in the kinase active site. This leads to 
inhibition of signaling through the B-cell receptor (BCR) in sensitive cells. In nonclinical and 
clinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling 
proteins CD86 and CD69 and inhibited malignant B-cell proliferation and survival.
11.2.1
Clinical Experience with Acalabrutinib
As of 30 October 2020, more than 6000 participants have participated in acalabrutinib clinical 
studies, with approximately 4500 participants receiving acalabrutinib as monotherapy or in 
combination with other agents in the oncology program. Clinical studies have included 
participants with haematological malignancies, solid tumours, or rheumatoid arthritis, and 
participants who are healthy subjects or those with mild to moderate hepatic impairment.
No DLTs have been identified in any studies for acalabrutinib monotherapy and very few with 
acalabrutinib (given as 100 mg twice daily) in combination with other agents. Important 
identified risks for acalabrutinib are haemorrhage, atrial fibrillation/flutter, infections, 
cytopenias, and second primary malignancies. Transaminase elevations (ALT/AST) are 
considered an important potential risk when the drug is given as monotherapy.
Efficacy data summarised below are based on two pivotal clinical studies in CLL/SLL 
(ACE-CL-007 and ACE-CL-309) and 3 supportive clinical studies in CLL/SLL 
(ACE-CL-001, ACE-CL-003, and 15-H-0016). Assessment of overall response was based on 
modified International Workshop on Chronic Lymphocytic Leukemia (iwCLL) response 
criteria (Hallek et al 2008) for CLL/SLL participants, with incorporation of the clarification 
for treatment-related lymphocytosis (Cheson et al 2012).
Ongoing Phase III Pivotal Studies in CLL
Efficacy data for acalabrutinib monotherapy (100 mg twice daily) as well as efficacy data for 
the combination of acalabrutinib 100 mg twice daily with obinutuzumab from two pivotal 
ongoing Phase III studies in previously untreated CLL (ACE-CL-007; 
 
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 and r/r CLL (ACE-CL-309; 
 
 
Study ACE-CL-309 enrolled and randomised a total of 310 participants 
 
Acalabrutinib demonstrated a 69% reduction in risk of Independent Review Committee 
(IRC)-assessed disease progression or death compared with idelalisib + rituximab 
/bendamustine and rituximab (IR/BR; hazard ratio [HR] = 0.31 [95% CI: 0.20, 0.49], 
p < 0.0001). The clinical benefit with acalabrutinib was further demonstrated by a clinically 
relevant improvement in DoR for acalabrutinib compared with IR/BR, both by IRC 
assessment (HR = 0.33) and Investigator-assessment (HR = 0.20), and a significant 
prolongation of time to next treatment (TTNT) for acalabrutinib compared with IR/BR 
(HR = 0.35; p < 0.0001).
Study ACE-CL-007 enrolled and randomised a total of 535 participants 
 
Acalabrutinib + obinutuzumab demonstrated a statistically significant improvement in 
IRC-assessed PFS compared with obinutuzumab + chlorambucil, with a 90% reduction in risk 
of disease progression or death (HR = 0.10 [95% CI: 0.06, 0.17]; p < 0.0001). Acalabrutinib 
monotherapy also demonstrated a statistically significant improvement in IRC-assessed PFS 
compared with obinutuzumab + chlorambucil, with an 80% reduction in risk of disease 
progression or death (HR = 0.20 [95% CI: 0.13, 0.30]; p < 0.0001). The clinical benefit with 
acalabrutinib was further demonstrated by a significant prolongation of TTNT compared with 
obinutuzumab + chlorambucil for both acalabrutinib + obinutuzumab (HR=0.14 [95% CI: 
0.08, 0.26]; p < 0.0001) and acalabrutinib monotherapy (HR = 0.24 [95% CI: 0.15, 0.40]; 
p < 0.0001).
Supportive Studies
Efficacy data for acalabrutinib monotherapy (100 mg twice daily) as well as efficacy data for 
the combination of acalabrutinib 100 mg twice daily with obinutuzumab from 3 supportive 
ongoing studies in CLL: ACE-CL-001 
, 15-H-0016 
 
, and ACE-CL-003 
 
A total of 300 participants received acalabrutinib in the 3 supportive studies, including 166 r/r 
participants and 134 previously untreated participants. The efficacy results in the supportive 
studies in participants with r/r and previously untreated CLL are consistent with the results of 
the pivotal studies. Investigator-assessed ORR in all studies ranged from 87.5% to 100%. 
Across all cohorts, 6% of participants achieved CR, and 85% of participants achieved PR as a 
best response. The median DoR (PR or better) was not reached in any of the cohorts (range: 
0.07+ to 51.3+ months).
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Acalabrutinib has also been preliminarily assessed as monotherapy in participants with r/r de 
novo DLBCL (Denlinger et al 2018, Dyer et al 2018). In the latter study, among 21 
participants enrolled, an ORR of 24% (19% CRs) was observed.
 
 
 
11.3
Benefit/Risk Assessment – Module 1
For more detailed information about the known and expected benefits and potential risks of 
AZD4573, please refer to Section 2.3
More detailed information about the known and expected benefits and potential risks of 
AZD4573 and acalabrutinib in combination are summarised below.
 
 
As outlined in Section 2.2.6 and in Section 11.3.2, AZD4573 has shown preliminary activity 
in participants with DLBCL in the ongoing FTIH study (D8230C00001). Given the 
demonstrated activity of BTK inhibitors in B-cell malignancies, their relatively well-tolerated 
safety profile, and mechanism of action (non-overlapping with CDK9 inhibitors), combination 
therapy may reasonably be expected to yield greater clinical benefit than with either agent 
alone.
Given acalabrutinib’s previously demonstrated activity in B-cell malignancies, its initial 
demonstration of clinical activity as monotherapy in the difficult-to-treat population of r/r 
DLBCL and r/r MZL, and mechanism of action (Section 11.2), combination therapy with 
AZD4573 and acalabrutinib may reasonably be expected to yield greater clinical benefit than 
with either agent alone. This is supported by positive results in nonclinical studies with 
AZD4573 and acalabrutinib that demonstrated an increase in both the magnitude and duration 
of anti-tumour response compared with either single agent alone (Section 2.2.5.1 and 
Section 11.3.2).
11.3.1
Risk Assessment
Important identified risks for acalabrutinib are:

Haemorrhage

Atrial fibrillation
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
Infections

Cytopenias

Second primary malignancies
Potential for overlapping toxicities between AZD4573 and acalabrutinib include TLS, 
haemorrhage, cytopenias, infection including hepatitis B reactivation, gastrointestinal 
toxicities (nausea, vomiting, and diarrhoea), and liver enzyme abnormalities (Grade 3 and 
Grade 4 transaminase elevations) with the important potential risk of hepatic injury (Table 6).
Detailed descriptions of safety concerns and management are provided in Section 17.1.10. 
Investigators should be particularly alert to the possibility of TLS, significant bleeding and 
infection, including opportunistic and fungal infections, and care must be taken to monitor 
platelets and neutrophil counts in accordance with the SoA and more frequently as clinically 
indicated. ‘Rescue medications’, including platelet transfusions and granulocyte-colony-
stimulating factor (G-CSF), are permitted at any time during the study, at the discretion of the 
Investigator. Specific and detailed guidance is also given in this protocol regarding the 
management of events of hepatic dysfunction or toxicity.
Several measures, including project-specific, safety-related inclusion/exclusion criteria, 
physical examinations, evaluation of DLTs and AEs/SAEs, and laboratory testing throughout 
the study and study treatment modifications and toxicity management guidelines have been 
incorporated into the study protocol to mitigate any potential or identified risks associated 
with combining these agents. For further information, refer to the reference safety information 
for AZD4573 and/or Calquence accordingly.
Table 6
Risk Assessment
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention (s) AZD4573 and Acalabrutinib
Headache
Headache is an identified risk for acalabrutinib.
Refer to Section 17.1.10.1
Diarrhoea
Diarrhoea is an identified risk for AZD4573 and 
acalabrutinib.
Refer to Section 17.1.10.2
Nausea and vomiting
Nausea and/or vomiting are identified risks for 
AZD4573 and acalabrutinib.
Refer to Section 17.1.10.3
Hepatitis B 
reactivation
Serious or life-threatening reactivation of viral 
hepatitis have been reported in patients treated with 
acalabrutinib.
Refer to Section 17.1.10.4


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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Progressive 
multifocal 
leukoencephalopathy 
(PML)
Cases of PML have been reported in patients treated 
with acalabrutinib.
Refer to Section 17.1.10.5
Haemorrhage
Bleeding events, some fatal, including central nervous 
system, respiratory, and gastrointestinal haemorrhage, 
have been reported in patients treated with 
acalabrutinib.
Refer to Section 17.1.10.6
Infections
Serious infections, including fatal events, have been 
reported in patients treated with acalabrutinib and it is 
an important identified risk. Infection is an important 
potential risk for AZD4573.
Refer to Section 17.1.10.7
Cytopenia
Haematological toxicities including neutropenia, 
anaemia, and thrombocytopenia have occurred in 
patients treated with acalabrutinib, and neutropenia is 
an important identified risk for participants treated 
with AZD4573 or acalabrutinib.
Refer to Section 17.1.10.8
Liver chemistry test 
abnormalities
Grade 3 and Grade 4 transaminase elevations with 
bilirubin increase are an important potential risk for 
participants treated with acalabrutinib, and an 
important identified risk for participants treated with 
AZD4573.
Refer to Section 17.1.10.9
Hepatic injury
Events of hepatotoxicity have been reported in clinical 
studies with acalabrutinib however, no causal 
relationship has been established. Subjects with 
hepatotoxicity should be monitored for resolution, and 
dose modification or interruption of acalabrutinib may 
be indicated. In addition, subjects should be managed 
according to study protocols as well as institutional 
guidelines with supportive care.
Refer to Section 17.1.10.9
Tumour lysis 
syndrome (TLS)
TLS is an important identified risk for AZD4573 and 
an identified risk for acalabrutinib.
Refer to Section 17.1.10.10
Second primary 
malignancies
Second primary malignancies, including non-skin 
cancers, have been reported in patients treated with 
acalabrutinib.
Refer to Section 17.1.10.11
Atrial 
fibrillation/flutter
Atrial fibrillation/flutter have been reported in patients 
treated with acalabrutinib. Heart rate increase is a 
potential risk for AZD4573, and cases of atrial 
fibrillation have occurred in participants treated with 
AZD4573.
Refer to Section 17.1.10.12


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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Infection/Bone 
marrow toxicity with 
peripheral effect/ 
lymphoid tissue 
hypocellularity
Infection / bone marrow toxicity with peripheral effect 
/ lymphoid tissue hypocellularity is an important 
potential risk for AZD4573.
Refer to Section 17.1.10.13
Pancreatic and 
Cortical Adrenal 
Injury (as well as 
Surveillance for 
Renal, Thymus, and 
Spleen Toxicity)
Pancreatic injury and cortical adrenal injury are 
potential risks for AZD4573 based on preclinical 
observations.
Refer to Section 17.1.10.14
Drug-drug 
interactions
Specific drug-drug interaction studies have not yet 
been performed for AZD4573. Acalabrutinib may be 
affected by agents that reduce gastric acidity (antacids 
or proton-pump inhibitor).
Refer to Section 17.1.10.15
Myocardial 
ischaemia
Myocardial ischaemia and increased heart rate are 
considered potential risks for AZD4573.
Refer to Section 17.1.10.16
Study Procedures
Infusion site 
reactions
As with other drugs administered intravenously, local 
infusion site reactions (eg, infusion pain, infusion site 
reaction, skin or vein irritation) may occur.
Refer to Section 17.1.10.17
The Investigator sites participating in this study are all experienced oncology centres and are 
well equipped for treating patients with relapsed and refractory disease and in the management 
of haematological toxicities. Furthermore, the protocol has dose reductions and dose 
interruption criteria to also allow for the management of any potential dose-related toxicity.
11.3.2 Benefit Assessment
Preliminary anti-tumour activity has been observed with AZD4573 as monotherapy in 
participants with r/r haematological malignancies in the ongoing Phase I, FTIH, dose-
escalation study (D8230C00001; see Section 2.2.6). Best overall responses in participants 
with DLBCL (n=17) included 1 with CR, 1 with PR, and 4 with SD.
The addition of agents which in combination could provide more continuous anti-tumour 
activity may reasonably be expected to significantly enhance clinical benefit with manageable 
changes to risk. Acalabrutinib, a BTK inhibitor like ibrutinib, has been shown to inhibit 
proliferation and induce apoptosis in B-cell malignancies (Davis et al 2010, 
Harrington et al 2016). The latter is likely due to the ability of BTK inhibitors to increase 


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certain pro-apoptotic BCL2 family proteins, like Bim, (Deng 2017a, Deng et al 2017b, 
Sasi et al 2019) pushing the cancer cells closer to their apoptotic threshold, a mechanism 
known as ‘apoptotic priming’ (NCCN 2021, Ni Chonghaile et al 2011). Capitalising on this 
apoptotic priming, addition of AZD4573 following a short lead-in of acalabrutinib in the 
OCI-LY10 DLBCL xenograft model causes an increase in both the magnitude and duration of 
anti-tumour response, compared to either monotherapy, as demonstrated by more rapid and 
robust cleavage of caspase-3 and delayed time to tumour regrowth following treatment 
cessation (Patent WO2019/058348; data on file, Astra Zeneca).
Acalabrutinib is a highly selective, potent, covalent inhibitor of BTK with minimal off-target 
activity leading to a safety profile that may be attractive for combination strategies. It is 
therefore regarded as a promising agent for combination with AZD4573 in treatment of 
participants with DLBCL or MZL who have failed previously approved regimens
11.3.3 Overall Benefit/Risk Conclusion
Eligible participants will be r/r to prior treatments for their disease and considered to have no 
alternative treatment options available to them. Furthermore, participants will have varying 
levels of disease burden at study entry and almost certainly have acquired mutations as part of 
their disease course. Therefore, there is no guarantee that any participant will derive clinical 
benefit during this study.
AstraZeneca believes the anticipated benefits that may be afforded to participants with 
r/r haematological malignancies currently outweigh the identified and potential risks 
associated with AZD4573 in combination with acalabrutinib.
As described, the study design aims to minimise risks and build on the preliminary efficacy 
seen to date in the ongoing FTIH study (D8230C00001), reflecting clinical responses in a 
r/r participant population. Thus, the benefit/risk assessment for this Phase I/II combination 
study is considered acceptable for participants for whom there is no alternative standard 
therapy.
For an assessment of benefit and risks pertaining to the conduct of this study during the 
COVID-19 pandemic, refer to Appendix A 11.


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12
OBJECTIVES AND ENDPOINTS – MODULE 1
Objectives and Endpoints for Part A and Part B are outlined in Table 7.
Table 7
Objectives and Endpoints – Module 1
Objectives
Endpoints
Primary
Part A

Assess the safety and tolerability, describe 
the DLTs, and identify the MTD and/or 
RP2D of AZD4573 in combination with 
acalabrutinib (100 mg BID)

Adverse events, DLTs, laboratory data, 
vital signs, and ECG changes
Part B

Assess the efficacy of AZD4573 in 
combination with acalabrutinib by 
evaluation of objective response rate

Endpoint based on revised response criteria 
for malignant lymphoma 
(Cheson et al 2014):

ORR, defined 
as the 
proportion of 
participants 
who have a 
tumour 
response (CR 
and PR)a
Secondary
Part B

Assess efficacy of AZD4573 in 
combination with acalabrutinib by 
evaluation of tumour response and overall 
survival

Endpoints based on revised response 
criteria for malignant lymphoma
(Cheson et al 2014):

CR rate

DoR

TTR

PFS

OS


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Objectives
Endpoints

Assess the safety and tolerability of the 
RP2D of AZD4573 in combination with 
acalabrutinib (100 mg BID)

Adverse events, laboratory data, vital signs, 
and ECG changes
Part A and B

Assess the plasma PK of AZD4573 and 
acalabrutinib (plus its active metabolite 
ACP-5862), when given in combination

Plasma concentrations and derived PK 
parameters for AZD4573 summarised by 
cohort and dose level for the PK analysis 
set

Plasma concentrations and derived PK 
parameters for acalabrutinib and its 
metabolite ACP-5862 summarised by 
cohort and dose level for the PK analysis 
set
Exploratory
Part A

Assess efficacy of AZD4573 in 
combination with acalabrutinib by 
evaluation of objective response rate, 
tumour response, and overall survival

Endpoints based on revised response 
criteria for malignant lymphoma
(Cheson et al 2014):

ORR

CR rate

DoR

TTR

PFS

OS


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Objectives
Endpoints
Part A and B

Assess the PD of AZD4573
 
 
 

 

Assess
 
 

 
 
 
 
 

To evaluate 
 

 

To 
 
 
 
 

 
a
By Investigator assessment; however, if preliminary results suggest a major advantage over available 
therapy, AstraZeneca will consult with relevant Health Authorities to agree on modifications to the protocol 
and will conduct blinded independent central review of ORR (see Section 11.3.1).
Abbreviations: BID = twice daily; 
 9; CR = complete response; 
DLT = dose-limiting toxicity; DoR = duration of response; ECG = electrocardiogram; 
 
 
 MTD = maximum tolerated dose; ORR = objective response rate; 
OS = overall survival; 
 PFS = progression-free survival; 
PK = pharmacokinetics; PR = partial response; 
; 
 
 RP2D = recommended Phase II dose; TTR = time to response.
13
STUDY DESIGN – MODULE 1
Module 1 will enrol participants at approximately 30 sites in approximately 10 countries.
13.1
Overall Design
This is a modular, multicentre, open-label, non-randomised, Phase I/II, dose-setting and 
expansion study including an intra-patient ramp up. 
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In Part A (dose setting), this study module will enrol participants with r/r DLBCL or r/r MZL 
who have failed prior therapy(ies), are not eligible for curative treatment options, for whom 
there is no standard therapy available, and will initially explore once-weekly administration of 
AZD4573 at up to 3 target dose levels in combination with oral acalabrutinib 100 mg twice 
daily. The primary objective of Part A will be to identify the MTD and/or RP2D for further 
evaluation in Part B.
A 5-week DLT-assessment period will incorporate the whole of Cycle 1 in Part A, including 
the dose ramp up and the first 3 weeks at the target dose.
In Part B (expansion), separate expansion cohorts for participants with GCB and non-GCB 
DLBCL subtypes will be opened at the RP2D.
For both Part A and Part B, diagnosis must be confirmed by biopsy and cell of origin subtype 
characterised locally prior to enrolment and must be immunohistologically characterised. 
Tumour tissue must also be available for sending to AstraZeneca for central cell of origin 
testing (archival tissue or fresh biopsy, depending on the study part). A participant will be 
enrolled based on a prior pathology report.
Part A: Dose Setting (DLBCL and MZL)
Cycle 1 consists of 5 weeks, including an intra-patient dose ramp up (first 3 AZD4573 
administrations) to achieve the target dose level, and 3 weeks of observation at the target dose 
level (5-week DLT-assessment period in total). Subsequent cycles are 21 days (3 weeks) with 
once-weekly IV administration of AZD4573 in combination with oral administration of 
acalabrutinib 100 mg twice daily continuously. Acalabrutinib (100 mg twice daily) is taken 
orally continuously from Day 1 of Cycle 1 Week 1. AZD4573 should be administered at least 
5 days apart. For information on dosing schemes and cycle lengths, see Figure 5 and Table 8.


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Table 8
Dosing Schedule – Module 1
Dose/Schedule
DLT-
Assessment 
Perioda
Cycle Length
Dose level -1; target dose: 6 mg
Cycle 1, Weeks 1 to 5 (includes intra-patient ramp up): 
AZD4573 1.5 mg, 3 mg, 6 mg, 6 mg, 6 mg once weekly 
with acalabrutinib 100 mg BID continuously from Cycle 
1 Day 1.
Cycles 2+: AZD4573 6 mg once weekly with 
acalabrutinib 100 mg BID continuously.
5 weeks
Cycle 1 (includes ramp up): 
Cycle length of 5 weeks
Cycle 2 onwards:
Cycle length of 3 weeks
Starting dose level
Dose level 1; AZD4573 target dose: 9 mg
Cycle 1, Weeks 1 to 5 (includes ramp up): AZD4573 
3 mg, 6 mg, 9 mg, 9 mg, 9 mg once weekly with 
acalabrutinib 100 mg BID continuously from Cycle 1 
Day 1.
Cycles 2+: AZD4573 9 mg once weekly with 
acalabrutinib 100 mg BID continuously.
Dose level 2; target dose: 12 mg
Cycle 1, Weeks 1 to 5 (includes ramp up): AZD4573 
6 mg, 9 mg, 12 mg, 12 mg, 12 mg once weekly with 
acalabrutinib 100 mg BID continuously from Cycle 1 
Day 1.
Cycles 2+: AZD4573 12 mg once weekly with 
acalabrutinib 100 mg BID continuously.
a
The DLT-assessment period will be extended to incorporate any AZD4573 dosing delay(s), as long as each 
delay does not exceed 7 consecutive days (± 2 days). Following the delay, the next dose is to be 
administered at the next regularly scheduled timepoint (± 2 days). To be DLT-evaluable, the participant 
should have received 3 dose infusions at the target dose level. The DLT-assessment period will end on the 
original planned day (5 weeks after first dose) or, if there has been a dosing delay, up to ~1 week after the 
third dose of AZD4573 at the target dose level.
Abbreviations: BID = twice daily; DLT = dose-limiting toxicity.
All participants will begin treatment with an intra-patient ramp up in Cycle 1. In the dose 
setting cohorts this planned 5-week cycle (including the ramp up) is the DLT-assessment 
period.


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Dose Level 1 (Starting dose level): Once-weekly IV administration of AZD4573 with oral 
administration of acalabrutinib 100 mg twice daily continuously:

Week 1: 3 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 2: 6 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 3: 9 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 4: 9 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 5: 9 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily
Dose Level 2: Once-weekly IV administration of AZD4573 with oral administration of 
acalabrutinib 100 mg twice daily continuously. 

Week 1: 6 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 2: 9 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 3: 12 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 4: 12 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 5: 12 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily
Dose Level -1: Once-weekly IV administration of AZD4573 with oral administration of 
acalabrutinib 100 mg twice daily continuously. 

Week 1: 1.5 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 2: 3 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 3: 6 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 4: 6 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily

Week 5: 6 mg AZD4573 once weekly and 100 mg acalabrutinib twice daily
Upon completion of the 5-week DLT-assessment period, participants will remain on their 
target dose level of AZD4573 administered intravenously once weekly in combination with 
daily orally administered acalabrutinib 100 mg twice daily in 3-week treatment cycles until 
disease progression, an unacceptable drug-related toxicity occurs as defined in the protocol, or 
the participant withdraws or is withdrawn from the study for other reasons. No further intra-
patient dose escalation (other than the ramp up to the assigned target dose level) will be 
allowed.


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After completion of the 5-week DLT-assessment period, dose reduction of AZD4573 with 
each cycle or within a cycle may be applied, on an individual participant basis, based upon the 
grade of toxicity experienced by the participant. Dose modification provisions are provided in 
Section 15.12. All participants who discontinue study treatment (ie, both drugs) will have a 
SFU visit 30 (± 7) days after the last dose of study drug(s). 
All participants will be followed for survival until death, loss to follow-up, AstraZeneca closes 
the study, or withdrawal of consent, whichever occurs first.
Dose setting cohorts will initially enrol 3 to 6 participants for each new dose level. If a new 
dose level cohort has fewer than 3 DLT-evaluable participants, non-evaluable participants will 
be replaced before making an escalation or de-escalation decision unless unacceptable toxicity 
is observed prior to the enrolment of 3 participants. If 6 participants are initially enrolled, all 
6 must have the opportunity to complete the DLT-assessment period before making an 
escalation or de-escalation decision.
Dosing will be staggered by at least one week between the first and the second participant 
dosed in each new dose level cohort. Subsequent participants dosed will be staggered by a 
minimum of 3 days until a decision is made regarding dose escalation or de-escalation.
The dose-escalation decision will follow the decision rules based on the mTPI-2 design
(Guo et al 2017) with a 30% (±5% Equivalence Interval Margin) target DLT rate. The decision 
regarding dose escalation (stay at the current dose, escalate, de-escalate, or de-escalate and 
never be used again due to unacceptable toxicity) will be determined using the decision rules 
as discussed in detail in Section 15.2.
Although 3 to 9 participants per dose level may be evaluated to make dose escalation/ 
de-escalation decisions per mTPI-2, additional participants (up to approximately 21 evaluable 
per safe dose regimen) may be enrolled in backfilling to collect additional tolerability, PK, and 
exploratory data.
To assess potential delayed toxicity, an analysis of safety data will be performed and shared 
with the SRC after completion of the dose setting portion of the study, but prior to moving to 
dose expansion. This analysis will focus on treatment-emergent AEs beyond the 
DLT-assessment period and will be taken into account when selecting the RP2D to be taken 
into the Part B expansion phase.
If emerging data from backfilled participants would result in mTPI-2 directing a dose 
de-escalation at a previously-cleared dose level, the SRC will review safety data and 
determine whether the lower dose level of AZD4573 should be selected for further 
development.


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Part B: Expansion (DLBCL subtype cohorts)
After determining the RP2D in Part A (dose setting), separate expansion cohorts for GCB and 
non-GCB DLBCL subtypes may be opened at the RP2D in Part B.
Participants who start this study in Part B will enter the intra-patient ramp-up period, in which 
the once-weekly IV dose of AZD4573 is increased over 3 weeks until the RP2D is reached 
and administered at Weeks 3 to 5. From Cycle 2 onwards, the RP2D is administered once 
weekly in 3-week cycles. Acalabrutinib (100 mg twice daily) is taken orally continuously 
from Day 1 of Cycle 1 Week 1.
For primary analyses, a total of approximately 21 RP2D-treated response-evaluable 
participants of GCB subtype and approximately 21 RP2D-treated response-evaluable 
participants of non-GCB subtype will be incorporated, including participants from Part A and 
Part B. The total number of evaluable participants treated in Part B will be up to 
approximately 42.
The data cut-off for the primary analysis for each expansion subgroup will occur after all 
participants have had the opportunity to be followed for at least  6 months since their first dose 
in the expansion subgroup or when 75% of participants have progressed or died in the cohort, 
whichever occurs first.
Participants will continue to be followed for survival after objective disease progression until 
death, lost to follow-up, AstraZeneca closes study or withdrawal of consent, whichever occurs 
first.
Modifications to dose and/or schedule may be made moving forward based on emerging data. 
Alternate frequencies, schedules, and sequences may be instigated by protocol amendment.
13.2
Scientific Rationale for Study Design
13.2.1
DLBCL Participants
The study design proposed here is based on both preclinical and clinical data from DLBCL 
tumours which suggests that the underlying biology of the disease is influenced by the cell of 
origin (reviewed by Nowakowski et al 2019). Tumours of non-GCB subtypes (activated B 
cells in particular) exhibit significantly enhanced activity of the NF-B transcription factor 
family that mediates both B-cell survival and proliferation. As NF-B is activated by BTK 
signaling, it has been hypothesised that non-GCB DLBCLs may be particularly sensitive to 
inhibition of that kinase. In the FTIH study (D8230C0001), single-agent responses have been 
observed in both GCB and non-GCB subsets of participants; it is therefore important to 
identify efficacy in both GCB and non-GCB DLBCL subsets. Extensive genotyping of tumour 


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samples is also included to supplement and take advantage of further evolving information 
concerning the clinical course of participants with specific abnormalities (eg, “double hit” 
lymphomas).
Preclinical studies investigating a combination of AZD4573 and acalabrutinib in OCI-LY10 
NHL models indicate significantly improved DoR post-completion of dosing as compared to 
each drug alone and was well tolerated in combination. Additionally, combination of 
AZD4573 with acalabrutinib also resulted in more durable responses in an ABC DLBCL 
xenograft model 
Phase I/II clinical data with the first generation BTK inhibitor ibrutinib have also been 
regarded as promising, although monotherapy with this drug is insufficient for many 
r/r DLBCL participants. Overall, responses were observed in 25% (20/80) of participants, 
including partial responses (PR; n = 12) and complete responses (CR; n = 8). With a median 
post-treatment follow-up period of 11.53 months, median PFS and overall survival (OS) were 
1.64 months and 6.41 months, respectively (Wang et al 2020, Wilson et al 2015).
Given this mechanistic data, combination of a next generation BTK inhibitor (acalabrutinib) 
with an agent with a non-overlapping mechanism of action (CDK9 inhibition) that exhibits 
activity in GCB and non-GCB tumour types may prove still more valuable for r/r DLBCL 
participants.
Acalabrutinib exhibits monotherapy activity in participants with r/r CLL (Awan et al 2019) 
and has been preliminarily assessed as monotherapy in participants with r/r de novo DLBCL 
(Dreyling et al 2018, Dyer et al 2018) as well. In the latter study, among 21 participants 
enrolled, an ORR of 24% (including 19% CRs) was observed.
As is now typical for agents targeting cell death pathways (eg, venetoclax) and based on 
previous Phase I experience with AZD4573 (see Section 2.2.6), an intra-patient dose ramp up 
is employed to minimise the probability of TLS.
Given acalabrutinib’s previously demonstrated activity in a range of B-cell malignancies, its 
relatively well-tolerated side-effect profile, its initial demonstration of clinical activity in the 
difficult-to-treat population of r/r DLBCL as monotherapy, and mechanism of action 
(non-overlapping with CDK9 inhibitors), combination therapy may reasonably be expected to 
yield greater clinical benefit than with either agent alone in a population with significant 
unmet medical need.
13.2.2
MZL Participants
 
 
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These findings are similar to those reported in 
the Phase II open-label study which supported accelerated FDA approval of ibrutinib in 
participants with MZL: among 60 evaluable with a median of 2 prior treatments (range 1-9), 
the ORR was 48% (3% CR, 45% PR) (Noy et al 2017).
Given the demonstrated activity of BTK inhibitors in MZL (Lue et al 2020), their relatively 
well-tolerated safety profile, and a mechanism of action that is non-overlapping with CDK9 
inhibitors, it is hypothesised that combination therapy with AZD4573 and acalabrutinib may 
yield greater clinical benefit than with either agent alone in participants with MZL.
This first module of the protocol is intended to allow preliminary establishment of the safety 
and efficacy of AZD4573 and acalabrutinib together, potentially allowing sequential 
introduction of combinations with additional agents in subsequent modules.
13.3
Justification for Dose
The starting dose of AZD4573 selected for this study is 3 mg (Week 1 of Cycle 1) for the 
initial dose of the intra-patient ramp-up period in the dose setting cohorts. The initial target 
dose following the ramp up is 9 mg (dose level 1) attained on Week 3 of Cycle 1. During the 
first cycle, participants will receive a single dose of AZD4573 once weekly beginning with 3 
mg Week 1, 6 mg Week 2, and 9 mg for each of Weeks 3 to 5. Participants will also receive 
acalabrutinib 100 mg twice daily continuously from Day 1 of Cycle 1. Every cycle beyond 
Cycle 1 will be 3 weeks in length and participants will receive 9 mg infusions of AZD4573 
once weekly in combination with acalabrutinib 100 mg twice daily continuously.
The starting and target doses of AZD4573 are selected based on the ongoing Phase I, FTIH
study of AZD4573 in haematological tumours (D8230C00001).
The planned intra-patient dose escalation, the cohort escalation scheme, and the dosing 
schedule have the flexibility to be amended in light of emerging PK, safety, and 
pharmacodynamic and available efficacy data, which will be reviewed on an ongoing basis 
throughout the study.
The ongoing Phase I, FTIH study (D8230C00001) of AZD4573 in haematological 
malignancies, which includes DLBCL, has studied AZD4573 at two dose levels: 18 mg 
(2 days on/12 days off and/or once weekly) and 12 mg administered once weekly, 
continuously. At 18 mg, N = 5 participants were evaluable for DLT-assessment, of which 2 
had DLTs of clinical TLS and Grade 3 acute kidney injury regarded as secondary to TLS, 
respectively; all 5 participants in the 18 mg cohort had DLBCL. As a consequence of 
identifying 2 DLTs among 5 evaluable participants, the SRC agreed to de-escalate dosing from 
18 mg to 12 mg weekly and to recruit a further 10 participants in Cohort 2A. No DLTs of 
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clinical TLS were observed at the 12 mg target dose. At 12 mg, N = 6 participants (4 DLBCL 
and 2 MM) were evaluable for DLT-assessment. There were 3 events of isolated Grade 4 AST 
elevations in 2 participants (1 with DLBCL, 1 with MM). These Grade 4 AST elevations met 
the definition of DLT in versions 2 and 5 of the protocol (dated 7 July 2017 and 18 April 
2019), but were transient (less than 4 days duration) and were not accompanied by clinical 
signs and symptoms of significant hepatic dysfunction. Review of the data (December 2019) 
by AstraZeneca’s Hepatic Safety Knowledge Group and external industry experts concluded 
that isolated asymptomatic reversible Grade 4 enzyme elevations should not be regarded as 
DLTs unless prolonged and accompanied by other clinical changes. Study investigators 
concurred with this interpretation and the protocol was amended accordingly to update the 
DLT definition. The protocol version including the revised DLT definition has been approved 
by competent authorities in the United Kingdom, Netherlands, and Germany. Sponsor review 
of the data 
 from participants treated weekly with 12 mg AZD4573 
has revealed no instances of DLT under the active CSP v7.0 definition.
The SRC for Study D8230C00001 met 
 to review the safety data for Arm A 
(ie, participants with r/r haematological malignancies excluding AML/ALL/high risk 
MDS/CMML/CLL and Richter’s syndrome), including Cohort 1A (target dose of 18 mg; 
2 days on/12 days off and/or once weekly) and Cohort 2A (target dose 12 mg once weekly). 
The outcome of this meeting was a unanimous vote that the 12-mg once-weekly regimen be 
declared as a tolerated dose for AZD4573 monotherapy in this setting.
Given the clinical experience outlined above, AstraZeneca believes it is prudent to open 
Study D8230C00002 with a dosing regimen for AZD4573 (in combination with acalabrutinib) 
one dose level below the SRC-approved tolerated dose for AZD4573 monotherapy in Arm A 
of Study D8230C00001; hence, a target dose of AZD4573 9 mg once weekly in combination 
with 100 mg twice daily acalabrutinib is proposed for inclusion in Study D8230C00002.
The clinical data will be used to refine a PK/PD/efficacy model, and future decisions on dose 
regimens and escalations will be based on the observed clinical data to date and this refined 
model.
The acalabrutinib 100 mg twice daily regimen is the recommended regimen for use in adult 
participants with mantle cell lymphoma (MCL) who have received at least one prior therapy 
and in adult patients with CLL or SLL (Calquence United States Prescribing Information). 
Acalabrutinib 100 mg twice daily has been evaluated in various indications (ie, B-cell 
malignancies and solid tumours) alone and in combination with anti-CD20 antibodies, 
chemotherapy, a phosphatidylinositol-3-kinase (PI3K) inhibitor, and an anti-programmed cell 
death 1 (anti-PD-1) antibody. No DLTs have been identified for acalabrutinib alone or when 
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given in combination with these agents. Therefore, the proposed dosage for this protocol for 
acalabrutinib is 100 mg twice daily.
13.4
End of Study Definition
Please refer to Section 4.5 for the definition of the end of the study. Module 1 will be 
considered complete once the last participant enrolled in this Module undergoes a 30-Day 
Safety Follow-up visit, or if the treating site has confirmed the SFU visit will not be 
performed. Participants still receiving clinical benefit from AZD4573 and continuing 
treatment after the data cut-off for the primary analysis will be considered to have completed 
Module 1 on the date AZD4573 is permanently discontinued.
In addition, the study may be terminated, or individual centres closed at the discretion of 
AstraZeneca (please refer to Appendix A 9). AstraZeneca may also terminate the module 
prematurely if concerns for safety arise within this study or in any other study with AZD4573 
and/or acalabrutinib.
The data cut-off for the primary analysis for each expansion subgroup will occur 
approximately 6 months following last participant first dose in the expansion subgroup or 
when 75% of participants have progressed or died in the cohort, whichever occurs first. 
The results from Module 1 will be reported to Regulatory Authorities within one year of the 
end of module.
14
STUDY POPULATION – MODULE 1
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Participants must meet the inclusion and exclusion criteria of both the core and module 
protocol. Where there are differences in stringency or cut-off values, the specific module takes 
precedence. For example, if haematological medication parameters are stricter in the module 
than in the core, the Investigator should adhere to the module criteria.
14.1
Inclusion Criteria
Each participant should meet all the inclusion criteria (and none of the exclusion criteria) for 
this study in order to be assigned to a study cohort. Under no circumstances can there be 
exceptions to this rule.
NOTE: This Module will be enrolling participants with DLBCL or MZL only.
For inclusion in the study, participants must fulfil all of the following criteria:


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1
Participants must meet the eligibility criteria described in Section 5.1.
2
Participants with histologically confirmed, r/r DLBCL or r/r MZL, for whom a clinical 
study is the best option (in the opinion of the Investigator) for next treatment based on 
response and/or tolerability to prior lines of therapy.
PART A

Participants with r/r DLBCL, including subtypes such as DLBCL not otherwise specified 
[NOS], high-grade B-cell lymphoma [HGBCL], primary mediastinal large B-cell 
lymphoma [PMBCL], or large B-cell lymphoma transformed from indolent B-cell 
lymphomas (including but not limited to Richter Syndrome, transformed Follicular 
Lymphoma, transformed MZL), or r/r MZL:

Diagnosis must be confirmed by biopsy and be immunohistologically characterised.

For participants with DLBCL, cell of origin subtype shall be characterised locally and 
tumour tissue must also be available for sending to AstraZeneca for central cell of 
origin/pathology testing (see below).
All participants in Part A (dose setting) must consent to and provide archival tumour 
specimens, preferably in the form of a formalin-fixed paraffin embedded block 
(tissue derived from the diagnostic tumour or a metastatic site). If this is not possible, 
an appropriate number of slides of freshly prepared unstained 5-micron sections from 
the archival tumour block may be provided as defined in the study Laboratory 
Manual. Archival tumour specimens must be obtained within 24 months before the 
first dose of IP. If archival material is unavailable or unsuitable for use, participants 
must consent to and undergo a fresh tumour biopsy during the screening period. A 
fresh biopsy is strongly encouraged and preferred, however, a participant will be 
enrolled based on the prior pathology report.
PART B
Participants with r/r de novo DLBCL, GCB or non-GCB subtype:

Must have received SoC first-line therapy.

Diagnosis must be confirmed by biopsy and cell of origin subtype characterised 
locally prior to enrolment and DLBCL be immunohistologically characterised.

A newly obtained tumour biopsy is strongly encouraged and preferred at Screening to 
confirm cell of origin status and determine DLBCL subtype. The participant will be 
enrolled based on a prior pathology report.
A recent biopsy that was taken as part of SoC prior to screening consent for this 
study is acceptable if no treatment was administered between the biopsy and the first 
dose of study treatment, and the biopsy was taken within 60 days prior to receiving 
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If fresh biopsy is not feasible/safe per local interventional radiologist or biopsy 
attempt fails to retrieve viable lymphoma tissue the participant can still be considered 
for the study (Part B) after discussion with the Sponsor’s medical monitor.
3
Presence of radiographically measurable lymphadenopathy or extranodal lymphoid 
malignancy (according to the Lugano criteria [Cheson et al 2014]).
4
Participants must have failed at least two prior therapies for the treatment of current 
disease. Participants shall not be eligible for curative treatment options, and have no 
standard therapy available (including CAR-T cell therapy).
5
Adequate haematologic function at Screening, as defined in Table 9:
(a) No growth factor support within 14 days prior to the date of the screening laboratory 
assessment.
(b) No transfusions within 7 days prior to the date of the screening laboratory 
assessment.
Table 9
Criteria for Adequate Haematological Function
Category
Parameter
Value
Haematologic
Haemoglobin
≥ 8.0 g/dL
Absolute neutrophil count
≥ 1000 cells/mm3 (1.0 × 109/L)

Platelet count
≥ 75,000 cells/mm3 (75 × 109/L) without bone 
marrow involvement
≥50,000 cells/mm3 (50 × 109/L) with bone 
marrow involvement

If indicated, transfusions or growth factors can be administered during the screening 
period, but such cases of deterioration of haematological function must be discussed 
with the Medical Monitor, to confirm start of study treatment.
6
Optional tumour biopsy on study: Participants are also encouraged to consent to and 
undergo an optional tumour biopsy at disease progression to support correlative 
biomarker studies.
7
All participants must be willing and able to provide mandatory baseline bone marrow 
biopsy/aspirate.
14.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1
Participants must comply with the exclusion criteria described in Section 5.2.


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2
Current refractory nausea and vomiting, malabsorption syndrome, disease significantly 
affecting gastrointestinal function, resection of the stomach, extensive small bowel 
resection that is likely to affect absorption, symptomatic inflammatory bowel disease, 
partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as 
gastric bypass.
3
Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of 
receiving the first dose of study treatment.
4
Requires treatment with strong CYP3A inhibitors or inducers (please refer to Appendix F
for a list of strong inhibitors and inducers of CYP3A).
5
Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Participants receiving 
proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for
enrolment to this study (see Section 15.11.4).
6
Serologic status reflecting active hepatitis B or C infection:
(a) Participants who are anti-HBc positive and who are surface antigen negative will 
need to have a negative PCR result before enrolment. Those who are hepatitis B 
surface antigen positive or hepatitis B PCR positive will be excluded.
(b) Participants who are hepatitis C antibody positive will need to have a negative PCR 
result before enrolment. Those who are hepatitis C PCR positive will be excluded.
7
Active Cytomegalovirus (CMV) infection (positive CMV immunoglobulin M [IgM] and 
positive PCR result).
8
Requires or receiving therapeutic anticoagulants, with the exception of short-acting 
heparins, within 7 days of first dose of study treatment. Novel oral anticoagulants are 
allowed except for the initial high dose treatment period.
9
Participants on dual antiplatelet and therapeutic anticoagulant therapy (eg, aspirin and 
therapeutic doses of low molecular weight heparin).
10 Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
11 History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
14.3
Lifestyle Considerations
Please refer to Section 5.3, in addition to Section 14.3.1.
14.3.1
Meals and Dietary Restrictions – Module 1
Acalabrutinib is best taken with water and can be taken with or without food. As acalabrutinib 
is metabolised by CYP3A, participants should be strongly cautioned against using herbal 
remedies or dietary supplements (in particular, St John’s wort, which is a potent CYP3A 
inducer).


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Otherwise, participants should maintain their regular diet unless modifications are required to 
manage an AE such as diarrhoea, nausea, or vomiting.
14.4
Screen Failures
Please refer to Section 5.4.


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15
STUDY INTERVENTION – MODULE 1
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
15.1
Study Intervention(s) Administered
15.1.1
Investigational Products
AZD4573 will be administered as an absolute (flat) dose, 2-hour (± 15 minutes) IV infusion 
once weekly, at least 5 days apart, in combination with orally administered acalabrutinib 100 
mg twice daily continuously. For both Part A and Part B of this study, Cycle 1 consists of 5 
weeks, with a dose ramp up. Subsequent cycles are 21 days (3 weeks) with once-weekly 
dosing of AZD4573 in combination with acalabrutinib 100 mg twice daily continuously.
AZD4573 and acalabrutinib will be supplied by AstraZeneca. 
 
Detailed 
information on the drug products and administration guidelines are in the AZD4573 Handling 
Instructions and acalabrutinib participant leaflet.
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines and will be translated into the local language. The labels will fulfil Good 
Manufacturing Practice Annex 13 requirements for labelling.
All IPs should be kept in a secure place under appropriate storage conditions. The IP label on 
the vial (AZD4573) or bottle (acalabrutinib) specifies the appropriate storage conditions.
Participants enrolled in this study module will receive acalabrutinib in combination with 
AZD4573, in accordance with the dosing scheme provided in Section 13.1. Acalabrutinib is 
intended to be administered orally every day, twice daily with approximately 240 mL of water 
and can be administered without regard to food. Doses should be administered 12 hours apart 
(a window of ± 1 hour is allowed) at approximately the same times each day. Treatment with 
AZD4573 and acalabrutinib, in Part A and Part B, may be continued until disease progression, 
an unacceptable drug-related toxicity occurs as defined in the protocol, or the participant 
withdraws or is withdrawn from the study for other reasons. The acalabrutinib capsules should 
be swallowed intact. Participants should not attempt to open capsules or dissolve in water. If 
vomiting occurs after taking acalabrutinib, the participant should not retake acalabrutinib until 
the next scheduled dose.
CCI


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On the day of PK collection, acalabrutinib capsules should be brought to site by the 
participant and taken within 5 minutes before initiation of AZD4573. The actual date and time 
of AZD4573 and acalabrutinib dosing will be recorded.
Table 10
Investigational Products
Intervention Name
AZD4573
Acalabrutinib
Type 
Drug
Drug
Dose Formulation
Concentrate for solution for 
infusion
Capsules
Unit Dose Strength(s)
1.5 mg/mL
100 mg
Dosage Level(s)
1.5 mg – 12.0 mg
100 mg BID
Route of 
Administration
IV infusion
Oral
Use
Experimental
Experimental
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by AstraZeneca 
Provided centrally by AstraZeneca
Packaging and 
Labelling
Study Intervention will be provided 
in vials. Each vial will be labelled 
as required per country requirement
Study Intervention will be provided 
in bottles. Each bottle will be 
labelled as required per country 
requirement
Current/Former 
Name(s) or Alias(es)
AZD4573/
AZ13810325
Acalabrutinib/ACP-196/Calquence
Abbreviations: BID = twice daily; IMP = investigational medicinal product; IV = intravenous; 
NIMP = non-investigational medicinal product.
If an acalabrutinib dose is not taken within the allowed window, it can be taken up to 2 hours 
after the scheduled time with a return to the normal schedule the same or following day. If it 
has been > 2 hours, the dose should not be taken, and the participant should take the next dose 
at the next scheduled time. The missed dose will not be made up and must be returned to the 
site at the next scheduled visit. If a participant needs to take a dose earlier than scheduled, the 
participant can take the dose up to 2 hours earlier than the scheduled time except on scheduled 
site visit days. Participants should make every reasonable effort to take the acalabrutinib on 
time. Guidance on co-administration of acalabrutinib with agents that affect gastric pH is 
provided in Section 15.11.


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15.2
Starting Dose, Dose-Escalation Scheme, and Stopping Criteria
The starting dose of AZD4573 selected for this study is 3 mg (Week 1 of Cycle 1) for the 
initial dose of the ramp-up period in the dose setting cohorts. The initial target dose following 
the ramp up is 9 mg (dose level 1). The starting and target dose were based on clinical data 
from an ongoing Phase I FTIH study of AZD4573 monotherapy (D8230C00001, see 
Section 13.3). The initial starting dose of AZD4573 was selected based on the safety 
information for AZD4573 monotherapy in the ongoing first-in-human study 
(Study D8230C00001) and is at least one dose level below the RP2D for monotherapy.
A study-specific SRC in accordance with its charter, will be responsible for providing ongoing 
safety surveillance of the study, with regularly scheduled reviews of safety, PK , and other 
relevant data (see Section 18.6). This committee will be responsible for making 
recommendations for dose escalation or dose de-escalation recommendations, including 
recommendations on opening cohorts for backfill, as well as making recommendations 
regarding further conduct of the study.
This study includes intra-patient dose escalation (ie, ramp-up dosing) in each cohort to reach 
the target dose level as a safety precaution. The intra-patient dose-escalation scheme and/or 
dose schedule for each cohort may be modified based on the safety and PK findings of a 
previous dose level.
For each new dose level, the initial dose setting cohort will require at least 3 evaluable 
participants and a maximum of 6. A recommendation about the dose level for each next cohort 
will be made by the SRC, guided by rules based on the mTPI-2 design (Guo et al 2017) with a 
30% target DLT rate (± 5%) for MTD (see Table 11): dose escalation (E), stay (S) at the 
current dose, de-escalation (D), or de-escalation and current dose is unsafe (DU).
Table 11
Decision Rules Based on mTPI-2 for Dose Escalation
Number 
of DLTs
Number of DLT-Evaluable Participants Treated at Current Dose Level
n = 1
n = 2
n = 3
n = 4
n = 5
n = 6
n = 7
n = 8
n = 9
0
Sa
Sa
E
E
E
E
E
E
E
1
Sb
Sb
S
S
E
E
E
E
E
2
DU
D
D
D
S
S
S
E
3
DU
DU
D
D
D
D
S
4
DU
DU
DU
D
D
D
5
DU
DU
DU
DU
DU
6
DU
DU
DU
DU


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Number 
of DLTs
Number of DLT-Evaluable Participants Treated at Current Dose Level
7
DU
DU
DU
8
DU
DU
9
DU
a
Changed from E to S as a minimum of 3 evaluable participants are needed to make a dose-escalation decision.
b
Changed from D to S as a minimum of 3 evaluable participants are needed to make a dose de-escalation decision.
Note: E = escalate to the next higher dose level, S = stay at the current dose level, D = de-escalate to the next 
lower dose level; DU = de-escalate to the previous lower dose and the current dose will never be used again due 
to unacceptable toxicity. 
Abbreviations: D = de-escalation; DLT = dose-limiting toxicity; DU = dose unsafe; E = escalation; 
mTPI-2 = modified toxicity probability interval; S = stay.
A dose level will be considered as having unacceptable toxicity, with no additional 
participants enrolled at that dose level and above, if it has an estimated 95% or more 
probability of exceeding the 30% target DLT rate. Otherwise, dose escalation is terminated 
when the prespecified maximum target dose is reached (AZD4573 12 mg).
If a stay decision is made, additional participants may be enrolled (usually in cohorts of 2 to 
6 participants) up to a maximum of 9 total evaluable participants for a given dose level and a 
maximum of 24 evaluable participants for dose setting (ie, a maximum of 9 evaluable 
participants at each of two dose levels and 6 evaluable participants at the third dose level).
At any timepoint during the study, the occurrence of a fatal AE deemed related to study 
therapy (after full etiological work-up and in discussion with the SRC) will result in accrual 
stoppage and a comprehensive review of safety. In addition, potential safety signals arising 
from Grade ≤4 treatment-related AEs will be reviewed in the context of the overall 
benefit/risk. On review any event deemed to adversely affect overall benefit risk will trigger 
an ad hoc SRC for comprehensive safety review.
In the case of PHL, if bilirubin remains elevated (compared to baseline) at 96 hours 
(-2/+12 hours) after the start of the infusion, the participant must be discontinued from the 
study and biochemistry followed until resolution. The Sponsor must be notified immediately.
Part A participants, including backfills, receiving the RP2D of AZD4573 + acalabrutinib 
combination therapy beyond the Cycle 1 DLT-assessment period and Part B participants 
receiving AZD4573 + acalabrutinib combination therapy from their first Cycle 1 dose 
onwards will be monitored for safety using the same DLT criteria employed during dose 
setting. If, on an ongoing basis, > 30% of participants experience any safety events that meet 
the criteria of a DLT or > 30% of participants discontinue study treatment due to TLS, 
enrolment into the expansion cohorts may be paused for evaluation of the study data by the 


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SRC. Following SRC review additional monitoring may be implemented and/or enrolment 
and dosing may resume at a lower combination dose level or a modified schedule as defined 
in the dose setting phase. Further details will be provided in the Medical Monitoring Plan.
15.3
Definition of Dose-limiting Toxicity (DLT)
A Dose Limiting Toxicity is defined as any event that meets the DLT criteria listed in this 
section, unless unequivocally due to underlying malignancy or an extraneous cause.
Any participants receiving AZD4573 beyond the dose escalation/DLT-assessment period will 
be monitored for safety using the same DLT criteria used during the DLT-assessment period.
The SRC will make a recommendation to stop or continue recruitment after review of the data 
from each cohort (see Section 18.6).
The DLT-assessment period applicable in Part A of this module is normally 5 weeks (DLT 
observation will continue throughout the study for Part A and Part B). Any participant who 
does not complete the DLT-assessment period in Part A may be replaced, with the exception of 
a participant who experiences a DLT; these participants will not be replaced.
Additional participants enrolled at a previously-cleared dose level to provide supplemental 
safety, efficacy, PK, and pharmacodynamics data will not be replaced or evaluated for DLT in 
support of dose-escalation decisions. However, these additional participants will be included 
in the determination of MTD/RP2D at the end of the dose-escalation process.
Any AE that meets the DLT criteria in the opinion of the principal Investigator should be 
reported to the Medical Monitor within 24 hours of knowledge of the event.
A DLT will be defined as the occurrence of any of the following, unless unequivocally due to 
underlying malignancy or an extraneous cause:
DLT criteria (CTCAE version 5.0):

Any Grade ≥3 non-haematological toxicity except:

Grade 3 nausea, vomiting, or diarrhoea despite premedication that respond to medical 
management (eg, improve by 1 or more severity grade within 72 hours of onset of 
toxicity, or 96 hours [-2/+12 hours] from the start of dose, whichever is the sooner).

Grade ≥3 serum lipase and/or amylase that return to initial eligibility criteria within 
72 hours of onset of toxicity or 96 hours (-2/+12 hours) post start of dose, whichever 
is the sooner. Grade ≥3 serum lipase and/or amylase that do not return to meet initial 
eligibility criteria within 72 hours of onset of toxicity or 96 hours (-2/+12 hours) post 
start of dose, whichever is the sooner, will be considered a DLT.


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
A delay in dosing of more than approximately 7 consecutive days (± 2 days), in other 
words, more than 1 missed dose, due to a dose-related toxicity occurring during the 
5-week DLT-assessment period (toxicity that is clearly and directly related to the primary 
disease or to another aetiology is excluded from this definition).
Isolated elevations of transaminases:

Grade 3 elevations (≥5 × ULN) in ALT or AST, without concomitant elevation in total 
bilirubin > 2 × ULN, that do not return to Grade 1 within 7 days from start of dosing.

Grade 4 elevations in ALT (≥20 × ULN) of any duration irrespective of total bilirubin.

Grade 4 elevations in AST (≥20 × ULN) without concomitant elevation in ALT 
≥20 × ULN or total bilirubin ≥2 × ULN that do not return to Grade 1 within 7 days from 
start of dosing.
Elevations in transaminases with concomitant elevation of bilirubin (Potential Hy’s Law 
[PHL]):

Elevations in ALT or AST ≥3 × ULN with concomitant elevation in total bilirubin 
≥2 × ULN where bilirubin does not return to meet initial eligibility criteria within 
72 hours of onset or 96 hours of start of dosing (-2/+12 hours) whichever is the sooner, 
and/or ALT or AST do not return to meet initial eligibility criteria within 7 days post start 
of dose.

Elevations in ALT or AST ≥3 × ULN with concomitant elevation in total bilirubin 
≥2 × ULN and INR > 1.5 × ULN (or > 1.5 × baseline, if elevated at baseline) of any 
duration.

Elevations in ALT or AST ≥3 × ULN with concomitant elevation in total bilirubin 
≥2 × ULN of any duration if associated with symptoms or signs of liver impairment 
(eg, appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia > 5%).
Any of the following haematological toxicities:

CTCAE Grade 4 neutrophil count decrease lasting > 7 days, despite growth factor 
support.

Grade ≥3 febrile neutropenia (absolute neutrophil count [ANC] < 1.0 ×109/L, fever 
> 100.9°F [or > 38.3°C]) of any duration despite supportive care.

CTCAE Grade 4 thrombocytopenia lasting more than 7 days or Grade ≥ 3 
thrombocytopenia, of any duration, associated with ≥ Grade 2 bleeding.


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
CTCAE Grade 4 anaemia despite transfusion.
Any Tumour Lysis Syndrome meeting the following criteria:

Grade ≥3 clinical TLS (Appendix F) that occurs despite protocol-recommended 
management will be considered a DLT.

Laboratory TLS (Appendix F) will be considered a DLT if the metabolic abnormalities do 
not resolve within 5 days despite protocol-recommended management.
Note: All DLT events of TLS should be graded according to the Howard modification of the 
Cairo-Bishop criteria as part of TLS monitoring (Section 17.1.5 and Appendix F), while 
CTCAE grade should be applied on AE/SAE reports.
The definition of DLT excludes:
1
Grade 3 fatigue for ≤7 days after onset.
2
Isolated laboratory changes of any grade without clinical sequelae or clinical significance, 
with the exception of transaminase and bilirubin abnormalities described above.
3
Isolated changes in GGT (ie, with no corresponding elevation in AST, ALT, ALP, Total 
bilirubin or INR, and no symptoms suggestive of hepatic injury) will not be classified as a 
DLT.
15.4
Definition of Maximum Tolerated Dose (MTD)
The MTD is defined as the highest dose level associated with the target DLT rate of 30% 
(± 5%) during the DLT-assessment period.
15.5
Definition of Recommended Phase II Dose (RP2D)
The RP2D is the recommended dose selected in consultation with the SRC based on an 
assessment of aggregate safety data and all relevant clinical and nonclinical data available at 
that time. The RP2D for continued clinical development of AZD4573 + acalabrutinib will be 
assessed as safe and tolerable and will not exceed the MTD.


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15.6
Definition of DLT-evaluable Participant
A DLT-evaluable participant is defined as a participant enrolled in the dose setting part of the 
study (Part A) that has received AZD4573 in combination with acalabrutinib and either:

Has received at least 75% of acalabrutinib doses during the AZD4573 treatment weeks 
and has completed sufficient safety assessments (as determined by SRC review) through 
the DLT-assessment period.
Or

Has experienced a DLT during the DLT-assessment period.
15.7
Duration of Therapy
Treatment with AZD4573 and acalabrutinib, in Part A and Part B, may be continued until 
disease progression, an unacceptable drug-related toxicity occurs as defined in the protocol, or 
the participant withdraws or is withdrawn from the study for other reasons.
For both Part A and Part B, Cycle 1 comprises 5 weeks with a ramp-up period. Cycle lengths 
are 3 weeks from Cycle 2 onwards. For information on dosing schemes and cycle lengths, see 
Figure 5 and Table 8.
Any participant who is still on treatment and is receiving clinical benefit from the IP by the 
end of data collection for the primary analysis will be allowed to continue study treatment. 
Such participants will continue to be monitored for all SAEs up to 30 days after the last dose 
of IP. However, the database will be closed following end of data collection, and participants
remaining on treatment will only be followed for SAEs (paper report). If a participant is 
continuing study treatment after the end of data collection, the Investigator should refer to the 
current IB for treatment guidance and safety surveillance.
15.8
Preparation/Handling/Storage/Accountability of Interventions
Please refer to Section 6.8 for general instructions and instructions specific to AZD4573.
Acalabrutinib drug accountability
Participant reported drug administration for acalabrutinib needs to be done on every AZD4573 
dosing day, ideally prior to dosing (± 24 hours) and is also to be done after the last 
acalabrutinib capsule is taken and the leftover capsules returned to site. Drug accountability 
for acalabrutinib will occur every two weeks (on an AZD4573 dosing day, ideally prior to 
dosing [± 24 hours]).


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The returned number of acalabrutinib capsules needs to be counted and the participant will be 
asked whether or not acalabrutinib was taken according to the instructed dosing schedule. 
Deviations from the instructed schedule should be discussed with the participant and recorded 
both in the source documents and the eCRF.
Discrepancies between the expected and returned number of capsules should be discussed 
with the participant and recorded in the source documents.
15.9
Measures to Minimise Bias: Randomisation and Blinding
This is an open-label, non-randomised study (please refer to Section 6.9).
15.10
Study Intervention Compliance
AZD4573
Participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study-site staff other than the person administering the 
study intervention. 
Acalabrutinib
Acalabrutinib drug accountability will be conducted as described in Section 15.8 and this will 
be recorded by the site. If the participant made an error or dropped/lost capsules the site will 
need to check that the participant will have sufficient capsules for the following week. 
Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF.
A record of the number of acalabrutinib capsules dispensed to and taken by each participant 
must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the eCRF.
15.11
Concomitant Therapy
The Investigator must be informed as soon as possible about any concomitant medication 
taken from the time of screening until the end of the clinical phase of the study (final study 
visit). Any concomitant therapy(ies), including over-the-counter medications, herbal remedies, 
vaccines, and supplements, taken during the study will be recorded.


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15.11.1
Permitted Concomitant Therapy
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 15.11.2. Specifically, participants should receive full supportive care during 
the study and treatment with antibiotics, anti-emetics, antidiarrheals, and analgesics, and other 
care as deemed appropriate, and in accordance with their institutional guidelines.
After the start of AZD4573 and acalabrutinib administration, blood and platelet transfusions 
are allowed as clinically indicated at any time during the study and can be given as per local 
institutional guidelines. If indicated, transfusions or growth factors can be administered during 
the screening period, but such cases of deterioration of haematological function must be 
discussed with the Medical Monitor, to confirm start of study treatment.
Supportive care (eg, recombinant growth factor support) and other medications that are 
considered necessary for the participant’s wellbeing, (eg, bisphosphonates), may be given at 
the discretion of the Investigator and in accordance with local institutional guidelines.
Concomitant use of paracetamol is permitted but is limited to a maximum dose of 4 grams per 
day.
AstraZeneca recommends administering non-live inactivated vaccines 72 hours prior to 
administration of the first dose of any IP to avoid biases in the interpretation of safety data due 
to the potential overlap of vaccine-related AEs with IP AEs.
Permitted concomitant therapy for the management of safety concerns for AZD4573 and 
acalabrutinib (including TLS) is specified in Section 17.1.10. For participants considered at 
risk for TLS (see Section 17.1.10.10), administer appropriate hydration and allopurinol or 
rasburicase per institutional standards before initiating treatment.
15.11.2
Prohibited Concomitant Therapy
Participants must be instructed not to take any medications, including over-the-counter 
products, herbal remedies, and supplements without first consulting with the Investigator.
The following medications are considered exclusionary during the study. AstraZeneca must be 
notified if a participant receives any of these during the study:

Any investigational anti-cancer therapy.

Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of 


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hormones for noncancer-related conditions (eg, insulin for diabetes and hormone 
replacement therapy) is acceptable.

Participants may use topical or inhaled corticosteroids as therapy for comorbid 
conditions. Ongoing use of low-dose systemic corticosteroids (≤10 mg/day prednisolone 
or equivalent is permitted (Section 6.11).

Warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) are prohibited for all 
participants in the study. Participants who require anticoagulation prophylaxis before 
study treatment start or therapeutic anticoagulation for thrombosis while on study will be 
allowed to receive anticoagulation with a non-vitamin K inhibitor class of anticoagulants. 
Should participants require either a vitamin K antagonist or combined administration of 
antiplatelet and therapeutic anticoagulation while on study, acalabrutinib treatment must 
be discontinued.
For further restrictions on the concomitant use of therapies and possible drug-drug interactions 
with AZD4573 and acalabrutinib, please refer to Section 6.11 and Section 15.11.4, 
respectively.
15.11.3
AZD4573 and Concomitant Therapy
For further specific information on AZD4573 and concomitant therapy, please refer to 
Section 6.11.
15.11.4
Acalabrutinib and Concomitant Treatments
The effect of agents that reduce gastric acidity (antacids or proton-pump inhibitors) on 
acalabrutinib absorption was evaluated in a healthy volunteer study (ACE-HV-004). Results 
from this study indicate that participants should avoid the use of calcium carbonate containing
drugs or supplements for a period of at least 2 hours before and at least 2 hours after taking 
acalabrutinib. Use of omeprazole, esomeprazole, lansoprazole, or any other proton-pump 
inhibitors while taking acalabrutinib is not recommended due to a potential decrease in study 
treatment exposure. However, the decision to treat with proton-pump inhibitors during the 
study is at the Investigator’s discretion, with an understanding of the potential benefit to the 
participant’s gastrointestinal condition and a potential risk of decreased exposure to 
acalabrutinib. Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) 
on acalabrutinib absorption has not been evaluated, if treatment with an H2-receptor antagonist 
is required, the H2-receptor antagonist should be taken approximately 10 hours before or 2 
hours after acalabrutinib.
Acalabrutinib is not a strong direct inhibitor or inducer of CYP isoforms; thus, acalabrutinib, 
at the currently used clinical doses, is unlikely to be a perpetrator of a drug-drug interaction at 
the level of inhibition or induction of CYP isoforms. The concomitant use of strong 


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inhibitors/inducers of CYP3A should be avoided (please refer to Appendix F). Because 
acalabrutinib is metabolised by CYP3A, participants should be strongly cautioned against 
consumption of grapefruit, grapefruit juice, or Seville orange juice (which contain potent 
CYP3A inhibitors) or using herbal remedies or dietary supplements (in particular, St. John’s 
wort, which is a potent CYP3A inducer). If a participant requires short-term treatment with a 
strong CYP3A inhibitor (such as anti-infectives for up to 7 days), interrupt acalabrutinib 
treatment. From Cycle 2 onwards, if a participant requires a moderate CYP3A inhibitor while 
on study, decrease acalabrutinib dose to 100 mg once daily. Avoid co-administration of strong 
CYP3A inducers. If a participant requires treatment with a strong CYP3A inducer, increase 
the acalabrutinib dose to 200 mg twice daily during concomitant administration with the 
strong CYP3A inducer and return to recommended dose of 100 mg twice daily after stopping 
the strong CYP3A inducer.
Concomitant use of paracetamol is permitted but is limited to a maximum dose of 4 grams per 
day. For participants dosed with AZD4573 and acalabrutinib non-steroidal anti-inflammatory 
agents such as ibuprofen should also be avoided.
15.12
Dose Modification
Table 12 provides dose reductions options for acalabrutinib.
Table 12
Acalabrutinib Dose Reduction Options
Starting dose
1st dose reductiona
2nd dose reduction
100 mg twice daily
100 mg once daily
Discontinue
a
When reducing to 100 mg acalabrutinib once daily, the morning dose should be retained. If considering 
dose reduction, please discuss with the Medical Monitor.
Note: Temporary withholding of acalabrutinib for as little as 7 days can cause a transient 
worsening of disease in DLBCL and/or of constitutional symptoms. Transient worsening of 
disease during temporary interruption of acalabrutinib (eg, for drug-related toxicity, surgery, 
or intercurrent illness) may not indicate disease progression. In such circumstances, and if 
medically appropriate, following discussion with the Medical Monitor, participants may 
resume therapy and relevant clinical, laboratory, and/or radiologic assessments should be done 
to document whether tumour control can be maintained or whether actual disease progression 
has occurred.
If the dose of acalabrutinib is reduced for apparent treatment-related AE/SAE, the dose of 
acalabrutinib should not be re-escalated unless the participant tolerates the reduced dose for 
greater than 4 weeks and at the Investigator’s discretion and in consultation with the Medical 
Monitor. Such re-escalation may be particularly warranted if further evaluation reveals that the 


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AE/SAE that led to the dose reduction was not treatment-related. Any changes to the dosing 
regimen must be recorded on the appropriate eCRF.
Acalabrutinib dose reduction options are described in Table 12 and dose modification and 
discontinuation guidelines for haematological and non-haematological toxicities (excluding 
abnormal liver chemistry results) are shown below in Table 13. Dose modifications for 
AZD4573 and acalabrutinib for abnormal liver chemistry results are described in Table 14.
In general, if a participant experiences a Grade 1 or Grade 2 haematological or 
non-haematological toxicity, no dose modification is required. If a participant experiences a 
Grade 3 or Grade 4 toxicity, not attributable to the disease or disease-related processes under 
investigation, dosing might be interrupted and/or the dose reduced (see Table 12 for 
acalabrutinib reduction options and Table 13 for recommended dose modifications for 
AZD4573 and acalabrutinib) and supportive therapy administered as required. If the toxicity 
resolves or reverts to CTCAE Grade ≤2 within 21 days and the participant was showing 
clinical benefit, treatment with study treatment(s) may be restarted.
If the toxicity does not resolve to CTCAE Grade ≤2 within 21 days, then the participant 
should be withdrawn from the study and observed until resolution of the toxicity. Maximal 
drug interruption allowed for related toxicity for both AZD4573 and acalabrutinib is 
≤21 consecutive days.
Table 13
Recommended Dose Modifications for AZD4573 and Acalabrutinib
Eventa
Occurrence
Action with AZD4573
Action with Acalabrutinib
Tumour Lysis Syndrome (TLS) – Howard Modification of Cairo-Bishop Criteria
Changes in uric acid, 
potassium, 
phosphorus, 
creatinine or calcium, 
or symptoms 
suggestive of 
clinically significant 
TLS, in the 
Investigator's 
judgement
Any
For any abnormal changes 
present before dosing, initiate 
supportive therapy and hold 
drug for up to 7 days. If not 
resolved, reduce by 1 dose level.
Withhold acalabrutinib until 
resolved, resume dosing at the 
same dose level upon resolution.
For events of Grade 1 or 2 TLS, 
resume at same dose level upon 
resolution.
For events of Grade 1 or 2 TLS, 
resume at same dose level upon 
resolution.
For 1st occurrence of Grade 3 
TLS resume at the same dose 
upon resolution to Grade 1.
For 1st occurrence of Grade 3 
TLS resume at the same dose 
upon resolution.


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Table 13
Recommended Dose Modifications for AZD4573 and Acalabrutinib
Eventa
Occurrence
Action with AZD4573
Action with Acalabrutinib
For 2nd occurrence of Grade 3 
TLS, after resolution to Grade 1, 
reduce dose by one dose level 
when restarting AZD4573 
except events that in the opinion 
of the Investigator, in 
consultation with the Medical 
Monitor, are not dose-limiting.
For subsequent occurrences of 
Grade 3 TLS, further 
rechallenge and dose level to be 
discussed with the Medical 
Monitor.
For events of Grade 4 TLS, 
discontinue AZD4573.
For 2nd occurrence of Grade 3 
TLS, after resolution to Grade 1, 
reduce dose by one dose level 
when restarting or discontinue 
acalabrutinib except events that 
in the opinion of the 
Investigator, in consultation with 
the Medical Monitor, are not 
dose-limiting.
For subsequent occurrences of 
Grade 3 TLS, further 
rechallenge and dose level to be 
discussed with the Medical 
Monitor.
For events of Grade 4 TLS, 
discontinue acalabrutinib.


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Table 13
Recommended Dose Modifications for AZD4573 and Acalabrutinib
Eventa
Occurrence
Action with AZD4573
Action with Acalabrutinib
Non-haematological toxicities (except liver dysfunction)
Grade 3 or 4 
non-haematological 
toxicities
1st occurrence 
Withhold dosing with AZD4573 
until the toxicity has resolved to 
Grade 1, but no longer than 
21 daysb.
Adequate supportive therapy as 
per institutional guidelines 
should be given. AZD4573 
therapy may be resumed at the 
same dose. No dose 
modification is required.
Withhold acalabrutinib until 
recovery to Grade ≤2.
Restart acalabrutinib at the same 
dose level.
2nd and 
subsequent 
occurrences
Withhold dosing AZD4573 up 
to 21 daysb.
Adequate supportive therapy as 
per institutional guidelines 
should be given.
After resolution to Grade 1, 
reduce dose by one dose level 
when restarting AZD4573.
If no resolution within 21 days 
discontinue AZD4573b.
In case of subsequent 
occurrences, dosing may be 
modified to skip weekly dose(s) 
(eg, 2 weeks on/1 week off or to 
1 week on/1 to 2 weeks off), 
after discussing with the 
Medical Monitor.
Withhold acalabrutinib until 
recovery to Grade ≤2.
Restart acalabrutinib with 
1 level dose reduction or 
discontinue (see Table 12).


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Table 13
Recommended Dose Modifications for AZD4573 and Acalabrutinib
Eventa
Occurrence
Action with AZD4573
Action with Acalabrutinib
Haematological Toxicities
Grade 3 or 4 
neutropenia without 
fever or infection, 
lasting ˃ 7 days 
despite growth factor 
support
1st occurrence
Withhold dosing AZD4573 until 
Grade ≤2 or baseline level.
Restart at same dose level 
following resolution.
Withhold acalabrutinib if 
Grade 4 neutropenia lasting 
> 7 days until resolution to 
Grade ≤2 or baseline level and 
then restart at same dose for 1st 
occurrence.
2nd and 
subsequent 
occurrence
Withhold dosing AZD4573 until 
Grade ≤2 or baseline level.
Restart with one dose level 
reduction following resolution.
In case of subsequent 
occurrences, dosing may be 
modified to skip weekly dose(s) 
(eg, 2 weeks on/1 week off or to 
1 week on/1 to 2 weeks off), 
after discussing with the 
Medical Monitor.
Withhold acalabrutinib if 
Grade 4 neutropenia lasting 
> 7 days until resolution to 
Grade ≤2 or baseline level and 
then restart at a reduced dose or 
discontinue (see Table 12).


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Table 13
Recommended Dose Modifications for AZD4573 and Acalabrutinib
Eventa
Occurrence
Action with AZD4573
Action with Acalabrutinib
Grade 3 or 4 
neutropenia with 
infection or fever
1st occurrence
Withhold dosing AZD4573. 
To reduce the infection risks 
associated with neutropenia, 
G-CSF may be administered 
with AZD4573 if clinically 
indicated/required as per 
Institutional practice.
Consider secondary prophylaxis 
with G-CSF as per 
ASCO/ESMO guidelines. Once 
the toxicity has resolved to 
≤Grade 2 or to baseline level, 
AZD4573 therapy may be 
resumed at the same dose.
Withhold acalabrutinib until 
infection is resolved, antibiotics 
no longer required and ANC 
Grade ≤2 or baseline level.
Following resolution, resume 
acalabrutinib with 1 level dose 
reduction or discontinue (see 
Table 12).
2nd occurrence
Withhold dosing AZD4573.
Consider using G-CSF as 
clinically indicated/as per 
Institutional practice. Follow 
dose reduction guidelines when 
resuming treatment with 
AZD4573 after resolution.
Reduce dose by one dose level.
Withhold acalabrutinib until 
infection is resolved, antibiotics 
no longer required and ANC 
Grade ≤2 or baseline level.
Following resolution, resume 
acalabrutinib with 1 level dose 
reduction or discontinue (see 
Table 12).
3rd occurrence
Discontinue AZD4573.
Discontinue acalabrutinib.
Grade 3 
thrombocytopenia 
without bleeding
Any
Withhold AZD4573 until 
Grade ≤2 or baseline level.
Restart AZD4573 at the same 
dose level.
Continued dosing can be 
considered at the discretion of 
the investigator after discussion 
with the medical monitor.
No action.
Grade 4 
thrombocytopenia 
without bleeding 
requiring blood or 
platelet transfusion
1st occurrence
Withhold AZD4573 until 
Grade ≤2 or baseline level.
Restart AZD4573 at the same 
dose level.
Withhold acalabrutinib until 
Grade ≤2 or baseline level.
Restart acalabrutinib at the same 
dose level.


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Table 13
Recommended Dose Modifications for AZD4573 and Acalabrutinib
Eventa
Occurrence
Action with AZD4573
Action with Acalabrutinib
2nd occurrence
Withhold AZD4573 until 
Grade ≤2 or baseline level.
Restart AZD4573 with 1 level 
dose reduction.
If not recovered to Grade ≤2 or 
baseline level discontinue.
Withhold acalabrutinib until 
Grade ≤2 or baseline level.
Restart acalabrutinib with 
1 level dose reduction or 
discontinue (see Table 12).
3rd occurrence
Discontinue AZD4573.
Discontinue acalabrutinib.
Grade 3 or 4 
thrombocytopenia 
with bleeding 
requiring blood or 
platelet transfusion
1st occurrence
Withhold AZD4573 until 
Grade ≤2 or baseline level.
Restart AZD4573 with 1 level 
dose reduction.
If not recovered to Grade ≤2 or 
baseline level discontinue.
Withhold acalabrutinib until 
Grade ≤2 or baseline level.
Restart acalabrutinib with 
1 level dose reduction or 
discontinue (see Table 12).
2nd occurrence
Discontinue AZD4573.
Discontinue acalabrutinib.
a
Adverse reactions are graded using National Cancer Institute CTCAE version 5.0. All grades refer to 
CTCAE grading except for TLS, which uses the Howard modification of Cairo-Bishop criteria 
(Howard et al 2011).
b
In cases where more than 21 days are needed, a decision to continue, modify, or discontinue study treatment 
will be made on a case-by-case basis in consultation with the principal Investigator and the Medical 
Monitor.
Abbreviations: ANC = absolute neutrophil count; ASCO = American Society of Clinical Oncology; 
CTCAE = Common Terminology Criteria for Adverse Events; ESMO = European Society for Medical 
Oncology; G-CSF = granulocyte-colony-stimulating factor; TLS = tumour lysis syndrome.
Dose modifications for AZD4573 and acalabrutinib for abnormal liver chemistry results are 
described in Table 14.
Table 14
Recommended Dose Modifications for AZD4573 and Acalabrutinib for 
Abnormal Liver Chemistry Results
Eventa
Action
AZD4573
Acalabrutinib
Isolatedb elevations in ALT, AST, or bilirubin
Grade 1
Isolated ALT/AST ≤3 × ULN
or
Isolated Bilirubin ≤1.5 × ULN
Maintain current dose level.
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week.
Maintain current dose level and
schedule. 
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week.


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Eventa
Action
AZD4573
Acalabrutinib
Grade 2
Isolated ALT/AST > 3 to 
≤5 × ULN
or
Isolated Bilirubin > 1.5-
≤3 × ULN
After 7 days if hepatic enzymes 
resolve to Grade ≤1, rechallenge 
at same dose level.
Withhold or continue acalabrutinib 
(at Investigator discretion, after 
discussion with the Medical 
Monitor). To prevent disease 
progression, monitor disease 
parameters closely.
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week.
After 7 days if hepatic enzymes 
appear to be improving and 
acalabrutinib was withheld, restart 
acalabrutinib at current dose level.
Grade 3
Isolated ALT/AST > 5-20 × ULN
If recovered to Grade ≤1 within 
7 days, allow rechallenge at same 
dose level.
If not recovered to baseline level 
within 7 days, discontinue 
AZD4573.
Withhold or continue acalabrutinib 
(at Investigator discretion, after 
discussion with the Medical 
Monitor). To prevent disease 
progression, monitor disease 
parameters closely.
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week. 
After 7 days if hepatic enzymes 
appear to be improving and 
acalabrutinib was withheld, restart 
acalabrutinib with 1 level dose 
reduction or discontinue.
Grade 3
Isolated Bilirubin > 3-10 × ULN
If recovered to baseline level 
within 96 hours (-2/+12 hours) of 
the start of the infusion allow 
rechallenge at same dose level.
If not, discontinue AZD4573
Grade 4c
Isolated ALT > 20 × ULN
or
Isolated Bilirubin > 10 × ULN
Discontinue AZD4573.
Discontinue acalabrutinib.
Grade 4
Isolated elevation (≥ 20 × ULN) in
AST without concomitant 
elevation in ALT ≥ 20 × ULN or 
concomitant elevation in TBL 
≥2 × ULN that fails to return to 
baseline level within 7 days from 
start of dosing
Discontinue AZD4573.
Discontinue acalabrutinib.


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Eventa
Action
AZD4573
Acalabrutinib
Grade 4c
Isolated AST elevation 
≥20 × ULN without concomitant 
elevation in ALT ≥20 × ULN or 
TBL ≥2 × ULN
1st occurrence
If recovered to Grade ≤1 or 
baseline level within 7 days of the 
start of the infusion allow 
rechallenge at same dose level
Withhold or continue acalabrutinib 
(at Investigator discretion, after 
discussion with the Medical 
Monitor). To prevent disease 
progression, monitor disease 
parameters closely.
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week. 
After 7 days if hepatic enzymes 
appear to be improving and 
acalabrutinib was withheld, restart 
acalabrutinib at current dose level 
at the 1st occurrence and with 
1 level dose reduction at the 2nd
occurrence.
Discontinue acalabrutinib at the 
3rd occurrence.
2nd occurrence
If recovered to Grade ≤1 or 
baseline level within 7 days of the 
start of the infusion allow 
rechallenge with 1 dose level 
reduction
3rd occurrence
Discontinue AZD4573
Concurrent elevations in ALT, AST, or bilirubin
(Please also refer to Appendix E for actions to be taken in the event of PHL)
ALT or AST ≥3 × ULN with 
TBL ≥2 × ULN (Potential Hy’s 
Law) AND INR ≥1.5 × ULN (or 
≥1.5 × baseline if elevated at 
baseline) of any duration
Discontinue AZD4573.
Discontinue acalabrutinib.
ALT or AST ≥3 × ULN with the 
appearance of fatigue, nausea, 
vomiting, right upper quadrant 
pain or tenderness, fever, rash, 
and/or eosinophilia > 5%
Discontinue AZD4573.
Discontinue acalabrutinib.
ALT or AST ≥ 3 × ULN and TBL
≥ 2 × ULN where TBL does not 
return to baseline level within 
96 hours (-2/+12 hours) from start 
of dose and/or AST or ALT do not 
return to baseline level within 
7 days from start of dose
Discontinue AZD4573.
Discontinue acalabrutinib.


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Eventa
Action
AZD4573
Acalabrutinib
Grade 3 elevation (≥ 5 × ULN) in
ALT or AST with TBL elevation
above baseline level or ULN, but
< 2 × ULN that do not return to 
baseline level within 7 days
Discontinue AZD4573.
Discontinue acalabrutinib.
ALT and AST ≥ 3 × ULN with 
concomitant TBL ≥ 2 × ULN, NO 
increase in INR ≥ 1.5 × ULN (or 
1.5 × baseline), and NO fatigue, 
nausea, vomiting, right upper 
quadrant pain or tenderness, fever, 
rash, and/or eosinophilia > 5%
If recovered to Grade ≤1 or 
baseline level within 96 (-2/+12) 
hours, rechallenge at same dose 
levelc
Withhold acalabrutinib until 
recovered. Once recovered, restart 
acalabrutinib at same dose.
a
Adverse reactions are graded using National Cancer Institute CTCAE version 5.0. All grades refer to 
CTCAE grading except for TLS, which uses the Howard modification of Cairo-Bishop criteria 
(Howard et al 2011).
b
Elevations in ALT or AST are considered isolated if bilirubin remains below Grade 1, and elevations in 
bilirubin are considered isolated if ALT and AST remain below Grade 1.
c
Participants who are considered for rechallenge in the event of Grade 4 transaminase increases or PHL must 
discuss possible risk of hepatotoxicity with the treating physician, who will document this discussion and 
participant agreement for continued treatment in the medical records.
Note: Adequate supportive therapy as per institutional guidelines should be given for all toxicities.
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CTCAE = Common Terminology Criteria for Adverse Events; INR = international normalised ratio; 
PHL = Potential Hy’s Law; TBL = total bilirubin; ULN = upper limit of normal.
15.12.1
Retreatment Criteria
Retreatment is defined as the first dose of study drug after a significant period of intentional 
pause in study drug treatment (other than missed doses, eg, study treatment put on hold until 
resolution of COVID-19).  
Retreatment criteria (criteria to be met before participant restarts study drug infusions 
[and capsules, as applicable]):
All participants:
1
Participant has recovered from all treatment-related non-haematological toxicity to 
CTCAE Grade ≤2.
2
Recovery of neutrophils ≥1000/μL and platelets ≥50,000/μL.
3
Participant has recovered from all hepatic toxicity events within the timeframes described 
in Table 14 above. If biochemical changes in transaminase(s) and total bilirubin are 
consistent with the definition of HL, the participant may continue to receive study drug 


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only if all abnormalities have resolved within the timeframes specified in Table 14 above, 
there are no symptoms of liver injury and INR has not increased above 1.5 × ULN (or 
1.5 × baseline). In these circumstances the participant must be made aware of the 
unknown potential for liver damage with continued exposure to AZD4573 prior to 
retreatment. Documentation of continued consent is required.
4
Recovery of uric acid to < ULN.
5
Recovery of changes in uric acid, potassium, phosphorus, creatinine or calcium, or 
symptoms suggestive of TLS as defined in Table 13.
6
In case of any new deterioration in laboratory values, not fulfilling eligibility criteria and 
deeded as clinically significant by the Investigator, the Medical Monitor must be 
contacted to discuss whether AZD4573 dosing can be continued.
15.13
Intervention After the End of the Study
No intervention is planned after the end of the study. However, provisions will be in place for 
patients still enrolled at the end of the trial to continue to receive study intervention if, in the 
opinion of the Investigator, they are continuing to receive benefit from treatment.


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16
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL –
MODULE 1
16.1
Discontinuation of Study Intervention
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
Please refer to Section 7.1 for information on discontinuation of study intervention.
16.1.1
Temporary Discontinuation
Refer to Section 15.12 for information on temporary discontinuation and restarting of study 
intervention.
16.1.2
Rechallenge
Refer to Section 15.12 for information on rechallenge with study intervention.
16.2
Participant Withdrawal from the Study
Please refer to Section 7.2 for information on participant withdrawal from the study.
16.3
Procedures for Handling Participants Incorrectly Initiated on 
AZD4573 or Combination Therapy
Please refer to Section 7.3 for information on procedures for handling participants incorrectly 
initiated on AZD4573 or combination therapy.
16.4
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
Please refer to Section 7.4 for actions to be taken if a participant fails to return to the clinic for 
a required study visit.
For handling of discontinuation of specific sites or of the study as a whole please refer to 
Appendix A 9.


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17
STUDY ASSESSMENTS AND PROCEDURES – MODULE 1

Study procedures and their timing are summarised in the SoA (Section 10.2). 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 participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

The amount of blood collected from each participant for the scheduled assessments, is not 
anticipated to exceed 440 mL in Cycle 1 (cycle duration 5 weeks), 135 mL in Cycle 2 
(cycle duration 3 weeks) and 80 mL in each subsequent cycle (cycle duration 3 weeks). If 
a participant experiences TLS, maximum 30 mL extra blood will be collected per cycle 
(5 weeks) for safety reasons.
 
 Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples.
17.1
Safety Assessments
17.1.1
Enrolment and Screening
Each potential participant approved for screening is assigned a unique participant enrolment 
number. If a participant withdraws from the study, then the enrolment number cannot be 
reused.
Demographic data and other characteristics will be recorded and will include date of birth, 
race and ethnicity, and alcohol use.
A standard medical, medication and surgical history will be obtained with review of the 
selection criteria with the participant. Concurrent medical signs and symptoms must be 
documented to establish baseline severities. Previous and concomitant treatments (coded 
CCI


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according to the World Health Organization Drug Dictionary [WHODRUG]) will be collected 
for each participant. A disease history, including the date of initial diagnosis, staging within 
30 days of first dose of AZD4573, prognostic indices/disease profiling for DLBCL (derived 
from local laboratory results) and list of all prior anti-cancer treatments, and responses and 
DoR to these treatments, will also be recorded.
Each participant will undergo screening (see Section 10.2) during the 30 days before 
admission to confirm eligibility (see Sections 14.1 and 14.2).
17.1.2
Physical Examinations
A complete physical examination, including a standard neurological examination should be 
completed at Screening and will include, at a minimum: the general appearance of the 
participant, height, weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, 
abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system. 
Investigators should pay special attention to clinical signs related to previous serious illnesses 
and new or worsening abnormalities may qualify as AEs.
Symptom-directed physical exams are done thereafter at the visits indicated in the SoA, 
including the SFU visit (Section 10.2).
17.1.3
Vital Signs
Vital signs will be performed at timepoints specified in the SoA (Section 10.2)
Changes from baseline abnormalities should be recorded in participant notes. New or 
worsened clinically significant abnormalities should be recorded as AEs on the Adverse Event 
eCRF.
Pulse rate and blood pressure
Blood pressure and pulse/heart rate measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.
Blood pressure and pulse measurements should be preceded by at least 10 minutes of rest for 
the participant in a quiet setting.
Pulse rate and blood pressure measurement timepoints are:

Screening

Cycle 1 (Weeks 1 to 3) :

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
1 hour after the start of the infusion (± 10 mins)

At the end of the infusion (up to 10 minutes post dose)

4 hours after the start of the infusion (± 30 minutes)

6 hours after the start of the infusion (± 30 minutes)

From Cycle 1, Week 4 onwards:

Predose (up to 30 minutes prior to infusion)

At the end of the infusion (up to 30 minutes post dose) on each dosing day

30-Day SFU
Body temperature
Body temperature will be measured in degrees Celsius at the following timepoints:

Predose (up to 2 hours prior to all infusions)
Weight
Weight will be measured in kilograms at the following times:

Screening, 

Cycle 1 (Weeks 1-3) (predose)

Cycle 1 Week 4 onwards, of each cycle predose

30-Day SFU
17.1.4
WHO/ECOG Performance Status
ECOG performance status will be assessed at the following times (see Section 10.2):

Screening

Cycle 1 through Cycle 8:

Predose each dose of AZD4573

Cycles 9+, Day 1 of each cycle:

Predose each dose of AZD4573

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Performance status should be measured using the ECOG Performance Status Scale (Table 15). 
It is recommended, where possible, that a participant’s performance status be assessed by the 
same person throughout the study.
Table 15
ECOG Performance Status Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
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 all selfcare but unable to carry out any work activities; up and about 
more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5
Dead
17.1.5
B Symptoms
Information on B symptoms (eg, unintentional weight loss, fevers, and night sweats) will be 
collected at the following times (Section 10.2).

Screening

Cycle 1 through Cycle 8:

Predose AZD4573

Cycle 9+, Day 1 of each cycle:

Predose AZD4573 

30-day SFU
17.1.6
Clinical Safety Laboratory Assessments
For all participants, results of safety laboratory testing (haematology and clinical chemistry at 
a minimum) must be available within 72 hours prior to dosing and must be reviewed by the 
Investigator prior to administration of AZD4573 (all cohorts). If clinically indicated, 
additional clinical laboratory tests and evaluations may be performed by the Investigator 
(eg, additional haematology/clinical chemistry panels, TLS parameters, liver enzyme tests); 
these need to be entered into the eCRF.
This study will use local laboratories.


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The following laboratory variables will be measured:
Haematology: complete blood count (CBC) with automated and/or manual differential 
including, but not limited to, white blood cell count, haemoglobin, haematocrit, platelet count, 
ANC, and absolute lymphocyte count (ALC), and blast cells. Haematology should be 
evaluated before dosing while participants are receiving treatment.
Haematology samples will be collected at the following timepoints:

Screening

Cycles 1, 2, and 3

Predose AZD4573 (within 72h prior to infusion)

24 hours after the start of the infusion

Cycles 4+

Predose AZD4573 (within 72 hours prior to infusion)

If clinically indicated, 24 hours after the start of the infusion

30-Day SFU
The Investigator may take additional, unscheduled samples throughout the study if deemed 
clinically warranted and these need to be entered into the eCRF.
Haematology tests do not need to be repeated before first dose if the first-dose visit is within 
3 days of the Screening sample.
Clinical Chemistry: albumin, chloride, bicarbonate, calcium total, magnesium, phosphorous, 
glucose (fasting preferred), CK, ALP, ALT, ammonia (where available at local institution; to 
be tested every 2 weeks), AST, urea, , cholesterol, C-reactive protein, creatinine, Factor V 
(where available at local institution), GGT, lactate dehydrogenase (LDH), phosphate, 
potassium, sodium, triglycerides, total bilirubin, direct and indirect bilirubin, total protein, uric 
acid.
Clinical chemistry samples will be collected at the following timepoints:

Screening

Cycles 1, 2, and 3

Predose AZD4573 (within 72 hours prior to infusion)

24 hours after the start of the infusion

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
Predose AZD4573 (within 72 hours prior to infusion)

If clinically indicated, 24-hour after the start of the infusion

30-Day SFU
The Investigator may take additional, unscheduled samples throughout the study if deemed 
clinically warranted and these need to be entered into the eCRF.
Clinical chemistry and haematology tests do not need to be repeated before first dose if the 
first-dose visit is within 3 days of the Screening sample.
In addition, GLDH and CPK will be measured at Screening for all participants. If GLDH 
cannot be performed locally, LDH will be analysed locally and a serum sample must be 
collected for central retrospective GLDH analysis, which will be performed as applicable. 
Refer to the Laboratory Manual for details.
Coagulation testing includes aPTT (partial thromboplastin time)/PT (prothrombin time), 
INR, D-dimer (where available at institution), and fibrinogen.
Samples for coagulation testing will be collected at the following timepoints:

Screening

Cycles 1, 2, and 3

Predose AZD4573 (within 72 hours prior to infusion)

24 hours after the start of the infusion

Cycles 4 through 8

Predose AZD4573 (within 72 hours prior to infusion)

If clinically indicated, 24-hour after the start of the infusion

Cycles 9+ on Day 1 of each cycle

Predose AZD4573 (within 72 hours prior to infusion)

30-Day SFU
The Investigator may take additional, unscheduled samples throughout the study if deemed 
clinically warranted and these need to be entered into the eCRF.
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose. Urine samples 
should be collected at the following timepoints:

Screening


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
Cycles 1 through 8

Predose AZD4573 (within 72 hours prior to infusion)

Within approximately 2 hours after the end of the infusion

Cycles 9+ on Day 1 of each Cycle

Predose AZD4573 (within approximately 72 hours prior to infusion)

Within approximately 2 hours after the end of the infusion

30-Day SFU
Cardiac troponin I or troponin T measurements are required at the timepoints below. Either a 
troponin I or troponin T assay can be used per SoC at the respective hospital. If the hospital 
has both a SoC troponin I and troponin T assay available, the investigator should use only one 
consistently for the duration of the study.

Screening

Cycle 1, Weeks 1 through 5

Predose (within 72 hours prior to infusion)

24 hours post start of the infusion

Cycles 2+ on Day 1 of each cycle

Predose (within 72 hours prior to infusion)

30-Day SFU
Electrolyte panel: calcium, magnesium, potassium.
If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, 
potassium), and troponin must be done to coincide with the ECG testing.
Supra-renal glands: T4, cortisol, adrenocorticotropic hormone (ACTH) and 
thyroid-stimulating hormone (TSH) should be measured at the following timepoints:

Screening

Cycle 2 Day 1

Predose AZD4573 (within 72 hours prior to infusion)

30-Day SFU
Pancreas: Lipase and amylase measurements are required at the following timepoints:


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
Screening

Cycles 1 through Cycle 8

Predose AZD4573 (within 72 hours prior to infusion)

Cycles 9+ on Day 1 of each Cycle

Predose AZD4573 (within 72 hours prior to infusion)

30-Day SFU
Lipase/amylase tests do not need to be repeated before first dose if the first-dose visit is within 
3 days of the Screening sample.
TLS monitoring will include: potassium, calcium, phosphate, uric acid, and creatinine.
TLS monitoring will be performed at the following timepoints:

Cycle 1, Weeks 1 through 3

Predose AZD4573

6 hours (± 30 minutes) after the start of the infusion

24 hours (± 1 hour) after the start of the infusion (and prior to acalabrutinib dosing)
Participants showing signs of clinical or laboratory TLS at 6 hours after the start of the 
infusion must be admitted for in-patient TLS monitoring for a minimum of 24 hours after the 
start of the infusion and monitored every 4 to 6 hours during this time (or more frequently if 
clinically indicated).
For each TLS monitoring timepoint, a TLS Monitoring page in the eCRF is to be filled out.
Hepatitis serology will be conducted at Screening. Hepatitis serology must include hepatitis 
B surface antigen (HbsAg), hepatitis B surface antibody (anti-HBs), anti-HBc, and hepatitis C 
(HCV) antibody. Participants who are anti-HBc positive, or have a known history of hepatitis 
B virus (HBV) infection, should be monitored every 3 months with a quantitative PCR test for 
HBV DNA (Section 17.1.10.4). In addition, any participants testing positive for any hepatitis 
serology must have PCR testing for verification purposes.
Pregnancy: a sample for a pregnancy test will be collected from all female participants of 
childbearing potential at:

Screening (serum)

Cycle 1, Week 1


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
Predose

Cycles 2+ once every 21 days (± 7 days) prior to initiating a new cycle

30-day SFU visit
Pregnancy tests after Screening may be serum or urine. Urine β-hCG and quantitative serum 
β-hCG tests are permitted. If a urine β-hCG test is positive or indeterminate, quantitative 
serum β-hCG will be performed for confirmation. Additional testing may be performed at 
Investigator discretion, for example in the event of suspected contraception failure.
Liver chemistry tests: For any participant on study who experiences elevated ALT /AST 
≥ 3 × ULN and/or elevated total bilirubin ≥ 2 × ULN: repeated liver chemistry tests (INR, 
fibrinogen, D-dimer [where available at institution], ALP, ALT, AST, GLDH, CPK, total 
bilirubin, direct bilirubin, indirect bilirubin) are required at 48 hours (-2/+12 hours) and 96
hours (-2/+12 hours) after the start of the infusion and every 48 hours (-2/+12 hours)  
thereafter until resolution of the event. If an event is not resolved within 96 hours the medical 
monitor shall be contacted. If GLDH cannot be performed locally, LDH will be analysed 
locally and a serum sample must be collected for central retrospective GLDH analysis. Refer 
to the Laboratory Manual for details.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets PHL 
criteria at any point during the study. The Investigator participates, together with the Sponsor, 
in review and assessment of these cases. Hy’s Law (HL) criteria are met if there is no 
alternative explanation for the elevations in transaminases and total bilirubin levels.
If an unscheduled ECG is done at any time: troponin and an electrolyte panel* must be done 
to coincide with the ECG testing.
* can include: sodium, calcium, potassium, chloride, phosphate, magnesium.
If a participant is assessed as meeting PHL criteria, please refer to Appendix E.
CMV: All subjects will have CMV testing at Screening including serology testing for CMV 
immunoglobulin (Ig)G and CMV IgM and CMV DNA PCR testing. Subjects must have a 
negative result for CMV DNA PCR such that CMV DNA is not detected by PCR at Screening, 
to be eligible for the study. The Screening CMV serologies will be advisory only, to guide 
investigators in assessing the risk of new infection or reactivation of CMV while on study.
17.1.7
Other Safety Assessments


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Monitoring for TLS per the SoA (Section 10.2) and prophylaxis for TLS are outlined in detail 
in Section 17.1.10.10.
Blood samples for 
 will be collected per the SoA (Section 10.2) and as 
outlined in Section 17.9.6.
Additional safety assessment requirements include:

Echocardiograms (ECHOs): In addition to Screening, an ECHO should be done within 
14 days after an abnormal ECG finding (eg, T-wave inversion/flattening) or as soon as 
possible when clinically indicated. If an ECHO cannot be taken, a multigated acquisition 
(MUGA) scan to assess left ventricular ejection fraction (LVEF) will be done. In case of 
any T-wave abnormality, the ECHO (or MUGA) should be repeated at the 30-day SFU 
visit to address the question of recovery, during the off-treatment period.

CD4, CD8, CD19, CD16/NK cell count and serum immunoglobulins (IgA, IgM, IgG)

Screening

Day 1 of Cycles 2, 4, 7, 9, 13, 16, 19
o
Predose

Every 6 months thereafter (predose)

30-Day SFU
17.1.8
Electrocardiograms (ECGs)
Twelve-lead ECGs will be obtained after the participant has been resting semi-supine for at 
least 10 minutes before the times indicated. All ECGs should be recorded with the participant 
in the same physical position where possible.
If an abnormal ECG finding at Screening or baseline is considered to be clinically significant 
by the Investigator, it should be reported as a concurrent condition. If a clinically significant 
abnormal ECG finding occurs on study, contact the Medical Monitor.
Single ECGs will be collected for local and central analysis at the following timepoints:

Screening

Cycle 1, Weeks 1 through 5 and Cycle 2, Day 1:

Predose (at the day of infusion prior to infusion)

End of infusion (within 30 minutes of end of infusion)

Cycles 3+, Day 1 of each cycle:
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
Within 30 minutes after the end of infusion

30-Day SFU
Any abnormal finding in the ECG tracing will be evaluated by the Investigator and will be 
specifically documented and registered in the eCRF. Throughout the study, clinically relevant 
new findings or worsening of a pre-existing finding in the ECGs (parameters or abnormal 
findings in the tracing) must be considered an AE and must be recorded in the AE CRF form.
If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, 
potassium) and troponin I/troponin T must be done to coincide with the ECG testing. Note: 
either a troponin I or troponin T assay can be used per SoC at the respective hospital. If the 
hospital has both a SoC troponin I and troponin T assay available, the investigator shall use 
only one consistently for the duration of the study.
17.1.9
Follow-up
17.1.9.1
30-day SFU Visit
An SFU visit will be performed 30 (± 7) days from the time that both study drugs are 
permanently discontinued (see the SoA [Section 10.2]). Tumour assessments will be repeated 
at this visit if they have not been performed within 9 weeks if the participant discontinued 
before Week 53, or 12 weeks if the participant discontinued after Week 53.
17.1.9.2
Long-term Follow-up Visits
Participants who discontinue both study drugs before documented disease progression will be 
followed according to SoC until documented disease progression or the start of new anti-
cancer therapy. Disease progression or start of new anti-cancer therapy will be captured in the 
eCRF. During this period, only information on any SAEs considered related to IP or study 
procedures will be collected. If a participant is unable to attend site for this visit, the long-term 
follow-up may be performed via phone call. Long-term follow-up visits will cease at disease 
progression or start of a new anti-cancer therapy, whichever comes first. The long-term 
follow-up will not apply to participants who withdraw consent or are lost to follow-up.
17.1.9.3
Survival Follow-up
All participants will be followed for survival until death, loss to follow-up, AstraZeneca closes 
the study, or withdrawal of consent, whichever occurs first. Participants will be followed for 
survival by telephone calls or clinic visits approximately every 3 months. Site personnel will 
attempt to collect the vital status of the participant within legal and ethical boundaries for all 
participants who received investigational product. Public sources may be searched for vital 
status information. If vital status is determined as deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be involved in 


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any attempts to collect vital status information. During this period, information will be 
collected in the eCRF on survival status and any new anti-cancer therapies, and on any SAEs 
considered related to study drug(s) or study procedures. 
The follow-up calls/clinic visits for survival should occur every three months, starting 3 
months after end of treatment/discontinuation (ie, 3/6/9/12 months after treatment). In case a 
shorter/longer interval between two follow-up calls occurs the frequency should return to the 
multiple of 3 months after treatment (eg, 3/6/9/12 months after treatment and so on). 
In preparation for an analysis, survival calls will be made in the week following the data-cut-
off for the analysis. 
17.1.10
Prevention and Management of Safety Concerns for AZD4573 in 
Combination with Acalabrutinib
This section provides recommendations for treatment of potential toxicities associated with 
acalabrutinib, or the combination of AZD4573 with acalabrutinib, and guidance about 
modifying the doses of acalabrutinib and AZD4573 due to those toxicities. For complete 
safety information refer to 
 and Calquence United
States Prescribing Information.
Generally, Grade 1 or 2 non-haematological and/or haematological toxicities do not require 
AZD4573 or acalabrutinib dose reductions and should be managed as medically indicated 
(with or without short dose interruptions) by the treating physician. Grade 3 and 4 toxicities 
require dose modifications, temporary treatment interruptions, or discontinuation of AZD4573 
and acalabrutinib. These are described in Table 13 and Table 14.
17.1.10.1
Headache
Headache is an identified risk for acalabrutinib. Participants with headache should be 
managed per institutional guidelines with supportive care and diagnostic evaluations as 
clinically indicated.
Note: encouraging adequate hydration for participants experiencing headaches has anecdotally 
been helpful in some cases.
17.1.10.2
Diarrhoea
Diarrhoea is an identified risk for AZD4573 and acalabrutinib. Participants with diarrhoea 
during therapy should be managed per institutional guidelines with maximal supportive care 
and diagnostic evaluations as clinically indicated. After excluding infectious aetiologies, 
symptomatic management should be considered. Participants experiencing prolonged or 
severe diarrhoea should be closely monitored and managed as appropriate if dehydration 
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and/or electrolyte abnormalities are observed. Participants should be made aware of the risk of 
possible overlapping toxicities of diarrhoea while receiving combination study treatments.
Prophylaxis for diarrhoea with atropine is strongly recommended for all participants enrolled 
into the study as an anti-cholinergic drug, administered at 0.5 mg subcutaneously 15 to 30 
minutes prior to all scheduled AZD4573 infusions. In the event of multiple episodes of 
diarrhoea despite atropine prophylaxis, one additional atropine dose may be considered and 
administered as outlined above.
In addition, in the event of diarrhoea, participants should remain fully hydrated with additional 
IV fluids.
17.1.10.3
Nausea and Vomiting
Nausea and/or vomiting are identified risks for AZD4573 and acalabrutinib. Participants with 
nausea and/or vomiting during therapy should be managed per institutional guidelines with 
maximal supportive care and diagnostic evaluations as clinically indicated. Participants 
experiencing prolonged or severe vomiting should be closely monitored and managed as 
appropriate if dehydration and/or electrolyte abnormalities are observed. Participants should 
be made aware of the risk of possible overlapping toxicities of nausea and vomiting while 
receiving combination study treatments.
Nausea and vomiting are considered important identified risks for AZD4573. Events of nausea 
and vomiting have been observed in approximately half of all participants dosed with 
AZD4573 and have occurred at all dose levels tested to date (except 3 mg). Prophylaxis with a 
5-HT3 antagonist (eg, ondansetron ± dexamethasone) has been implemented in the Phase I 
study (D8230C00001) to help alleviate this toxicity.
Therefore, prophylaxis for nausea and vomiting is recommended as follows: administer 
dexamethasone 8 mg (IV administration preferable but orally also permitted) plus a 5-HT3 
antagonist (e.g. ondansetron initially 8 mg to be taken before treatment, then 8 mg every 
12 hours for up to 3 days) as anti-emetics for all participants, approximately 30 to 60 minutes 
prior to all scheduled AZD4573 infusions. Additional doses of dexamethasone 8 mg may be 
administered if deemed clinically warranted. In addition, in the event of vomiting, participants 
should remain fully hydrated with additional fluids. Participants experiencing prolonged or 
severe nausea and vomiting should be closely monitored and managed as appropriate if 
dehydration and/or electrolyte abnormalities are observed.
17.1.10.4
Hepatitis B Reactivation
Serious or life-threatening reactivation of viral hepatitis have been reported in participants 
treated with acalabrutinib. Therefore, participants who are anti-HBc positive, or have a known 
history of HBV infection, should be monitored every 3 months with a quantitative PCR test 


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for HBV DNA. Monitoring should continue until 12 months after last dose of acalabrutinib. 
Any participant with a rising viral load (above lower limit of detection) should discontinue 
acalabrutinib and have antiviral therapy instituted and a consultation with a physician with 
expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming 
acalabrutinib in participants who develop HBV reactivation.
17.1.10.5
Progressive Multifocal Leukoencephalopathy (PML)
Cases of PML have been reported in participants treated with acalabrutinib. Signs and 
symptoms of PML may include cognitive and behavioural changes, language disturbances, 
visual disturbances, sensory deficits, weakness, and coordination and gait difficulties.
If PML is suspected, hold further treatment with acalabrutinib until PML is excluded. A 
diagnostic evaluation may include (but is not limited to):

Neurologic consultation

Brain magnetic resonance imaging (MRI)

PCR analysis for John Cunningham (JC) virus DNA in cerebrospinal fluid
If PML is confirmed, permanently discontinue acalabrutinib.
17.1.10.6
Haemorrhage
Bleeding events, some fatal, including CNS, respiratory, and gastrointestinal haemorrhage, 
have been reported in participants treated with acalabrutinib. Participants receiving antiplatelet 
or anticoagulant therapies may be at increased risk of haemorrhage and should be monitored 
for signs of bleeding. Should participants require either a vitamin K antagonist or combined 
administration of antiplatelet and therapeutic anticoagulation while on study, acalabrutinib 
treatment must be discontinued. As a precaution, it is suggested per protocol that acalabrutinib 
be withheld for at least 3 days pre- and post-surgery. Participants should be made aware of the 
risk of possible overlapping toxicities of haemorrhage while receiving both study treatments. 
Participants with haemorrhage should be managed per institutional guidelines or as clinically 
indicated. Coagulation should be monitored regularly as per the SoA. Avoidance of ibuprofen 
is advised.
17.1.10.7
Infections
Serious infections, including fatal events, have been reported in participants treated with 
acalabrutinib. Infection is an important potential risk for AZD4573 and an important identified 
risk for acalabrutinib. Participants should be made aware of the risk of possible serious 
infections while receiving combination study treatments. Investigators should be vigilant for 
signs of infection, especially opportunistic or fungal infections, and the possibility of hepatitis 


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B reactivation. Infections should be managed as per standard clinical practice. In case of 
Grade 3 infections, the guidelines provided in Table 13 should be followed.
17.1.10.8
Cytopenia
Haematological toxicities including neutropenia, anaemia, and thrombocytopenia have 
occurred in participants treated with acalabrutinib. Neutropenia is an important identified risk 
for participants treated with AZD4573 or acalabrutinib. Cytopenia should be considered an 
overlapping toxicity for AZD4573 and acalabrutinib. In the presence of CTCAE Grade 3/4 
neutropenia/leucopoenia/thrombocytopenia/anaemia, participant’s blood counts should be 
monitored, using local laboratories, at least every 48 hours until recovery.
In the clinical setting to date, Grade 3/Grade 4 neutropenia (~ 45% to 50%) has been observed 
in several participants with an onset around 24 hours after dosing AZD4573 monotherapy. 
Usually, neutrophils recovered spontaneously even without G-CSF.
Colony-stimulating factors including G-CSF, or pegylated G-CSF have been shown to work 
rapidly and may be used according to each Investigator site’s institutional guidelines. 
Anti-infective prophylaxis including anti-fungal prophylaxis should be used according to 
institutional guidelines. Antiviral or cotrimoxazole prophylaxis may not be used unless CD4 
helper cell counts are less than 100 to 200 per microlitre.
Primary prophylaxis with G-CSF is not generally recommended. Anti-infective prophylaxis 
(antibiotics and antifungals) should be given in accordance with local hospital and 
International National Comprehensive Cancer Network (NCCN)/European Society for 
Medical Oncology (ESMO)/American Society of Clinical Oncology (ASCO) guidelines.
Please refer to Table 13 for dose modifications due to haematological toxicities.
If the table indicates that the acalabrutinib dose should be reduced and the participant is 
already on 100 mg/day (see Table 12), acalabrutinib should be discontinued.
17.1.10.9
Liver Chemistry Test Abnormalities and the Risk of Liver Injury
Transaminase elevations are an important potential risk for patients treated with acalabrutinib, 
and an important identified risk for participants treated with AZD4573. Reactivation of 
hepatitis B infection has been observed in patients treated with acalabrutinib. Participants
should be made aware of the risk of possible overlapping toxicities of transaminase elevations 
while receiving both drugs. Evidence of abnormal liver chemistry should be monitored as per 
the protocol guidelines. Increased levels of AST, ALT, or serum bilirubin should trigger an 
investigation of the cause, which may include viral infection or disease progression with liver 
infiltration. The Investigator should consider whether the abnormal liver chemistry meets the 
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Bilirubin increase with transaminase increase is included as an important identified risk for 
AZD4573. Biochemical changes of increased transaminases with concomitant increase in 
bilirubin fulfilling criteria for Hy's law have been observed in participants treated with
AZD4573. These events resolve rapidly and have to date not been associated with any adverse 
clinical sequelae or lasting liver damage. Upon rechallenge with AZD4573, there is no 
consistent pattern of recurrence, nor is there any consistent increase in severity of the events. 
As such, while the events follow the biochemical definition of Hy's law, the clinical pattern is 
rapidly self-limiting and does not seem to predict any lasting liver damage.
Participants who experience elevated ALT/AST ≥ 3 × ULN and/or elevated total bilirubin ≥ 2 
× ULN after AZD4573 dosing must be closely monitored with repeated liver chemistry tests 
(INR, fibrinogen, D-dimer [where available at institution], ALP, ALT, AST, GLDH (if a 
GLDH test cannot be performed at the site or locally, LDH will be sufficient), CPK, total 
bilirubin, direct bilirubin, indirect bilirubin) are required at least every 48 hours (-2/+12 hours) 
after the start of the infusion and until resolution of the event. 
 
 will also be collected (see Section 17.9.6).
If bilirubin fails to resolve within 96 hours (-2/+12 hours) or transaminases fail to resolve 
within 7 days, or if the event is associated with significant clotting abnormality or clinical 
symptoms of liver disease, study treatment must be permanently discontinued (the participant
remains on study for the 30-day SFU and long-term follow-up [LTFU] visits), and the event 
must be immediately communicated to AstraZeneca.
For guidance on treating liver toxicity, please refer to Table 14 of this protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets PHL 
criteria at any point during the study.
Please refer to Appendix E for the process to be followed to identify and appropriately report 
cases of PHL. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries.
The Investigator will participate, together with the Medical Monitor, in review and assessment 
of PHL events to agree whether HL criteria are met. HL criteria are met if there is no 
alternative explanation for the elevations in liver biochemistry.
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
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Regarding the hepatic toxicity events encountered to date with AZD4573, it has been observed 
that while the biochemical changes of increased transaminase with concomitant elevation in 
bilirubin seen in some participants could be classified as HL by its strict definition, they do 
not follow a pattern that is consistent with true HL predictive of hepatic injury, and are 
therefore ‘PHL’ cases. The events are rapidly resolved and to date have not led to any clinical 
sequelae or lasting hepatic injury. Repeated dosing with AZD4573 following these events has 
demonstrated that there is no consistent pattern of recurrence and no consistent increase in 
severity of the events if they do recur.
Available transcriptomic and clinical pathology data from the Phase I, FTIH study of 
AZD4573 monotherapy (D8230C00001) suggest the presence of an acute phase response in 
participants showing signs of liver injury. Thus, anti-inflammatory prophylaxis with steroids 
(eg, dexamethasone) could be expected to have a beneficial effect on incidence and severity of 
adverse effects on the liver related to AZD4573.
While, in the absence of a suitably-sized control group without prophylactic steroid 
administration, there is no confirmatory evidence for a positive effect of dexamethasone on 
liver safety profiles from available Phase I clinical data as yet, assessment of ALT changes 
from baseline versus cumulative dexamethasone dose suggests a possible trend towards a 
negative correlation, ie, higher dexamethasone doses being associated with smaller increases 
in ALT post-baseline.
17.1.10.10 Tumour Lysis Syndrome (TLS)
Tumour lysis syndrome is an important identified risk for AZD4573 and an identified risk for 
acalabrutinib. TLS prophylaxis is mandatory for all participants starting 3 days before the 
first dose of AZD4573, which should be followed in addition to institutional guidelines.
Tumour lysis syndrome is characterised by the rapid and/or massive release of intracellular 
constituents (potassium, phosphorus and nucleic acids that can be metabolised to uric acid) 
following tumour cell lysis, resulting in life-threatening complications including acute kidney 
injury, arrhythmias, and neurological complications. While TLS can be seen in solid tumours, 
it is most prevalent in haematological malignancies, particularly bulky, chemosensitive 
diseases such as AML. Prevention and management of TLS is dependent on risk stratification, 
and risk-based prophylaxis and management (Howard et al 2011). Participants identified with 
TLS potential per published risk guidelines (Coiffier et al 2008; Table 16) should be provided 
with adequate hydration, pharmacological pre-treatment with allopurinol or rasburicase, and 
be carefully monitored for development of TLS.
Instructions for TLS prophylaxis are presented in Section 17.1.10.10.1, instructions for 
management of hydration are presented in Section 17.1.10.10.2, and instructions for 


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monitoring and maintenance of TLS are presented in Section 17.1.10.10.3. The Howard 
modification of Cairo-Bishop criteria for clinical and laboratory TLS are included in 
Appendix F.
Laboratory or clinical TLS (please refer to Appendix F for definitions) may trigger dose 
modification in accordance with guidelines provided in Table 13.
17.1.10.10.1 TLS Prophylaxis
Tumour lysis syndrome prophylaxis is mandatory for all patients starting 3 days before the 
first dose of AZD4573. TLS prophylaxis is mandatory for all infusions as outlined below in 
Table 16, which provides TLS prophylaxis guidance that should be followed in addition to 
institutional guidelines. In the event of a discrepancy between the protocol guidelines for the 
management of TLS and the institutional guidelines of a given Investigator/centre, the 
Investigator should discuss with the Medical Monitor.
In addition to the criteria outlined in Table 16 below, any patient with creatinine clearance 
(CrCL) < 80 mL/min must be considered at higher risk of developing TLS and managed 
appropriately.
TLS prophylaxis/management with rasburicase/allopurinol and IV fluid is permitted at any 
time during screening and treatment, however rasburicase and allopurinol must not be 
co-administered (Howard et al 2011; Howard et al 2016; Jones et al 2015).


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Table 16
Mandatory TLS Prophylaxis Guidance (in Addition to Institutional 
Guidance)
Type of Cancer
Intermediate/High Risk
NHL
DLBCL OR
Any LN ≥5 cm
Prophylaxis
Hydrationa
Oral (1.5-2.0 L/day) plus additional IV fluid: Normal saline 500 mL over 2-4 h prior to 
AZD4573, then 100-175 mL/h as tolerated to maintain urine output
Antihyperuricemics
Allopurinol 300 mg orally QD beginning 3 days prior to AZD4573 and continuing at 
least through the end of Week 1b.
Consider prophylactic rasburicasec if baseline uric acid is elevated above ULNd, LDH 
> 2 × ULN, or high tumour burden/leukemic cells
a
Administer more aggressive IV fluid hydration for any patient who cannot tolerate or maintain oral 
hydration.
b
Administration of allopurinol should not be stopped at the end of Week 1, however the dose or frequency of 
administration may be reduced after discussion with the Medical Monitor.
c
The recommended dose for rasburicase is 0.20 mg/kg IV over 30 minutes. Rasburicase is contraindicated in 
patients with G6PD deficiency, so patients at higher risk for G6PD deficiency (eg, African or 
Mediterranean ancestry) should be screened for this condition prior to starting rasburicase. Rasburicase and 
allopurinol must not be co-administered.
d
Uric acid levels should be < ULN before each dosing of AZD4573.
Notes: Adequate supportive therapy as per institutional guidelines should be given for all toxicities.
TLS prophylaxis/management with rasburicase/allopurinol and IV fluid is permitted at any time during screening 
and treatment. Rasburicase and allopurinol must not be co-administered.
Abbreviations: DLBCL = diffuse large B-cell lymphoma; G6PD = glucose-6-phosphate dehydrogenase; 
IV = intravenous; LDH = serum lactate dehydrogenase; LN = lymph node; NHL = non-Hodgkin lymphoma; 
QD - once daily; TLS = tumour lysis syndrome; ULN = upper limit of normal.
Modified from Coiffier et al 2008.
17.1.10.10.2 Management of Hydration
Adequate fluid intake for all patients enrolled into the study is mandatory, in particular, around 
the times of AZD4573 dosing.
All patients are mandated to receive IV fluid hydration with normal saline (NaCl 0.9%). For 
patients at intermediate or high risk for TLS, normal saline 500 mL should be administered 
over 2 to 4 hours prior to AZD4573 and then continued at a rate of 100 to 175 mL/h as 
tolerated to maintain urine output.
In case of diarrhoea/nausea/vomiting, more aggressive IV fluid hydration may be needed as 
clinically indicated. Patients are also encouraged to drink enough fluid before and after each 
dosing. Please use diuretics carefully, do not use them prophylactically, only if patients have 
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17.1.10.10.3 TLS Prophylaxis, Monitoring, and Management
Please refer to Appendix F for definitions of the Howard modification of Cairo-Bishop criteria 
for clinical and laboratory TLS.
All patients will receive TLS prophylaxis during the intra-patient ramp up and be monitored
for TLS during the first 24 hours post start of dose. Monitoring for TLS includes checking 
potassium, calcium, phosphate, uric acid, and creatinine. Fluid balance must be monitored 
according to institutional standards.
Patients will be required to be monitored for TLS for up to 24 hours post dose until they have 
received at least one AZD4573 dose at the target dose level (ie, for at least the first 
3 AZD4573 once-weekly doses). If a patient has no signs of laboratory TLS at the 6-hour TLS 
monitoring assessment, the patient may leave the clinic after the collection of other laboratory 
samples, as per the SoA, at 7 hours after the start of the infusion and managed as an 
outpatient, at the discretion of the Investigator. These patients must  return to the clinic the 
next morning to complete the 24 hour TLS monitoring period as per the SoA (Cycle 1 Weeks 
1-3). Patients with TLS at the 6-hour TLS monitoring assessment must be admitted for in-
patient TLS monitoring for a minimum of 24 hours after the start of the infusion and 
monitored every 4 to 6 hours during this time (or more frequently if clinically indicated).
Sites retain the option to hospitalise patients based on clinical judgement, despite normal TLS 
laboratory results 6 hours after the start of the infusion. Admitting the patient for subsequent 
dose administrations will be done at Investigator discretion.
Any hospitalisation due to occurrence of an AE must be reported as an SAE, per definition. 
However, if hospitalisation is purely for the purposes of extended observation then this does 
not qualify as an SAE and does not need to be reported.
For all patients, results of safety laboratory testing (haematology and clinical chemistry at a 
minimum) must be available within 72 hours prior to dosing and must be reviewed by the 
Investigator prior to each administration of AZD4573.
In particular, the uric acid level must be < ULN prior to the start of each AZD4573 infusion.
It is strongly recommended that for all patients with elevated uric acid (hyperuricaemia) and 
intermediate/high risk of TLS, rasburicase (0.20 mg/kg/d IV over 30 minutes) should be 
administered as prophylaxis prior to AZD4573 and repeated as clinically indicated thereafter 
as per local standard.
NOTE: If hyperuricaemia is present at Screening and/or during intra-patient ramp up, 
SoC therapy for hyperuricaemia should be administered (including IV fluid and 


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rasburicase or allopurinol) to reduce the uric acid levels to < ULN before each 
administration of AZD4573. Rasburicase and allopurinol must not be co-administered.
Any patient developing laboratory TLS must be treated promptly for electrolyte abnormalities 
(such as hyperkalaemia) to prevent arrhythmias/seizures and for elevated uric acid 
(hyperuricaemia) with rasburicase (0.20 mg/kg/d IV over 30 minutes for up to 5 days) to 
prevent acute renal failure and monitored closely for signs of progression to clinical TLS.
If these measures are inadequate, then haemodialysis represents definitive therapy and 
should be initiated promptly.
Any patient with hyperkalaemia should receive cardiac monitoring with continuous telemetry 
for ECG changes associated with potentially life-threatening arrhythmias.
Patients with TLS or suspicion of TLS will remain in hospital to undergo additional 
investigations until the TLS has resolved.
In patients at high risk of TLS based on high tumour burden/bulky disease (> 10 cm), high 
proliferation rate (LDH > 2 x ULN), and/or impaired renal function (Coiffier et al 2008), 
24-hour hospitalisation for TLS monitoring is recommended during the intra-patient ramp up.
17.1.10.11 Second Primary Malignancies
Second primary malignancies, including non-skin cancers, have been reported in patients 
treated with acalabrutinib. The most frequent second primary malignancy was skin cancer 
(squamous cell carcinoma of the skin). Monitor patients for the appearance of skin cancers. If 
a patient develops a second primary malignancy (other than non-melanoma skin cancer), 
discontinue acalabrutinib. Patients with a second primary malignancy should be managed 
according to institutional guidelines with diagnostic evaluations as clinically indicated.
17.1.10.12 Atrial Fibrillation/Flutter and Sinus Tachycardia
Atrial fibrillation/flutter have been reported in patients treated with acalabrutinib. Atrial 
fibrillation has also been observed in patients treated with AZD4573, although positive 
causality has not been established.
17.1.10.13 Infection/Bone Marrow Toxicity with Peripheral Effect / Lymphoid Tissue 
Hypocellularity
Infection/bone marrow toxicity with peripheral effect/lymphoid tissue hypocellularity is an 
important potential risk for AZD4573, based on findings in preclinical studies. Severe 
infection is considered as an important risk with the combination therapy (Section 17.1.10.7).
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As observed in preclinical studies, this important potential risk refers to haematological 
changes (decreased platelets, red blood cell count/haematocrit, reticulocytes, neutrophils, 
lymphocytes) that may be/may not be accompanied by secondary infections.
AEs of thrombocytopenia should be managed as deemed appropriate by the Investigator as per 
standard institutional guidelines and in some cases, management of thrombocytopenia may
require platelet transfusions, again these should be done according to local hospital guidelines. 
If indicated, transfusions or growth factors can be administered during the screening period, 
but such cases of deterioration of haematological function must be discussed with the Medical 
Monitor, to confirm start of study treatment.
Common treatable causes of anaemia (eg, iron, vitamin B12, or folate deficiencies and 
hypothyroidism) should be excluded. In some cases, management of anaemia may require 
blood transfusions which should be given as per local institutional guidelines.
17.1.10.14 Pancreatic and Cortical Adrenal Injury (as well as Surveillance for Renal, 
Thymus, and Spleen Toxicity)
Pancreatic injury and cortical adrenal injury are potential risks for AZD4573 based on 
preclinical observations, however, to date, there are no clinical data suggestive of these risks, 
but safety surveillance will continue.
Regular complete blood counts, clinical chemistry and coagulation tests will be performed 
throughout the conduct of the study to monitor for any abnormal laboratory parameters, for 
example; monitoring of lipase and amylase levels for potential pancreas toxicity, creatinine 
values and regular urinalysis testing for kidney function, potassium, sodium, cortisol levels 
along with adrenocorticotropic hormone levels for adrenal glands and thyroid-stimulating 
hormone (TSH) for any thyroid toxicity.
17.1.10.15 Drug-Drug interactions
Specific drug-drug interaction studies have not yet been performed for AZD4573. For 
guidance please refer to Section 15.11.
Acalabrutinib may be affected by agents that reduce gastric acidity (antacids or proton-pump 
inhibitor). Acalabrutinib is not a strong direct inhibitor or inducer of CYP isoforms and is 
therefore unlikely to perpetrate drug-drug interactions through affecting CYP isoforms 
(see Section 15.11).
17.1.10.16 Myocardial Ischaemia and Heart Rate Increased
Myocardial ischaemia and heart rate increased are considered potential risks for AZD4573. 
There has been an isolated case report of possible myocardial infarction in association with 
AZD4573, but positive causality could not be established. The same patient experienced heart 


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rate increase during the event of ST-segment elevation myocardial infarction. A thorough 
evaluation of all participants dosed to date has not revealed any further cases suggestive of 
myocardial ischaemia or other cardiovascular toxicity causally related to AZD4573 
administration.
Safety surveillance related to this potential toxicity will include ECG and 
troponin I/troponin T measurements for all patients as described in the SoA (Section 10.2). 
ECG and troponin I/troponin T measurements must be performed for all patients who develop 
symptoms suggestive of myocardial ischaemia. Note: either a troponin I or troponin T assay 
can be used per SoC at the respective hospital. If the hospital has both a SoC troponin I and 
troponin T assay available, the investigator shall use only one consistently for the duration of 
the study.
17.1.10.17 Management of Other Events: Infusion Site Reactions
As with other drugs administered intravenously, local infusion site reactions (eg, infusion 
pain, infusion site reaction, skin or vein irritation) may occur and these can be managed 
according to local institutional guidelines. Implantable port insertions (eg, Portacath) may be 
considered.
17.2
Adverse Events and Serious Adverse Events
A formal assessment of AEs will occur at the visits marked in the SoA (Section 10.2), but AEs 
reported at any time during the study must also be recorded in the eCRF.
Please refer to Section 8.2.
17.2.1
Adverse Events of Special Interest for Acalabrutinib
The following events are Adverse Events of Special Interest (AESIs) for acalabrutinib and 
must be reported to the Sponsor expeditiously, irrespective of regulatory seriousness criteria or 
causality:

Ventricular arrhythmias (eg, ventricular extrasystoles, ventricular tachycardia, ventricular 
arrhythmia, ventricular fibrillation)
Adverse events of special interest for AZD4573 are described in Section 8.2.11.
17.3
Overdose
Please refer to Section 8.3 for general information and information related to AZD4573.
An acalabrutinib overdose is defined as any dose that is higher than the investigated dose. For 
any patient experiencing an acalabrutinib overdose, observation for any symptomatic side 


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effects should be instituted, and vital signs, biochemical and haematological parameters 
should be followed closely (consistent with the protocol or more frequently, as needed). 
Appropriate supportive management to mitigate adverse effects should be initiated. If the 
overdose ingestion of acalabrutinib is recent and substantial, and if there are no medical 
contraindications, use of gastric lavage or induction of emesis may be considered.
17.4
Efficacy Assessments
All assessments of anti-tumour activity will be done by the investigators using standard 
response criteria as specified below (Table 18).
17.4.1
Disease Assessment Criteria
Disease staging at baseline for DLBCL and MZL will be done by a modified Ann Arbor 
classification system (Table 17; Cheson et al 2014). Response assessments will be done by the 
investigator using standard Lugano 2014 response criteria as specified in Table 18.
Table 17
Lugano Modification of Ann Arbor Staging System (for Primary Nodal 
Lymphomas)
Stage
Involvement
Extranodal (E) Status
Limited
I
One node or a group of adjacent 
nodes
Single extranodal lesions without 
nodal involvement
II
Two or more nodal groups on the 
same side of the diaphragm
Stage I or II by nodal extent with 
limited contiguous extranodal 
involvement
II Bulky
Whether stage II bulky disease is 
treated as limited or advanced 
disease may be determined by 
histology and a number of 
prognostic factors
II as above with “bulky” disease
Not applicable
Advanced
III
Nodes on both sides of the 
diaphragm; nodes above the 
diaphragm with spleen 
involvement
Not applicable
IV
Additional noncontiguous 
extralymphatic involvement
Not applicable
Note: Extent of disease is determined by PET-CT for avid lymphomas and CT for nonavid histologies. 
Tonsils, Waldeyer’s ring, and spleen are considered nodal tissue.
Abbreviations: CT = computed tomography; PET = positron emission tomography.
Reproduced from Table 2.


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Table 18
The Lugano Response Criteria for Non-Hodgkin’s Lymphoma
Response and Site
PET-CT-Based Response
CT-Based Response
Complete: 
Complete metabolic response: 
Complete radiologic response (all 
of the following): 
Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3a with or without a 
residual mass on 5PSb,c
It is recognised that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with activation 
within spleen or marrow (eg, with 
chemotherapy or myeloid colony-
stimulating factors), uptake may be 
greater than normal mediastinum 
and/or liver. In this circumstance, 
complete metabolic response may be 
inferred if uptake at sites of initial 
involvement is no greater than 
surrounding normal tissue even if the 
tissue has high physiologic uptake
Target nodes/nodal masses must 
regress to ≤1.5 cm in LDi 
No extralymphatic sites of disease
Nonmeasured lesion
Not applicable 
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow 
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if 
indeterminate, IHC negative
Partial:
Partial metabolic response: 
Partial remission (all of the 
following): 
Lymph nodes and 
extralymphatic sites
Score 4 or 5b with reduced uptake 
compared with baseline and residual 
mass(es) of any size
≥50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites
At interim, these findings suggest 
responding disease 
When a lesion is too small to 
measure on CT, assign 5 mm × 5 
mm as the default valve
At end of treatment, these findings 
indicate residual disease
When no longer visible 0 × 0 mm
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
Nonmeasured lesions
Not applicable
Absent/normal, regressed, but no 
increase 
Organ enlargement 
Not applicable
Spleen must have regressed by 
> 50% in length beyond normal
New lesions 
None
None


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


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Response and Site
PET-CT-Based Response
CT-Based Response
Extranodal lesions
New FDG-avid foci consistent with 
lymphoma at interim or 
end-of-treatment assessment
In the setting of splenomegaly, the 
splenic length must increase by 
> 50% of the extent of its prior 
increase beyond baseline (eg, a 
15 cm spleen must increase to 
> 16 cm). If no prior splenomegaly, 
must increase by at least 2 cm from 
baseline
New or recurrent splenomegaly
Nonmeasured lesions
None
New or clear progression of 
pre-existing nonmeasured lesions
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another 
aetiology (eg, infection, 
inflammation). If uncertain regarding 
aetiology of new lesions, biopsy or 
interval scan may be considered
Regrowth of previously resolved 
lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
a
The Lugano 2014 criteria are used in this study for disease assessment. In line with these criteria, it should 
be clarified that the study definition of CMR is a Deauville score 1-3.
b
A score of 3 in many participants indicates a good prognosis with standard treatment, especially if at the 
time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid under treatment). Measured dominant 
lesions: Up to 6 of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly 
measurable in 2 diameters. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid 
organs (eg, liver spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or those noted on 
palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of 
suspected disease that would be difficult to follow quantitatively with measurement, including pleural 
effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be 
confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone 
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but 
should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of 
chemotherapy of myeloid growth factors).
c
PET 5PS: 1, no uptake above background; 2, uptake ≤mediastinum; 3, uptake > mediastinum but ≤liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma.


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Abbreviations: 5PS = 5-point scale; CT = computed tomography; CMR = complete metabolic response; 
FDG = fluorodeoxyglucose; GI = gastrointestinal; IHC = immunohistochemistry; LDi = longest transverse 
diameter; MRI = magnetic resonance imaging; PET = positron-emission tomography; PPD = product of the 
perpendicular diameters; SDi = shortest axis perpendicular to LDi; SPD = sum of the product of the diameters.
Cheson et al 2014
17.4.2
Disease Assessment Schedule
Baseline tumour assessments will be performed using radiologic imaging by computed 
tomography (CT) with contrast and positron- emission tomograph (PET)-CT during the 
screening period. CT scans with contrast will cover neck, chest, abdomen, pelvis and any 
other disease sites; PET scans will cover the whole body from base of skull to mid-thigh.
Radiologic scans (ie, contrast CT) and PET scans will be performed as specified in Table 19, 
to confirm CR or as clinically indicated. Unscheduled radiologic scans may be performed at 
Investigator discretion if deemed clinically indicated.
Table 19
Radiologic Scans and PET Scans for Tumour Assessments
Timepoints
Required Radiologic Scansa
Screening
Contrast CT
PET
During studyb
After 8 weeks (~2 cycles)
Contrast CT
PET
After 17 weeks (~5 cycles)
Contrast CT
After 26 weeks (~8 cycles)
Contrast CT
PET
After 38 weeks (~12 cycles)
Contrast CT
After 50 weeks (~16 cycles)
Contrast CT
PET
After 62 weeks (~20 cycles)
Contrast CT
After 74 weeks (~24 cycles)
Contrast CT
PET
After 86 weeks (~28 cycles)
Contrast CT
After 98 weeks (~32 cycles)
Contrast CT
PET
Every 12 weeks (~4 cycles) 
thereafter until the end of the study
Contrast CT
Every 24 weeks (~8 cycles) 
thereafter until the end of the study
Contrast CT
PET
30-day Follow-up visitc
Contrast CT
PET
a
Following complete metabolic response, subsequent scheduled PET assessments are no longer mandatory.
b
Window of ± 1 week for all timepoints.
c
Tumour assessments will be repeated at this visit for discontinued participants if not previously performed 
within the required timeframe ie, 9 weeks for participants that discontinued before or during Week 26, and 
12 weeks for those that discontinued after Week 26.


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If a PET-CT is not available, an independent PET and a diagnostic quality CT scan (with 
contrast) can be used. If PET and CT scans are done on the same day, the PET must be 
performed prior to the contrast-enhanced CT not to compromise the PET read-out.
Post-screening, the CT portion of a PET-CT (without contrast) may replace a contrast CT per 
local institutional practice; however, certain radiographic requirements are needed for 
acceptance, as described in the Site Radiology Manual, provided separately from this protocol.
Where contrast CT is contraindicated or unobtainable, MRI or CT (without contrast) with 
diagnostic quality (sufficient resolution to allow bi-dimensional measurements) may be used 
instead. In cases where MRI is desirable, the MRI must be obtained at baseline and at all 
subsequent response evaluations.
Following complete metabolic response, subsequent scheduled PET assessments are no longer 
mandatory. For participants 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.
All response assessments will be made by the Investigator. All images for the assessment of 
response will be collected and stored for central review.
Participants should have radiographic tumour measurements done at the participating study 
centre or an acceptable alternate imaging facility using an identical imaging protocol and 
similar equipment. The same imaging equipment should be used for all scans whenever 
possible. The same radiologist should be assigned to read all the scans for a given participant 
throughout the study.
Participants who discontinue study intervention for reasons other than PD will continue to be 
scanned for disease response following the same schedule until documented PD, regardless of 
the start of new anti-lymphoma treatment.
17.4.3
Bone Marrow Assessments
For all patients, bone marrow biopsy and aspirate samples are required for local standard 
disease profiling (eg, immunohistochemistry, flow cytometry, cytogenetics, fluorescence in 
situ hybridisation [FISH]). Bone marrow biopsies/aspirates will be collected:

at Screening (before first dose of AZD4573)

during the study as part of disease assessment (Cheson et al 2014), when indicated

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If bone marrow/aspirate samples are collected on a AZD4573 dosing day, collection should 
preferably take place pre-infusion. If this is not possible, the collection should take place 
between 2 hours and 4 hours after the start of the infusion.
If a bone marrow biopsy/aspirate cannot be performed, the Investigator must document in the 
patient’s medical notes the reason why the procedure cannot be performed. Archival bone 
marrow biopsy/aspirate can replace the assessment performed at Screening if necessary, after 
discussion with the Sponsor’s Medical Monitor.
Bone marrow biopsies/aspirates will be read at each site’s local laboratory. The results will be 
entered into the eCRF.
 
17.4.4
Tumour Assessment
Initial disease assessments for DLBCL include:

Staging by Ann Arbor classification (Cheson et al 2014: see Table 17).

Physical exam: attention to node-bearing areas, including Waldeyer’s ring, and to size of 
liver and spleen.

Complete blood count, platelets, differential, chemistry profile, lactate dehydrogenase

Whole-body fluorodeoxyglucose (FDG)-PET/CT scan.

Brain imaging (MRI with contrast preferred). MRI of the brain will be performed at 
Screening only if there is a prior history of CNS involvement or if there are neurologic 
signs or symptoms present.

Bone marrow biopsy and aspirate (Section 17.4.1).
DLBCL response criteria: Lugano Response Criteria for Non-Hodgkin’s Lymphoma 
(Cheson et al 2014, see Table 18).
Baseline tumour assessments will be performed using radiologic imaging by CT with contrast 
and PET-CT covering neck, chest, abdomen, and pelvis within 30 days before the first dose of 
AZD4573 (Table 19). For participants 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. Unscheduled radiologic scans may be performed at 
investigator discretion if deemed clinically indicated. Magnetic resonance imaging may be 
used for imaging assessments if a contrast CT scan is contraindicated or unobtainable. In cases 
where MRI is desirable, the MRI must be obtained at baseline and at all subsequent response 
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evaluations.
For MZL patients with FDG-avid disease at baseline, disease response to study treatment will 
be based on both PET and CT-based criteria. For MZL patients with no FDG-avid disease at 
baseline, disease response to study treatment will be based CT-based criteria only. After the 
first year of treatment in MZL patients, Lugano tumour assessment with CT with contrast 
every 24 weeks is sufficient, and additional CT and PET assessments can be performed as 
clinically indicated.
Tumour assessments will be made for measurable disease, non-measurable disease, and new 
lesions on CT and combined with visual assessment of PET-CT for response assessment 
according to the revised response criteria for malignant lymphoma (Cheson et al 2014). 
See Table 19.
All response assessments will be made by the Investigator. All images for the assessment of 
response will be collected and stored for central review. Additional disease assessments may 
be performed as clinically indicated.
CT scans
Bi-dimensional measurements will be recorded for lymph nodes ≥1.5 cm in longest diameter 
in the eCRF. Up to a maximum of 6 dominant, measurable lymph nodal lesions should be 
assessed as target lesions. These nodes or masses should be selected according to all of the 
following: 

They should be clearly measurable in at least two perpendicular dimensions.

If possible, they should be from disparate regions of the body.

They should include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved.
The perpendicular long and short axis diameters will be measured and recorded in the 
transverse plane at baseline and follow-up. When appropriate, measurable extranodal disease, 
defined as extranodal lesions (eg, hepatic nodules) with the longest diameter ≥1.0 cm, may be 
included in the 6 representative, measured lesions. 
For the selected target lymph nodal lesions, the sum of the product of the perpendicular 
diameters will be calculated with the percentage change from baseline for assessment of 
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All other lesions (including nodal, extranodal, and assessable disease) should be followed as 
nonmeasured disease (eg, cutaneous, gastrointestinal, bone, spleen, liver, kidneys, pleural or 
pericardial effusions, ascites) and should be factored into overall response assessment.
Visual interpretation of PET-CT scans
The International Working Group criteria for reviewing PET scans were based on visual 
interpretation, using mediastinal blood pool as the comparator. The current recommendation is 
to use the 5-point scale (Cheson et al 2014).
Assessment of non-measurable lesions
An overall assessment for all other non-target lesions of present, absent, or present with 
progression will be recorded and factored into response assessment.
Assessment of new lesions
Appearance of any new lesions more than 1.5 cm in any axis during or at the end of therapy, 
even if all other lesions are decreasing should be considered progression.
Increased FDG uptake in a previously unaffected site should only be considered progression 
after confirmation with other modalities (eg, CT, MRI, or X-ray).
In patients with no history of pulmonary lymphoma, new nodules identified by CT are benign 
and should be considered negative for lymphoma. These lesions typically represent infectious 
or inflammatory lesions; therefore, if FDG positive, should not be considered positive for 
lymphoma in the absence of confirmatory tests, (eg, histology).
The presence or absence of new lesions will be recorded in the eCRF.
17.5
Human Biological Samples
Please refer to Section 8.5 for general information on collection and handling of biological 
samples.
17.6
Pharmacokinetics
Venous blood samples for determination of concentrations of AZD4573 and acalabrutinib and 
its metabolite ACP-5862 will be taken as the times presented below (see Section 10.2).
Samples for PK should be collected from the arm that is not used for the infusion where 
possible. If this is not possible, then separate lines should be used for drug infusion and 
sampling. If there is no other option than to use a central line (PICC-line) for drug 
administration/sample collection, it is mandatory this is a multi-lumen line. This information 
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from the one which is used for sample collection. The sample collection lumen needs to be 
flushed twice prior to collecting the sample. AZD4573 administration needs to be paused 
during the time the samples are collected to prevent sample contamination.
Sample collection date, time, and exact dosing will be recorded for both AZD4573 and 
acalabrutinib. Samples will be collected, labelled, stored, and shipped as detailed in the 
Laboratory Manual.
On the day of PK collection, acalabrutinib capsules should be brought to site by the patient 
and taken within 5 minutes before initiation of AZD4573. The actual date and time of 
AZD4573 and acalabrutinib dosing will be recorded.
If the patient, in error, takes acalabrutinib at home before coming to the site on the day of PK 
collection, PK sampling should be conducted at the timepoints listed according to AZD4573 
dose provided that the exact time of acalabrutinib dosing was recorded. If there is no record 
for acalabrutinib dosing, PK should not be collected.
Part A
Plasma samples for PK analysis will be taken at the following time points:

Cycle 1 of Weeks 1 to 3 and Cycle 2, Day 1

Predose (within 2 hours prior to AZD4573 and acalabrutinib administration)

1 hour (± 15 minutes) after the start of the infusion

2 hours (± 15 minutes) after the start of the infusion

4 hours (± 30 minutes) after the start of the infusion

7 hours (± 1 hour), after the start of the infusion

24 hours (± 1 hour) after the start of the infusion (and prior to acalabrutinib dosing)
The timing and frequency of the PK samples may be adjusted during the study, dependent on 
emerging data, to ensure appropriate characterisation of the plasma concentration-time 
profiles.
Part B
Plasma samples for PK analysis will be taken at the following time points:

Cycle 1 of Weeks 1 to 3 and Cycle 2, Day 1

Predose (within 2 hours before AZD4573 and acalabrutinib administration)

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
4 hours (± 30 minutes) after the start of the infusion
The timing of these samples may be adjusted dependent upon ongoing PK analysis and 
interpretation.
17.6.1
Determination of Drug Concentration
Samples for determination of AZD4573, acalabrutinib, and its metabolite ACP-5862 
concentrations in plasma will be analysed by Covance Laboratories on behalf of AstraZeneca, 
using appropriate validated bioanalytical methods. Full details of the analytical methods used 
will be described in a separate bioanalytical report.
All samples still within the known stability of the analytes of interest (ie, AZD4573) at the 
time of receipt by the bioanalytical laboratory will be analysed. Incurred sample 
reproducibility analysis or additional assay development work, if any, will be performed 
alongside the bioanalysis of the test samples. The results from the evaluation, if performed, 
will be reported in a separate bioanalytical report.
17.7
Pharmacodynamics
17.7.1
Collection of Samples (Part A and Part B)
Whole blood samples will be collected and immediately processed within 30 minutes on site 
for 
 
 
 
 
 
In addition, whole blood will be collected at limited timepoints to analyse pharmacodynamic 
readouts for acalabrutinib.
Pharmacodynamic (whole blood) samples will be collected at the following timepoints (see 
Section 10.2):
Pharmacodynamic Samples for AZD4573 
Part A

Cycle 1, Week 1 and Week 2:

Predose (within 2 hours prior to dosing)

2 hours (± 15 minutes) after the start of the infusion
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
4 hours (± 30 minutes) after the start of the infusion

24 hours (± 2 hours) after the start of the infusion (and prior to acalabrutinib dosing)

Cycle 1, Week 3:

Predose (within 2 hours prior to dosing)

2 hours (± 15 minutes) after the start of the infusion

4 hours (± 30 minutes) after the start of the infusion

7 hours (± 1 hour) after the start of the infusion

24 hours (± 2 hours) after the start of the infusion (and prior to acalabrutinib dosing)
Part B

Cycle 1, Weeks 1 to 3:

Predose (within 2 hours prior to dosing)

2 hours (± 15 minutes) after the start of the infusion

4 hours (± 30 minutes) after the start of the infusion

7 hours (± 1 hour) after the start of the infusion 

24 hours (± 2 hours) after the start of the infusion (and prior to acalabrutinib dosing)
Pharmacodynamic Samples for Acalabrutinib (whole blood) (Part A and B)

Cycle 1, Week 1 

Predose (within 2 hours prior to dose and prior to acalabrutinib dosing)

Cycle 1, Week 4

Predose (within 2 hours prior to dose and prior to acalabrutinib dosing)
 must be collected at each sample at each pharmacodynamics 
timepoint once patients have reached the target dose. Refer to instructions in the Laboratory 
Manual.
Note: The timing of these samples may be adjusted dependent upon ongoing PK and 
pharmacodynamic analysis and interpretation.
For storage, re-use and destruction of pharmacodynamic samples, please refer to  Appendix C.
Further details on sample processing, handling and shipment are provided in the Laboratory 
Manual.
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17.8
Exploratory 
 Samples (Part A and 
Part B)
 samples will be collected from all patients to assess exploratory 
 
These samples will be collected as per the timepoints in Section 10.2.
Table 20
 Sampling Schedule (All Patients)
Day
Timing for 
Window
Screening
At any screening visit
Not applicable
Cycle 1, Weeks 1-3
Predose
Within 2 hours before the start of 
the infusion
4 hours after the start of the infusion
± 30 minutes
7 hours after the start of the infusion
± 1 hour
24 hours after the start of the 
infusion
± 1 hour
 
48 hours after the start of the 
infusion
-2/+12 hours
96 hours after the start of the 
infusion
-2/+12 hours
Predose the following infusion
Within 4 hours before the start of 
the infusion
Each timepoint where chemistry 
panel testing is performed
N/A
Any visit from Cycle 1, Week 4 
onwards
 
 
Same schedule as Cycle 1, 
Weeks 1-3
N/A
For all patients, 
 samples will be collected during Cycle 1, Weeks 1 to 3. In addition, if 
a patient has 
 
samples should also be taken at 48 hours and 96 hours after 
the start of the infusion (-2/+12 hours), predose the following infusion (within 4 hours), and 
whenever chemistry panel testing is being performed, until resolution of the event.
 
 sampling should be performed using the timepoints at least at 48 hours and 
96 hours after the start of the infusion (-2/+12 hours) as outlined in Table 20 (excluding 
Screening sample).
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17.9
Exploratory Whole Blood Analyses Samples
By consenting to participate in the study, the patient consents to participate in the mandatory 
research components of the study.
Samples for 
 are required and will be collected from all patients.
Mandatory whole blood samples will be collected from all patients as per the schedule in 
Table 21 and the sections below.
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Table 21
Exploratory Whole Blood Analyses Samples (All Patients) - MODULE 1
Samples
Timepointsa
Screening
C1
Week 1
C1
Week 2
C1
Week 3
C1
W5
C2
D1
C2
D15
C3
D1
C5
D1
C6
D1
C7
D1
Tumour 
Assessment 
Scansb
EOTc
Pre
Post 
(2h)
24h
Pre
Post 
(2h)
24h
Pre
Post 
(2h)
24h
Pre
Pre
Pre
Pre
Pre
Pre
Pre
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
XB
X
X
X
X
X
X
X
X
X
X
X
X
X
X
XB
XB
XB
XB
XB
XB
XB
XB
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Timepoints include the following windows: pre-dose = within 2 h prior to dosing; post-dose = 2 h (± 15 min) after start of infusion, and 24h = 24 h(± 2 h) after 
start of infusion.
b
Every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion)
c
Disease progression/End of Treatment; if not collected at End of Treatment, the sample should be collected at the 30d Safety Follow-Up visit
d
e
f
g
h
Note: For all analytes, if a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
Abbreviations: B = Part B only; C1W5 = Cycle 1 Week 5; C2D1 = Cycle 2, Day 1; EOT= end of treatment; 
 
 post = post-dose; pre = pre-dose; 24h = 24 h after infusion; SFU = safety follow-up.
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17.9.1
Whole Blood for Exploratory 
 
 (Part A and B)
Mandatory whole blood samples to enable exploratory 
 
analysis will be collected as specified below. Note: Collection time begins with the start 
of the infusion.

Screening

Cycle 1, Weeks 1, 3, and 5:

Predose (within 2 hours prior to dosing)

Cycle 2, Days 1 and 15:

Predose (within 2 hours prior to dosing)

Day 1 of Cycles 3, 5, 6, and 7:

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
17.9.2
Whole Blood for 
 Analysis (Part A and B)
Mandatory whole blood samples
 
 
 Note: Collection time begins with the 
start of the infusion.

Screening

Cycle 1, Weeks 1, 3, and 5:

Predose (within 2 hours prior to dosing)

Cycle 2, Days 1 and 15:

Predose (within 2 hours prior to dosing)

Day 1 of Cycles 3, 5, 6, and 7:

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, 
collect pre- infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
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17.9.3
Whole Blood Samples for 
Mandatory whole blood samples will be collected from all patients at the timepoints 
indicated below.
 
 Note: 
Collection time begins with the start of the infusion.
Part A

Screening

Cycle 1, Weeks 1 and 3:

Predose (within 2 hours prior to dosing)

Cycle 2, Days 1 and 15:

Predose (within 2 hours prior to dosing)

Day 1 of Cycles 3, 5, and 7:

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
Part B

Screening

Cycle 1, Week 1:

Predose (within 2 hours prior to dosing)

Cycle 1, Week 3:

Predose (within 2 hours prior to dosing)

24 hours (± 2 hours) after the start of the infusion (and prior to acalabrutinib 
dosing)

Cycle 2, Days 1 and 15:

Predose (within 2 hours prior to dosing)

Day 1 of Cycles 3, 5, and 7

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)
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
Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
17.9.4
Whole Blood Samples for 
 (Part A and B)
Mandatory whole blood samples will be collected from all patients at the timepoints 
indicated below.
 
Note: Collection 
time begins with the start of the infusion.
Part A

Screening

Cycle 1, Week 1:

Predose (within 2 hours prior to dosing)

Cycle 1, Week 3

Predose (within 2 hours prior to dosing)

Cycle 2, Days 1 and 15:

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
Part B

Screening

Cycle 1, Week 1:

Predose (within 2 hours prior to dosing)

Cycle 1, Week 3

Predose (within 2 hours prior to dosing)

Cycle 2, Days 1 and 15

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
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17.9.5
Whole Blood for 
 Exploratory Analysis (Part B Only)
Mandatory whole blood samples will be collected from all patients in 
 
 at the timepoints indicated below to analyse 
 
 Note: 
Collection time begins with the start of the infusion.

Screening

Cycle 1, Week 1:

Predose (within 2 hours prior to dosing)

Day 1 of Cycles 2, 3, 5, and 7 

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
17.9.6
Exploratory Blood 
 Samples
Mandatory whole blood samples will be collected in 
 from all 
patients at the timepoints indicated below. 
 
 Note: Collection time begins 
with the start of the infusion (see Section 10.2).
Part A and Part B

Screening

Cycle 1, Weeks 1 through 3 (AZD4573 first and second ramp-up and target dose and 
target dose):

Predose (within 2 hours prior to dosing)

2 hours (± 15 minutes) after the start of the infusion

24 hours (± 2 hours) after the start of the infusion (and prior to acalabrutinib 
dosing)

Day 1 of Cycles 2, 3, 5, and 7:

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on the day of infusion, 
collect pre-infusion)
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
Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
Further details on sample processing, handling, and shipment are provided in the 
Laboratory Manual.
17.10
 
 
 
 
 
17.10.1
Collection of Archival Tumour Samples
All patients in Part A (dose setting) must consent to and provide a sample of their archival 
tumour obtained within 24 months before the first dose of treatment. The archival tumour 
biopsy sample formalin-fixed paraffin embedded (FFPE) tumour block should be 
provided with sufficient material to produce 20 slides, or where an archival tumour 
biopsy FFPE tumour block is unavailable, archival tumour biopsy FFPE unstained slides 
(20 unstained slides preferable, minimum 15 slides acceptable) must be provided. 
Archival tissues must have been obtained as a core biopsy and meet the specified criteria 
detailed in the Laboratory Manual. Associated pathology report(s) for archival tissue 
samples must be obtained at Screening for all patients enrolled into the study.
If archival material is unavailable or unsuitable for use, patients must consent to and 
undergo a tumour biopsy during the screening period. A new biopsy is strongly 
encouraged and preferred over an archival sample (see Section 17.10.2) as these samples 
will be used to confirm cell of origin status and to determine additional DLBCL 
subtyping. A patient will be enrolled based on a prior pathology report.
Further details on sample processing, handling and shipment are provided in the 
Laboratory Manual.
17.10.2
Collection of Tumour Biopsy Samples
Patients in Part A who are unable to provide archival tumour specimens obtained within 
24 months before the first dose of treatment will be asked to undergo a tumour biopsy at 
Screening. A new biopsy is strongly encouraged and preferred over an archival sample.
All patients in Part B (Phase II cohort expansions) will be asked to provide a newly 
obtained tumour biopsy at Screening. This sample will be used to confirm cell of origin 
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status, determine additional DLBCL subtype, and evaluate potential patient selection 
biomarkers through methods such as, but not limited to, immunohistochemistry 
(eg, baseline expression of Bfl1), gene expression analysis, and DNA sequencing. A 
patient will not be enrolled into Part B if he/she is unable to provide a newly obtained or 
recent biopsy. A recent biopsy that was taken as part of SoC prior to screening consent for 
this study is acceptable if no treatment was administered between the biopsy and the first 
dose of study treatment, and the biopsy was taken within 60 days prior to receiving the 
first dose.
All patients are also encouraged to consent to an additional optional tumour biopsy at 
disease progression. The optional disease progression sample may be taken at the 30-day 
SFU visit if not collected previously (see Section 17.10.5).
The tumour biopsy procedure will be performed by core needle, under radiological 
guidance, or surgically if the site of disease is superficial and palpable or visible 
(eg, palpable lymph node). Tumour biopsies should be preferentially obtained from 
tumour tissues that are safely accessible, as determined by the Investigator, and are not 
obtained from sites that require significant risk procedures. Patients will undergo 6 core 
image-guided needle biopsies. It is mandated that the core biopsy be removed directly 
from the tumour in situ and not cored from a surgically removed tumour. This is to ensure 
the best possible quality of the biopsy, as the blood/nutrient supply to the tumour is not 
disrupted prior to biopsy collection. Fine-needle aspirate specimens are not acceptable. 
Failure to obtain sufficient tumour sample after making best efforts to biopsy the tumour 
will not be considered a protocol deviation.
Sites should confirm the adequacy of tumour biopsy material at the time of the procedure. 
The exact time that the biopsy was taken should be clearly noted in the associated 
documentation. For mandatory and optional biopsy patients, the associated pathology 
report(s) for fresh tumour samples will be required at Screening and requested on 
treatment for all patients enrolled into the study.
Further details on sample processing, handling, and shipment are provided in the 
Laboratory Manual.
17.10.3
Collection of Bone Marrow
For all patients, when bone marrow biopsy and aspirate samples are collected for local 
standard disease profiling (refer to Section 17.4.3 for timepoints),
 
 
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Instructions on sample collection, labelling, processing, storage, and shipping will be 
provided in the laboratory manual.
17.10.4
Other Study Related 
 Research
17.10.4.1
 Sample for 
 Isolation
 
 
The sample should be collected from patients before receiving study treatment (Cycle 1, 
Week 1: Predose).
Details on sample processing, handling, and shipment are provided in the Laboratory 
Manual.
17.10.5
Collection of Optional 
 Samples
Collection of optional samples for 
 research is also part of this study as 
specified in the SoA (Section 10.2) and is subject to agreement to optional consent.
17.10.5.1
Optional Tumour Biopsy at Disease Progression
For patients who consent to the optional tumour biopsy, a biopsy will be taken at disease 
progression. The disease progression sample may be taken at the SFU visit if not 
collected previously.
Details on sample processing, handling, shipment, and storage are provided in the 
Laboratory Manual.
17.11
Optional Genomics Initiative Sample
Collection of optional saliva samples for genomics initiative research is also part of this 
study as specified in the SoA (Section 10.2) and is subject to agreement in the ICF 
addendum.
A saliva sample for DNA isolation will be collected from patients who have consented to 
participate in the genetic analysis component of the study. Participation is optional. 
Patients who do not wish to participate in the genetic research may still participate in the 
study.
The saliva sample for exploratory genetic research will be obtained from the patients 
before the first dose of IP. If for any reason the sample is not taken before dosing it may 
be taken at any visit until the last study visit. Only one sample should be collected per 
patient for genetics during the study. Samples will be collected, labelled, stored, and 
shipped as detailed in the Laboratory Manual.
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Please refer to 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, please refer to Appendix D.
17.12
Medical Resource Utilisation and Health Economics
Health Economics/Medical Resource Utilisation and Health Economics parameters are 
not evaluated in this study.
17.13
Important Medical Procedures to be Followed by the 
Investigator
17.13.1
Medical Emergencies and Contacts
The principal Investigator(s) 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, please refer to Section 8.2.10.
In the case of a medical emergency the Investigator may contact the Medical Monitor. If 
the Medical Monitor is not available, contact the Medical Scientist.


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18
STATISTICAL CONSIDERATIONS – MODULE 1
18.1
Statistical Hypotheses
No hypotheses are planned to be tested.
18.2
Sample Size Determination
Depending on dose escalation/de-escalation and enrolment in the expansion groups, up to 
a maximum of 105 evaluable patients will be treated with AZD4573 + acalabrutinib in 
this module.
The primary objective of Part A (dose setting) will be to identify the MTD and/or RP2D. 
In Part A, 3 to 9 evaluable patients may be treated in each of up to 3 dose levels using an 
mTPI-2 design permitting up to a maximum of 24 DLT-evaluable patients for dose setting 
(ie, a maximum of 9 evaluable patients at each of two dose levels and 6 evaluable 
patients at the third dose level). In addition, any safe dose level may be backfilled to 
include up to approximately 21 evaluable patients to collect additional tolerability and 
exploratory data. The maximum number of evaluable patients in Part A is therefore 63. 
This limits the number of patients exposed consistent with the expected safety profiles of 
the study drugs, but includes sufficient patients to explore safety of the combination 
treatment, PK, and effects on pharmacodynamic biomarkers, and to collect preliminary 
efficacy data.
In Part B (expansion), separate RP2D expansion cohorts will be opened for GCB and 
non-GCB DLBCL subtypes. For primary analyses, approximately 21 RP2D treated 
response evaluable patients of GCB subtype and approximately 21 RP2D-treated 
response-evaluable patients of non-GCB subtype will be incorporated, including patients 
from Part A and Part B. The total number of evaluable patients treated in Part B will be 
up to approximately 42. This sample size is large enough to evaluate further the safety 
and pharmacokinetics/pharmacodynamics (PKPD) of the chosen dose/schedule for 
AZD4573 + acalabrutinib from Part A and gives a reasonable chance of detecting an 
efficacy signal.
Historical response rates in r/r DLBCL are in the region of 30% to 60%, with some 
evidence that response rates are higher for the non-GCB subtype (Hernandez‐Ilizaliturri 
et al 2011, Morschhauser et al 2014, Van den Neste et al 2016, Van den Neste et al 2017, 
Wang et al 2018, Wang et al 2020, Wilson et al 2015, Witzig et al 2011). The following 
examples give an indication of the level of precision that will be achieved in this study:

 
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
 

 
In addition to ORR, the criteria for success will take into account the observed safety and 
tolerability data, and the other efficacy endpoints, in particular the DoR.
The data cut-off for the primary analysis for each expansion subgroup will occur 
approximately 6 months following last patient first dose in the expansion subgroup or 
when 75% of patients have progressed or died in the cohort, whichever occurs first.
Treatment with AZD4573 and acalabrutinib, in Part A and Part B, may be continued until 
disease progression or an unacceptable drug-related toxicity occurs as defined in the 
protocol, or the patient withdraws or is withdrawn from the study for other reasons. 
Patients who discontinue both study drugs before documented disease progression will be 
followed according to SoC until documented disease progression or the start of new 
anti-cancer therapy. All patients will be followed for survival until death, loss to 
follow-up, AstraZeneca closes study or withdrawal of consent, whichever occurs first.
18.3
Populations for Analyses
The analysis of data will be based on different subsets according to the purpose of the 
analysis. 
Analysis sets are presented in Table 22.
Table 22
Analysis Sets 
Analysis Set
Definition
Enrolled
All participants who sign the ICF
Safety
All patients who received any amount of 
AZD4573 and/or acalabrutinib.
DLT-evaluable
Patients that have received AZD4573 in 
combination with acalabrutinib and either:
•
Have received at least 3 doses of 
AZD4573 at the designated target dose 
level, have received at least 75% of 
acalabrutinib doses, and have completed 
the SFU through the DLT-assessment 
period.
Or
•
Have experienced a DLT
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Analysis Set
Definition
Pharmacokinetics
All dosed patients with reportable plasma 
concentrations and no important adverse events or 
protocol deviations that may impact PK.
Response evaluable
Patients dosed with AZD4573 or acalabrutinib with a 
baseline tumour assessment.
Interim response evaluable
Participants dosed with AZD4573 or acalabrutinib, or 
both AZD4573 and acalabrutinib with baseline tumour 
assessment and have their first post-baseline disease 
assessment performed, or have discontinued study 
treatment for any reasons before their first post-baseline 
disease assessment
FAS/ITT
All participants who received any amount of study 
intervention
Abbreviations: DLT = dose-limiting toxicity; ICF = informed consent form; FAS=Full analysis set; ITT = 
intent-to-treat; PK = pharmacokinetics.
18.4
Statistical Analyses
The Statistical Analysis Plan (SAP) will be finalised prior to database lock and it will 
include a more technical and detailed description of the statistical analyses described in 
this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints, as defined in 
Section 3 (Table 7).
18.4.1
General Considerations
Descriptive statistics (including means, standard deviations, and medians for continuous 
variables and proportions and CIs for discrete variables) will be used to summarise data 
by dose level/cohort as appropriate. KM methods will be used to estimate DoR, PFS and 
OS; corresponding quartiles (including the median) and 6-month and 12-month rates may 
be presented as appropriate.
18.4.2
Demographics, Baseline Characteristics, and Study Status
Characteristics of the participants, including medical history, disease characteristics at 
baseline, and previous and concomitant treatments (coded according to WHODRUG) will 
be listed for each participant and summarised by dose level/cohort where appropriate.
Reasons for discontinuation of study treatment and withdrawal from study will be listed 
including the study day of treatment discontinuation/study withdrawal and will be 
summarised by dose level/cohort if appropriate.
18.4.3
Exposure
Exposure to AZD4573 and acalabrutinib will be listed for all participants.


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Exposure amounts, durations, and dose modifications and interruptions/delays will be 
summarised by study drug, separately for Cycle 1 (including intra-patient ramp up) and 
for other treatment cycles.
18.4.4
Safety
Safety and tolerability will be assessed in terms of AEs, laboratory data, vital signs, and 
ECG changes.
For Part A, where safety is the primary objective, DLTs will be listed and summarised; 
MTD (if determined) will be reported. For both study parts, appropriate listings and 
summaries of all safety data will be produced, as defined below.
Adverse events will be listed individually by participant and dose level/cohort. The 
number of participants experiencing each AE will be summarised by the Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class, MedDRA preferred 
term and CTCAE grade, with the exception of TLS which will use both CTCAE grade 
and Howard modification of Cairo-Bishop criteria (see Appendix F). The number and 
percentage of participants with AEs in different categories (eg, causally related and
CTCAE Grade ≥3) will be summarised by dose level/cohort, and events in each category 
will be further summarised by MedDRA system organ class and preferred term. SAEs 
will be summarised separately if a sufficient number occur.
AE summary tables will include only treatment-emergent AEs. AEs will be defined as 
treatment-emergent if they have an onset or worsen (by Investigator report of a change in 
intensity/severity), during the study treatment until 30 days from the last dose of any 
study intervention, but prior to subsequent cancer therapy. AEs occurring outside this 
period will be flagged in listings.
Haematology, clinical chemistry, vital signs, ECG data, and other laboratory values will 
be listed individually by participant and suitably summarised. For all laboratory 
variables, which are included in the current version of CTCAE, the CTCAE grade will be 
calculated.
Details of any deaths will be listed for all participants.
Graphical presentations of safety data will be presented as is deemed appropriate. This 
may include, but is not restricted to, presentation of parameters against time, 
concentration, or shift plots. Appropriate scatter plots will also be considered to 
investigate trends in parameters compared to baseline level.
Depending on the extent of any impact, summaries of data relating to participants 
diagnosed with COVID-19, and impact of COVID-19 on the study conduct (for example, 


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missed visits, delayed or discontinued IP, and other protocol deviations) may be 
generated. More detail will be provided in the SAP.
ECG Changes
QTc will be calculated using Fridericia’s formula.
Creatinine Clearance
Estimated creatinine clearance will be calculated using the Cockcroft and Gault formula.
Other Significant Adverse Events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will 
review the list of AEs that were not reported as SAEs and AEs leading to discontinuation 
of study treatment. Based on the expert’s judgement, AEs of particular clinical 
importance may, after consultation with the Global Safety Physician, be considered other 
significant adverse events (OAEs) and reported as such in the CSR. A similar review of 
laboratory values, vital signs, ECGs, and other safety assessments will be performed for 
identification of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and 
certain events that lead to intervention (other than those already classified as serious), 
dose reduction or significant additional treatment.
18.4.5
Efficacy
Tumour response data will be listed and summarised by dose level/cohort, if appropriate, 
using the standard response criteria as defined in Section 17.4.
For GCB and non-GCB RP2D expansion cohorts, the primary endpoint is ORR; other 
efficacy endpoints are secondary. For Part A participants who are not included in the 
GCB and non-GCB RP2D expansion cohorts, all efficacy endpoints are exploratory.
18.4.5.1
Objective Response Rate and Proportion of Participants with Complete 
Response
Objective Response (OR) is defined as a best overall response of CR or PR that occurs 
prior to the initiation of subsequent anti-cancer treatment and prior to progression, or last 
evaluable assessment in the absence of progression. Objective Response Rate (ORR) is 
defined as the percentage of subjects with objective response (Cheson et al 2014). ORR 
and complete response rate (CRR) will be presented with corresponding 80% and 95% 
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18.4.5.2
Time to Response (TTR)
TTR is defined as the time from the first dose of study treatment to the first documented 
objective response. TTR data will be listed and summarised in participants who achieved 
an objective response.
18.4.5.3
Duration of Response (DoR)
DoR is defined as the time from the first objective response to the time of documented 
disease progression or death due to any cause, whichever occurs first. KM curves and 
estimates may be presented, if appropriate.
18.4.5.4
Progression-free Survival (PFS)
Disease progression will be determined by the investigators according to the revised 
response criteria for malignant lymphoma (Cheson et al 2014). PFS is defined as the time 
from first dose date to documented disease progression, or death (from any cause in the 
absence of progression), regardless of whether the participant withdraws from therapy or 
receives another anti-cancer therapy prior to progression. Participants who have not 
progressed or died at the time of analysis will be censored at the time of the latest date of 
assessment from their last evaluable disease assessment. However, if the participant 
progresses or dies immediately after 2 or more consecutive missed visits, the participant 
is censored at the time of the latest evaluable disease assessment prior to the 2 missed 
visits.
The PFS time will always be derived, based on scan/assessment dates, not visit dates.
Tumour assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied:

Date of progression will be determined, based on the earliest of the dates of the 
component that triggered the progression.

When censoring a participant for PFS, the participant will be censored at the latest of 
the dates contributing to a particular overall visit assessment.
Kaplan-Meier plots will be provided.
18.4.5.5
Overall Survival (OS)
OS is defined as the time from first dose until the date of death from any cause. 
Participants who have not died by the analysis data cut-off date will be censored at their 
last date known to be alive before the cut-off date. Participants known to be alive or dead 
after the data cut-off date will be censored at the data cut-off date. Participants who are 
lost to follow-up will be censored at the date the participant is last known to have been 
alive. KM curves and estimates may be presented, if appropriate.


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18.4.6
Pharmacokinetics
Pharmacokinetics is a secondary objective for Part A and Part B.
Plasma concentrations of AZD4573 plus acalabrutinib and its metabolite ACP-5862 will 
be summarised by nominal sample time. Plasma concentrations and derived PK 
parameters will be summarised by cohort and dose level. Plasma concentrations and the 
derived PK parameters at each time point will be summarised according to dose 
level/cohort by the following summary statistics:

The geometric mean (gmean)

Coefficient of variation (CV)

Gmean ± standard deviation 

Arithmetic mean calculated using untransformed data

Standard deviation calculated using untransformed data

Minimum

Median

Maximum

Number of observations
The pharmacokinetic data for AZD4573, acalabrutinib and its metabolite ACP-5862 will 
also be displayed graphically. Displays will include plasma concentration participant 
profiles (on the linear and log-scale) versus time and gmean concentration (± standard 
deviation) versus time, stratified by dose.
Scatter plots of PK parameters versus dose, or log-dose, will also be considered to assess 
dose proportionality.
Derived PK parameters to be determined include Cmax, AUC0-t, AUClast, AUC0-inf, 
tmax, and t1/2. Additional PK parameters may be determined.
18.5
Interim Analyses 
No interim analyses are planned for the study due to the decision to permanently halt 
enrolment. 
18.6
Safety Review Committee – Module 1
An SRC, which includes the principal investigators, is tasked with the review of the 
available safety data (AEs and available pharmacokinetics/pharmacodynamics [PKPD] 
data) for AZD4573 in combination with acalabrutinib prior to the SRC making 


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recommendations on opening next cohorts or changing the dose schedule. All decisions 
are and will be documented in writing in the form of meeting minutes.
Please refer to Appendix A 5 and the SRC Charter for further information on the SRC.
In Part A, once all participants in a given dose setting cohort have had the opportunity to 
become DLT-evaluable, the SRC will review and assess all available safety data, together 
with available PK data, to make a decision on the dose for the subsequent combination 
therapy cohort of participants. At least 3 evaluable participants are required before a 
dose-escalation decision can be made. Any dose interruptions and reductions will be 
taken into account.
The decision (guided by mTPI-2) may be to:
1
Proceed with dose escalation for the next cohort, up to a maximum of 9 evaluable 
participants per dose level.
2
Treat the next cohort at the same level, up to a maximum of 9 evaluable participants 
at any one dose level.
3
De-escalate the dose for the next cohort, up to a maximum of 9 evaluable 
participants at the lower dose level.
4
Stop the dose-escalation part of the study.
5
Evaluate alternative/intermittent dose schedules or change dosing to weight-based or 
body surface-area based dosing.
Additionally, as described in Section 15.2, beyond the dose setting phase Part A and Part 
B participants, including backfills, receiving the RP2D of AZD4573 + acalabrutinib 
combination therapy will be monitored for any DLTs and for TLS events resulting in 
study treatment discontinuations using the same DLT criteria employed during dose 
setting. If, on an ongoing basis, > 30% of participants experience any safety events that 
meet the criteria of a DLT or > 30% of participants discontinue study treatment due to 
TLS, enrolment into the expansion cohorts may be paused for evaluation of the study 
data by the SRC. Following SRC review additional monitoring may be implemented 
and/or enrolment and dosing may resume at a lower combination dose level or modified 
schedule as defined in the dose setting phase. Further details will be provided in the 
Medical Monitoring Plan.
Any participant started on treatment in error, as he/she failed to comply with all of the 
selection criteria but meets the criteria of an evaluable participant, will be reviewed on a 
case-by-case basis by the SRC to determine if the participant should be included or 
excluded in the decision for dose escalation.


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The decisions and decision-making of the SRC on the next dose level will be documented 
and provided to the investigators before dosing any new participants.


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MODULE 2: AZD4573 MONOTHERAPY WINDOW STUDY 
FOLLOWED BY AZD4573 PLUS ACALABRUTINIB IN PATIENTS 
WITH RELAPSED OR REFRACTORY MANTLE CELL 
LYMPHOMA
19
PROTOCOL SUMMARY – MODULE 2
19.1
Scheme


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Figure 6
Overall Study Design for AZD4573 Monotherapy Window Study Followed by AZD4573 Plus Acalabrutinib in 
Participants with Relapsed or Refractory Mantle Cell Lymphoma – Module 2, Part A
Notes: FTIH study = D8230c00001. All participants will start on AZD4573 monotherapy (Period 1) and will thereafter follow the schedule in Table 29.
Abbreviations: BID = twice a day; PO = by mouth; IV = intravenous; MCL = mantle cell lymphoma; TD-c = target dose for combination recommended Phase 2 dose.
There is a SoA for each Period of Part A (Table 23 and Table 24).
The study design of Part B of this module will be determined from the data emerging from Part A. Specifics for Part B will be defined in a 
future protocol amendment.


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19.2
Schedules of Activities – Module 2
Table 23
Schedule of Activities: (AZD4573 Monotherapy) Module 2, Part A, Period 1
Assessment
Screena
Period 1 AZD4573 Monotherapy
Disease 
Assessmentb
/End of 
Treatmentkk
30-Day 
SFUc
LTFU
Details 
in CSP 
Section
Cycle 1
Weeks 1 - 5
Cycles 2-8
(Cycle = 21 days)
Cycles 9+
(Cycle = 21 
days)jj
Days
Days
Day
1
8
15
22
29
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Informed consentd
X
Section 
26.1.1
Inclusion/exclusion
X
Section 
26.1.1
Medical history and 
demographics
X
Section 
26.1.1
Physical examinationf
X
X
X
X
X
X
X
X
X
X
X
Section 
26.1.2
ECOG performance 
status
X
X
X
X
X
X
X
X
X
X
X
Section 
26.1.5
Archival tumour 
sample or new biopsy
X
Section 
26.10.1, 
26.10.2
Vital signse
X
X
X
X
X
X
X
X
X
X (each 
infusion)
X
Section 
26.1.3
Weightf
X
X
X
X
X
Section 
26.1.3
B symptoms
X
X
X
X
X
X
X
X
X
X
X
Section 
26.1.6


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Assessment
Screena
Period 1 AZD4573 Monotherapy
Disease 
Assessmentb
/End of 
Treatmentkk
30-Day 
SFUc
LTFU
Details 
in CSP 
Section
Cycle 1
Weeks 1 - 5
Cycles 2-8
(Cycle = 21 days)
Cycles 9+
(Cycle = 21 
days)jj
Days
Days
Day
1
8
15
22
29
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
12-lead ECGg
X
X
X
X
X
X
X
X
X
Section 
26.1.4
CMV immunoglobulin 
M [IgM] and PCRh
X
Section 
26.1.7
Cardiac troponini
X
X
X
X
X
X
X
X
X
Section 
26.1.7
T4, cortisol, ACTH 
and TSHj
X
Cycle 2 
only
X
Section 
26.1.7
ECHO/MUGAk
X
As clinically indicated
Xk
Section 
26.1.8
Haematologyl
X
X
X
X
X
X
X
X
X
X (each 
infusion)
X
Section 
26.1.7
Coagulationm
X
X
X
X
X
X
X
X
X
X
X
Section 
26.1.7
Clinical chemistryn
X
X
X
X
X
X
X
X
X
X (each 
infusion)
X
Section 
26.1.7
TLS monitoringo
X
X
X
Section 
26.1.7
Urinalysisp
X
X
X
X
X
X
X
X
X
X
X
Section 
26.1.7


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Assessment
Screena
Period 1 AZD4573 Monotherapy
Disease 
Assessmentb
/End of 
Treatmentkk
30-Day 
SFUc
LTFU
Details 
in CSP 
Section
Cycle 1
Weeks 1 - 5
Cycles 2-8
(Cycle = 21 days)
Cycles 9+
(Cycle = 21 
days)jj
Days
Days
Day
1
8
15
22
29
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Pregnancy testing 
(women of 
childbearing potential)q
X
(Serum
)
X
Once every 21 days
X
Section
26.1.7
Lipase/amylaser
X
X
X
X
X
X
X
X
X
X
X
Section 
26.1.7
Hepatitis serologys
X
See footnote
Section 
26.1.7
and 
Section 
26.1.10.
4
CD4, CD8, CD19, 
CD16/NK cell countt
X
X 
(predose)t
Every 6 months
X
Section 
26.1.8
Serum 
immunoglobulins (IgA, 
IgM, IgG)t
X
X 
(predose)t
Every 6 months
X
Section 
26.1.8
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X (each 
infusion)
X
X
X
Section 
24.8
Adverse event 
evaluation
X
X
X
X
X
X
X
X
X
X (each 
infusion)
X
X
X
Section 
8.2
AZD4573 plasma PKu
X
X
X
Cycle 2
Section 
26.6


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Assessment
Screena
Period 1 AZD4573 Monotherapy
Disease 
Assessmentb
/End of 
Treatmentkk
30-Day 
SFUc
LTFU
Details 
in CSP 
Section
Cycle 1
Weeks 1 - 5
Cycles 2-8
(Cycle = 21 days)
Cycles 9+
(Cycle = 21 
days)jj
Days
Days
Day
1
8
15
22
29
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Pharmacodynamic 
samples (blood) for 
AZD4573v
X
X
X
Section 
26.7.1
 
X
X
X
X
Section 
26.8
Whole blood for 
exploratory 
 
x
X
X
X
X
Cycles 2, 
3, 5, 6, 
and 7
Cycle 
2
X
(X)
Section 
26.9.1
Whole Blood for 
y
X
X
X
X
Cycles 2, 
3, 5, 6, 
and 7
Cycle 
2
X
(X)
Section 
26.9.2
Whole blood samples 
for
 
z
X
X
X
Cycles 2, 
3, 5, and 7
Cycle 
2
X
(X)
Section 
26.9.3
Whole blood samples 
for 
aa
X
X
X
Cycle 2
Cycle 
2
X
(X)
Section 
26.9.4
Whole blood for 
 exploratory 
analysisbb
X
X
Cycles 2, 
3, 5, and 7
X
(X)
Section 
26.9.5
Exploratory blood 
cc
X
X
X
X
Cycles 2, 
3, 5, ad 7
X
(X)
Section 
26.9.6
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Assessment
Screena
Period 1 AZD4573 Monotherapy
Disease 
Assessmentb
/End of 
Treatmentkk
30-Day 
SFUc
LTFU
Details 
in CSP 
Section
Cycle 1
Weeks 1 - 5
Cycles 2-8
(Cycle = 21 days)
Cycles 9+
(Cycle = 21 
days)jj
Days
Days
Day
1
8
15
22
29
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
 sample for 
 
isolationdd
(X)
X 
(pre-
dose)
Section 
26.10.4.
1
Genomics Initiative 
saliva sample 
(optional)ee
(X)
X 
(pre-
dose)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Section 
26.11
Tumour biopsy sample 
(optional)ff
At disease 
progression
(X)ff
Section 
26.10.2
Bone marrow biopsy & 
aspirategg
X
As clinically 
indicated 
and to 
confirm CR
Section 
26.4.3
and 
Section 
26.10.3
Disease assessmentb
and radiologic scanshh
X
See Table 37 schedule
X
Section 
26.4.2
AZD4573 intravenousii
Once weekly (from Cycle 1, Week 1 to end of treatment)ll
Section 
24.1
Disease progression 
follow-up (SoC)
X
Section 
26.1.9.2
Survival Follow-up
X
Section 
26.1.9.3
a
Screening tests should be performed within 30 days before the first administration of study drug, unless otherwise indicated.
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b
Disease assessments will be done by the Investigator using the Lugano Response Criteria for Non-Hodgkin’s Lymphoma (Cheson et al 2014). Additional disease assessments 
may be performed as clinically indicated.
c
The SFU visit will be performed 30 days (±7 days) after the last dose of all study drug. Tumour assessments will be repeated at this visit if they have not been performed 
within 9 weeks if the participant discontinued before or during Week 26, or 12 weeks if the participant discontinued after Week 26.
d
Informed consent must be obtained ≤30 days before the first dose of study drug and must be obtained before any protocol-defined screening procedures are done.
e
Vital signs (blood pressure, pulse rate, temperature) will be assessed after the participant has rested for at least 10 mins. Blood pressure and pulse rate will be measured at 
Screening, and on Day 1 of Cycle 1, Weeks 1-3 at the following timepoints: predose (within 2 h prior to infusion), 1 h after the start of the infusion (± 10 mins), at end of 
infusion (up to 10 mins post dose) and then 4 h (± 30 mins) and 6 h (± 30 mins) after start of infusion, from Cycle 1 Week 4 onwards, at predose (up to 30 mins prior to 
infusion), at the end of infusion (up to 30 mins post dose), and at the 30-day SFU. Temperature to be taken pre-infusion (up to 2 h prior to all infusions).
f
As the study is intended to recruit adults, height should only be measured at Screening. Weight to be measured at Screening, prior to infusion on Day 1 of each cycle, and at 
the 30-day SFU visit.
g
Participants should be in semi-supine position and resting for ≥ 10 mins before the ECGs. Single ECGs for local and central analysis are required at Screening and at the 
following timepoints: for Cycle 1, Weeks 1-5 and Cycle 2 Day 1 predose (at the day of infusion  prior to infusion) and within 30 mins of the end of infusion; for Cycles 3+ 
on Day 1 within 30 mins after the end of infusion, and at the 30-day SFU visit.
h
All subjects will have CMV testing at Screening including serology testing for CMV immunoglobulin (Ig)G and CMV IgM and CMV DNA PCR testing
i
Cardiac troponin measurements are required at the following timepoints: Screening, Cycle 1, Weeks 1-5, predose (within 72 hours prior to infusion) and at 24 h after the start 
of the infusion, and Cycles 2+ on Day 1 of each cycle, predose (within 72 hours prior to infusion), and at the 30-day SFU visit. Note: either a troponin I or troponin T 
assay can be used per SoC at the respective hospital. If the hospital has both a SoC troponin I and troponin T assay available, the investigator shall use only 
one consistently for the duration of the study.
j
T4, cortisol, ACTH, and TSH to be taken at Screening, predose (within 72 hours prior to infusion) on Cycle 2, Day 1, and at the 30-day SFU.
k
ECHO should be done at Screening and within 14 days after an abnormal ECG finding (eg, T-wave inversion/flattening) or as soon as possible when clinically indicated. If 
an ECHO cannot be taken, a MUGA scan to assess LVEF will be done. In case of any T-wave abnormality, the ECHO (or MUGA) should be repeated at the 30-day 
follow-up visit to address the question of recovery, during the off-treatment period.
l
Haematology testing should be measured at Screening, Cycles 1, 2, and 3 predose (within 72 h prior to infusion) and 24 h after the start of the infusion. From Cycle 4 
onwards, haematology testing should be predose (within 72 h prior to infusion) and (if clinically indicated) 24 h after the start of the infusion. A sample will also be drawn at 
the 30-day SFU. The Investigator may take additional, unscheduled samples throughout the study if deemed clinically warranted and these need to be entered into the eCRF. 
Haematology tests do not need to be repeated before first dose if the first-dose visit is within 3 days of the Screening sample.
m
Coagulation testing should be measured at Screening, Cycles 1, 2, and 3 predose (within 72 h prior to infusion) and 24 h post-infusion of AZD4573. For Cycles 4-8, predose 
(within 72 h prior to the infusion); the 24-h sample can be omitted unless clinically indicated. For Cycles 9+, on Day 1 of each cycle, an AZD4573 pre-infusion sample will 
be drawn within 72 h prior to infusion. A sample will also be drawn at the 30-day SFU. The Investigator may take additional, unscheduled samples throughout the study if 
deemed clinically warranted and these need to be entered into the eCRF.
n
Clinical chemistry should be measured at Screening, Cycles 1, 2, and 3 predose (within 72 h prior to infusion), and 24 h post-infusion of AZD4573. From Cycle 4 onwards, 
clinical chemistry testing should be measured predose (within 72 h prior to infusion) and (if clinically indicated) 24 h after the start of the infusion.A sample will also be 
drawn at the 30-day SFU. The investigator may take additional, unscheduled samples throughout the study if deemed clinically warranted and these need to be entered into 
the eCRF. Clinical chemistry tests do not need to be repeated before first dose if the first-dose visit is within 3 days of the Screening sample.
In addition, GLDH and CPK will be measured at Screening for all participants. If GLDH cannot be performed locally, LDH will be analysed locally and a serum sample 
must be collected for central retrospective GLDH analysis, which will be performed as applicable. Refer to the Laboratory Manual for details.
If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, potassium) and troponin must be done to coincide with the ECG testing.


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o
All participants will receive TLS prophylaxis during the intra-patient ramp up and be monitored for TLS during the first 24 hours post start of dose; this requirement will 
continue until they have received at least one AZD4573 dose at the target dose level (i.e., for at least the first 3 AZD4573 once-weekly doses). TLS monitoring will be 
performed at the following timepoints: Cycle 1, Weeks 1-3, predose AZD4573, 6 h after the start of the infusion, and 24 h (± 1 h) after the start of the infusion. Participants 
showing signs of clinical or laboratory TLS at 6 h after start of infusion must be admitted for in-patient TLS monitoring for a minimum of 24 h after the start of the infusion 
and monitored every 4 to 6 h during this time (or more frequently if clinically indicated). For each TLS monitoring timepoint, a TLS Monitoring page in the eCRF is to be 
filled out. Fluid balance must be monitored according to local institutional standards.
p
Urine samples will be collected at the following timepoints: Screening, Cycles 1-8, predose AZD4573 (within 72 hours prior to infusion) and within approximately 2 hours 
after the end of infusion, Cycles 9+ on Day 1 of each cycle, predose AZD4573 and within approximately 2 hours after the end of infusion, and at the 30-day SFU.
q
Pregnancy test to be performed at Screening (serum) and predose (serum or urine) on Cycle 1, Week 1, then once every 21 days (± 7 days) prior to initiating a new cycle 
and at the 30-day SFU visit. Additional testing may be performed at Investigator discretion (eg, in the event of suspected contraception failure).
r
Lipase and amylase should be evaluated at Screening, Cycles 1-8 predose AZD4573 (within 72 hours prior to infusion), Cycles 9+, predose AZD4573 (within 72 hours prior 
to infusion) on Day 1 of each cycle, and at the 30-day SFU visit.
s
In addition to hepatitis serology as specified, participants who are anti-HBc positive, or have a known history of HBV infection, should be monitored every 3 months with a 
quantitative PCR test for HBV DNA. In addition, any participants testing positive for any hepatitis serology must have PCR testing for verification purposes.
t
CD4, CD8, CD19, CD16/NK and serum immunoglobulins (IgA, IgM, IgG) will be drawn at Screening, Day 1 (predose) of Cycles 2, 4, 7, 9, 13, 16, 19 and every 6 months 
thereafter (predose), and at the 30-day SFU.
u
Plasma samples for PK analysis will be taken at the following time points: For Cycle 1, of Weeks 1-3 and Cycle 2, Day 1: predose (up to 2 h prior to AZD4573) and 1 h 
(± 15 mins), 2 h (± 15 mins), 4 h (± 30 mins), 7 h (± 1 h), and 24 h (± 1 h) (ie, Day 2 of dosing) after the start of the infusion.
v
Pharmacodynamic evaluations for AZD4573 blood samples will be collected at Cycle 1, Weeks 1 and 2 at predose (up to 2 h prior to dosing) and 2 h (± 15 mins), 4 h (± 30 
mins), and 24 h (± 2 h) (ie, Day 2) after the start of the infusion. Cycle 1 Week 3, predose (up to 2h prior to dosing), 2 h (± 15 mins), 4 h (± 30 mins), 7 h (± 1 h), and 24 h (± 
2 h) (ie, Day 2) after the start of the infusion.
w
 Samples will be taken for all participants at Screening and Cycle 1, Weeks 1-3: predose (up to 2 h prior to dosing) and 4 h (± 30 mins), 7 h (± 1 h), 
and 24 h (± 1 h) after start of infusion. 
 at 
24 h after start of infusion, samples will be drawn at 48 h(-2 h/+12 h prior to infusion), 96 h (- 2 h/+12 h prior to infusion), predose-the-following infusion (within 4 h prior to 
infusion), and at each point chemistry panel testing is being performed. 
 sampling 
should be performed the same as for Cycle 1, Weeks 1-3.
x
Whole blood for exploratory 
 samples will be collected at Screening, Cycle 1, Weeks 1, 3, and 5 predose (within 2 h prior to dosing), 
Cycle 2, Days 1 and 15 predose (within 2 h prior to dosing), Day 1 of Cycles 3, 5, 6 and 7 predose (within 2 h prior to dosing), and at every scheduled or unscheduled tumour 
assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken at End of Treatment, a sample should be 
obtained at the 30-day SFU.
y
Whole Blood for 
 analysis will be collected at Screening, Cycle 1, Weeks 1, 3, 
and 5 predose (within 2 h prior to dosing), Cycle 2, Days 1 and 15, predose (within 2 h prior to dosing), and on Day 1 of Cycles 3, 5, 6, and 7 predose (within 2 h prior to 
dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a 
sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
z
Whole blood samples for 
 will be collected at Screening, Cycle 1, Weeks 1 and 3 predose (within 2 h prior to dosing), Cycle 2, Days 1 and 15, predose 
(within 2 h prior to dosing), Day 1 of Cycles 3, 5, and 7 predose (within 2 h prior to dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of 
infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
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aa
Whole blood samples for 
 will be collected at Screening, Cycle 1, Weeks 1 and 3 predose (within 2 h prior to dosing), Cycle 2, Days 1 and 15 predose 
(within 2 h prior to dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of 
treatment. If a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
bb
Whole blood for 
 exploratory analysis samples will be collected at, Cycle 1, Week 1 predose (within 2 h prior to dosing), Day 1 of Cycles 2, 3, 5, and 7 predose 
(within 2 h prior to dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of 
treatment. If a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
cc
Exploratory blood 
Whole blood samples will be collected at Screening and Cycle 1 Weeks 1-3 at predose (within 2 h prior to dosing), 2 h (± 15 mins) 
and 24 h (± 2 h) after the start of the infusion and on Day 1 of Cycles 2, 3, 5, and 7 predose (within 2 h prior to dosing), and at every scheduled or unscheduled tumour 
assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken at End of Treatment, a sample should be 
obtained at the 30-day SFU.
dd
 sample for 
 isolation will be collected at Cycle 1, Week 1 predose.
ee
An optional saliva sample for genomics initiative research will be taken from consenting participants prior to the first dose of IP. If for any reason the sample is not taken 
before dosing it may be taken at any visit until the last study visit. Only one sample should be collected per participant for genetics during the study.
ff
A biopsy will be taken at disease progression for participants who consent. The disease progression sample may be taken at the SFU visit if not collected previously.
gg
Bone marrow biopsy and aspirate: 
 
hh
See Table 37 for schedule of disease assessments, including mandatory PET assessments. Disease assessments will be done by the Investigator using the Lugano Response 
Criteria for Non-Hodgkin’s Lymphoma (Cheson et al 2014). Additional disease assessments may be performed as clinically indicated.
ii
AZD4573 is to be administered as an absolute (flat) dose, 2-h (± 15 mins) IV infusion on a once-weekly schedule.
jj
If a participant is attending Cycle 9+ visits according to a modified schedule, in which AZD4573 is not infused and assessments are not performed every week, the Day 1 
assessments should be performed at least once per cycle.
kk
The End of Treatment visit is the last visit attended by the participant prior to the 30-Day SFU on the study. At this visit, the participant does not receive IMP and should 
undergo the applicable assessments associated with the Cycle and visit they have reached, plus those shown in the “Disease Assessment/End of Treatment” column of the 
SoA.
ll
AZD4573 should be administered at least 5 days apart
Abbreviations: ACTH = adrenocorticotropic hormone; BID = twice daily; CPK = creatinine phosphokinase; CMV = cytomegalovirus; CSP = clinical study protocol; 
DNA = deoxyribonucleic acid; ECG = electrocardiogram, ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; 
GLDH = glutamic dehydrogenase; HBV = Hepatitis B virus; h = hour; Ig = immunoglobulin; IP = investigational product; 
 LTFU = long-term 
follow-up; LVEF = left ventricular ejection fraction; min = minutes; 
 MUGA = multigated acquisition; 
PCR = polymerase chain reaction; 
 PHL = Potential Hy’s Law; PK = pharmacokinetics; SFU = safety follow-up; SoC = standard of 
care; T4 = thyroxine; TLS = tumour lysis syndrome; TSH = thyroid-stimulating hormone.
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Table 24
Schedule of Activities: (AZD4573 + Acalabrutinib) – Module 2, Part A, Period 2
Assessment
Period 2 AZD4573 +Acalabrutinib
Disease 
Assessmenta
/End of 
Treatmentii
30-Day 
SFUb
LTFU
Details 
in CSP 
Section
Cycle 1
Weeks 1 - 5
Cycles 2-8
(Cycle = 21 days)
Cycles 9+
(Cycle = 
21 days)hh
Days
Days
Day
1
8
15
22
29
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Physical examinationd
X
X
X
X
X
X
X
X
X
X
Section 
26.1.2
ECOG performance status
X
X
X
X
X
X
X
X
X
X
Section 
26.1.5
Vital signsc
X
X
X
X
X
X
X
X
X (each 
infusion)
X
Section 
26.1.3
Weightd
X
X
X
X
Section 
26.1.3
B symptoms
X
X
X
X
X
X
X
X
X
X
Section 
26.1.6
12-lead ECGe
X
X
X
X
X
X
X
X
Section 
26.1.4
Cardiac troponinf
X
X
X
X
X
X
X
X
Section 
26.1.7
T4, cortisol, ACTH and TSHg
X (Cycle 2 
only)
X
Section 
26.1.7
ECHO/MUGAh
As clinically indicated
Section 
26.1.8
Haematologyi
X
X
X
X
X
X
X
X
X (each 
infusion)
X
Section 
26.1.7


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Assessment
Period 2 AZD4573 +Acalabrutinib
Disease 
Assessmenta
/End of 
Treatmentii
30-Day 
SFUb
LTFU
Details 
in CSP 
Section
Cycle 1
Weeks 1 - 5
Cycles 2-8
(Cycle = 21 days)
Cycles 9+
(Cycle = 
21 days)hh
Days
Days
Day
1
8
15
22
29
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Coagulationj
X
X
X
X
X
X
X
X
X
X
Section 
26.1.7
Clinical chemistryk
X
X
X
X
X
X
X
X
X (each 
infusion)
X
Section 
26.1.7
Urinalysisl
X
X
X
X
X
X
X
X
X
X
Section 
26.1.7
Pregnancy testing (women of 
childbearing potential)m
Once every 21 days
X
Section
26.1.7
Lipase/amylasen
X
X
X
X
X
X
X
X
X
X
Section 
26.1.7
Hepatitis serologyo
See footnote
Section 
26.1.7
and 
Section 
26.1.10.4
CD4, CD8, CD19, CD16/NK cell 
countp
X (predose)p
Every 6 months
X
Section 
26.1.8
Serum immunoglobulins (IgA, 
IgM, IgG)p
X (predose)p
Every 6 months
X
Section 
26.1.8
Concomitant medication
X
X
X
X
X
X
X
X
X (each 
infusion)
X
X
X
Section 
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Assessment
Period 2 AZD4573 +Acalabrutinib
Disease 
Assessmenta
/End of 
Treatmentii
30-Day 
SFUb
LTFU
Details 
in CSP 
Section
Cycle 1
Weeks 1 - 5
Cycles 2-8
(Cycle = 21 days)
Cycles 9+
(Cycle = 
21 days)hh
Days
Days
Day
1
8
15
22
29
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Adverse event evaluation
X
X
X
X
X
X
X
X
X (each 
infusion)
X
X
X
Section 
8.2
AZD4573/
acalabrutinib plasma PKq
X
X
Section 
26.6
Pharmacodynamic samples 
(blood) for AZD4573r
X
Section 
26.7.1
Pharmacodynamic samples 
(blood) for acalabrutinibs
X
X
Section 
26.7.1
X
Section 
26.8
Whole blood for exploratory 
 
u
X
X
X
Cycles 2, 3, 
5, 6, and 7
Cycle 
2
X
(X)
Section 
26.9.1
Whole Blood for 
v
X
X
X
Cycles 2, 3, 
5, 6, and 7
Cycle 
2
X
(X)
Section 
26.9.2
Whole blood samples for 
 
w
X
X
Cycles 2, 3, 
5, and 7
Cycle 
2
X
(X)
Section 
26.9.3
Whole blood samples for 
x
X
X
Cycle 2
Cycle 
2
X
(X)
Section 
26.9.4
Whole blood for 
 
exploratory analysisy
X
Cycles 2, 3, 
5, and 7
X
(X)
Section
26.9.5
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Assessment
Period 2 AZD4573 +Acalabrutinib
Disease 
Assessmenta
/End of 
Treatmentii
30-Day 
SFUb
LTFU
Details 
in CSP 
Section
Cycle 1
Weeks 1 - 5
Cycles 2-8
(Cycle = 21 days)
Cycles 9+
(Cycle = 
21 days)hh
Days
Days
Day
1
8
15
22
29
1
8
15
1
(±2 Days)
(±2 Days)
(-2 to +5 
Days)
(±7 Days)
(±7 Days)
Exploratory blood 
 
z
X
Cycles 2, 3, 
5, and 7
X
(X)
Section 
26.9.6
Genomics Initiative saliva 
sample (optional)aa
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Section 
26.11
Tumour biopsy sample 
(optional)bb
At disease 
progression
(X)
Section 
26.10.2
Bone marrow biopsy & aspiratecc
As clinically 
indicated and 
to confirm 
CR
Section 
26.4.3an
d Section 
26.10.3
Disease assessmenta and 
radiologic scansdd
See Table 38 schedule
X
Section 
26.4.2
AZD4573 intravenousee
Once weekly (from Cycle 1, Week 1 to end of treatment)jj
Section 
24.1
Acalabrutinib oral, BIDff
Twice daily (from Cycle 1, Week 1 to end of treatment)
Section 
24.1
Acalabrutinib drug 
accountabilitygg
X
X
X
X
X
X
X
X
X
Section 
24.5
Disease progression follow-up 
(SoC)
X
Section 
26.1.9.2
Survival Follow-up
X
Section 
26.1.9.3
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a
Disease assessments will be done by the Investigator using the Lugano Response Criteria for Non-Hodgkin’s Lymphoma (Cheson et al 2014). Additional disease assessments 
may be performed as clinically indicated.
b
The SFU visit will be performed 30 days (±7 days) after the last dose of all study drug. Tumour assessments will be repeated at this visit if they have not been performed 
within 9 weeks if the participant discontinued before or during Week 26, or 12 weeks if the participant discontinued after Week 26.
c
Vital signs (blood pressure, pulse rate, temperature) will be assessed after the participant has rested for at least 10 mins. Blood pressure and pulse rate will be measured on 
Day 1 of Cycle 1, Weeks 1-3 at the following timepoints: predose (up to 2 h prior to infusion), 1 h after the start of the infusion (± 10 mins), at end of infusion (up to 10 mins 
post dose) and then 4 h (± 30 mins) and 6 h (± 30 mins) after start of infusion, from Cycle 1 Week 4, at predose (up to 30 mins prior to infusion), at the end of infusion (up to 
30 mins post dose), and at the 30-day SFU. Temperature to be taken pre-infusion (up to 2 h prior to all infusions).
d
As the study is intended to recruit adults, height should only be measured at Screening. Weight to be measured prior to infusions on Day 1 of each cycle, and at the 30-day 
SFU visit.
e
Participants should be in semi-supine position and resting for ≥ 10 mins before the ECGs. Single ECGs for local and central analysis are required at the following timepoints: 
for Cycle 1, Weeks 1-5 and Cycle 2 Day 1 predose (at the day of infusion prior to infusion) and within 30 mins of the end of infusion; for Cycles 3+ on Day 1 within 30 mins 
after the end of infusion, and at the 30-day SFU visit.
f
Cardiac troponin measurements are required at the following timepoints: Cycle 1, Weeks 1-5, predose (within 72 hours prior to infusion) and at 24 h after the start of the 
infusion, and Cycles 2+ on Day 1 of each cycle, predose (within 72 hours prior to infusion), and at the 30-day SFU visit. Note: either a troponin I or troponin T assay can be 
used per SoC at the respective hospital. If the hospital has both a SoC troponin I and troponin T assay available, the investigator shall use only one consistently for the 
duration of the study.
g
T4, cortisol, ACTH, and TSH to be taken predose (within 72 hours prior to infusion) on Cycle 2, Day 1, and at the 30-day SFU visit.
h
ECHO should be done within 14 days after an abnormal ECG finding (eg, T-wave inversion/flattening) or as soon as possible when clinically indicated. If an ECHO cannot 
be taken, a MUGA scan to assess LVEF will be done. In case of any T-wave abnormality, the ECHO (or MUGA) should be repeated at the 30-day follow-up visit to address 
the question of recovery, during the off-treatment period.
i
Haematology testing should be measured at Cycles 1, 2, and 3 predose (within 72 h prior to infusion) and 24 h after the start of the infusion. From Cycle 4 onwards, 
haematology testing should be predose (within 72 h prior to infusion) and (if clinically indicated) 24 h after the start of the infusion. A sample will also be drawn at the 30-
day SFU. The Investigator may take additional, unscheduled samples throughout the study if deemed clinically warranted and these need to be entered into the eCRF.
j
Coagulation testing should be measured at Cycles 1, 2, and 3 predose (within 72 h prior to infusion) and 24 h post-infusion of AZD4573. For Cycles 4-8, predose (within 
72 h of infusion); the 24-h sample can be omitted unless clinically indicated. For Cycles 9+, on Day 1 of each cycle, an AZD4573 pre-infusion sample will be drawn within 
72 h prior to infusion. A sample will also be drawn at the 30-day SFU. The Investigator may take additional, unscheduled samples throughout the study if deemed clinically 
warranted and these need to be entered into the eCRF.
k
Clinical chemistry should be measured at Cycles 1, 2, and 3 predose (within 72 h prior to infusion), and 24 h post-infusion of AZD4573. From Cycle 4 onwards, clinical 
chemistry testing should be measured predose (within 72 h prior to infusion) and (if clinically indicated) 24 h after the start of the infusion. A sample will also be drawn at 
the 30-day SFU. The investigator may take additional, unscheduled samples throughout the study if deemed clinically warranted and these need to be entered into the eCRF. 
Clinical chemistry tests do not need to be repeated before first dose if the first-dose visit is within 3 days of the most recently available sample.
In addition, GLDH and CPK will be measured before the first dose in Period 2 for all participants. If GLDH cannot be performed locally, LDH will be analysed locally and a 
serum sample must be collected for central retrospective GLDH analysis, which will be performed as applicable. Refer to the Laboratory Manual for details.
If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, potassium) and troponin must be done to coincide with the ECG testing.
l
Urine samples will be collected at the following timepoints: Cycles 1-8, predose AZD4573 (within 72 hours prior to infusion) and within approximately 2 hours after the end 
of infusion, Cycles 9+ on Day 1 of each cycle, predose AZD4573 and within approximately 2 hours after the end of infusion, and at the 30-day SFU.
m
Pregnancy test to be performed once every 21 days (± 7 days) prior to initiating a new cycle and at the 30-day SFU visit (serum or urine). Additional testing may be 
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n
Lipase and amylase should be evaluated at Cycles 1-8 predose AZD4573 (within 72 hours prior to infusion), Cycles 9+, predose AZD4573 (within 72 hours prior to infusion) 
on Day 1 of each cycle, and at the 30-day SFU visit.
o
Participants who are anti-HBc positive, or have a known history of HBV infection, should be monitored every 3 months with a quantitative PCR test for HBV DNA. Any 
participants testing positive for any hepatitis serology must have PCR testing for verification purposes.
p
CD4, CD8, CD19, CD16/NK and serum immunoglobulins (IgA, IgM, IgG) will be drawn at Day 1 (predose) of Cycles 2, 4, 7, 9, 13, 16, 19 and every 6 months thereafter 
(predose), and at the 30-day SFU.
q
Plasma samples for PK analysis will be taken at the following time points: For Cycle 1, of Weeks 1 and 3 : predose (up to 2 h prior to AZD4573) and 1 h (± 15 mins), 2 h (± 
15 mins), 4 h (± 30 mins), 7 h (± 1 h), and 24 h (± 1 h) (ie, Day 2 of dosing) after the start of the infusion.
r
Pharmacodynamic evaluations for AZD4573 blood samples will be collected at Cycle 1, Week 1 at predose (up to 2 h prior to dosing) and 2 h (± 15 mins), 4 h (± 30 mins), 
7 h (± 1 hour), and 24 h (± 2 h) (ie, Day 2) after the start of the infusion.
s
Pharmacodynamic evaluations for acalabrutinib: blood samples (whole blood) are to be taken predose on Cycle 1, Week 1, predose (up to 2 h prior to dosing and prior to 
acalabrutinib dose), and on Cycle 1, Week 4, (up to 2 h prior to dosing and prior to acalabrutinib dose).
t
 Samples will be taken for all participants at Cycle 1, Week 1: predose (within 2 h prior to dosing) and 4 h (± 30 mins), 7 h (± 1 h), and 24 h (± 1 
h) after start of infusion. If the participant has 
 at 24 h after start 
of infusion, samples will be drawn at 48 h (-2 h/+12 h prior to infusion), 96 h (- 2 h/+12 h prior to infusion), predose-the-following infusion (within 4 h prior to infusion), and 
at each point chemistry panel testing is being performed. 
 sampling should be 
performed the same as for Cycle 1, Weeks 1. 
u
Whole blood for exploratory 
 samples will be collected at Cycle 1, Weeks 1, 3, and 5 predose (within 2 h prior to dosing), Cycle 2, Days 
1 and 15 predose (within 2 h prior to dosing), Day 1 of Cycles 3, 5, 6 and 7 predose (within 2 h prior to dosing), and at every scheduled or unscheduled tumour assessment 
scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken at End of Treatment, a sample should be obtained at 
the 30-day SFU.
v
Whole Blood for 
 will be collected at Cycle 1, Weeks 1, 3, and 5 
predose (within 2 h prior to dosing), Cycle 2, Days 1 and 15, predose (within 2 h prior to dosing), and on Day 1 of Cycles 3, 5, 6, and 7 predose (within 2 h prior to dosing), 
and at every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not 
taken at End of Treatment, a sample should be obtained at the 30-day SFU.
w
Whole blood samples for 
 will be collected at Cycle 1, Weeks 1 and 3 predose (within 2 h prior to dosing) and 24 h (± 2 h), Cycle 2, Days 1 and 15, 
predose (within 2 h prior to dosing), Day 1 of Cycles 3, 5, and 7 predose (within 2 h prior to dosing), and at every scheduled or unscheduled tumour assessment scan (if on 
the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken at End of Treatment, a sample should be obtained at the 30-day 
SFU.
x
Whole blood samples for 
 will be collected at Cycle 1, Weeks 1 and 3 predose (up to 2 h prior to dosing), Cycle 2, Days 1 and 15 predose (within 2 h 
prior to dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of treatment. 
If a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
y
Whole blood for 
 exploratory analysis samples will be collected at, Cycle 1, Week 1 predose (within 2 h prior to dosing), Day 1 of Cycles 2, 3, 5, and 7 predose 
(within 2 h prior to dosing), and at every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion), and at disease progression/end of 
treatment. If a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
z
Exploratory blood 
 Whole blood samples will be collected at Cycle 1 Week 1 at predose (within 2 h prior to dosing), 2 h (± 15 mins) and 24 h (± 2 h) 
after the start of the infusion and on Day 1 of Cycles 2, 3, 5, and 7 predose (within 2 h prior to dosing), and at every scheduled or unscheduled tumour assessment scan (if on 
the day of infusion, collect pre-infusion), and at disease progression/end of treatment. If a sample is not taken at End of Treatment, a sample should be obtained at the 30-day 
SFU.
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aa
An optional saliva sample for genomics initiative research will be taken from consenting participants prior to the first dose of IP in Period 1. If for any reason the sample is 
not taken before dosing it may be taken at any visit until the last study visit. Only one sample should be collected per participant for genetics during the study.
bb
A biopsy will be taken at disease progression for participants who consent. The disease progression sample may be taken at the SFU visit if not collected previously.
cc
Bone marrow biopsy and aspirate: 
 
dd
See Table 38 for schedule of disease assessments, including mandatory PET assessments. Disease assessments will be done by the Investigator using the Lugano Response 
Criteria for Non-Hodgkin’s Lymphoma (Cheson et al 2014). Additional disease assessments may be performed as clinically indicated.
ee
AZD4573 is to be administered as an absolute (flat) dose, 2-h (± 15 mins) IV infusion on a once-weekly schedule.
ff
Acalabrutinib 100 mg oral capsule to be given twice per day.
gg
Participant-reported drug administration for acalabrutinib needs to be done on every AZD4573 dosing day, ideally prior to dosing (± 24 h) and is also to be done after the 
last acalabrutinib capsule is taken and the leftover capsules returned to site. Drug accountability for acalabrutinib will occur every 2 weeks, (on an AZD4573 dosing day, 
ideally prior to dosing [± 24 h]).
hh
If a participant is attending Cycle 9+ visits according to a modified schedule, in which AZD4573 is not infused and assessments are not performed every week, the Day 1 
assessments should be performed at least once per cycle.
ii
The End of Treatment visit is the last visit attended by the participant prior to the 30-Day SFU on the study. At this visit, the participant does not receive IMP and should 
undergo the applicable assessments associated with the Cycle and visit they have reached, plus those shown in the “Disease Assessment/End of Treatment” column of the 
SoA. 
jj
AZD4573 should be administered at least 5 days apart
Abbreviations: ACTH = adrenocorticotropic hormone; BID = twice daily; CMV = cytomegalovirus; CSP = clinical study protocol; ECG = electrocardiogram; eCRF = electronic 
case report form; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; GLDH = glutamic dehydrogenase; Ig = immunoglobulin; 
 
LTFU = long-term follow-up; 
 MUGA = multigated acquisition; 
 PCR = polymerase chain 
reaction; PK = pharmacokinetics; SFU = safety follow-up; SoC = standard of care; T4 = thyroxine; TLS = tumour lysis syndrome; TSH = thyroid-stimulating hormone.
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20
INTRODUCTION – MODULE 2
20.1
Study Rationale – Module 2
Mantle cell lymphoma (MCL) is clinically characterised by its heterogenous behaviour, 
ranging from indolent disease that may not require therapy for many years, to aggressive 
disease with poor prognosis. Although MCL generally responds to initial treatment, a majority 
of patients relapse (Goy and Kahl 2011). Treatment options for r/r MCL include 
immunochemotherapy, molecular targeted therapy including BTK inhibitors, and 
immunotherapies, including CAR-T therapy (Silkenstedt et al 2021).
Acalabrutinib, a potent and selective BTK inhibitor, is approved by the Food and Drug 
Administration (FDA) for the treatment of adults with MCL who have received at least one 
prior therapy. In a Phase II study of acalabrutinib involving 124 participants with relapsed or 
refractory (r/r) MCL, 81% of participants had a complete response (complete response [CR], 
40%) or partial response (PR 41%) after a median of 15.2 months of follow-up. Kaplan-Meier 
(KM) estimates of median duration of response (DoR), progression-free survival (PFS) and 
overall survival (OS) were not reached (Wang et al 2018). At long-term follow-up after a 
median of 38.1 months, the median DoR was 28.6 months (95% confidence interval (CI) 
17.5-39.1 months] and median PFS was 22.0 months (16.6-33.3 months) (Wang et al 2020).
The combination of AZD4573 and acalabrutinib may yield greater clinical benefit than either 
treatment alone. The effect of acalabrutinib in lowering the apoptotic threshold by induction of 
pro-apoptotic proteins or reduction of anti-apoptotic proteins (Deng 2017a) is expected to play 
an additive or synergistic role in targeting the apoptotic defects when administered in 
combination with AZD4573.
20.2
Acalabrutinib Background
For background information on AZD4573, please refer to Section 2.2.
Acalabrutinib is also known as ACP-196 and Calquence®. Calquence is approved in the 
United States and is either approved or under regulatory assessment in other countries as:

Monotherapy for the treatment of adult patients with MCL who have received at least one 
prior therapy.

Monotherapy and in combination with obinutuzumab for the treatment of adult patients 
with CLL or small lymphocytic lymphoma (SLL).
Acalabrutinib is a selective, irreversible small molecule BTK inhibitor. In B cells, BTK 
signaling results in activation of pathways necessary for B-cell proliferation, trafficking, 
chemotaxis, and adhesion. Acalabrutinib and its major metabolite ACP-5862 inactivate BTK 


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by forming a covalent bond with a cysteine residue in the kinase active site. This leads to 
inhibition of signaling through the B-cell receptor (BCR) in sensitive cells. In nonclinical and 
clinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling 
proteins CD86 and CD69 and inhibited malignant B-cell proliferation and survival.
20.2.1
Clinical Experience with Acalabrutinib
As of 30 October 2020, more than 6000 participants have participated in acalabrutinib clinical 
studies, with approximately 4500 participants receiving acalabrutinib as monotherapy or in 
combination with other agents in the oncology program. Clinical studies have included 
participants with haematological malignancies, solid tumours, or rheumatoid arthritis, and 
participants who are healthy subjects or those with mild to moderate hepatic impairment.
No DLTs have been identified in any studies for acalabrutinib monotherapy and very few with 
acalabrutinib (given as 100 mg twice daily) in combination with other agents. Important 
identified risks for acalabrutinib are haemorrhage, atrial fibrillation/flutter, infections, 
cytopenias, and second primary malignancies. Transaminase elevations (ALT/AST) are 
considered an important potential risk when the drug is given as monotherapy.
Efficacy data summarised below are based on two pivotal clinical studies in CLL/SLL 
(ACE-CL-007 and ACE-CL-309) and 3 supportive clinical studies in CLL/SLL 
(ACE-CL-001, ACE-CL-003, and 15-H-0016). Assessment of overall response was based on 
modified International Workshop on Chronic Lymphocytic Leukemia (iwCLL) response 
criteria (Hallek et al 2008) for CLL/SLL participants, with incorporation of the clarification 
for treatment-related lymphocytosis (Cheson et al 2012).
Ongoing Phase III Pivotal Studies in CLL
Efficacy data for acalabrutinib monotherapy (100 mg twice daily) as well as efficacy data for 
the combination of acalabrutinib 100 mg twice daily with obinutuzumab from two pivotal 
ongoing Phase III studies in previously untreated CLL (ACE-CL-007; 
 
, and r/r CLL (ACE-CL-309;
 
Study ACE-CL-309 enrolled and randomised a total of 310 participants 
 
Acalabrutinib demonstrated a 69% reduction in risk of Independent Review Committee 
(IRC)-assessed disease progression or death compared with idelalisib + rituximab 
/bendamustine and rituximab (IR/BR; hazard ratio [HR] = 0.31 [95% CI: 0.20, 0.49], 
p < 0.0001). The clinical benefit with acalabrutinib was further demonstrated by a clinically 
relevant improvement in DoR for acalabrutinib compared with IR/BR, both by IRC 
assessment (HR = 0.33) and Investigator-assessment (HR = 0.20), and a significant 
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prolongation of time to next treatment (TTNT) for acalabrutinib compared with IR/BR 
(HR = 0.35; p < 0.0001).
Study ACE-CL-007 enrolled and randomised a total of 535 participants 
 
Acalabrutinib + obinutuzumab demonstrated a statistically significant improvement in 
IRC-assessed PFS compared with obinutuzumab + chlorambucil, with a 90% reduction in risk 
of disease progression or death (HR = 0.10 [95% CI: 0.06, 0.17]; p < 0.0001). Acalabrutinib 
monotherapy also demonstrated a statistically significant improvement in IRC-assessed PFS 
compared with obinutuzumab + chlorambucil, with an 80% reduction in risk of disease 
progression or death (HR = 0.20 [95% CI: 0.13, 0.30]; p < 0.0001). The clinical benefit with 
acalabrutinib was further demonstrated by a significant prolongation of TTNT compared with 
obinutuzumab + chlorambucil for both acalabrutinib + obinutuzumab (HR=0.14 [95% CI: 
0.08, 0.26]; p < 0.0001) and acalabrutinib monotherapy (HR = 0.24 [95% CI: 0.15, 0.40]; 
p < 0.0001).
Supportive Studies
Efficacy data for acalabrutinib monotherapy (100 mg twice daily) as well as efficacy data for 
the combination of acalabrutinib 100 mg twice daily with obinutuzumab from 3 supportive 
ongoing studies in CLL: ACE-CL-001 
, 15-H-0016 
 
, and ACE-CL-003 
 
A total of 300 participants received acalabrutinib in the 3 supportive studies, including 166 r/r 
participants and 134 previously untreated participants. The efficacy results in the supportive 
studies in participants with r/r and previously untreated CLL are consistent with the results of 
the pivotal studies. Investigator assessed objective response rate (ORR) in all studies ranged 
from 87.5% to 100%. Across all cohorts, 6.0% of participants achieved CR, and 85.3% of 
participants achieved PR as a best response. The median DoR (PR or better) was not reached 
in any of the cohorts (range: 0.07+ to 51.3+ months).
Acalabrutinib, is approved by the FDA for the treatment of adults with MCL who have 
received at least one prior therapy. In a Phase II study of acalabrutinib involving 124 
participants with r/r MCL, 81% of participants had a CR (40%) or PR (41%) after a median of 
15.2 months of follow-up. Kaplan-Meier estimates of median DoR, PFS, and overall survival 
(OS) were not reached (Wang et al 2018). At long-term follow-up after a median of 38.1 
months, the median DoR was 28.6 months (95% CI 17.5-39.1 months] and median PFS was 
22.0 months (16.6-33.3 months) (Wang et al 2020).
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Acalabrutinib has also been preliminarily assessed as monotherapy in patients with r/r de novo 
DLBCL (Dreyling et al 2018, Dyer et al 2018). In the latter study, among 21 participants 
enrolled, an ORR of 24% (19% CRs) was observed.
For more detailed information on the clinical experience for acalabrutinib, refer to the 
20.3
Benefit/Risk Assessment – Module 2
For more detailed information about the known and expected benefits and potential risks of 
AZD4573, please refer to Section 2.3
More detailed information about the known and expected benefits and potential risks of 
AZD4573 and acalabrutinib in combination are summarised below. 
 
 
20.3.1
Risk Assessment
Important identified risks for acalabrutinib are:

Haemorrhage

Atrial fibrillation

Infections

Cytopenias

Second primary malignancies
Potential for overlapping toxicities between AZD4573 and acalabrutinib include TLS, 
haemorrhage, cytopenias, infection including hepatitis B reactivation, gastrointestinal 
toxicities (nausea, vomiting, and diarrhoea), and liver enzyme abnormalities (Grade 3 and 
Grade 4 transaminase elevations) with the important potential risk of hepatic injury (Table 
25).
Detailed descriptions of safety concerns and management are provided in Section 26.1. 
Investigators should be particularly alert to the possibility of TLS, significant bleeding and 
infection, including opportunistic and fungal infections, and care must be taken to monitor 
platelets and neutrophil counts in accordance with the SoA and more frequently as clinically 
indicated. ‘Rescue medications’, including platelet transfusions and granulocyte-colony-
stimulating factor (G-CSF), are permitted at any time during the study, at the discretion of the 
Investigator. Specific and detailed guidance is also given in this protocol regarding the 
management of events of hepatic dysfunction or toxicity.
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Several measures, including project-specific, safety-related inclusion/exclusion criteria, 
physical examinations, evaluation AEs/SAEs, and laboratory testing throughout the study and 
study treatment modifications and toxicity management guidelines have been incorporated 
into the study protocol to mitigate any potential or identified risks associated with combining 
these agents. For further information, refer to the reference safety information for AZD4573 
and/or Calquence accordingly.
Table 25
Risk Assessment – AZD4573 Monotherapy
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Study Intervention AZD4573 Monotherapy
Diarrhoea
Diarrhoea is an identified risk for AZD4573.
Refer to Section 26.1.10.2
Nausea and vomiting
Nausea and/or vomiting are identified risks for 
AZD4573.
Refer to Section 26.1.10.3
Infections
Infection is an important potential risk for AZD4573.
Refer to Section 26.1.10.7
Cytopenia
Neutropenia is an important identified risk for 
participants treated with AZD4573.
Refer to Section 26.1.10.8
Liver chemistry test 
abnormalities
Grade 3 and Grade 4 transaminase elevations with 
bilirubin increase are an important identified risk for 
participants treated with AZD4573.
Refer to Section 17.1.10.9
Hepatic injury
Events of hepatotoxicity have been reported in clinical 
studies with acalabrutinib however, no causal 
relationship has been established. Subjects with 
hepatotoxicity should be monitored for resolution, and 
dose modification or interruption of acalabrutinib may 
be indicated. In addition, subjects should be managed 
according to study protocols as well as institutional 
guidelines with supportive care.
Refer to Section 17.1.10.9
Tumour lysis 
syndrome (TLS)
TLS is an important identified risk for AZD4573.
Refer to Section 26.1.10.10
Infection/Bone 
marrow toxicity with 
peripheral effect/ 
lymphoid tissue 
hypocellularity
Infection / bone marrow toxicity with peripheral effect 
/ lymphoid tissue hypocellularity is an important 
potential risk for AZD4573.
Refer to Section 26.1.10.13
Pancreatic and 
Cortical Adrenal 
Injury (as well as 
Surveillance for 
Pancreatic injury and cortical adrenal injury are 
potential risks for AZD4573 based on preclinical 
observations.
Refer to Section 26.1.10.14


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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Renal, Thymus, and 
Spleen Toxicity)
Drug-drug 
interactions
Specific drug-drug interaction studies have not yet 
been performed for AZD4573. 
Refer to Section 26.1.10.15
Myocardial 
ischaemia
Myocardial ischaemia and increased heart rate are 
considered potential risks for AZD4573.
Refer to Section 26.1.10.16
Study Procedures
Infusion site 
reactions
As with other drugs administered intravenously, local 
infusion site reactions (eg, infusion pain, infusion site 
reaction, skin or vein irritation) may occur.
Refer to Section 26.1.10.17
Risk Assessment – AZD4573 + Acalabrutinib Combination Therapy
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Study Intervention (s) AZD4573 and acalabrutinib
Headache
Headache is an identified risk for acalabrutinib.
Refer to Section 26.1.10.1
Diarrhoea
Diarrhoea is an identified risk for AZD4573 and 
acalabrutinib.
Refer to Section 26.1.10.2
Nausea and vomiting
Nausea and/or vomiting are identified risks for 
AZD4573 and acalabrutinib.
Refer to Section 17.1.10.3
Hepatitis B 
reactivation
Serious or life-threatening reactivation of viral 
hepatitis have been reported in patients treated with 
acalabrutinib.
Refer to Section 26.1.10.4
Progressive 
multifocal 
leukoencephalopathy 
(PML)
Cases of PML have been reported in patients treated 
with acalabrutinib.
Refer to Section 26.1.10.5
Haemorrhage
Bleeding events, some fatal, including central nervous 
system, respiratory, and gastrointestinal haemorrhage, 
have been reported in patients treated with 
acalabrutinib.
Refer to Section 26.1.10.6
Infections
Serious infections, including fatal events, have been 
reported in patients treated with acalabrutinib and it is 
an important identified risk. Infection is an important 
potential risk for AZD4573.
Refer to Section 26.1.10.7
Cytopenia
Haematological toxicities including neutropenia, 
anaemia, and thrombocytopenia have occurred in 
patients treated with acalabrutinib, and neutropenia is 
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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
an important identified risk for participants treated 
with AZD4573 or acalabrutinib.
Liver chemistry test 
abnormalities
Transaminase elevations are an important potential 
risk for patients treated with acalabrutinib, and an 
important identified risk for participants treated with 
AZD4573.
Refer to Section 26.1.10.9
Hepatic injury
Self-limiting biochemical events fulfilling potential 
Hy’s law criteria are very common with AZD4573 
monotherapy, but there have been no cases of 
fulminant hepatotoxicity to date.
Refer to Section 26.1.10.9
Tumour lysis 
syndrome (TLS)
TLS is an important identified risk for AZD4573 and 
an identified risk for acalabrutinib.
Refer to Section 26.1.10.10
Second primary 
malignancies
Second primary malignancies, including non-skin 
cancers, have been reported in patients treated with 
acalabrutinib.
Refer to Section 26.1.10.11
Atrial 
fibrillation/flutter
Atrial fibrillation/flutter have been reported in patients 
treated with acalabrutinib. Heart rate increase is a 
potential risk for AZD4573, and cases of atrial 
fibrillation have occurred in participants treated with 
AZD4573.
Refer to Section 26.1.10.12
Infection/Bone 
marrow toxicity with 
peripheral effect/ 
lymphoid tissue 
hypocellularity
Infection / bone marrow toxicity with peripheral effect 
/ lymphoid tissue hypocellularity is an important 
potential risk for AZD4573.
Refer to Section 26.1.10.13
Pancreatic and 
Cortical Adrenal 
Injury (as well as 
Surveillance for 
Renal, Thymus, and 
Spleen Toxicity)
Pancreatic injury and cortical adrenal injury are 
potential risks for AZD4573 based on preclinical 
observations.
Refer to Section 26.1.10.14
Drug-drug 
interactions
Specific drug-drug interaction studies have not yet 
been performed for AZD4573. Acalabrutinib may be 
affected by agents that reduce gastric acidity (antacids 
or proton-pump inhibitor).
Refer to Section 26.1.10.15
Myocardial 
ischaemia
Myocardial ischaemia and increased heart rate are 
considered potential risks for AZD4573.
Refer to Section 26.1.10.16


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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Study Procedures
Infusion site 
reactions
As with other drugs administered intravenously, local 
infusion site reactions (eg, infusion pain, infusion site 
reaction, skin or vein irritation) may occur.
Refer to Section 26.1.10.17
The Investigator sites participating in this study are all experienced oncology centres and are 
well equipped for treating patients with relapsed and refractory disease and in the management 
of haematological toxicities. Furthermore, the protocol has dose reductions and dose 
interruption criteria to also allow for the management of any potential dose-related toxicity.
20.3.2
Benefit Assessment
Preliminary anti-tumour activity has been observed with AZD4573 as monotherapy in 
participants with r/r haematological malignancies in the ongoing Phase I, FTIH, dose-
escalation study (D8230C00001; see Section 2.2.6). 
 
Clinical benefit in patients with MCL has been reported for other CDK inhibitors. In a 
Phase II study of MCL participants receiving flavopiridol, PR occurred in 11% (95% CI, 2%-
28%) of participants and the median duration of response was 3.3 months (range 2.8-13.2) 
(Kouroukis et al 2003). In a Phase I study among 16 participants with lymphoma receiving 
dinaciclib, one participant had MCL; this participant had an 8% reduction in tumour mass 
(Baiocchi et al 2010).
The addition of agents which in combination could provide more continuous anti-tumour 
activity may reasonably be expected to significantly enhance clinical benefit with manageable 
changes to risk. Acalabrutinib , a BTK inhibitor like ibrutinib, has been shown to inhibit 
proliferation and induce apoptosis in B-cell malignancies (Davis et al 2010, 
Harrington et al 2016). The latter is likely due to the ability of BTK inhibitors to increase 
certain pro-apoptotic BCL2 family proteins, like Bim, (Deng 2017a, Deng et al 2017b, 
Sasi et al 2019) pushing the cancer cells closer to their apoptotic threshold, a mechanism 
known as ‘apoptotic priming’ (NCCN 2021, Ni Chonghaile et al 2011). Capitalising on this 
apoptotic priming, addition of AZD4573 following a short lead-in of acalabrutinib in the OCI-
LY10 DLBCL xenograft model causes an increase in both the magnitude and duration of anti-
tumour response, compared to either monotherapy, as demonstrated by more rapid and robust 
cleavage of caspase-3 and delayed time to tumour regrowth following treatment cessation 
(Patent WO2019/058348; data on file, AstraZeneca). Acalabrutinib is a highly selective, 
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potent, covalent inhibitor of BTK with minimal off-target activity leading to a safety profile 
that may be attractive for combination strategies.
20.3.3
Overall Benefit/Risk Conclusion
Eligible participants will be r/r to prior treatments for their disease, have received one prior 
line of therapy, and for whom a clinical study is the best option (in the opinion of the 
Investigator) for next treatment based on response and/or tolerability to prior lines of therapy. 
Furthermore, participants will have varying levels of disease burden at study entry and almost 
certainly have acquired mutations as part of their disease course. Therefore, there is no 
guarantee that any participant will derive clinical benefit during this study.
AstraZeneca believes the anticipated benefits that may be afforded to participants with 
r/r haematological malignancies currently outweigh the identified and potential risks 
associated with AZD4573 in combination with acalabrutinib.
As described, the study design aims to minimise risks and build on the preliminary efficacy 
seen to date in the ongoing FTIH study (D8230C00001), reflecting clinical responses in a r/r 
participant population. Thus, the benefit/risk assessment for administration of AZD4573 with 
acalabrutinib is considered acceptable for participants with r/r MCL.
For an assessment of benefit and risks pertaining to the conduct of this study during the 
COVID-19 pandemic, refer to Appendix A 11.


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21
OBJECTIVES AND ENDPOINTS – MODULE 2
Objectives and Endpoints for Part A are outlined in Table 26. An additional primary objective 
was included for Module 2, regarding AZD4573 monotherapy in MCL.
Table 26
Objectives and Endpoints – Module 2
Objectives
Endpoints
Primary
Part A

Assess the safety and tolerability of the 
RP2D of AZD4573 in combination with 
acalabrutinib (100 mg BID) for participants 
who are administered AZD4573 
monotherapy

Adverse events (including SAEs), dose 
modifications, treatment discontinuation 
due to AE, AESIs, laboratory data, vital 
signs, and ECG changes

Assess the safety and tolerability and 
confirm the RP2D of AZD4573 
monotherapy in MCL

Adverse events (including SAEs), dose 
modifications, treatment discontinuation 
due to AE, AESIs, laboratory data, vital 
signs, and ECG changes
Secondary
Part A

Assess the plasma PK of AZD4573 (when 
given alone and in combination with 
acalabrutinib 100 mg) and acalabrutinib 
(plus its active metabolite ACP-5862)

Plasma concentrations and derived PK 
parameters for AZD4573 for the PK 
analysis set

Plasma concentrations and derived PK 
parameters for acalabrutinib and its 
metabolite ACP-5862 for the PK analysis 
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Objectives
Endpoints
Exploratory
Part A

Explore activity of AZD4573 alone, and in 
combination with acalabrutinib by 
evaluation of tumour responses and overall 
survival

Endpoints based on revised response 
criteria for malignant lymphoma 
(Cheson et al 2014):

ORR

Proportion of participants 
with CR

DoR

TTR

PFS

OS

Assess the PD of AZD4573 (alone and in 
combination with acalabrutinib) and the PD 
of acalabrutinib (in combination with 
AZD4573)

 
 

 
 

 
 
 
 
 
 

 
 
 
 

 
 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; BID = twice daily; CR = complete 
response; 
 ECG = electrocardiogram; MCL = mantle cell lymphoma; 
 
PK = pharmacokinetics; 
 
RP2D = recommended Phase II dose; SAE = serious adverse event; 
The study design of Part B of this module will be determined from the data emerging from 
Part A. Specifics for Part B will be defined in a future protocol amendment.
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22
STUDY DESIGN – MODULE 2
Module 2 will not open for enrolment until the RP2D for AZD4573 + acalabrutinib has been 
established in Part A of Module 1.
22.1
Overall Design
Module 2 is a window study comprising 2 cycles (8 weeks) of AZD4573 monotherapy 
(Period 1) followed by AZD4573 + acalabrutinib combination treatment (Period 2). It will 
enrol participants with r/r MCL who have failed at least one line of prior therapy, are not 
eligible for curative treatment options. AZD4573 will be administered in Part A as 
monotherapy (Period 1) and in combination with acalabrutinib 100 mg twice daily (Period 2). 
Cycle 1 of each dosing period has a duration of 35 days; subsequent cycles have a duration of 
21 days. AZD4573 should be administered at least 5 days apart.
The AZD4573 monotherapy RP2D includes an intra-patient ramp up; participants will receive 
AZD4573 6 mg at Cycle 1 Week 1, AZD4573 9 mg at Cycle 1 Week 2, and AZD4573 12 mg 
from Week 3 and thereafter.
The AZD4573 FTIH study (Study D8230C00001) established the AZD4573 monotherapy 
RP2D in DLBCL (12 mg once weekly), but the dose setting did not include any MCL 
participants. Hence, in Part A, Period 1 of Module 2 aims to confirm the AZD4573 
monotherapy RP2D in MCL participants. If AZD4573 monotherapy is not tolerated in r/r 
MCL participants, there will be no dose exploration/dose setting conducted in this study. At 
this time, it is unlikely that AZD4573 monotherapy would be developed at a dose lower than 
12 mg in MCL.
Participants will move from AZD4573 monotherapy to combination treatment (AZD4573 + 
acalabrutinib) based on the Lugano overall response (Cheson et al 2014). See Table 36 for 
details.
In Period 2, the safety and tolerability of the RP2D of AZD4573 + acalabrutinib established in 
Module 1 will be assessed in participants with MCL. As participants will have reached an 
AZD4573 dose of 12 mg 1QW (the maximum dose in combination with acalabrutinib in dose 
setting Module 1) during Period 1, a further intra-patient ramp up will not be required in 
Period 2 Cycle 1. Treatment with AZD4573 + acalabrutinib combination therapy may be 
continued until disease progression, an unacceptable drug-related toxicity occurs, or the 
participant withdraws or is withdrawn from the study as defined in the protocol.
The SRC will meet after the first 6 participants have completed Part A, Period 1, Cycle 1, and 
again after the first 6 participants entering Period 2 have completed Cycle 1. The SRC will 


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continue to monitor safety and tolerability data for all participants in Part A. For further details 
refer to Section 27.5.
The data cut-off for the primary analysis of Part A will occur approximately 6 months 
following last-participant first-dose of AZD4573 monotherapy or when 75% of participants 
have progressed or died in Part A, whichever occurs first. All available data from Period 1 
(AZD4573 monotherapy) and Period 2 (AZD4573 plus acalabrutinib) will be analysed.
Additional data cuts may also be performed.
All participants will be followed for survival until death, loss to follow-up, the Sponsor closes 
the study, or withdrawal of consent, whichever occurs first.
The study design of Part B of Module 2 will be determined from the data emerging from 
Part A. Specifics of Part B will be defined in a future protocol amendment.
The final analysis will be conducted at the end of the module.
22.2
Scientific Rationale for Study Design
The study design proposed is based on both preclinical and clinical data. Mcl‐1 has been 
shown to be highly expressed in 2 human MCL cell lines and in tumours from 12 of 
36 patients with MCL, and expression appeared to correlate with high-grade morphology 
(Khoury et al 2003). Aberrant expression of MCL‐1 has recently been implicated in 
lymphomagenesis (Zhou et al 2001), and it is hypothesised that the expression of MCL-1
could contribute to the pathogenesis of MCL. 
 
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 Clinical benefit in participants with MCL has also been reported for 
other CDK inhibitors. Partial response occurred in 11% (95% CI, 2%-28%) of participants 
with MCL receiving flavopiridol in a Phase II study, the median DoR was 3.3 months (range 
2.8-13.2) (Kouroukis et al 2003). Among 16 participants with lymphoma receiving dinaciclib 
in a Phase I study, one participant had MCL and an 8% reduction in tumour mass was 
recorded (Baiocchi et al 2010).
Acalabrutinib, is approved by the FDA for the treatment of adults with MCL who have 
received at least one prior therapy. In a Phase II study of acalabrutinib involving 124 
participants with r/r MCL, 81% of participants had a CR (40%) or PR (41%) after a median of 
15.2 months of follow-up. Kaplan-Meier estimates of median DoR, PFS, and OS were not 
reached (Wang et al 2018). At long-term follow-up after a median of 38.1 months, the median 
DoR was 28.6 months (95% CI 17.5-39.1 months] and median PFS was 22.0 months 
(16.6-33.3 months) (Wang et al 2020).
The combination of AZD4573 and acalabrutinib may yield greater clinical benefit than either 
treatment alone. The effect of acalabrutinib in lowering the apoptotic threshold by induction of 
pro-apoptotic proteins or reduction of anti-apoptotic proteins (Deng 2017a) is expected to play 
an additive or synergistic role in targeting the apoptotic defects when administered in 
combination with AZD4573. 
 
 
 As there are limited data 
available on AZD4573 monotherapy in patients with MCL, Part A of the Module 2 study 
design includes a window study of 2 cycles of AZD4573 monotherapy in each participant 
before starting combination treatment with acalabrutinib. This approach will allow AZD4573 
monotherapy dose confirmation in participants with MCL before investigating the anti-cancer 
activity of the AZD4573 and acalabrutinib combination treatment.
For a monotherapy study using AZD4573 in MCL, participants with at least 2 prior lines of 
treatment including a BTK inhibitor would normally have been enrolled. Notably, the current 
study implements a window study design where the BTK inhibitor acalabrutinib will be 
subsequently added, as a combination treatment, to all participants who do not achieve a 
treatment response after 2 cycles of AZD4573 monotherapy. Hence, MCL participants who 
are BTK-inhibitor naive and have progressed after one prior line of treatment can be safely 
enrolled in the current window study, keeping in mind that they will receive appropriate BTK 
inhibition per protocol.
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23
STUDY POPULATION – MODULE 2
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Participants must meet the inclusion and exclusion criteria of both the core and module 
protocol. Where there are differences in stringency or cut-off values, the specific module takes 
precedence. For example, if haematological medication parameters are stricter in the module 
than in the core, the Investigator should adhere to the module criteria.
23.1
Inclusion Criteria
Each participant should meet all the inclusion criteria (and none of the exclusion criteria) for 
this study in order to be assigned to a study cohort. Under no circumstances can there be 
exceptions to this rule.
NOTE: This Module will be enrolling participants with r/r MCL only.
For inclusion in the study, participants must fulfil all of the following criteria:
1
Participants must meet the eligibility criteria described in Section 5.1.
2
Participants with histologically confirmed r/r MCL for whom a clinical study is the best 
option (in the opinion of the investigator) for next treatment based on response and/or 
tolerability to prior lines of therapy.
PART A

Participants with r/r MCL:

Diagnosis must be confirmed by biopsy and be immunohistologically characterised.

Tumour tissue must also be available for sending to AstraZeneca for pathology
testing.
All participants in Part A must consent to and provide archival tumour specimens, 
preferably in the form of a formalin-fixed paraffin embedded block (tissue derived 
from the diagnostic tumour or a metastatic site). If this is not possible, an appropriate 
number of slides of freshly prepared unstained 5-micron sections from the archival 
tumour block may be provided as defined in the study Laboratory Manual. Archival 
tumour specimens must be obtained within 24 months before the first dose of IP. If 
archival material is unavailable or unsuitable for use, participants must consent to and 
undergo a fresh tumour biopsy during the screening period. A fresh biopsy is strongly 
encouraged and preferred, however, a participant will be enrolled based on the prior 
pathology report.


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3
Presence of radiographically measurable lymphadenopathy or extranodal lymphoid 
malignancy (according to the Lugano criteria [Cheson et al 2014]).
4
Participants must have failed at least one prior therapy for the treatment of current disease 
and not be eligible for treatment with curative intent (e.g. allogenichaematopoietic cell 
transplantation [HCT]). Eligible participants include both BTKi-naïve and BTKi-exposed.
5
Adequate haematologic function at Screening, as defined in Table 27:
(a) No growth factor support within 14 days prior to the date of the screening laboratory 
assessment.
(b) No transfusions within 7 days prior to the date of the screening laboratory 
assessment.
Table 27
Criteria for Adequate Haematological Function
Category
Parameter
Value
Haematologic
Haemoglobin
≥ 8.0 g/dL
Absolute neutrophil count
≥ 1000 cells/mm3 (1.0 × 109/L)
Platelet count
≥ 75,000 cells/mm3 (75 × 109/L) 
without bone marrow involvement
≥50,000 cells/mm3 (50 × 109/L) 
with bone marrow involvement

If indicated, transfusions or growth factors can be administered during the screening 
period, but such cases of deterioration of haematological function must be discussed 
with the Medical Monitor, to confirm start of study treatment.
6
Optional tumour biopsy on study: Participants are also encouraged to consent to and 
undergo an optional tumour biopsy at disease progression to support correlative 
biomarker studies.
7
All participants must be willing and able to provide mandatory baseline bone marrow 
biopsy/aspirate.
23.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1
Participants must comply with the exclusion criteria described in Section 5.2.
2
Current refractory nausea and vomiting, malabsorption syndrome, disease significantly 
affecting gastrointestinal function, resection of the stomach, extensive small bowel 
resection that is likely to affect absorption, symptomatic inflammatory bowel disease, 


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partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as 
gastric bypass.
3
Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of 
receiving the first dose of study treatment.
4
Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
5
Requires treatment with strong CYP3A inhibitors or inducers (please refer to Appendix F
for a list of strong inhibitors and inducers of CYP3A).
6
Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Participants receiving 
proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for 
enrolment to this study (see Section 24.8.4).
7
Serologic status reflecting active hepatitis B or C infection:
(a) Participants who are anti-HBc positive and who are surface antigen negative will 
need to have a negative PCR result before enrolment. Those who are hepatitis B 
surface antigen positive or hepatitis B PCR positive will be excluded.
(b) Participants who are hepatitis C antibody positive will need to have a negative PCR 
result before enrolment. Those who are hepatitis C PCR positive will be excluded.
8
Active Cytomegalovirus (CMV) infection (positive CMV immunoglobulin M [IgM] and 
positive PCR result).
9
Requires or receiving therapeutic anticoagulants, with the exception of short-acting 
heparins, within 7 days of first dose of study treatment. Novel oral anticoagulants are 
allowed except for the initial high dose treatment period.
10 Participants on dual antiplatelet and therapeutic anticoagulant therapy (eg, aspirin and 
therapeutic doses of low molecular weight heparin).
11 History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
23.3
Lifestyle Considerations
Please refer to Section 5.3, in addition to Section 23.3.1.
23.3.1
Meals and Dietary Restrictions – Module 2
Acalabrutinib is best taken with water and can be taken with or without food. As acalabrutinib 
is metabolised by CYP3A, participants should be strongly cautioned against using herbal 
remedies or dietary supplements (in particular, St John’s wort, which is a potent CYP3A 
inducer).
Otherwise, participants should maintain their regular diet unless modifications are required to
manage an AE such as diarrhoea, nausea, or vomiting.


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23.4
Screen Failures
Please refer to Section 5.4.
23.5
Justification for Dose
Part A
The ongoing FTIH study (D8230C00001) has demonstrated that administration of AZD4573 
is tolerated in participants with r/r haematological malignancies. The study has established a 
recommended Phase II dose (RP2D) of AZD4573 monotherapy in DLBCL participants 
involving intra-patient dose ramp up in Cycle 1 from a starting dose on Day 1 (6 mg), with 
subsequent titration to the intermediate dose on Day 8 (9 mg), and to the target dose of 12 mg 
on Day 15, with weekly IV administration thereafter at the target dose (data on file, 
AstraZeneca). This established dose of AZD4573 monotherapy in DLBCL participants will be 
administered in Part A, Period 1 of Module 2 to participants with r/r MCL.
Acalabrutinib 100 mg BID is the approved dosage for patients with MCL (Calquence United 
States Prescribing Information). Module 1 of this study evaluates the safety and tolerability of 
AZD4573 in combination with acalabrutinib 100 mg BID in participants with DLBCL. The 
target dose of AZD4573 9 mg was tolerated in combination with acalabrutinib, and the target 
dose level of 12 mg is being explored in participants with DLBCL (data on file, AstraZeneca).
The dose of AZD4573 administered in combination with acalabrutinib during the combination 
Period 2 of Module 2 to participants with MCL will be established based on emerging data 
from Module 1 and will be a dose deemed by the SRC to be tolerated in combination with 
acalabrutinib in participants with DLBCL (ie, the RP2D in DLBCL).
23.6
End of Study Definition
Please refer to Section 4.5 for the definition of the end of the study. The end of Module 2 is 
defined as the last scheduled visit or contact of the last participant enrolled in this Module. In 
addition, the study may be terminated, or individual centres closed at the discretion of 
AstraZeneca (please refer to Appendix A 9). AstraZeneca may also terminate the module 
prematurely if concerns for safety arise within this study or in any other study with AZD4573 
and/or acalabrutinib.
The data cut-off for the primary analysis will occur approximately 6 months following 
last-participant first-dose or when 75% of participants have progressed or died in Part A, 
whichever occurs first. 
Any patients still receiving study intervention at the completion of the primary analysis will 
be able to continue to receive the intervention if still considered to be deriving clinical benefit. 


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Such patients will continue to be monitored for all SAEs up to 30 days after the last dose of 
the intervention therapy. Participants may be eligible to enrol in either a future rollover study 
of AZD4573 monotherapy or a future rollover study of the combination of AZD4573 and 
other anti-cancer agents, respectively.
The results from Module 2 will be reported to Regulatory Authorities within one year of the 
end of module.
24
STUDY INTERVENTION – MODULE 2
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
24.1
Study Intervention(s) Administered
24.1.1
Investigational Products
AZD4573 will be administered as an absolute (flat) dose, 2-hour (± 15 minutes) IV infusion 
once weekly, at least 5 days apart, alone and in combination with acalabrutinib 100 mg twice 
daily continuously.
AZD4573 and acalabrutinib will be supplied by AstraZeneca.
 
 Detailed 
information on the drug products and administration guidelines are in the AZD4573 Handling 
Instructions and acalabrutinib participant leaflet.
Table 28
Investigational Products
Intervention Name
AZD4573
Acalabrutinib
Type
Drug
Drug
Dose Formulation
Concentrate for solution for 
infusion
Capsules
Unit Dose Strength(s)
1.5 mg/mL
100 mg
Dose
Part A Period 1: 12 mg*
Part A Period 2: dose to be 
established based on emerging data 
from Module 1
100 mg BID
Route of 
Administration
IV infusion
Oral
Use
Experimental
Experimental
IMP and NIMP
IMP
IMP
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Intervention Name
AZD4573
Acalabrutinib
Sourcing
Provided centrally by AstraZeneca 
Provided centrally by AstraZeneca
Packaging and 
Labelling
Study Intervention will be provided 
in vials. Each vial will be labelled 
as required per country requirement
Study Intervention will be provided 
in bottles. Each bottle will be 
labelled as required per country 
requirement
Current/Former 
Name(s) or Alias(es)
AZD4573/
AZ13810325
Acalabrutinib/ACP-196 /Calquence
*In Period 1, target dose of 12 mg achieved through intra-patient ramp up from starting dose on Day 1 (6 mg), 
with subsequent titration to the intermediate dose on Day 8 (9 mg), and to target dose of 12 mg on Day 15.
Abbreviations: BID = twice daily; IMP = investigational medicinal product; IV = intravenous; 
NIMP = non-investigational medicinal product.
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines and will be translated into the local language. The labels will fulfil Good 
Manufacturing Practice Annex 13 requirements for labelling.
All IPs should be kept in a secure place under appropriate storage conditions. The IP label on 
the vial (AZD4573) or bottle (acalabrutinib) specifies the appropriate storage conditions.
Participants enrolled in this study module will receive AZD4573 alone and in combination 
with 100 mg acalabrutinib. Acalabrutinib is intended to be administered orally every day, 
twice daily with approximately 240 mL of water and can be administered without regard to 
food. Doses should be administered 12 hours apart (a window of ± 1 hour is allowed) at 
approximately the same times each day. The acalabrutinib capsules should be swallowed 
intact. Participants should not attempt to open capsules or dissolve in water. If vomiting 
occurs after taking acalabrutinib, the participant should not retake acalabrutinib until the next
scheduled dose.
On the day of PK collection, acalabrutinib capsules should be brought to site by the 
participant and taken within 5 minutes before initiation of AZD4573. The actual date and time 
of AZD4573 and acalabrutinib dosing will be recorded.
If an acalabrutinib dose is not taken within the allowed window, it can be taken up to 2 hours 
after the scheduled time with a return to the normal schedule the same or following day. If it 
has been > 2 hours, the dose should not be taken, and the participant should take the next dose 
at the next scheduled time. The missed dose will not be made up and must be returned to the 
site at the next scheduled visit. If a participant needs to take a dose earlier than scheduled, the 
participant can take the dose up to 2 hours earlier than the scheduled time except on scheduled 
site visit days. Participants should make every reasonable effort to take the acalabrutinib on 


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time. Guidance on co-administration of acalabrutinib with agents that affect gastric pH is 
provided in Section 24.8.
24.2
Starting Dose, Dose-Escalation Scheme, and Stopping Criteria
Module 2, Part A, Period 1 will confirm in MCL the AZD4573 monotherapy RP2D dose, 
established in DLBCL in the FTIH study (D8230C00001), as the dose setting in the FTIH 
study did not include MCL participants. The AZD4573 monotherapy RP2D is 12 mg once 
weekly with an intra-patient ramp over 3 weeks (1st week 6 mg; 2nd week 9 mg; 3rd week 
and onwards 12 mg).
In Module 2, Part A, Period 2, the dose of AZD4573 administered in combination with 
acalabrutinib will be established based on emerging data from Module 1 and will be a dose 
deemed by the SRC to be tolerated in combination with acalabrutinib in participants with 
DLBCL (ie, the RP2D in DLBCL).
A study-specific SRC in accordance with its charter, will be responsible for providing ongoing 
safety surveillance of the study, with regularly scheduled reviews of safety, PK, and other 
relevant data (see Section 18.6). The SRC will be responsible for making recommendations 
regarding the conduct of the study.
At any timepoint during the study, the occurrence of a fatal AE deemed related to study 
therapy (after full etiological work-up and in discussion with the SRC) will result in accrual 
stoppage and a comprehensive review of safety. In addition, potential safety signals arising 
from Grade ≤4 treatment-related AEs will be reviewed in the context of the overall 
benefit/risk. On review any event deemed to adversely affect overall benefit risk will trigger 
an ad hoc SRC for comprehensive safety review.
In the case of PHL, if bilirubin remains elevated (compared to baseline) at 96 hours 
(-2/+12 hours) after the start of the infusion, the participant must be discontinued from the 
study and biochemistry followed until resolution. The Sponsor must be notified immediately.
24.3
Definition of Evaluable Participant 
In Module 2, Part A, an evaluable participant is any participant who received a dose of study 
drug.
24.4
Duration of Therapy
Participants will move from AZD4573 monotherapy to combination treatment (AZD4573 + 
acalabrutinib) based on the Lugano overall response (Table 36) (Cheson et al 2014).


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Table 29
Part A - Duration of AZD4573 Monotherapy
Disease 
Assessment 
Lugano 2014 
Overall Response
Treatment
Next Scheduled Disease 
Assessment
Period 1, Cycle 2, 
Week 3a
CR
Continue AZD4573 monotherapy 
(Period 1, Cycle 3)
Period 1, at Cycle 5, Week 3
PR
Continue AZD4573 monotherapy 
(Period 1, Cycle 3)
Period 1, at Cycle 5, Week 3
SD
Continue AZD4573 monotherapy 
(Period 1, Cycle 3)b
Period 1, at Cycle 5, Week 3
PD
Start combination therapy 
(Period 2, Cycle 1)
Period 2, after 2 cycles 
(Section 26.4.2)
Period 1, Cycle 5, 
Week 3a
CR
Continue AZD4573 monotherapy 
(Period 1, Cycle 6)
Period 1, after 8 cycles 
(Section 26.4.2)
PR
Continue AZD4573 monotherapy 
(Period 1, Cycle 6) b
Period 1, after 8 cycles 
(Section 26.4.2)
SD
Start combination therapy 
(Period 2, Cycle 1)
Period 2, after 2 cycles 
(Section 26.4.2)
PD
Start combination therapy 
(Period 2, Cycle 1)
Period 2, after 2 cycles 
(Section 26.4.2)
a
Schedule the disease assessment to ensure availability of Lugano overall response (Cheson et al 2014) 
before Day 1 of the subsequent cycle.
b
AZD4573 + acalabrutinib combination treatment (Period 2, Cycle 1) can be started at the discretion of the 
investigator.
Note: AZD4573 + acalabrutinib combination treatment (Part A, Period 2) shall be started, if the participant 
develops PD at any time during the AZD4573 monotherapy (Part A, Period 1).
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.
24.5
Preparation/Handling/Storage/Accountability of Interventions
Please refer to Section 6.8 for general instructions and instructions specific to AZD4573.
Acalabrutinib drug accountability
Participant reported drug administration for acalabrutinib needs to be done on every AZD4573 
dosing day, ideally prior to dosing (± 24 hours) and is also to be done after the last 
acalabrutinib capsule is taken and the leftover capsules returned to site. Drug accountability 
for acalabrutinib will occur every two weeks (on an AZD4573 dosing day, ideally prior to 
dosing [± 24 hours]).
The returned number of acalabrutinib capsules needs to be counted and the participant will be 
asked whether or not acalabrutinib was taken according to the instructed dosing schedule. 


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Deviations from the instructed schedule should be discussed with the participant and recorded 
both in the source documents and the eCRF.
Discrepancies between the expected and returned number of capsules should be discussed 
with the participant and recorded in the source documents.
24.6
Measures to Minimise Bias: Randomisation and Blinding
This is an open-label, non-randomised study (please refer to Section 6.9).
24.7
Study Intervention Compliance
AZD4573
Participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study-site staff other than the person administering the 
study intervention.
Acalabrutinib
Acalabrutinib drug accountability will be conducted as described in Section 24.5 and this will 
be recorded by the site. If the participant made an error or dropped/lost capsules the site will 
need to check that the participant will have sufficient capsules for the following week. 
Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF.
A record of the number of acalabrutinib capsules dispensed to and taken by each participant 
must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the eCRF.
24.8
Concomitant Therapy
The Investigator must be informed as soon as possible about any concomitant medication 
taken from the time of screening until the end of the clinical phase of the study (final study 
visit). Any concomitant therapy(ies), including over-the-counter medications, herbal remedies, 
vaccines, and supplements, taken during the study will be recorded.
24.8.1
Permitted Concomitant Therapy
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 24.8.2. Specifically, participants should receive full supportive care during 


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the study and treatment with antibiotics, anti-emetics, antidiarrheals, and analgesics, and other 
care as deemed appropriate, and in accordance with their institutional guidelines.
After the start of AZD4573 and acalabrutinib administration, blood and platelet transfusions 
are allowed as clinically indicated at any time during the study and can be given as per local 
institutional guidelines.
Supportive care (eg, recombinant growth factor support) and other medications that are 
considered necessary for the participant’s wellbeing, (eg, bisphosphonates), may be given at 
the discretion of the Investigator and in accordance with local institutional guidelines.
Concomitant use of paracetamol is permitted but is limited to a maximum dose of 4 grams per 
day.
AstraZeneca recommends administering non-live inactivated vaccines 72 hours prior to 
administration of the first dose of any IP to avoid biases in the interpretation of safety data due 
to the potential overlap of vaccine-related AEs with IP AEs.
Permitted concomitant therapy for the management of safety concerns for AZD4573 and 
acalabrutinib (including TLS) is specified in Section 26.1.10. For guidance on additional 
prophylaxis for TLS, see Section 26.1.10.10. Administer appropriate hydration and allopurinol 
or rasburicase per institutional standards before initiating treatment.
24.8.2
Prohibited Concomitant Therapy
Participants must be instructed not to take any medications, including over-the-counter 
products, herbal remedies, and supplements without first consulting with the Investigator.
The following medications are considered exclusionary during the study. AstraZeneca must be 
notified if a participant receives any of these during the study:

Any investigational anti-cancer therapy.

Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of 
hormones for noncancer-related conditions (eg, insulin for diabetes and hormone 
replacement therapy) is acceptable.

Participants may use topical or inhaled corticosteroids as therapy for comorbid 
conditions. Ongoing use of low-dose systemic corticosteroids (≤10 mg/day prednisolone 
or equivalent is permitted (Section 6.11).

Warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) are prohibited for all 
participants in the study. Participants who require anticoagulation prophylaxis before 


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study treatment start or therapeutic anticoagulation for thrombosis while on study will be 
allowed to receive anticoagulation with a non-vitamin K inhibitor class of anticoagulants.
Should participants require either a vitamin K antagonist or combined administration of 
antiplatelet and therapeutic anticoagulation while on study, acalabrutinib treatment must 
be discontinued.
For further restrictions on the concomitant use of therapies and possible drug-drug interactions 
with AZD4573 and acalabrutinib, please refer to Section 6.11 and Section 24.8.4, respectively.
24.8.3
AZD4573 and Concomitant Therapy
For further specific information on AZD4573 and concomitant therapy, please refer to 
Section 6.11.
24.8.4
Acalabrutinib and Concomitant Treatments
The effect of agents that reduce gastric acidity (antacids or proton-pump inhibitors) on 
acalabrutinib absorption was evaluated in a healthy volunteer study (ACE-HV-004). Results 
from this study indicate that participants should avoid the use of calcium carbonate containing 
drugs or supplements for a period of at least 2 hours before and at least 2 hours after taking 
acalabrutinib. Use of omeprazole, esomeprazole, lansoprazole, or any other proton-pump 
inhibitors while taking acalabrutinib is not recommended due to a potential decrease in study 
treatment exposure. However, the decision to treat with proton-pump inhibitors during the 
study is at the Investigator’s discretion, with an understanding of the potential benefit to the 
participant’s gastrointestinal condition and a potential risk of decreased exposure to 
acalabrutinib. Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) 
on acalabrutinib absorption has not been evaluated, if treatment with an H2-receptor antagonist 
is required, the H2-receptor antagonist should be taken approximately 10 hours before or 2 
hours after acalabrutinib.
Acalabrutinib is not a strong direct inhibitor or inducer of CYP isoforms; thus, acalabrutinib, 
at the currently used clinical doses, is unlikely to be a perpetrator of a drug-drug interaction at 
the level of inhibition or induction of CYP isoforms. The concomitant use of strong 
inhibitors/inducers of CYP3A should be avoided (please refer to Appendix F). Because 
acalabrutinib is metabolised by CYP3A, participants should be strongly cautioned against 
consumption of grapefruit, grapefruit juice, or Seville orange juice (which contain potent 
CYP3A inhibitors) or using herbal remedies or dietary supplements (in particular, St. John’s 
wort, which is a potent CYP3A inducer). If a participant requires short-term treatment with a 
strong CYP3A inhibitor (such as anti-infectives for up to 7 days), interrupt acalabrutinib 
treatment. From Cycle 2 onwards, if a participant requires a moderate CYP3A inhibitor while 
on study, decrease acalabrutinib dose to 100 mg once daily. Avoid co-administration of strong 


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CYP3A inducers. If a participant requires treatment with a strong CYP3A inducer, increase 
the acalabrutinib dose to 200 mg twice daily during concomitant administration with the 
strong CYP3A inducer and return to recommended dose of 100 mg twice daily after stopping 
the strong CYP3A inducer.
Concomitant use of paracetamol is permitted but is limited to a maximum dose of 4 grams per 
day. For participants dosed with AZD4573 and acalabrutinib non-steroidal anti-inflammatory 
agents such as ibuprofen should also be avoided.
24.9
Dose Modification
Table 30 provides dose reductions options for acalabrutinib.
Table 30
Acalabrutinib Dose Reduction Options
Starting dose
1st dose reductiona
2nd dose reduction
100 mg twice daily
100 mg once daily
Discontinue
a
When reducing to 100 mg acalabrutinib once daily, the morning dose should be retained. If considering 
dose reduction, please discuss with the Medical Monitor.
Note: Temporary withholding of acalabrutinib for as little as 7 days can cause a transient 
worsening of disease in MCL and/or of constitutional symptoms. Transient worsening of 
disease during temporary interruption of acalabrutinib (eg, for drug-related toxicity, surgery, 
or intercurrent illness) may not indicate disease progression. In such circumstances, and if 
medically appropriate, following discussion with the Medical Monitor, participants may 
resume therapy and relevant clinical, laboratory, and/or radiologic assessments should be done 
to document whether tumour control can be maintained or whether actual disease progression 
has occurred.
If the dose of acalabrutinib is reduced for apparent treatment-related AE/SAE, the dose of 
acalabrutinib should not be re-escalated unless the participant tolerates the reduced dose for 
greater than 4 weeks and at the Investigator’s discretion and in consultation with the Medical 
Monitor. Such re-escalation may be particularly warranted if further evaluation reveals that the 
AE/SAE that led to the dose reduction was not treatment-related. Any changes to the dosing 
regimen must be recorded on the appropriate eCRF.
Acalabrutinib dose reduction options are described in and dose modification and 
discontinuation guidelines for haematological and non-haematological toxicities (excluding 
abnormal liver chemistry results) are shown below in Table 30. Dose modifications for 
AZD4573 and acalabrutinib for abnormal liver chemistry results are described in Table 31.


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In general, if a participant experiences a Grade 1 or Grade 2 haematological or 
non-haematological toxicity, no dose modification is required. If a participant experiences a 
Grade 3 or Grade 4 toxicity, not attributable to the disease or disease-related processes under 
investigation, dosing will be interrupted and/or the dose reduced (see Table 30 for 
acalabrutinib reduction options and Table 31 for recommended dose modifications for 
AZD4573 and acalabrutinib) and supportive therapy administered as required. If the toxicity 
resolves or reverts to CTCAE Grade ≤2 within 21 days and the participant was showing 
clinical benefit, treatment with study treatment(s) may be restarted.
If the toxicity does not resolve to CTCAE Grade ≤2 within 21 days, then the participant 
should be withdrawn from the study and observed until resolution of the toxicity. Maximal 
drug interruption allowed for related toxicity for both AZD4573 and acalabrutinib is 
≤21 consecutive days.


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Table 31
Recommended Dose Modifications for AZD4573 and Acalabrutinib
Eventa
Occurrence
Action with AZD4573
Action with Acalabrutinib
Tumour Lysis Syndrome (TLS) – Howard Modification of Cairo-Bishop Criteria
Changes in uric acid, 
potassium, 
phosphorus, 
creatinine or calcium, 
or symptoms 
suggestive of 
clinically significant 
TLS, in the 
Investigator's 
judgement
Any
For any abnormal changes 
present before dosing, initiate 
supportive therapy and hold 
drug for up to 7 days. If not 
resolved, reduce by 1 dose level.
Withhold acalabrutinib until 
resolved, resume dosing at the 
same dose level upon resolution.
For events of Grade 1 or 2 TLS, 
resume at same dose level upon 
resolution.
For events of Grade 1 or 2 TLS, 
resume at same dose level upon 
resolution.
For 1st occurrence of Grade 3 
TLS resume at the same dose 
upon resolution to Grade 1.
For 1st occurrence of Grade 3 
TLS resume at the same dose 
upon resolution.
For 2nd occurrence of Grade 3 
TLS, after resolution to Grade 1, 
reduce dose by one dose level 
when restarting AZD4573 
except events that in the opinion 
of the Investigator, in 
consultation with the Medical 
Monitor, are not dose-limiting.
For subsequent occurrences of 
Grade 3 TLS, further 
rechallenge and dose level to be 
discussed with the Medical 
Monitor.
For events of Grade 4 TLS, 
discontinue AZD4573.
For 2nd occurrence of Grade 3 
TLS, after resolution to Grade 1, 
reduce dose by one dose level 
when restarting or discontinue 
acalabrutinib except events that 
in the opinion of the 
Investigator, in consultation with 
the Medical Monitor, are not 
dose-limiting.
For subsequent occurrences of 
Grade 3 TLS, further 
rechallenge and dose level to be 
discussed with the Medical 
Monitor.
For events of Grade 4 TLS, 
discontinue acalabrutinib.


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Table 31
Recommended Dose Modifications for AZD4573 and Acalabrutinib
Eventa
Occurrence
Action with AZD4573
Action with Acalabrutinib
Non-haematological Toxicities (Except Liver Dysfunction)
Grade 3 or 4 
non-haematological 
toxicities
1st occurrence 
Withhold dosing with AZD4573 
until the toxicity has resolved to 
Grade 1, but no longer than 
21 daysb.
Adequate supportive therapy as 
per institutional guidelines 
should be given. AZD4573 
therapy may be resumed at the 
same dose. No dose 
modification is required.
Withhold acalabrutinib until 
recovery to Grade ≤2.
Restart acalabrutinib at the same 
dose level.
2nd and 
subsequent 
occurrences
Withhold dosing AZD4573 up 
to 21 daysb.
Adequate supportive therapy as 
per institutional guidelines 
should be given.
After resolution to Grade 1, 
reduce dose by one dose level 
when restarting AZD4573.
If no resolution within 21 days 
discontinue AZD4573b.
In case of subsequent 
occurrences, dosing may be 
modified to skip weekly dose(s) 
(eg, 2 weeks on/1 week off or to 
1 week on/1 to 2 weeks off), 
after discussing with the 
Medical Monitor.
Withhold acalabrutinib until 
recovery to Grade ≤2.
Restart acalabrutinib with 
1 level dose reduction or 
discontinue (see Table 30).


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Table 31
Recommended Dose Modifications for AZD4573 and Acalabrutinib
Eventa
Occurrence
Action with AZD4573
Action with Acalabrutinib
Haematological Toxicities
Grade 3 or 4 
neutropenia without 
fever or infection, 
lasting ˃ 7 days 
despite growth factor 
support
1st occurrence
Withhold dosing AZD4573 until 
Grade ≤2 or baseline level.
Restart at same dose level 
following resolution.
Withhold acalabrutinib if 
Grade 4 neutropenia lasting 
> 7 days until resolution to 
Grade ≤2 or baseline level and 
then restart at same dose for 1st 
occurrence.
2nd and 
subsequent 
occurrence
Withhold dosing AZD4573 until 
Grade ≤2 or baseline level.
Restart with one dose level 
reduction following resolution.
In case of subsequent 
occurrences, dosing may be 
modified to skip weekly dose(s) 
(eg, 2 weeks on/1 week off or to 
1 week on/1 to 2 weeks off), 
after discussing with the 
Medical Monitor.
Withhold acalabrutinib if 
Grade 4 neutropenia lasting 
> 7 days until resolution to 
Grade ≤2 or baseline level and 
then restart at a reduced dose or 
discontinue (see Table 30).
Grade 3 or 4 
neutropenia with 
infection or fever
1st occurrence
Withhold dosing AZD4573. 
To reduce the infection risks 
associated with neutropenia, 
G-CSF may be administered 
with AZD4573 if clinically 
indicated/required as per 
Institutional practice.
Consider secondary prophylaxis 
with G-CSF as per 
ASCO/ESMO guidelines. Once 
the toxicity has resolved to 
≤Grade 2 or to baseline level, 
AZD4573 therapy may be 
resumed at the same dose.
Withhold acalabrutinib until 
infection is resolved, antibiotics 
no longer required and ANC 
Grade ≤2 or baseline level.
Following resolution, resume 
acalabrutinib with 1 level dose 
reduction or discontinue (see 
Table 30).


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Table 31
Recommended Dose Modifications for AZD4573 and Acalabrutinib
Eventa
Occurrence
Action with AZD4573
Action with Acalabrutinib
2nd occurrence
Withhold dosing AZD4573.
Consider using G-CSF as 
clinically indicated/as per 
Institutional practice. Follow 
dose reduction guidelines when 
resuming treatment with 
AZD4573 after resolution.
Reduce dose by one dose level.
Withhold acalabrutinib until 
infection is resolved, antibiotics 
no longer required and ANC 
Grade ≤2 or baseline level.
Following resolution, resume 
acalabrutinib with 1 level dose 
reduction or discontinue (see 
Table 30).
3rd occurrence
Discontinue AZD4573.
Discontinue acalabrutinib.
Grade 3 
thrombocytopenia 
without bleeding
Any
Withhold AZD4573 until 
Grade ≤2 or baseline level.
Restart AZD4573 at the same 
dose level.
Continued dosing can be 
considered at the discretion of 
the investigator after discussion 
with the medical monitor.
No action.
Grade 4 
thrombocytopenia 
without bleeding 
requiring blood or 
platelet transfusion
1st occurrence
Withhold AZD4573 until 
Grade ≤2 or baseline level.
Restart AZD4573 at the same 
dose level.
Withhold acalabrutinib until 
Grade ≤2 or baseline level.
Restart acalabrutinib at the same 
dose level.
2nd occurrence
Withhold AZD4573 until 
Grade ≤2 or baseline level.
Restart AZD4573 with 1 level 
dose reduction.
If not recovered to Grade ≤2 or 
baseline level discontinue.
Withhold acalabrutinib until 
Grade ≤2 or baseline level. 
Restart acalabrutinib with 
1 level dose reduction or 
discontinue (see Table 30).
3rd occurrence
Discontinue AZD4573.
Discontinue acalabrutinib.
Grade 3 or 4 
thrombocytopenia 
with bleeding 
requiring blood or 
platelet transfusion
1st occurrence
Withhold AZD4573 until 
Grade ≤2 or baseline level.
Restart AZD4573 with 1 level 
dose reduction.
If not recovered to Grade ≤2 or 
baseline level discontinue.
Withhold acalabrutinib until 
Grade ≤2 or baseline level.
Restart acalabrutinib with 
1 level dose reduction or 
discontinue (see Table 30).


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Table 31
Recommended Dose Modifications for AZD4573 and Acalabrutinib
Eventa
Occurrence
Action with AZD4573
Action with Acalabrutinib
2nd occurrence
Discontinue AZD4573.
Discontinue acalabrutinib.
a
Adverse reactions are graded using National Cancer Institute CTCAE version 5.0. All grades refer to 
CTCAE grading except for TLS, which uses the Howard modification of Cairo-Bishop criteria 
(Howard et al 2011).
b
In cases where more than 21 days are needed, a decision to continue, modify, or discontinue study treatment 
will be made on a case-by-case basis in consultation with the principal Investigator and the Medical 
Monitor.
Abbreviations: ANC = absolute neutrophil count; ASCO = American Society of Clinical Oncology; 
CTCAE = Common Terminology Criteria for Adverse Events; ESMO = European Society for Medical 
Oncology; G-CSF = granulocyte-colony-stimulating factor; TLS = tumour lysis syndrome.
Dose modifications for AZD4573 and acalabrutinib for abnormal liver chemistry results are 
described in Table 32.
Table 32
Recommended Dose Modifications for AZD4573 and Acalabrutinib for 
Abnormal Liver Chemistry Results
Eventa
Action
AZD4573
Acalabrutinib
Isolatedb Elevations in ALT, AST, or Bilirubin
Grade 1
Isolated ALT/AST ≤3 × ULN 
or
Isolated Bilirubin ≤1.5 × ULN
Maintain current dose level.
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week.
Maintain current dose level and
schedule. 
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week.
Grade 2
Isolated ALT/AST > 3 to 
≤5 × ULN
or
Isolated Bilirubin > 1.5-
≤3 × ULN
After 7 days if hepatic enzymes 
resolve to Grade ≤1, rechallenge 
at same dose level.
Withhold or continue acalabrutinib 
(at Investigator discretion, after 
discussion with the Medical 
Monitor). To prevent disease 
progression, monitor disease 
parameters closely.
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week.
After 7 days if hepatic enzymes 
appear to be improving and
acalabrutinib was withheld, restart 
acalabrutinib at current dose level.


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Eventa
Action
AZD4573
Acalabrutinib
Grade 3
Isolated ALT/AST > 5-20 × ULN
If recovered to Grade ≤1 within 
7 days, allow rechallenge at same 
dose level.
If not recovered to baseline level 
within 7 days, discontinue 
AZD4573.
Withhold or continue acalabrutinib 
(at Investigator discretion, after 
discussion with the Medical 
Monitor). To prevent disease 
progression, monitor disease 
parameters closely.
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week. 
After 7 days if hepatic enzymes 
appear to be improving and 
acalabrutinib was withheld, restart 
acalabrutinib with 1 level dose 
reduction or discontinue.
Grade 3
Isolated Bilirubin > 3-10 × ULN
If recovered to baseline level 
within 96 hours (-2/+12 hours) of 
the start of the infusion allow 
rechallenge at same dose level.
If not, discontinue AZD4573
Grade 4c
Isolated ALT > 20 × ULN
or
Isolated Bilirubin > 10 × ULN
Discontinue AZD4573.
Discontinue acalabrutinib.
Grade 4
Isolated elevation (≥ 20 × ULN) in
AST without concomitant 
elevation in ALT ≥ 20 × ULN or 
concomitant elevation in TBL 
≥2 × ULN that fails to return to 
baseline level within 7 days from 
start of dosing
Discontinue AZD4573.
Discontinue acalabrutinib.
Grade 4c
Isolated AST elevation 
≥20 × ULN without concomitant 
elevation in ALT ≥20 × ULN or 
TBL ≥2 × ULN
1st occurrence
If recovered to Grade ≤1 or 
baseline level within 7 days of the 
start of the infusion allow 
rechallenge at same dose level
Withhold or continue acalabrutinib 
(at Investigator discretion, after 
discussion with the Medical 
Monitor). To prevent disease 
progression, monitor disease 
parameters closely.
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week. 
After 7 days if hepatic enzymes 
appear to be improving and 
2nd occurrence
If recovered to Grade ≤1 or 
baseline level within 7 days of the 
start of the infusion allow 
rechallenge with 1 dose level 
reduction


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Eventa
Action
AZD4573
Acalabrutinib
3rd occurrence
Discontinue AZD4573
acalabrutinib was withheld, restart 
acalabrutinib at current dose level 
at the 1st occurrence and with 
1 level dose reduction at the 2nd
occurrence.
Discontinue acalabrutinib at the 
3rd occurrence.
Concurrent elevations in ALT, AST, or bilirubin
(Please also refer to Appendix E for actions to be taken in the event of PHL)
ALT or AST ≥3 × ULN with 
TBL ≥2 × ULN (PHL) AND INR 
≥1.5 × ULN (or ≥1.5 × baseline if 
elevated at baseline) of any 
duration
Discontinue AZD4573.
Discontinue acalabrutinib.
ALT or AST ≥3 × ULN with the 
appearance of fatigue, nausea, 
vomiting, right upper quadrant 
pain or tenderness, fever, rash, 
and/or eosinophilia > 5%
Discontinue AZD4573.
Discontinue acalabrutinib.
ALT or AST ≥ 3 × ULN and TBL
≥ 2 × ULN where TBL does not 
return to baseline level within 
96 hours (-2/+12 hours) from start 
of dose and/or AST or ALT do not 
return to baseline level within 
7 days from start of dose
Discontinue AZD4573.
Discontinue acalabrutinib.
Grade 3 elevation (≥ 5 × ULN) in
ALT or AST with TBL elevation
above baseline level or ULN, but
< 2 × ULN that do not return to 
baseline level within 7 days
Discontinue AZD4573.
Discontinue acalabrutinib.
ALT and AST ≥ 3 × ULN with 
concomitant TBL ≥ 2 × ULN, NO 
increase in INR ≥ 1.5 × ULN (or 
1.5 × baseline), and NO fatigue, 
nausea, vomiting, right upper 
quadrant pain or tenderness, fever, 
rash, and/or eosinophilia > 5%
If recovered to Grade ≤1 or 
baseline level within 96 (-2/+12) 
hours, rechallenge at same dose 
levelc
Withhold acalabrutinib until 
recovered. Once recovered, restart 
acalabrutinib at same dose.
a
Adverse reactions are graded using National Cancer Institute CTCAE version 5.0. All grades refer to 
CTCAE grading except for TLS, which uses the Howard modification of Cairo-Bishop criteria 
(Howard et al 2011).


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b
Elevations in ALT or AST are considered isolated if bilirubin remains below Grade 1, and elevations in 
bilirubin are considered isolated if ALT and AST remain below Grade 1.
c
Participants who are considered for rechallenge in the event of Grade 4 transaminase increases or PHL must 
discuss possible risk of hepatotoxicity with the treating physician, who will document this discussion and 
participant agreement for continued treatment in the medical records.
Note: Adequate supportive therapy as per institutional guidelines should be given for all toxicities.
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CTCAE = Common Terminology Criteria for Adverse Events; INR = international normalised ratio; 
PHL = Potential Hy’s Law; TBL = total bilirubin; ULN = upper limit of normal.
24.9.1
Retreatment Criteria
Retreatment is defined as the first dose of study drug after a significant period of intentional 
pause in study drug treatment (other than missed doses, eg, study treatment put on hold until 
resolution of COVID 19) 
Retreatment criteria (criteria to be met before participant restarts study drug infusions 
[and capsules, as applicable]):
All participants:
1
Participant has recovered from all treatment-related non-haematological toxicity to 
CTCAE Grade ≤2.
2
Recovery of neutrophils ≥1000/μL and platelets ≥50,000/μL.
3
Participant has recovered from all hepatic toxicity events within the timeframes described 
in Table 32 above. If biochemical changes in transaminase(s) and total bilirubin are 
consistent with the definition of Hy’s Law, the participant may continue to receive study 
drug only if all abnormalities have resolved within the timeframes specified in Table 32
above, there are no symptoms of liver injury and INR has not increased above 1.5 × ULN 
(or 1.5 × baseline). In these circumstances the participant must be made aware of the 
unknown potential for liver damage with continued exposure to AZD4573 prior to 
retreatment. Documentation of continued consent is required.
4
Recovery of uric acid to < ULN.
5
Recovery of changes in uric acid, potassium, phosphorus, creatinine or calcium, or 
symptoms suggestive of TLS as defined in Table 31.
6
In case of any new deterioration in laboratory values, not fulfilling eligibility criteria and 
deeded as clinically significant by the Investigator, the Medical Monitor must be 
contacted to discuss whether AZD4573 dosing can be continued.


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24.10
Intervention After the End of the Study
Treatment with AZD4573 and acalabrutinib may be continued until disease progression or an 
unacceptable drug-related toxicity occurs as defined in the protocol, or the patient withdraws 
or is withdrawn from the study for other reasons.
Patients who discontinue AZD4573 may continue to receive acalabrutinib if they are deriving 
benefit in the opinion of the Investigator. In addition, patients who discontinue acalabrutinib 
may continue to receive AZD4573 if they are deriving benefit in the opinion of the 
Investigator.


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25
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL –
MODULE 2
25.1
Discontinuation of Study Intervention
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
Please refer to Section 7.1 for information on discontinuation of study intervention.
25.1.1
Temporary Discontinuation
Refer to Section 24.2 for information on temporary discontinuation and restarting of study 
intervention.
25.1.2
Rechallenge
Refer to Section 24.9 for information on rechallenge with study intervention.
25.2
Patient Withdrawal from the Study
Please refer to Section 7.2 for information on participant withdrawal from the study.
In addition for Module 2, participants who experience an AE during the dosing ramp up 
(Period 1 Weeks 1-3) that result in inability to complete the dosing ramp up will permanently 
discontinue AZD4573 and exit the study.
25.3
Procedures for Handling Participants Incorrectly Initiated on 
AZD4573 or Combination Therapy
Please refer to Section 7.3 for information on procedures for handling participants incorrectly 
initiated on AZD4573 or combination therapy.
25.4
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
Please refer to Section 7.4 for actions to be taken if a participant fails to return to the clinic for 
a required study visit.
For handling of discontinuation of specific sites or of the study as a whole please refer to 
Appendix A 9.


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26
STUDY ASSESSMENTS AND PROCEDURES – MODULE 2

Study procedures and their timing are summarised in the SoA (Section 19.2). 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 participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

For Part A, Period 1, the amount of blood collected from each participant for the 
scheduled assessments, is not anticipated to exceed 440 mL in Cycle 1 (cycle duration 
5 weeks), 140 mL in Cycle 2 (cycle duration 3 weeks) and 80 mL in each subsequent 
cycle (cycle duration 3 weeks). If a participant experiences TLS, maximum 30 mL extra 
blood will be collected per cycle (5 weeks) for safety reasons. 
 
 
 Repeat or unscheduled samples may be taken 
for safety reasons or for technical issues with the samples.

In Part A, Period 2, the amount of blood collected from each participant for the scheduled 
assessments, is not anticipated to exceed 350 mL in Cycle 1 (cycle duration 5 weeks), 
140 mL in Cycle 2 (cycle duration 3 weeks) and 80 mL in each subsequent cycle (cycle 
duration 3 weeks). If a participant experiences TLS, maximum 30 mL extra blood will be 
collected per cycle (5 weeks) for safety reasons.
 
 
 Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples.
26.1
Safety Assessments
26.1.1
Enrolment and Screening
At enrolment, each potential participant will provide informed consent before starting any 
study-specific procedures (please refer to Appendix A for Regulatory and Ethical 
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Considerations). Each potential participant approved for screening is assigned a unique 
participant enrolment number. If a participant withdraws from the study, then the enrolment 
number cannot be reused.
Demographic data and other characteristics will be recorded and will include date of birth, 
race and ethnicity, and alcohol use.
A standard medical, medication and surgical history will be obtained with review of the 
selection criteria with the participant. Concurrent medical signs and symptoms must be 
documented to establish baseline severities. Previous and concomitant treatments (coded 
according to the World Health Organization Drug Dictionary [WHODRUG]) will be collected 
for each participant. A disease history, including the date of initial diagnosis, staging within 
30 days of first dose of AZD4573, prognostic indices/disease profiling for MCL (derived from 
local laboratory results) and list of all prior anti-cancer treatments, and responses and DoR to 
these treatments, will also be recorded.
Each participant will undergo screening (see Section 19.2) during the 30 days before 
admission to confirm eligibility (see Sections 23.1 and 23.2).
26.1.2
Physical Examinations
A complete physical examination, including a standard neurological examination should be 
completed at Screening and will include, at a minimum: the general appearance of the 
participant, height, weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, 
abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system. 
Investigators should pay special attention to clinical signs related to previous serious illnesses 
and new or worsening abnormalities may qualify as AEs.
Symptom-directed physical exams are done thereafter for each dosing day as outlined in the 
SoA, including the SFU visit (Section 19.2) in Period 1 and Period 2.
26.1.3
Vital Signs
Vital signs will be performed at timepoints specified in the SoA (Section 19.2).
Changes from baseline abnormalities should be recorded in participant notes. New or 
worsened clinically significant abnormalities should be recorded as AEs on the Adverse Event 
eCRF.
Pulse rate and blood pressure
Blood pressure and pulse/heart rate measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 


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available.
Blood pressure and pulse measurements should be preceded by at least 10 minutes of rest for 
the participant in a quiet setting.
Pulse rate and blood pressure measurement timepoints are:

Screening
Period 1 and Period 2

Cycle 1 (Weeks 1 to 3):

Predose (up to 2 hours prior to infusion)

1 hour after the start of the infusion (± 10 minutes)

At the end of the infusion (up to 10 minutes post dose)

4 hours after the start of the infusion (± 30 minutes)

6 hours after the start of the infusion (± 30 minutes)

From Cycle 1 Week 4 onwards:

Predose (up to 30 minutes prior to infusion)

At the end of the infusion (up to 30 minutes post dose) on each dosing day

30-Day SFU
Body temperature
Body temperature will be measured in degrees Celsius at the following timepoints in Period 1 
and Period 2:

Predose (up to 2 hours prior to all infusions)
Weight
Weight will be measured in kilograms at the following times:

Screening
Period 1 and Period 2

Cycle 1 (weeks 1-3) predose

Cycle 1 Week 4 onwards, Day 1 of each cycle predose


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
30-Day SFU
26.1.4
Electrocardiograms (ECGs)
ECG will be performed at timepoints specified in the SoA (Section 19.2).
Twelve-lead ECGs will be obtained after the participant has been resting semi-supine for at 
least 10 minutes before the times indicated. All ECGs should be recorded with the participant 
in the same physical position where possible.
If an abnormal ECG finding at Screening or baseline is considered to be clinically significant 
by the Investigator, it should be reported as a concurrent condition. If a clinically significant 
abnormal ECG finding occurs on study, contact the Medical Monitor.
Single ECGs will be collected for local and central analysis at the following timepoints:

Screening
Period 1 and Period 2

Cycle 1, Weeks 1 through 5, and Cycle 2, Day 1:

Predose (at the day of infusion prior to infusion)

End of infusion (within 30 minutes of end of infusion)

Cycles 3+ Day 1 of each cycle:

Within 30 minutes after the end of infusion

30-Day SFU
Any abnormal finding in the ECG tracing will be evaluated by the Investigator and will be 
specifically documented and registered in the eCRF. Throughout the study, clinically relevant 
new findings or worsening of a pre-existing finding in the ECGs (parameters or abnormal 
findings in the tracing) must be considered an AE and must be recorded in the AE CRF form.
If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, 
potassium), and troponin I/troponin T must be done to coincide with the ECG testing. Note: 
either a troponin I or troponin T assay can be used per SoC at the respective hospital. If the 
hospital has both a SoC troponin I and troponin T assay available, the investigator shall use 
only one consistently for the duration of the study.
26.1.5
WHO/ECOG Performance Status
ECOG performance status will be assessed at the following times (see Section 19.2):


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
Screening
Period 1 and Period 2

Cycle 1 through Cycle 8:

Predose each dose of AZD4573

Cycles 9+, Day 1 of each cycle:

Predose each dose of AZD4573

30-day SFU
Performance status should be measured using the ECOG Performance Status Scale (Table 33). 
It is recommended, where possible, that a participant’s performance status be assessed by the 
same person throughout the study.
Table 33
ECOG Performance Status Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
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 all selfcare but unable to carry out any work activities; up and about 
more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5
Dead
26.1.6
B Symptoms
Information on B symptoms (eg, unintentional weight loss, fevers, and night sweats) will be 
collected at the following times (Section 19.2).

Screening
Period 1 and Period 2

Cycle 1 through Cycle 8:

Predose AZD4573

Cycles 9+, Day 1 of each cycle:


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
Predose AZD4573

30-day SFU
26.1.7
Clinical Safety Laboratory Assessments
For all participants, results of safety laboratory testing (haematology and clinical chemistry at 
a minimum) must be available within 72 hours prior to dosing and must be reviewed by the 
Investigator prior to administration of AZD4573 (all cohorts). If clinically indicated, 
additional clinical laboratory tests and evaluations may be performed by the Investigator 
(eg, additional haematology/clinical chemistry panels, TLS parameters, liver enzyme tests); 
these need to be entered into the eCRF.
This study will use local laboratories.
The following laboratory variables will be measured in Period 1 and Period 2.
Haematology: complete blood count (CBC) with automated and/or manual differential 
including, but not limited to, white blood cell count, haemoglobin, haematocrit, platelet count, 
ANC, and absolute lymphocyte count (ALC), and blast cells. Haematology should be 
evaluated before dosing while participants are receiving treatment. 
Haematology samples will be collected at the following timepoints:

Screening
Period 1 and Period 2

Cycles 1, 2, and 3

Predose AZD4573 (within 72 hours prior to infusion)

24 hours after the start of the infusion

Cycles 4+

Predose AZD4573 (within 72 hours prior to infusion)

If clinically indicated, 24-hour after the start of the infusion

30-day SFU
The Investigator may take additional, unscheduled samples throughout the study if deemed 
clinically warranted and these need to be entered into the eCRF.


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Haematology tests do not need to be repeated before first dose if the first-dose visit is within 
3 days of the Screening sample.
Clinical Chemistry: albumin, chloride, bicarbonate, calcium total, magnesium, phosphorous, 
glucose (fasting preferred), CK, ALP, ALT, ammonia (where available at local institution; to 
be tested every 2 weeks), AST, urea, cholesterol, C-reactive protein, creatinine, Factor V 
(where available at local institution), GGT, lactate dehydrogenase (LDH), phosphate, 
potassium, sodium, triglycerides, total bilirubin, direct and indirect bilirubin, total protein, uric 
acid.
Clinical chemistry samples will be collected at the following timepoints:

Screening
Period 1 and Period 2

Cycles 1, 2, and 3

Predose AZD4573 (within 72 hours prior to infusion)

24 hours after the start of the infusion

Cycles 4+

Predose AZD4573 (within 72 hours prior to infusion)

If clinically indicated, 24-hour after the start of the infusion

30-Day SFU
The Investigator may take additional, unscheduled samples throughout the study if deemed 
clinically warranted and these need to be entered into the eCRF.
Clinical chemistry and haematology tests do not need to be repeated before first dose if the 
first-dose visit is within 3 days of the Screening sample.
In addition, GLDH and CPK will be measured at Screening for all participants. If GLDH 
cannot be performed locally, LDH will be analysed locally and a serum sample must be 
collected for central retrospective GLDH analysis, which will be performed as applicable. 
Refer to the Laboratory Manual for details.


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Coagulation testing includes aPTT (partial thromboplastin time)/PT (prothrombin time), 
INR, D-dimer (where available at institution), and fibrinogen.
Samples for coagulation testing will be collected at the following timepoints:

Screening
Period 1 and Period 2

Cycles 1, 2, and 3

Predose AZD4573 (within 72 hours prior to infusion)

24 hours post-infusion

Cycles 4 through 8

Predose AZD4573 (within 72 hours prior to infusion)

If clinically indicated, 24-hour after the start of the infusion

Cycles 9+, on Day 1 of each cycle

Predose AZD4573 (within 72 hours prior to infusion)

30-Day SFU
The Investigator may take additional, unscheduled samples throughout the study if deemed 
clinically warranted and these need to be entered into the eCRF.
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose. On dosing 
days, urinalysis should be performed at the following timepoints:

Screening
Period 1 and Period 2

Cycles 1 through Cycle 8

Predose AZD4573 (within 72 hours prior to infusion)

Within approximately 2 hours after the end of the infusion

Cycles 9+, on Day 1 of each cycle

Predose AZD4573 (within 72 hours prior to infusion)

Within approximately 2 hours after the end of the infusion

30-Day SFU


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Cardiac troponin I or troponin T measurements (note: either a troponin I or troponin T assay 
can be used per SoC at the respective hospital. If the hospital has both a SoC troponin I and 
troponin T assay available, the investigator shall use only one consistently for the duration of 
the study.) are required at the following timepoints:

Screening
Period 1 and Period 2

Cycle 1, Weeks 1 through 5

Predose AZD4573 (within 72 hours prior to infusion)

24 hours post start of the infusion

Cycles 2+ Day 1 of each cycle

Predose (within 72 hours prior to infusion)

30-Day SFU
Electrolyte panel: sodium, chloride, calcium, magnesium, potassium.
If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, 
potassium), and troponin must be done to coincide with the ECG testing.
Supra-renal glands: T4, cortisol, adrenocorticotropic hormone (ACTH) and thyroid-
stimulating hormone (TSH) should be measured at the following timepoints:

Screening
Period 1 and Period 2

Cycle 2, Day 1

Predose AZD4573 (within 72 hours prior to infusion)

30-Day SFU
Pancreas: Lipase and amylase measurements are required at the following timepoints:

Screening
Period 1 and Period 2

Cycles 1 through 8:

Predose AZD4573 (within 72 hours prior to infusion)


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
Cycles 9+, on Day 1 of each Cycle:

Predose AZD4573 (within 72 hours prior to infusion)

30-Day SFU
Lipase/amylase tests do not need to be repeated before first dose if the first-dose visit is within 
3 days of the Screening sample.
TLS monitoring will include: potassium, calcium, phosphate, uric acid, and creatinine. TLS 
monitoring will be performed at the following timepoints:
Period 1 and Period 2

Cycle 1, Weeks 1 through 3

Predose AZD4573

6 hours (± 30 minutes) after the start of the infusion

24 hours (± 1 hour) after the start of the infusion (and prior to acalabrutinib dosing in 
Period 2)
Participants showing signs of clinical or laboratory TLS at 6 hours after the start of the 
infusion must be admitted for in-patient TLS monitoring for a minimum of 24 hours after the 
start of the infusion and monitored every 4 to 6 hours during this time (or more frequently if 
clinically indicated).
For each TLS monitoring timepoint, a TLS Monitoring page in the eCRF is to be filled out.
Liver chemistry tests: For any participant on study who experiences elevated ALT /AST 
≥ 3 × ULN and/or elevated total bilirubin ≥ 2 × ULN: repeated liver chemistry tests (INR, 
fibrinogen, D-dimer [where available at institution], ALP, ALT, AST, GLDH, CPK, total 
bilirubin, direct bilirubin, indirect bilirubin) are required at 48 hours (-2/+12 hours) and 96 
hours (-2/+12 hours) after the start of the infusion and until resolution of the event. However, 
in case the event is not resolved within 96 hours the medical monitor should be contacted. If 
GLDH cannot be performed locally, LDH will be analysed locally and a serum sample must 
be collected for central retrospective GLDH analysis. Refer to the Laboratory Manual for 
details.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets 
PHL criteria at any point during the study. The Investigator participates, together with the 


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Sponsor, in review and assessment of these cases. Hy’s Law (HL) criteria are met if there is 
no alternative explanation for the elevations in transaminases and total bilirubin levels.
If an unscheduled ECG is done at any time: troponin and an electrolyte panel* must be done 
to coincide with the ECG testing.
* can include: sodium, calcium, potassium, chloride, phosphate, magnesium. 
If a participant is assessed as meeting PHL criteria, please refer to Appendix E.
Hepatitis serology will be conducted at Screening. Hepatitis serology must include hepatitis 
B surface antigen (HbsAg), hepatitis B surface antibody (anti-HBs), anti-HBc, and hepatitis C 
(HCV) antibody. Participants who are anti-HBc positive, or have a known history of hepatitis 
B virus (HBV) infection, should be monitored every 3 months with a quantitative PCR test for 
HBV DNA (Section 17.1.10.4). In addition, any participants testing positive for any hepatitis 
serology must have PCR testing for verification purposes.
Pregnancy: a sample for a pregnancy test will be collected from all female participants of 
childbearing potential at:

Screening (serum)

Cycle 1, Week 1:

Predose

Cycles 2+: once every 21 days (± 7 days) prior to initiating a new cycle

30-day SFU
Pregnancy tests after Screening may be serum or urine. Urine β-hCG and quantitative serum 
β-hCG tests are permitted. If a urine β-hCG test is positive or indeterminate, quantitative 
serum β-hCG will be performed for confirmation. Additional testing may be performed at 
Investigator discretion for example in the event of suspected contraception failure.
CMV: All subjects will have CMV testing at Screening including serology testing for CMV 
immunoglobulin (Ig)G and CMV IgM and CMV DNA PCR testing. Subjects must have a 
negative result for CMV DNA PCR such that CMV DNA is not detected by PCR at Screening, 
to be eligible for the study. The Screening CMV serologies will be advisory only, to guide 
investigators in assessing the risk of new infection or reactivation of CMV while on study.
26.1.8
Other Safety Assessments
Monitoring for TLS per the SoA (Section 19.2) and prophylaxis for TLS are outlined in detail 
in Section 26.1.10.10.


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Blood samples for 
 will be collected per the SoA (Section 19.2) and as 
outlined in Section 26.1.7.
Additional safety assessment requirements include:

Echocardiograms (ECHOs): In addition to Screening, an ECHO should be done within 
14 days after an abnormal ECG finding (eg, T-wave inversion/flattening) or as soon as 
possible when clinically indicated. If an ECHO cannot be taken, a multigated acquisition 
(MUGA) scan to assess left ventricular ejection fraction (LVEF) will be done. In case of 
any T-wave abnormality, the ECHO (or MUGA) should be repeated at the 30-day SFU 
visit to address the question of recovery, during the off-treatment period.

CD4, CD8, CD19, CD16/NK cell count and serum immunoglobulins (IgA, IgM, IgG):

Screening

Day 1 of Cycles 2, 4, 7, 9, 13, 16, 19
o
Predose

Every 6 months thereafter (predose)

30-Day SFU
26.1.9
Follow-up
26.1.9.1
30-day SFU Visit
An SFU visit will be performed 30 (± 7) days from the time that study drug(s) are 
permanently discontinued (see the SoA [Section 19.2]). Tumour assessments will be repeated 
at this visit if they have not been performed within 9 weeks if the participant discontinued 
before Week 53, or 12 weeks if the participant discontinued after Week 53.
26.1.9.2
Long-term Follow-up Visits
Participants who discontinue study drug(s) before documented disease progression will be 
followed according to standard of care (SoC) until documented disease progression or the start 
of new anti-cancer therapy. Disease progression or start of new anti-cancer therapy will be 
captured in the eCRF. During this period, only information on any SAEs considered related to 
IP or study procedures will be collected. If a participant is unable to attend site for this visit, 
the long-term follow-up may be performed via phone call. Long-term follow-up visits will 
cease at disease progression or start of a new anti-cancer therapy, whichever comes first. The 
long-term follow-up will not apply to participants who withdraw consent or are lost to follow-
up.
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26.1.9.3
Survival Follow-up
All participants will be followed for survival until death, loss to follow-up, AstraZeneca closes 
the study, or withdrawal of consent, whichever occurs first. Participants will be followed for 
survival by telephone calls or clinic visits approximately every 3 months. Site personnel will 
attempt to collect the vital status of the participant within legal and ethical boundaries for all 
participants who received investigational product. Public sources may be searched for vital 
status information. If vital status is determined as deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information. During this period, information will be 
collected in the eCRF on survival status and any new anti-cancer therapies, and on any SAEs 
considered related to study drug(s) or study procedures.
The follow-up for survival should occur every three months, starting 3 months after end of 
treatment/discontinuation (ie, 3/6/9/12 months after treatment). In case a shorter/longer 
interval between two follow-up calls occurs the frequency should return to the multiple of 
3 months after treatment (eg, 3/6/9/12 months after treatment and so on).
26.1.10
Prevention and Management of Safety Concerns for AZD4573 in 
Combination with Acalabrutinib
This section provides recommendations for treatment of potential toxicities associated with 
acalabrutinib, or the combination of AZD4573 with acalabrutinib, and guidance about 
modifying the doses of acalabrutinib and AZD4573 due to those toxicities. For complete 
safety information refer to 
 and Calquence United 
States Prescribing Information.
Generally, Grade 1 or 2 non-haematological and/or haematological toxicities do not require 
AZD4573 or acalabrutinib dose reductions and should be managed as medically indicated 
(with or without short dose interruptions) by the treating physician. Grade 3 and 4 toxicities 
require dose modifications, temporary treatment interruptions, or discontinuation of AZD4573 
and acalabrutinib. These are described in Table 31 and Table 32.
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26.1.10.1
Headache
Headache is an identified risk for acalabrutinib. Participants with headache should be 
managed per institutional guidelines with supportive care and diagnostic evaluations as 
clinically indicated.
Note: encouraging adequate hydration for participants experiencing headaches has anecdotally 
been helpful in some cases.
26.1.10.2
Diarrhoea
Diarrhoea is an identified risk for AZD4573 and acalabrutinib. Participants with diarrhoea 
during therapy should be managed per institutional guidelines with maximal supportive care 
and diagnostic evaluations as clinically indicated. After excluding infectious aetiologies, 
symptomatic management should be considered. Participants experiencing prolonged or 
severe diarrhoea should be closely monitored and managed as appropriate if dehydration 
and/or electrolyte abnormalities are observed. Participants should be made aware of the risk of 
possible overlapping toxicities of diarrhoea while receiving combination study treatments.
Prophylaxis for diarrhoea with atropine is strongly recommended for all participants enrolled 
into the study as an anti-cholinergic drug, administered at 0.5 mg subcutaneously 15 to 30 
minutes prior to all scheduled AZD4573 infusions. In the event of multiple episodes of 
diarrhoea despite atropine prophylaxis, one additional atropine dose may be considered and 
administered as outlined above.
In addition, in the event of diarrhoea, participants should remain fully hydrated with additional 
IV fluids.
26.1.10.3
Nausea and Vomiting
Nausea and/or vomiting are identified risks for AZD4573 and acalabrutinib. Participants with 
nausea and/or vomiting during therapy should be managed per institutional guidelines with 
maximal supportive care and diagnostic evaluations as clinically indicated. Participants 
experiencing prolonged or severe vomiting should be closely monitored and managed as 
appropriate if dehydration and/or electrolyte abnormalities are observed. Participants should 
be made aware of the risk of possible overlapping toxicities of nausea and vomiting while 
receiving combination study treatments. 
Nausea and vomiting are considered important identified risks for AZD4573. Events of nausea 
and vomiting have been observed in approximately half of all participants dosed with 
AZD4573 and have occurred at all dose levels tested to date (except 3 mg). Prophylaxis with a 
5-HT3 antagonist (eg, ondansetron ± dexamethasone) has been implemented in the Phase I 
study (D8230C00001) to help alleviate this toxicity.


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Regarding the hepatic toxicity events encountered to date with AZD4573, it has been observed 
that while the biochemical changes of increased transaminase with concomitant elevation in 
bilirubin seen in some patients could be classified as HL by its strict definition, they do not 
follow a pattern that is consistent with true HL predictive of hepatic injury, and are therefore 
‘PHL’ cases. The events are rapidly resolved and to date have not led to any clinical sequelae 
or lasting hepatic injury. Repeated dosing with AZD4573 following these events has 
demonstrated that there is no consistent pattern of recurrence and no consistent increase in 
severity of the events if they do recur.
Available transcriptomic and clinical pathology data from the Phase I FTIH study of 
AZD4573 monotherapy (D8230C00001) suggest the presence of an acute phase response in 
participants showing signs of liver injury. Thus, anti-inflammatory prophylaxis with steroids 
(eg, dexamethasone) could be expected to have a beneficial effect on incidence and severity of 
adverse effects on the liver related to AZD4573.
While, in the absence of a suitably sized control group without prophylactic steroid 
administration, there is no confirmatory evidence for a positive effect of dexamethasone on 
liver safety profiles from available Phase I clinical data as yet, assessment of ALT changes 
from baseline versus cumulative dexamethasone dose suggests a possible trend towards a 
negative correlation, ie, higher dexamethasone doses being associated with smaller increases 
in ALT post-baseline. 
Therefore, prophylaxis for nausea and vomiting is recommended as follows: administer 
dexamethasone 8 mg (IV administration preferable but orally also permitted) plus a 5-HT3 
antagonist (e.g. ondansetron initially 8 mg to be taken before treatment, then 8 mg every 
12 hours for up to 3 days) as anti-emetics for all participants, approximately 30 to 60 minutes 
prior to all scheduled AZD4573 infusions. Additional doses of dexamethasone 8 mg may be 
administered if deemed clinically warranted. In addition, in the event of vomiting, participants 
should remain fully hydrated with additional fluids. Participants experiencing prolonged or 
severe nausea and vomiting should be closely monitored and managed as appropriate if 
dehydration and/or electrolyte abnormalities are observed.
26.1.10.4
Hepatitis B Reactivation
Serious or life-threatening reactivation of viral hepatitis have been reported in patients treated 
with acalabrutinib. Therefore, patients who are anti-HBc positive, or have a known history of
HBV infection, should be monitored every 3 months with a quantitative PCR test for HBV 
DNA. Monitoring should continue until 12 months after last dose of acalabrutinib. Any patient 
with a rising viral load (above lower limit of detection) should discontinue acalabrutinib and 
have antiviral therapy instituted and a consultation with a physician with expertise in 


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managing hepatitis B. Insufficient data exist regarding the safety of resuming acalabrutinib in 
patients who develop HBV reactivation.
26.1.10.5
Progressive Multifocal Leukoencephalopathy (PML)
Cases of PML have been reported in patients treated with acalabrutinib. Signs and symptoms 
of PML may include cognitive and behavioural changes, language disturbances, visual 
disturbances, sensory deficits, weakness, and coordination and gait difficulties.
If PML is suspected, hold further treatment with acalabrutinib until PML is excluded. A 
diagnostic evaluation may include (but is not limited to):

Neurologic consultation

Brain magnetic resonance imaging (MRI)

PCR analysis for John Cunningham (JC) virus DNA in cerebrospinal fluid
If PML is confirmed, permanently discontinue acalabrutinib.
26.1.10.6
Haemorrhage
Bleeding events, some fatal, including CNS, respiratory, and gastrointestinal haemorrhage, 
have been reported in patients treated with acalabrutinib. Patients receiving antiplatelet or 
anticoagulant therapies may be at increased risk of haemorrhage and should be monitored for 
signs of bleeding. Should patients require either a vitamin K antagonist or combined 
administration of antiplatelet and therapeutic anticoagulation while on study, acalabrutinib 
treatment must be discontinued. As a precaution, it is suggested per protocol that acalabrutinib 
be withheld for at least 3 days pre- and post-surgery. Patients should be made aware of the risk 
of possible overlapping toxicities of haemorrhage while receiving both study treatments. 
Patients with haemorrhage should be managed per institutional guidelines or as clinically 
indicated. Coagulation should be monitored regularly as per the SoA. Avoidance of ibuprofen 
is advised.
26.1.10.7
Infections
Serious infections, including fatal events, have been reported in patients treated with 
acalabrutinib. Infection is an important potential risk for AZD4573 and an important identified 
risk for acalabrutinib. Patients should be made aware of the risk of possible serious infections 
while receiving combination study treatments. Investigators should be vigilant for signs of 
infection, especially opportunistic or fungal infections, and the possibility of hepatitis B 
reactivation. Infections should be managed as per standard clinical practice. In case of Grade 3 
infections, the guidelines provided in Table 31 should be followed.


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26.1.10.8
Cytopenia
Haematological toxicities including neutropenia, anaemia, and thrombocytopenia have 
occurred in patients treated with acalabrutinib. Neutropenia is an important identified risk for 
patients treated with AZD4573 or acalabrutinib. Cytopenia should be considered an 
overlapping toxicity for AZD4573 and acalabrutinib. In the presence of CTCAE Grade 3/4 
neutropenia/leucopoenia/thrombocytopenia/anaemia, patient’s blood counts should be 
monitored, using local laboratories, at least every 48 hours until recovery.
In the clinical setting to date, Grade 3/Grade 4 neutropenia (~ 45% to 50%) has been observed 
in several patients with an onset around 24 hours after dosing AZD4573 monotherapy. 
Usually, neutrophils recovered spontaneously even without G-CSF.
Colony-stimulating factors including G-CSF, or pegylated G-CSF have been shown to work 
rapidly and may be used according to each Investigator site’s institutional guidelines. Anti-
infective prophylaxis including anti-fungal prophylaxis should be used according to 
institutional guidelines. Antiviral or cotrimoxazole prophylaxis may not be used unless CD4 
helper cell counts are less than 100 to 200 per microlitre.
Primary prophylaxis with G-CSF is not generally recommended. Anti-infective prophylaxis 
(antibiotics and antifungals) should be given in accordance with local hospital and 
International National Comprehensive Cancer Network (NCCN)/European Society for 
Medical Oncology (ESMO)/American Society of Clinical Oncology (ASCO) guidelines.
Please refer to Table 31 for dose modifications due to haematological toxicities.
If the table indicates that the acalabrutinib dose should be reduced and the participant is 
already on 100 mg/day (see Table 30), acalabrutinib should be discontinued.
26.1.10.9
Liver Chemistry Test Abnormalities and the Risk of Liver Injury
Transaminase elevations are an important potential risk for patients treated with acalabrutinib, 
and an important identified risk for participants treated with AZD4573. Reactivation of 
hepatitis B infection has been observed in patients treated with acalabrutinib. Participants 
should be made aware of the risk of possible overlapping toxicities of transaminase elevations 
while receiving both drugs. Evidence of abnormal liver chemistry should be monitored as per 
the protocol guidelines. Increased levels of AST, ALT, or serum bilirubin should trigger an 
investigation of the cause, which may include viral infection or disease progression with liver 
infiltration. The Investigator should consider whether the abnormal liver chemistry meets the 
criteria for expedited reporting.
Bilirubin increase with transaminase increase is included as an important identified risk for 
AZD4573. Biochemical changes of increased transaminases with concomitant increase in 


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bilirubin fulfilling criteria for Hy's law have been observed in participants treated with 
AZD4573. These events resolve rapidly and have to date not been associated with any adverse 
clinical sequelae or lasting liver damage. Upon rechallenge with AZD4573, there is no 
consistent pattern of recurrence, nor is there any consistent increase in severity of the events. 
As such, while the events follow the biochemical definition of Hy's law, the clinical pattern is 
rapidly self-limiting and does not seem to predict any lasting liver damage.
Participants who experience elevated ALT/AST ≥ 3 × ULN and/or elevated total bilirubin ≥ 2 
× ULN after AZD4573 dosing must be closely monitored with repeated liver chemistry tests 
(INR, fibrinogen, D-dimer [where available at institution], ALP, ALT, AST, GLDH if a GLDH 
test cannot be performed at the site or locally, LDH will be sufficient), CPK, total bilirubin, 
direct bilirubin, indirect bilirubin) are required at least every 48 hours (-2/+12 hours) after the 
start of the infusion and until resolution of the event.
 will 
also be collected (see Section 26.8)
If bilirubin fails to resolve within 96 hours (-2/+12 hours) or transaminases fail to resolve 
within 7 days, or if the event is associated with significant clotting abnormality or clinical 
symptoms of liver disease, study treatment must be permanently discontinued (the participant 
remains on study for the 30-day SFU and long-term follow-up [LTFU] visits), and the event 
must be immediately communicated to AstraZeneca.
For guidance on treating liver toxicity, please refer to Table 32 of this protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets PHL 
criteria at any point during the study.
Please refer to Appendix E for the process to be followed to identify and appropriately report 
events of PHL. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries.
The Investigator will participate, together with the Medical Monitor, in review and assessment 
of PHL events to agree whether HL criteria are met. HL criteria are met if there is no 
alternative explanation for the elevations in liver biochemistry.
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
Regarding the hepatic toxicity events encountered to date with AZD4573, it has been observed 
that while the biochemical changes of increased transaminase with concomitant elevation in 
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bilirubin seen in some participants could be classified as HL by its strict definition, they do 
not follow a pattern that is consistent with true HL predictive of hepatic injury, and are 
therefore ‘PHL’ cases. The events are rapidly resolved and to date have not led to any clinical 
sequelae or lasting hepatic injury. Repeated dosing with AZD4573 following these events has 
demonstrated that there is no consistent pattern of recurrence and no consistent increase in 
severity of the events if they do recur. 
Available transcriptomic and clinical pathology data from the Phase I, FTIH study of 
AZD4573 monotherapy (D8230C00001) suggest the presence of an acute phase response in 
participants showing signs of liver injury. Thus, anti-inflammatory prophylaxis with steroids 
(eg, dexamethasone) could be expected to have a beneficial effect on incidence and severity of 
adverse effects on the liver related to AZD4573.
While, in the absence of a suitably-sized control group without prophylactic steroid 
administration, there is no confirmatory evidence for a positive effect of dexamethasone on 
liver safety profiles from available Phase I clinical data as yet, assessment of ALT changes 
from baseline versus cumulative dexamethasone dose suggests a possible trend towards a 
negative correlation, ie, higher dexamethasone doses being associated with smaller increases 
in ALT post-baseline.
26.1.10.10 Tumour Lysis Syndrome (TLS)
Tumour lysis syndrome is an important identified risk for AZD4573 and an identified risk for 
acalabrutinib. TLS prophylaxis is mandatory for all participants starting 3 days before the 
first dose of AZD4573, which should be followed in addition to institutional guidelines.
Tumour lysis syndrome is characterised by the rapid and/or massive release of intracellular 
constituents (potassium, phosphorus and nucleic acids that can be metabolised to uric acid) 
following tumour cell lysis, resulting in life-threatening complications including acute kidney 
injury, arrhythmias, and neurological complications. While TLS can be seen in solid tumours, 
it is most prevalent in haematological malignancies, particularly bulky, chemosensitive 
diseases such as AML. Prevention and management of TLS is dependent on risk stratification, 
and risk-based prophylaxis and management (Howard et al 2011, Howard et al 2016). 
Participants identified with TLS potential per published risk guidelines (Coiffier et al 2008; 
Table 33) should be provided with adequate hydration, pharmacological pre-treatment with 
allopurinol or rasburicase, and be carefully monitored for development of TLS.
Instructions for TLS prophylaxis are presented in Section 26.1.10.10.1, instructions for 
management of hydration are presented in Section 26.1.10.10.2, and instructions for 
monitoring and maintenance of TLS are presented in Section 26.1.10.10.3. The Howard 


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modification of Cairo-Bishop criteria for clinical and laboratory TLS are included in 
Appendix F.
Laboratory or clinical TLS (please refer to Appendix F for definitions) may trigger dose 
modification in accordance with guidelines provided in Table 31.
26.1.10.10.1 TLS Prophylaxis
Tumour lysis syndrome prophylaxis is mandatory for all patients starting 3 days before the 
first dose of AZD4573. TLS prophylaxis is mandatory for all infusions as outlined below in 
Table 34, which provides TLS prophylaxis guidance that should be followed in addition to 
institutional guidelines. In the event of a discrepancy between the protocol guidelines for the 
management of TLS and the institutional guidelines of a given Investigator/centre, the 
Investigator should discuss with the Medical Monitor.
In addition to the criteria outlined in Table 34 below, any participant with creatinine clearance 
(CrCL) < 80 mL/min must be considered at higher risk of developing TLS and managed 
appropriately.
TLS prophylaxis/management with rasburicase/allopurinol and IV fluid is permitted at any 
time during screening and treatment, however rasburicase and allopurinol must not be 
co-administered (Howard et al 2011; Howard et al 2016; Jones et al 2015)
.
Table 34
Mandatory TLS Prophylaxis Guidance (in Addition to Institutional 
Guidance)
Type of Cancer
Intermediate/High Risk
NHL
Any LN ≥5 cm
Prophylaxis
Hydrationa
Oral (1.5-2.0 L/day) plus additional IV fluid: Normal saline 500 mL over 2-4 h prior to 
AZD4573, then 100-175 mL/h as tolerated to maintain urine output
Antihyperuricemics
Allopurinol 300 mg orally QD beginning 3 days prior to AZD4573 and continuing at 
least through the end of Week 1b.
Consider prophylactic rasburicasec if baseline uric acid is elevated above ULNd, LDH 
> 2 × ULN, or high tumour burden/leukemic cells
a
Administer more aggressive IV fluid hydration for any participant who cannot tolerate or maintain oral 
hydration.
b
Administration of allopurinol should not be stopped at the end of Week 1, however the dose or frequency of 
administration may be reduced after discussion with the Medical Monitor.
c
The recommended dose for rasburicase is 0.20 mg/kg IV over 30 minutes. Rasburicase is contraindicated in 
participants with G6PD deficiency, so participants at higher risk for G6PD deficiency (eg, African or 
Mediterranean ancestry) should be screened for this condition prior to starting rasburicase. Rasburicase and 
allopurinol must not be co-administered. 


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d
Uric acid levels should be < ULN before each dosing of AZD4573.
Notes: Adequate supportive therapy as per institutional guidelines should be given for all toxicities. 
TLS prophylaxis/management with rasburicase/allopurinol and IV fluid is permitted at any time during screening 
and treatment. Rasburicase and allopurinol must not be co-administered.
Abbreviations: G6PD = glucose-6-phosphate dehydrogenase; IV = intravenous; LDH = serum lactate 
dehydrogenase; LN = lymph node; NHL = non-Hodgkin lymphoma; QD = once daily; TLS = tumour lysis 
syndrome; ULN = upper limit of normal.
Modified from Coiffier et al 2008.
26.1.10.10.2 Management of Hydration
Adequate fluid intake for all participants enrolled into the study is mandatory, in particular, 
around the times of AZD4573 dosing.
All participants are mandated to receive IV fluid hydration with normal saline (NaCl 0.9%). 
For participants at intermediate or high risk for TLS, normal saline 500 mL should be 
administered over 2 to 4 hours prior to AZD4573 and then continued at a rate of 100 to 
175 mL/h as tolerated to maintain urine output.
In case of diarrhoea/nausea/vomiting, more aggressive IV fluid hydration may be needed as 
clinically indicated. Participants are also encouraged to drink enough fluid before and after 
each dosing. Please use diuretics carefully, do not use them prophylactically, only if 
participants have signs of hyper-hydration.
26.1.10.10.3 TLS Prophylaxis, Monitoring, and Management
Please refer to Appendix F for definitions of the Howard modification of Cairo-Bishop criteria 
for clinical and laboratory TLS.
All participants will receive TLS prophylaxis during the intra-patient ramp up and be 
monitored for TLS during the first 24 hours post start of dose. Monitoring for TLS includes 
checking potassium, calcium, phosphate, uric acid, and creatinine. Fluid balance must be 
monitored according to institutional standards.
Participants will be required to be monitored for TLS for up to 24 hours post dose until they 
have received at least one AZD4573 dose at the target dose level (ie, for at least the first 3 
AZD4573 once-weekly doses). If a participant has no signs of laboratory TLS at the 6-hour 
TLS monitoring assessment, the participant may leave the clinic after the collection of other 
laboratory samples, as per the SoA, at 7 hours after the start of the infusion and managed as an 
outparticipant, at the discretion of the Investigator. These participants must return to the clinic 
the next morning to complete the 24 hour TLS monitoring period as per the SoA (Cycle 1 
Weeks 1-3). Participants with TLS at the 6-hour TLS monitoring assessment must be admitted 
for in-patient TLS monitoring for a minimum of 24 hours after the start of the infusion and 
monitored every 4 to 6 hours during this time (or more frequently if clinically indicated).


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Sites retain the option to hospitalise participants based on clinical judgement, despite normal 
TLS laboratory results 6 hours after the start of the infusion. Admitting the participant for 
subsequent dose administrations will be done at Investigator discretion.
Any hospitalisation due to occurrence of an AE must be reported as an SAE, per definition. 
However, if hospitalisation is purely for the purposes of extended observation then this does 
not qualify as an SAE and does not need to be reported.
For all participants, results of safety laboratory testing (haematology and clinical chemistry at 
a minimum) must be available within 72 hours prior to dosing and must be reviewed by the 
Investigator prior to each administration of AZD4573.
In particular, the uric acid level must be < ULN prior to the start of each AZD4573 infusion.
It is strongly recommended that for all participants with elevated uric acid (hyperuricaemia) 
and intermediate/high risk of TLS, rasburicase (0.20 mg/kg/d IV over 30 minutes) should be 
administered as prophylaxis prior to AZD4573 and repeated as clinically indicated thereafter 
as per local standard.
NOTE: If hyperuricaemia is present at Screening and/or during intra-patient ramp up, 
SoC therapy for hyperuricaemia should be administered (including IV fluid and 
rasburicase or allopurinol) to reduce the uric acid levels to < ULN before each 
administration of AZD4573. Rasburicase and allopurinol must not be co-administered.
Any participant developing laboratory TLS must be treated promptly for electrolyte 
abnormalities (such as hyperkalaemia) to prevent arrhythmias/seizures and for elevated uric 
acid (hyperuricaemia) with rasburicase (0.20 mg/kg/d IV over 30 minutes for up to 5 days) to 
prevent acute renal failure and monitored closely for signs of progression to clinical TLS. 
If these measures are inadequate, then haemodialysis represents definitive therapy and 
should be initiated promptly.
Any participant with hyperkalaemia should receive cardiac monitoring with continuous 
telemetry for ECG changes associated with potentially life-threatening arrhythmias.
Participants with TLS or suspicion of TLS will remain in hospital to undergo additional 
investigations until the TLS has resolved.
In participants at high risk of TLS based on high tumour burden/bulky disease (> 10 cm), high 
proliferation rate (LDH > 2 x ULN), and/or impaired renal function, (Coiffier et al 2008), 
24-hour hospitalisation for TLS monitoring is recommended during the intra-patient ramp up.


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26.1.10.11 Second Primary Malignancies
Second primary malignancies, including non-skin cancers, have been reported in patients 
treated with acalabrutinib. The most frequent second primary malignancy was skin cancer 
(squamous cell carcinoma of the skin). Monitor participants for the appearance of skin 
cancers. If a participant develops a second primary malignancy (other than non-melanoma 
skin cancer), discontinue acalabrutinib. Participants with a second primary malignancy should 
be managed according to institutional guidelines with diagnostic evaluations as clinically 
indicated.
26.1.10.12 Atrial Fibrillation/Flutter and Sinus Tachycardia
Atrial fibrillation/flutter have been reported in patients treated with acalabrutinib. Atrial 
fibrillation has also been observed in participants treated with AZD4573, although positive 
causality has not been established.
26.1.10.13 Infection/Bone Marrow Toxicity with Peripheral Effect / Lymphoid Tissue 
Hypocellularity
Infection/bone marrow toxicity with peripheral effect/lymphoid tissue hypocellularity is an 
important potential risk for AZD4573, based on findings in preclinical studies. Severe 
infection is considered as an important risk with the combination therapy (Section 26.1.10.7).
As observed in preclinical studies, this important potential risk refers to haematological 
changes (decreased platelets, red blood cell count/haematocrit, reticulocytes, neutrophils, 
lymphocytes) that may be/may not be accompanied by secondary infections.
AEs of thrombocytopenia should be managed as deemed appropriate by the Investigator as per 
standard institutional guidelines and in some cases, management of thrombocytopenia may 
require platelet transfusions, again these should be done according to local hospital guidelines. 
If indicated, transfusions or growth factors can be administered during the screening period, 
but such cases of deterioration of haematological function must be discussed with the Medical 
Monitor, to confirm start of study treatment.
Common treatable causes of anaemia (eg, iron, vitamin B12, or folate deficiencies and 
hypothyroidism) should be excluded. In some cases, management of anaemia may require 
blood transfusions which should be given as per local institutional guidelines.
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26.1.10.14 Pancreatic and Cortical Adrenal Injury (as well as Surveillance for Renal, 
Thymus, and Spleen Toxicity)
Pancreatic injury and cortical adrenal injury are potential risks for AZD4573 based on 
preclinical observations, however, to date, there are no clinical data suggestive of these risks, 
but safety surveillance will continue.
Regular complete blood counts, clinical chemistry and coagulation tests will be performed 
throughout the conduct of the study to monitor for any abnormal laboratory parameters, for 
example; monitoring of lipase and amylase levels for potential pancreas toxicity, creatinine 
values and regular urinalysis testing for kidney function, potassium, sodium, cortisol levels 
along with adrenocorticotropic hormone levels for adrenal glands and TSH for any thyroid 
toxicity.
26.1.10.15 Drug-Drug interactions
Specific drug-drug interaction studies have not yet been performed for AZD4573. For 
guidance please refer to Section 24.8.
Acalabrutinib may be affected by agents that reduce gastric acidity (antacids or proton-pump 
inhibitor). Acalabrutinib is not a strong direct inhibitor or inducer of CYP isoforms and is 
therefore unlikely to perpetrate drug-drug interactions through affecting CYP isoforms 
(see Section 24.8).
26.1.10.16 Myocardial Ischaemia and Heart Rate Increased
Myocardial ischaemia and heart rate increased are considered potential risks for AZD4573. 
There has been an isolated case report of possible myocardial infarction in association with
AZD4573, but positive causality could not be established. The same participant experienced 
heart rate increase during the event of ST-segment elevation myocardial infarction. A 
thorough evaluation of all participants dosed to date has not revealed any further cases 
suggestive of myocardial ischaemia or other cardiovascular toxicity causally related to 
AZD4573 administration.
Safety surveillance related to this potential toxicity will include ECG and troponin I/troponin 
T measurements for all participants as described in the SoA (Section 19.2). ECG and 
troponin I/troponin T measurements must be performed for all participants who develop 
symptoms suggestive of myocardial ischaemia. Note: either a troponin I or troponin T assay 
can be used per SoC at the respective hospital. If the hospital has both a SoC troponin I and 
troponin T assay available, the investigator shall use only one consistently for the duration of 
the study.


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26.1.10.17 Management of Other Events: Infusion Site Reactions
As with other drugs administered intravenously, local infusion site reactions (eg, infusion 
pain, infusion site reaction, skin or vein irritation) may occur and these can be managed 
according to local institutional guidelines. Implantable port insertions (eg, Portacath) may be 
considered.
26.2
Adverse Events and Serious Adverse Events
A formal assessment of AEs will occur at the visits marked in the SoA (Section 19.2) , but 
AEs reported at any time during the study must also be recorded in the eCRF.
Please refer to Section 8.2.
26.2.1
Adverse Events of Special Interest for Acalabrutinib
The following events are adverse events of special interest (AESIs) for acalabrutinib and must 
be reported to the Sponsor expeditiously in Part A, Period 2, irrespective of regulatory 
seriousness criteria or causality:

Ventricular arrhythmias (eg, ventricular extrasystoles, ventricular tachycardia, ventricular 
arrhythmia, ventricular fibrillation)
Adverse events of special interest for AZD4573 are described in Section 8.2.11.
26.3
Overdose
Please refer to Section 8.3 for general information and information related to AZD4573.
An acalabrutinib overdose is defined as any dose that is higher than the investigated dose. For 
any participant experiencing an acalabrutinib overdose, observation for any symptomatic side 
effects should be instituted, and vital signs, biochemical and haematological parameters 
should be followed closely (consistent with the protocol or more frequently, as needed). 
Appropriate supportive management to mitigate adverse effects should be initiated. If the 
overdose ingestion of acalabrutinib is recent and substantial, and if there are no medical 
contraindications, use of gastric lavage or induction of emesis may be considered.
26.4
Efficacy Assessments
All assessments of anti-tumour activity will be done by the investigators using standard 
response criteria as specified below (Table 36).


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26.4.1
Disease Assessment Criteria
Disease staging at baseline for MCL will be done by the modified Ann Arbor classification 
system (Table 35; Cheson et al 2014). Response assessments will be done by the investigator 
using standard Lugano 2014 response criteria as specified in Table 36.
Table 35
Lugano Modification of Ann Arbor Staging System (for Primary Nodal 
Lymphomas)
Stage
Involvement
Extranodal (E) Status
Limited
I
One node or a group of adjacent 
nodes
Single extranodal lesions without 
nodal involvement
II
Two or more nodal groups on the 
same side of the diaphragm
Stage I or II by nodal extent with 
limited contiguous extranodal 
involvement
II Bulky
Whether stage II bulky disease is 
treated as limited or advanced 
disease may be determined by 
histology and a number of 
prognostic factors
II as above with “bulky” disease
Not applicable
Advanced
III
Nodes on both sides of the 
diaphragm; nodes above the 
diaphragm with spleen 
involvement
Not applicable
IV
Additional noncontiguous 
extralymphatic involvement
Not applicable
Note: Extent of disease is determined by PET-CT for avid lymphomas and CT for nonavid histologies. 
Tonsils, Waldeyer’s ring, and spleen are considered nodal tissue.
Abbreviations: CT  computed tomography; PET  positron emission tomography.
Reproduced from Table 2.


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Table 36
The Lugano Response Criteria for Non-Hodgkin’s Lymphoma
Response and Site
PET-CT-Based Response
CT-Based Response
Complete: 
Complete metabolic response: 
Complete radiologic response (all 
of the following): 
Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3a with or without a 
residual mass on 5PSb
It is recognised that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with activation 
within spleen or marrow (eg, with 
chemotherapy or myeloid colony-
stimulating factors), uptake may be 
greater than normal mediastinum 
and/or liver. In this circumstance, 
complete metabolic response may be 
inferred if uptake at sites of initial 
involvement is no greater than 
surrounding normal tissue even if the 
tissue has high physiologic uptake
Target nodes/nodal masses must 
regress to ≤1.5 cm in LDi 
No extralymphatic sites of disease
Nonmeasured lesion
Not applicable 
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow 
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if 
indeterminate, IHC negative
Partial:
Partial metabolic response: 
Partial remission (all of the 
following): 
Lymph nodes and 
extralymphatic sites
Score 4 or 5b with reduced uptake 
compared with baseline and residual 
mass(es) of any size
≥50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites
At interim, these findings suggest 
responding disease 
When a lesion is too small to 
measure on CT, assign 5 mm × 5 
mm as the default valve
At end of treatment, these findings 
indicate residual disease
When no longer visible 0 × 0 mm
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation
Nonmeasured lesions
Not applicable
Absent/normal, regressed, but no 
increase
Organ enlargement 
Not applicable
Spleen must have regressed by 
> 50% in length beyond normal
New lesions 
None
None


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


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Response and Site
PET-CT-Based Response
CT-Based Response
Extranodal lesions
New FDG-avid foci consistent with 
lymphoma at interim or 
end-of-treatment assessment
In the setting of splenomegaly, the 
splenic length must increase by 
> 50% of the extent of its prior 
increase beyond baseline (eg, a 
15 cm spleen must increase to 
> 16 cm). If no prior splenomegaly, 
must increase by at least 2 cm from 
baseline
New or recurrent splenomegaly
Nonmeasured lesions
None
New or clear progression of 
pre-existing nonmeasured lesions
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another 
aetiology (eg, infection, 
inflammation). If uncertain regarding 
aetiology of new lesions, biopsy or 
interval scan may be considered
Regrowth of previously resolved 
lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
a
The Lugano 2014 criteria are used in this study for disease assessment. In line with these criteria, it should 
be clarified that the study definition of CMR is a Deauville score 1-3.
b
A score of 3 in many participants indicates a good prognosis with standard treatment, especially if at the 
time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid under treatment). Measured dominant 
lesions: Up to 6 of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly 
measurable in 2 diameters. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid 
organs (eg, liver spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or those noted on 
palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of 
suspected disease that would be difficult to follow quantitatively with measurement, including pleural 
effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be 
confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone 
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but 
should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of 
chemotherapy of myeloid growth factors).
c
PET 5PS: 1, no uptake above background; 2, uptake ≤mediastinum; 3, uptake > mediastinum but ≤liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma.


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Abbreviations: 5PS = 5-point scale; CT = computed tomography; CMR = complete metabolic response; 
FDG = fluorodeoxyglucose; GI = gastrointestinal; IHC = immunohistochemistry; LDi = longest transverse 
diameter; MRI = magnetic resonance imaging; PET = positron-emission tomography; PPD = product of the 
perpendicular diameters; SDi = shortest axis perpendicular to LDi; SPD = sum of the product of the diameters.
Cheson et al 2014
26.4.2
Disease Assessment Schedule
Baseline tumour assessments will be performed using radiologic imaging by CT with contrast 
and PET-CT during the screening period. CT scans with contrast will cover neck, chest, 
abdomen, pelvis and any other disease sites; PET scans will cover the whole body from base 
of skull to mid-thigh.
Radiologic scans (ie, contrast CT) and PET scans will be performed as specified in Table 37
for Period 1, and Table 38 for Period 2, to confirm PR/CR or as clinically indicated. 
Unscheduled radiologic scans may be performed at Investigator discretion if deemed clinically 
indicated.
Table 37
Radiologic Scans and PET Scans for Tumour Assessments During 
AZD4573 Monotherapy (Period 1)
Timepoints
Required Radiologic Scansa
Screening
Contrast CT
PET
During studyb
After 8 weeks (~2 cycles)c
Contrast CT
After 17 weeks (~5 cycles)c
Contrast CT
PET
After 26 weeks (~8 cycles)
Contrast CT
After 38 weeks (~12 cycles )
Contrast CT
PET
After 50 weeks (~16 cycles)
Contrast CT
After 62 weeks (~20 cycles)
Contrast CT
PET
After 74 weeks (~24 cycles)
Contrast CT
After 86 weeks (~28 cycles)
Contrast CT
PET
Every 12 weeks (~4 cycles) 
thereafter until the end of the study
Contrast CT
Every 24 weeks (~8 cycles) 
thereafter until the end of the study
Contrast CT
PET
30-day Follow-up visitd
Contrast CT
PET
a
Following complete metabolic response, subsequent scheduled PET assessments are no longer mandatory.
b
Window of ± 1 week for all timepoints.
c
Mandatory tumour assessments at 8 weeks and 17 weeks must be planned/scheduled to ensure availability 
of Lugano overall response (Cheson et al 2014) before starting Cycle 3 (Day 1) and Cycle 6 (Day 1), 
respectively.
d
Tumour assessments will be repeated at this visit for discontinued participants if not previously performed 
within the required timeframe ie 9 weeks for participants that discontinued before or during Week 26, and 
12 weeks for those that discontinued after Week 26.


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Note: At the time the participant moves from Period 1 AZD4573 monotherapy to Period 2 AZD4573 + 
acalabrutinib combination, contrast CT and PET should be performed.
Table 38
Radiologic Scans and PET Scans for Tumour Assessments During 
AZD4573 + Acalabrutinib Combination Therapy (Period 2)
Timepoints
Required Radiologic Scansa
During studyb
After 8 weeks (~2 cycles)c
Contrast CT
PET
After 17 weeks (~5 cycles)c
Contrast CT
After 26 weeks (~8 cycles)
Contrast CT
PET
After 38 weeks (~12 cycles )
Contrast CT
After 50 weeks (~16 cycles)
Contrast CT
PET
After 62 weeks (~20 cycles)
Contrast CT
After 74 weeks (~24 cycles)
Contrast CT
PET
After 86 weeks (~28 cycles)
Contrast CT
After 98 weeks (~32 cycles)
Contrast CT
PET
Every 12 weeks (~4 cycles) 
thereafter until the end of the study
Contrast CT
Every 24 weeks (~8 cycles) 
thereafter until the end of the study
Contrast CT
PET
30-day Follow-up visitd
Contrast CT
PET
a
Following complete metabolic response, subsequent scheduled PET assessments are no longer mandatory.
b
Window of ± 1 week for all timepoints.
c
Mandatory tumour assessments at 8 weeks and 17 weeks must be planned/scheduled to ensure availability 
of Lugano overall response (Cheson et al 2014) before starting Cycle 3 (Day 1) and Cycle 6 (Day 1), 
respectively.
d
Tumour assessments will be repeated at this visit for discontinued participants if not previously performed 
within the required timeframe ie 9 weeks for participants that discontinued before or during Week 26, and 
12 weeks for those that discontinued after Week 26.
If a PET-CT is not available, an independent PET and a diagnostic quality CT scan (with 
contrast) can be used. If PET and CT scans are done on the same day, the PET must be 
performed prior to the contrast-enhanced CT not to compromise the PET read-out.
Post-screening, the CT portion of a PET-CT (without contrast) may replace a contrast CT per 
local institutional practice; however, certain radiographic requirements are needed for 
acceptance, as described in the Site Radiology Manual, provided separately from this protocol.
Where contrast CT is contraindicated or unobtainable, MRI or CT (without contrast) with 
diagnostic quality (sufficient resolution to allow bi-dimensional measurements) may be used 
instead. In cases where MRI is desirable, the MRI must be obtained at baseline and at all 
subsequent response evaluations.


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Following complete metabolic response, subsequent scheduled PET assessments are no longer 
mandatory. For participants 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.
All response assessments will be made by the Investigator. All images for the assessment of 
response will be collected and stored for central review.
Participants should have radiographic tumour measurements done at the participating study 
centre or an acceptable alternate imaging facility using an identical imaging protocol and 
similar equipment. The same imaging equipment should be used for all scans whenever 
possible. The same radiologist should be assigned to read all the scans for a given participant 
throughout the study.
Participants who discontinue study intervention for reasons other than PD will continue to be 
scanned for disease response following the same schedule until documented PD, regardless of 
the start of new anti-lymphoma treatment.
26.4.3
Bone Marrow Assessments
For all participants, bone marrow biopsy and aspirate samples are required for local standard 
disease profiling (eg, immunohistochemistry, flow cytometry, cytogenetics, fluorescence in 
situ hybridisation [FISH]). Bone marrow biopsies/aspirates will be collected:

at Screening (before first dose of AZD4573)

during the study as part of disease assessment (Cheson et al 2014), when indicated

as clinically indicated (per SoC)
If bone marrow/aspirate samples are collected on a AZD4573 dosing day, collection should 
preferably take place pre-infusion. If this is not possible, the collection should take place 
between 2 hours and 4 hours after the start of the infusion.
If a bone marrow biopsy/aspirate cannot be performed, the Investigator must document in the 
participant’s medical notes the reason why the procedure cannot be performed.
Bone marrow biopsies/aspirates will be read at each site’s local laboratory. The results will be 
entered into the eCRF.
 
Refer to Section 26.10.3 for details.
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26.4.4
Tumour Assessment
Initial disease assessments include:

Staging by Ann Arbor classification (Cheson et al 2014: see Table 35).

Physical exam: attention to node-bearing areas, including Waldeyer’s ring, and to size of 
liver and spleen.

Complete blood count, platelets, differential, chemistry profile, lactate dehydrogenase

Whole-body fluorodeoxyglucose (FDG)-positron-emission tomography (PET)/computed 
tomography (CT) scan.

Brain imaging (MRI with contrast preferred). MRI of the brain will be performed at 
Screening only if there is a prior history of CNS involvement or if there are neurologic 
signs or symptoms present.

Bone marrow biopsy and aspirate (Section 26.4.1).
DLBCL response criteria: Lugano Response Criteria for Non-Hodgkin’s Lymphoma 
(Cheson et al 2014, see Table 36).
Baseline tumour assessments will be performed using radiologic imaging by CT with contrast 
and PET-CT covering neck, chest, abdomen, and pelvis within 30 days before the first dose of 
AZD4573 (Table 37). For participants 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. Unscheduled radiologic scans may be performed at 
investigator discretion if deemed clinically indicated. Magnetic resonance imaging may be 
used for imaging assessments if a contrast CT scan is contraindicated or unobtainable. In cases 
where MRI is desirable, the MRI must be obtained at baseline and at all subsequent response 
evaluations.
Tumour assessments will be made for measurable disease, non-measurable disease, and new 
lesions on CT and combined with visual assessment of PET-CT for response assessment 
according to the revised response criteria for malignant lymphoma (Cheson et al 2014). 
See Table 36.
All response assessments will be made by the Investigator. All images for the assessment of 
response will be collected and stored for central review. Additional disease assessments may 
be performed as clinically indicated.
CT scans
Bi-dimensional measurements will be recorded for lymph nodes ≥1.5 cm in longest diameter 
in the eCRF. Up to a maximum of 6 dominant, measurable lymph nodal lesions should be 


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assessed as target lesions. These nodes or masses should be selected according to all of the 
following:

They should be clearly measurable in at least two perpendicular dimensions.

If possible, they should be from disparate regions of the body.

They should include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved.
The perpendicular long and short axis diameters will be measured and recorded in the 
transverse plane at baseline and follow-up. When appropriate, measurable extranodal disease, 
defined as extranodal lesions (eg, hepatic nodules) with the longest diameter ≥1.0 cm, may be 
included in the 6 representative, measured lesions.
For the selected target lymph nodal lesions, the sum of the product of the perpendicular 
diameters will be calculated with the percentage change from baseline for assessment of 
response and nadir for assessment of progression.
All other lesions (including nodal, extranodal, and assessable disease) should be followed as 
nonmeasured disease (eg, cutaneous, gastrointestinal, bone, spleen, liver, kidneys, pleural or 
pericardial effusions, ascites) and should be factored into overall response assessment.
Visual interpretation of PET-CT scans
The International Working Group criteria for reviewing PET scans were based on visual 
interpretation, using mediastinal blood pool as the comparator. The current recommendation is 
to use the 5-point scale (Cheson et al 2014).
Assessment of non-measurable lesions
An overall assessment for all other non-target lesions of present, absent, or present with 
progression will be recorded and factored into response assessment.
Assessment of new lesions
Appearance of any new lesions more than 1.5 cm in any axis during or at the end of therapy, 
even if all other lesions are decreasing should be considered progression.
Increased FDG uptake in a previously unaffected site should only be considered progression 
after confirmation with other modalities (eg, CT, MRI, or X-ray).
In participants with no history of pulmonary lymphoma, new nodules identified by CT are 
benign and should be considered negative for lymphoma. These lesions typically represent 


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infectious or inflammatory lesions; therefore, if FDG positive, should not be considered 
positive for lymphoma in the absence of confirmatory tests, (eg, histology).
The presence or absence of new lesions will be recorded in the eCRF.
26.5
Human Biological Samples
Please refer to Section 8.5 for general information on collection and handling of al samples.
26.6
Pharmacokinetics
Venous blood samples for determination of concentrations of AZD4573 in plasma will be 
taken at the times presented below.
Samples for PK should be collected from the arm that is not used for the infusion where 
possible. If this is not possible, then separate lines should be used for drug infusion and 
sampling. If there is no other option than to use a central line (PICC-line) for drug 
administration/sample collection, it is mandatory this is a multi-lumen line. This information 
should be recorded where possible. AZD4573 should be administered using a different lumen 
from the one which is used for sample collection. The sample collection lumen needs to be 
flushed twice prior to collecting the sample. AZD4573 administration needs to be paused 
during the time the samples are collected to prevent sample contamination.
Sample collection date, time, and exact dosing will be recorded for both AZD4573 and 
acalabrutinib. Samples will be collected, labelled, stored, and shipped as detailed in the 
Laboratory Manual.
On the day of PK collection, acalabrutinib capsules should be brought to site by the 
participant and taken within 5 minutes before initiation of AZD4573. The actual date and time 
of AZD4573 and acalabrutinib dosing will be recorded.
If the participant, in error, takes acalabrutinib at home before coming to the site on the day of 
PK collection, PK sampling should be conducted at the timepoints listed according to 
AZD4573 dose provided that the exact time of acalabrutinib dosing was recorded. If there is 
no record for acalabrutinib dosing, PK should not be collected.
Part A – Period 1
Plasma samples for PK analysis will be taken at the following time points:

Cycle 1, Weeks 1 through 3 and Cycle 2, Day 1:

Predose (within 2 hours prior to AZD4573 administration)

1 hour (± 15 minutes) after the start of infusion


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
2 hours (± 15 minutes) after the start of infusion

4 hours (± 30 minutes) after the start of infusion

7 hours (± 1 hour) after the start of infusion, and

24 hours (± 1 hour) after the start of the infusion.
The timing and frequency of the PK samples may be adjusted during the study, dependent on 
emerging data, to ensure appropriate characterisation of the plasma concentration-time 
profiles.
Part A – Period 2
Plasma samples for PK analysis will be taken at the following time points:

Cycle 1, Weeks 1 and 3:

Predose (within 2 hours prior to AZD4573 [and acalabrutinib during Period 2] 
administration)

1 hour (± 15 minutes) after the start of infusion

2 hours (± 15 minutes) after the start of infusion

4 hours (± 30 minutes) after the start of infusion

7 hours (± 1 hour) after the start of infusion, and

24 hours (± 1 hour) after the start of the infusion (and prior to acalabrutinib dosing in 
Period 2).
The timing and frequency of the PK samples may be adjusted during the study, dependent on 
emerging data, to ensure appropriate characterisation of the plasma concentration-time 
profiles.
26.6.1
Determination of Drug Concentration
Samples for determination of AZD4573, acalabrutinib, and its metabolite ACP-5862 
concentrations in plasma will be analysed by Covance Laboratories on behalf of AstraZeneca, 
using appropriate validated bioanalytical methods. Full details of the analytical methods used 
will be described in a separate bioanalytical report.
All samples still within the known stability of the analytes of interest (ie, AZD4573) at the 
time of receipt by the bioanalytical laboratory will be analysed. Incurred sample 
reproducibility analysis or additional assay development work, if any, will be performed 


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alongside the bioanalysis of the test samples. The results from the evaluation, if performed, 
will be reported in a separate bioanalytical report.
26.7
Pharmacodynamics
26.7.1
Collection of Samples
Whole blood samples will be collected and immediately processed within 30 minutes on site 
for 
 
 
 
 
 
In addition, whole blood will be collected at limited timepoints to analyse pharmacodynamic 
readouts for acalabrutinib.
Mandatory pharmacodynamics (whole blood) samples will be collected at the following 
timepoints:
Pharmacodynamic Samples for AZD4573 (Site-Isolated PBMCs)
Period 1

Cycle 1, Weeks 1 and 2

Predose (up to 2 hours prior to dosing)

2 hours (± 15 minutes) after the start of the infusion

4 hours (± 30 minutes) after the start of the infusion

24 hours (± 2 hours) after the start of the infusion 

Cycle 1, Week 3

Predose (up to 2 hours prior to dosing)

2 hours (± 15 minutes) after the start of the infusion

4 hours (± 30 minutes) after the start of the infusion

7 hours (± 1 hour) after the start of the infusion 

24 hours (± 2 hours) after the start of the infusion 
Period 2

Cycle 1, Week 1

Predose (up to 2 hours prior to dosing)
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
2 hours (± 15 minutes) after the start of the infusion

4 hours (± 30 minutes) after the start of the infusion

7 hours (± 1 hour) after the start of the infusion 

24 hours (± 2 hours) after the start of the infusion (and prior to acalabrutinib dosing in 
Period 2)
Pharmacodynamic Samples for Acalabrutinib (Whole blood) 
Period 2

Cycle 1, Week 1

Predose (up to 2 hours prior to dosing and prior to acalabrutinib dose)

Cycle 1, Week 4

Predose (up to 2 hours prior to dosing and prior to acalabrutinib dose)
 must be collected at each sample at each pharmacodynamic timepoint 
once participants have reached the target dose. Refer to instructions in the Laboratory Manual.
Note: The timing of these samples may be adjusted dependent upon ongoing PK and 
pharmacodynamic analysis and interpretation.
For storage, re-use and destruction of pharmacodynamic samples, please refer to  Appendix C.
Further details on sample processing, handling and shipment are provided in the Laboratory 
Manual.
26.8
Exploratory 
 Samples
 samples will be collected from all participants to assess exploratory 
 
These samples will be collected as per the timepoints in Section 19.2.
Table 39
 Sampling Schedule (All Participants)
Day
Timing for Blood Samples
Window
Screening
At any Screening visit
Not applicable
Period 1: Cycle 1, Weeks 1-3
Period 2: Cycle 1, Week 1
Predose
Within 2 hours before the start of 
the infusion
4 hours after the start of the 
infusion
± 30 minutes
7 hours after the start of the 
infusion
± 1 hour
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24 hours after the start of the 
infusion
± 1 hour
 
 
48 hours after the start of the 
infusion
-2 / +12 hours
96 hours after the start of the 
infusion
-2/+12 hours
Predose the following infusion
Within 4 hours before the start of 
the infusion
Each timepoint where chemistry 
panel testing is performed
Not applicable
Period 1: Any visit from Cycle 1, 
Week 4 onwards and Period 2: 
Cycle 1 Week 2 
 
 
 
Same schedule as Cycle 1, 
Weeks 1-3
Not applicable
For all participants, 
 samples will be collected during Period 1, Cycle 1, Weeks 1 to 3 
and Period 2, Cycle 1, Week 1. In addition
 
samples should also be taken at 48 and 96 hours after the start of the infusion (-2 / +12 hours), 
predose the following infusion (within 4 hours) and whenever chemistry panel testing is being 
performed, until resolution of the event.
 
 sampling should be performed using the timepoints at least at 48 hours and 
96 hours after the start of the infusion (-2/+12 hours) as outlined in Table 39 (excluding 
Screening sample).
26.9
Exploratory Whole Blood Analyses Samples
By consenting to participate in the study, the participant consents to participate in the 
mandatory research components of the study.
Samples for 
 are required and will be collected from all participants.
Mandatory whole blood samples will be collected from all participants as per the schedule in 
Table 40 (Period 1) and Table 41 (Period 2) and the sections below.
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Table 40
Exploratory Whole Blood Analyses Samples (All Participants) - MODULE 2 Period 1
Samples
Timepointsa
Screening
C1
Week 1
C1
Week 2
C1
Week 3
C1
W5
C2
D1
C2
D15
C3
D1
C5
D1
C6
D1
C7
D1
Tumour 
Assessment 
Scansb
EOTc
Pre
Post 
(2h)
24h
Pre
Post 
(2h)
24h
Pre
Post 
(2h)
24h
Pre
Pre
Pre
Pre
Pre
Pre
Pre
d
X
X
X
X
X
X
X
X
X
X
X
X
e
X
X
X
X
X
X
X
X
X
X
X
X
f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
g
X
X
X
X
X
X
X
X
h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Timepoints include the following windows: pre-dose = within 2 h prior to dosing; post-dose = 2 h (± 15 min) after start of infusion, and 24h = 24 h (± 2 h) after 
start of infusion.
b
Every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion)
c
Disease progression/End of Treatment; if not collected at End of Treatment, the sample should be collected at the 30d Safety Follow-Up visit
d
e
f
g
h
Note: For all analytes, if a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
Abbreviations: C1W5 = Cycle 1 Week 5; C2D1 = Cycle 2, Day 1; EOT = end of treatment; 
 
 post = post-dose; pre = pre-dose; 24h = 24 h after infusion; SFU = safety follow-up.
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Table 41
Exploratory Whole Blood Analyses Samples (All Participants) - MODULE 2 Period 2
Samples
Timepointsa
C1
Week 1
C1
Week 2
C1
Week 3
C1 
W5
C2
D1
C2
D15
C3
D1
C5
D1
C6
D1
C7
D1
Tumour 
Assessment 
Scansb
EOTc
Pre
Post 
(2h)
24h
Pre
Post 
(2h)
24h
Pre
Post 
(2h)
24h
Pre
Pre
Pre
Pre
Pre
Pre
Pre
d
X
X
X
X
X
X
X
X
X
X
X
e
X
X
X
X
X
X
X
X
X
X
X
f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
g
X
X
X
X
X
X
X
h
X
X
X
X
X
X
X
X
X
a
Timepoints include the following windows: pre-dose = within 2 h prior to dosing; post-dose = 2 h (± 15 min) after start of infusion, and 24h = 24 h (± 2 h) after 
start of infusion.
b
Every scheduled or unscheduled tumour assessment scan (if on the day of infusion, collect pre-infusion)
c
Disease progression/End of Treatment; if not collected at End of Treatment, the sample should be collected at the 30d Safety Follow-Up visit
d
e
f
g
h
Exploratory Blood 
 Samples: samples 
 exploratory analysis (for the 24h sample: prior to next acalabrutinib dose)
Note: For all analytes, if a sample is not taken at End of Treatment, a sample should be obtained at the 30-day SFU.
Abbreviations: C1W5 = Cycle 1 Week 5; C2D1 = Cycle 2, Day 1; EOT = end of treatment; 
 
 post = post-dose; pre = pre-dose; 24h = 24 h after infusion; SFU = safety follow-up.
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26.9.1
Whole Blood for Exploratory 
 
Mandatory whole blood samples to enable exploratory 
 analysis will be collected as 
specified below. Note: Collection time begins with the start of the infusion.

Screening
Period 1 and Period 2

Cycle 1, Weeks 1, 3, and 5:

Predose (within 2 hours prior to dosing)

Cycle 2, Days 1 and 15:

Predose (within 2 hours prior to dosing)

Day 1 of Cycles 3, 5, 6, and 7:

Predose (within 2 hours prior to dosing)

Every scheduled and unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
26.9.2
Whole Blood for 
 Analysis
Mandatory whole blood samples to isolate 
 
 analysis will be collected
 
 
 Note: Collection time begins with the 
start of the infusion.

Screening
Period 1 and Period 2

Cycle 1, Weeks 1, 3, and 5:

Predose (within 2 hours prior to dosing)

Cycle 2, Days 1 and 15:

Predose (within 2 hours prior to dosing)

Day 1 of Cycles 3, 5, 6, and 7:

Predose (within 2 hours prior to dosing)
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
Every scheduled and unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
26.9.3
Whole Blood Samples for 
Mandatory whole blood samples will be collected from all participants at the timepoints 
indicated below.
 
 Note: 
Collection time begins with the start of the infusion.

Screening
Period 1

Cycle 1, Week 1:

Predose (within 2 hours prior to dosing)

Cycle 1, Week 3:

Predose (within 2 hours prior to dosing)

Cycle 2, Days 1 and 15:

Predose (up to 2 hours prior to dosing)

Day 1 of Cycles 3, 5, and 7:

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
Period 2

Cycle 1, Week 1:

Predose (within 2 hours prior to dosing)

24 hours (± 2 hours) after the start of the infusion (and prior to acalabrutinib 
dosing in Period 2)

Cycle 1, Week 3:

Predose (within 2 hours prior to dosing)

24 hours (± 2 hours) after the start of the infusion (and prior to acalabrutinib 
dosing in Period 2)
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
Cycle 2, Days 1 and 15:

Predose (within 2 hours prior to dosing)

Day 1 of Cycles 3, 5, and 7:

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
26.9.4
Whole Blood Samples for 
Mandatory whole blood samples will be collected from all participants at the timepoints 
indicated below.
 
Note: Collection 
time begins with the start of the infusion.

Screening
Period 1 and Period 2

Cycle 1, Week 1:

Predose (within 2 hours prior to dosing)

Cycle 1, Week 3:

Predose (within 2 hours prior to dosing)

Cycle 2, Days 1 and 15:

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
26.9.5
Whole Blood for 
 Exploratory Analysis
Mandatory whole blood samples will be collected from all participants 
 at the timepoints indicated below 
 
 Note: 
Collection time begins with the start of the infusion.

Screening
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Period 1 and Period 2

Cycle 1, Week 1:

Predose (within 2 hours prior to dosing)

Day 1 of Cycles 2, 3, 5, and 7:

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
26.9.6
Exploratory Blood 
 Samples
Mandatory whole blood samples will be collected 
 from all 
participants at the timepoints indicated below.
 
 Note: Collection time begins 
with the start of the infusion.

Screening 
Period 1

Cycle 1, Week 1, Week 2 and Week 3 (AZD4573 first and second ramp-up and 
target dose):

Predose (within 2 hours prior to dosing)

2 hours (± 15 minutes) after the start of the infusion

24 hours (± 2 hours) after the start of the infusion

Day 1 of Cycles 2, 3, 5, and 7:

Predose (within 2 hours prior to dosing)
Period 2

Cycle 1, Week 1:

Predose (within 2 hours prior to dosing)

2 hours (± 15 minutes) after the start of the infusion

24 hours (± 2 hours) after the start of the infusion (and prior to acalabrutinib 
dosing in Period 2)
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
Day 1 of Cycles 2, 3, 5, and 7:

Predose (within 2 hours prior to dosing)

Every scheduled or unscheduled tumour assessment scan (if on the day of infusion, 
collect pre-infusion)

Disease progression/End of treatment - if a sample is not taken at End of Treatment, 
a sample should be obtained at the 30-day SFU.
Further details on sample processing, handling, and shipment are provided in the 
Laboratory Manual.
26.10
 
 
 
 
 
26.10.1
Collection of Archival Tumour Samples
All participants in Part A (dose setting) must consent to and provide a sample of their 
archival tumour obtained within 24 months before the first dose of treatment. The 
archival tumour biopsy sample formalin-fixed paraffin embedded (FFPE) tumour block 
should be provided with sufficient material to produce 20 slides (minimum 15 slides 
acceptable), or where an archival tumour biopsy FFPE tumour block is unavailable, 
archival tumour biopsy FFPE unstained slides (20 unstained slides preferable, minimum 
15 slides acceptable) must be provided. Archival tissues must have been obtained as a 
core biopsy and meet the specified criteria detailed in the Laboratory Manual. Associated 
pathology report(s) for archival tissue samples must be obtained at Screening for all 
participants enrolled into the study.
If archival material is unavailable or unsuitable for use, participants must consent to and 
undergo a tumour biopsy during the Screening period. A new biopsy is strongly 
encouraged and preferred over an archival sample. A participant will be enrolled based on 
a prior pathology report.
Further details on sample processing, handling, and shipment are provided in the 
Laboratory Manual.
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26.10.2
Collection of Tumour Biopsy Samples
Participants in Part A who are unable to provide archival tumour specimens obtained 
within 24 months before the first dose of treatment will be asked to undergo a tumour 
biopsy at Screening. A new biopsy is strongly encouraged and preferred over an archival 
sample.
This sample will be used to evaluate potential participant selection biomarkers through 
methods such as, but not limited to, immunohistochemistry (eg, baseline expression of 
Bfl1), gene expression analysis, and DNA sequencing. A recent biopsy that was taken as 
part of SoC prior to screening consent for this study is acceptable if no treatment was 
administered between the biopsy and the first dose of study treatment, and the biopsy was 
taken within 60 days prior to receiving the first dose.
All participants are also encouraged to consent to an additional optional tumour biopsy at 
disease progression. The optional disease progression sample may be taken at the 30-day 
SFU visit if not collected previously (see Section 26.10.5).
The tumour biopsy procedure will be performed by core needle, under radiological 
guidance, or surgically if the site of disease is superficial and palpable or visible (eg, 
palpable lymph node). Tumour biopsies should be preferentially obtained from tumour 
tissues that are safely accessible, as determined by the Investigator, and are not obtained 
from sites that require significant risk procedures. Participants will undergo 6 core image-
guided needle biopsies. It is mandated that the core biopsy be removed directly from the 
tumour in situ and not cored from a surgically removed tumour. This is to ensure the best 
possible quality of the biopsy, as the blood/nutrient supply to the tumour is not disrupted 
prior to biopsy collection. Fine-needle aspirate specimens are not acceptable. Failure to 
obtain sufficient tumour sample after making best efforts to biopsy the tumour will not be 
considered a protocol deviation.
Sites should confirm the adequacy of tumour biopsy material at the time of the procedure. 
The exact time that the biopsy was taken should be clearly noted in the associated 
documentation. For mandatory and optional biopsy participants, the associated pathology 
report(s) for fresh tumour samples will be required at Screening and requested on 
treatment for all participants enrolled into the study.
Further details on sample processing, handling, and shipment are provided in the 
Laboratory Manual.
All participants are also encouraged to consent to an additional optional tumour biopsy at 
disease progression. The optional disease progression sample may be taken at the 30-day 
SFU visit if not collected previously (see Section 26.10.5.1).


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26.10.3
Collection of Bone Marrow
For all participants, when bone marrow biopsy and aspirate samples are collected for 
local standard disease profiling (refer to Section 26.4.3 for timepoints), 
 
Instructions on sample collection, labelling, processing, storage, and shipping will be 
provided in the laboratory manual.
26.10.4
Other Study Related 
 Research
26.10.4.1
 Sample for 
 Isolation
Per local regulations, a mandatory 
 sample for 
will be 
collected from all participants in this module. 
 
 
The sample should be collected from participants before receiving study treatment.
Details on sample processing, handling, and shipment are provided in the Laboratory 
Manual.
26.10.5
Collection of Optional 
 Samples
Collection of optional samples for 
 research is also part of this study as 
specified in the SoA (Section 19.2) and is subject to agreement to optional consent.
26.10.5.1
Optional Tumour Biopsy at Disease Progression
For participants who consent to the optional tumour biopsy, a biopsy will be taken at 
disease progression. The disease progression sample may be taken at the SFU visit if not 
collected previously.
Details on sample processing, handling, shipment, and storage are provided in the 
Laboratory Manual.
26.11
Optional Genomics Initiative Sample
Collection of optional saliva samples for genomics initiative research is also part of this 
study as specified in the SoA (Section 19.2) and is subject to agreement in the ICF 
addendum.
A saliva sample for DNA isolation will be collected from participants who have 
consented to participate in the genetic analysis component of the study. Participation is 
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optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
The saliva sample for exploratory genetic research will be obtained from the participants 
before the first dose of IP. If for any reason the sample is not taken before dosing it may 
be taken at any visit until the last study visit. Only one sample should be collected per 
participant for genetics during the study. Samples will be collected, labelled, stored, and 
shipped as detailed in the Laboratory Manual.
Please refer to 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, please refer to Appendix D.
26.12
Medical Resource Utilisation and Health Economics
Medical Resource Utilisation and Health Economics parameters are not evaluated in this 
study.
26.13
Important Medical Procedures to be Followed by the 
Investigator
26.13.1
Medical Emergencies and Contacts
The principal Investigator(s) 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, please refer to Section 8.2.10.
In the case of a medical emergency the Investigator may contact the Medical Monitor. If 
the Medical Monitor is not available, contact the Medical Scientist.


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27
STATISTICAL CONSIDERATIONS – MODULE 2
27.1
Statistical Hypotheses
No hypotheses are planned to be tested.
27.2
Sample Size Determination
Approximately 12 participants will be treated with AZD4573 ± acalabrutinib in this 
module.
The primary objective of Part A will be to assess safety and confirm the RP2D of 
AZD4573 monotherapy in MCL participants and assess the safety and tolerability of 
AZD4573 in combination with acalabrutinib in participants administered AZD4573 
monotherapy. Anti-tumour activity will also be explored in Part A.
Even though the sample size is not based on the expected ORR, the following examples 
(Table 42) give an indication of the information obtained with response data from 
n=12 participants in Period 1 and n=11, 10, 9, 8, 7, and 6 participants in Period 2. For 
example, for
 
Table 42
 
 
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Note: Probabilities are calculated based on the 
 
Abbreviations: ORR = objective response rate; Pr = probability.
27.3
Populations for Analyses
The analysis of data will be based on different subsets according to the purpose of the 
analysis.
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Analysis sets are presented in Table 43.
Table 43
Analysis Sets -Module 2
Analysis Set
Definition
Enrolled
All participants who sign the ICF.
Safety
All participants who received any amount of 
AZD4573 and/or acalabrutinib.
Pharmacokinetics
All dosed participants with reportable plasma 
concentrations and no important adverse events or 
protocol deviations that may impact PK.
Response evaluable
Participants dosed with AZD4573 or acalabrutinib 
with a baseline tumour assessment.
Interim response evaluable
Participants dosed with AZD4573 or acalabrutinib, or 
both AZD4573 and acalabrutinib with baseline tumour 
assessment and have their first post-baseline disease 
assessment performed, or have discontinued study 
treatment for any reasons before their first post-baseline 
disease assessment
Full Analysis Set (ITT)
All participants who received any amount of study 
intervention.
Abbreviations: ICF = Informed Consent Form; ITT = intent-to-treat; PK = pharmacokinetics.
27.4
Statistical Analyses
The SAP will be finalised prior to database lock and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints, as defined in Section 21 (Table 26).
27.4.1
General Considerations
Descriptive statistics (including means, standard deviations, medians for continuous 
variables and proportions, and CIs for discrete variables) will be used to summarise data 
by treatment period as appropriate. Kaplan-Meier methods will be used to estimate DoR, 
PFS, and OS; corresponding quartiles (including the median) and 3-month and 6-month 
and 12-month rates may be presented as appropriate.
27.4.2
Demographics, Baseline Characteristics, and Study Status
Characteristics of the participants, including medical history, disease characteristics at 
baseline, and previous and concomitant treatments (coded according to WHODRUG) will 
be listed for each participant and summarised by treatment period where appropriate.


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Reasons for discontinuation of study treatment and withdrawal from study will be listed 
including the study day of treatment discontinuation/study withdrawal and will be 
summarised by treatment period if appropriate.
27.4.3
Exposure
Exposure to AZD4573 and acalabrutinib will be listed for all participants.
Exposure amounts, durations, and dose modifications and interruptions/delays will be 
summarised by study drug and treatment period, separately for Cycle 1 (including intra-
patient ramp up) and for other treatment cycles.
27.4.4
Safety
Safety and tolerability will be assessed in terms of frequency and types of AEs, and 
changes in laboratory data, vital signs, and ECG, when compared to baseline.
Adverse events will be listed individually by participant and treatment period, separately 
for Cycle 1 and for other treatment cycles. The number of participants experiencing each 
AE will be summarised by the Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class, MedDRA preferred term and CTCAE grade, with the exception of 
clinical TLS which will use both CTCAE grade and Cairo-Bishop criteria (Howard 
modification); see Appendix F). The number and percentage of participants with AEs in 
different categories (eg, causally related and CTCAE Grade ≥3) will be summarised by 
treatment period, and events in each category will be further summarised by MedDRA 
system organ class and preferred term. SAEs will be summarised separately if a sufficient 
number occur.
AE summary tables will include only treatment-emergent AEs. AEs will be defined as 
treatment-emergent if they have an onset or worsen (by Investigator report of a change in 
intensity/severity), during the study treatment until 30 days from the last dose of any 
study intervention, but prior to subsequent cancer therapy. AEs occurring outside this 
period will be flagged in listings.
Haematology, clinical chemistry, coagulation, vital signs, ECG data, and other laboratory 
values will be listed individually by participant and suitably summarised. For all 
laboratory variables, which are included in the current version of CTCAE, the CTCAE 
grade will be calculated.
Details of any deaths will be listed for all participants.
Graphical presentations of safety data will be presented as is deemed appropriate. This 
may include, but is not restricted to, presentation of parameters against time, 


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concentration, or shift plots. Appropriate scatter plots will also be considered to 
investigate trends in parameters compared to baseline level.
ECG Changes
QTc will be calculated using Fridericia’s formula.
Creatinine Clearance
Estimated creatinine clearance will be calculated using the Cockcroft and Gault formula.
Other Significant Adverse Events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will 
review the list of AEs that were not reported as SAEs and AEs leading to discontinuation 
of study treatment. Based on the expert’s judgement, AEs of particular clinical 
importance may, after consultation with the Global Safety Physician, be considered 
OAEs and reported as such in the CSR. A similar review of laboratory values, vital signs, 
ECGs, and other safety assessments will be performed for identification of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and 
certain events that lead to intervention (other than those already classified as serious), 
dose reduction or significant additional treatment.
27.4.5
Efficacy
Tumour response data will be listed and summarised by treatment period, using the 
standard response criteria as defined in Section 26.4.1.
For Part A participants, all efficacy endpoints are exploratory. Planned analysis of 
exploratory endpoints will be outlined in the SAP.
27.4.5.1
Objective Response Rate and Proportion of Participants with Complete 
Response
The ORR is defined as the proportion of participants who achieve either a CR or PR, 
according to the Lugano Response Criteria for Non-Hodgkin’s Lymphoma 
(Cheson et al 2014). Data obtained from first dose of study treatment up until 
progression, or the last evaluable assessment in the absence of progression, will be 
included in the assessment of ORR, regardless of whether the participant withdraws from 
therapy. Participants who discontinue treatment without a response or progression, 
receive a subsequent therapy, and then respond will not be included as responders in the 
ORR.
ORR and proportion of participants with CR will be presented with corresponding 80% 
and 95% two-sided CIs.


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27.4.5.2
Time to Response (TTR)
Time to response is defined as the time from the first dose of study treatment to the first 
objective response observed for participants who achieved a CR or PR. The date of first 
documented response should coincide with that used for the DoR endpoint. TTR will not 
be defined for those participants who do not have a documented response. TTR data will 
be listed and summarised.
27.4.5.3
Duration of Response (DoR)
DoR is defined as the time from the first objective response to the time of documented 
disease progression or death due to any cause, whichever occurs first. KM curves and 
estimates may be presented, if appropriate.
27.4.5.4
Progression-Free Survival (PFS)
Disease progression will be determined by the investigators according to the revised 
response criteria for malignant lymphoma (Cheson et al 2014). PFS is defined as the time 
from first dose date to documented disease progression, or death (from any cause in the 
absence of progression), regardless of whether the participant withdraws from therapy or 
receives another anti-cancer therapy prior to progression. Participants who have not 
progressed or died at the time of analysis will be censored at the time of the latest date of 
assessment from their last evaluable disease assessment. However, if the participant 
progresses or dies immediately after 2 or more consecutive missed visits, the participant 
is censored at the time of the latest evaluable disease assessment prior to the 2 missed 
visits.
The PFS time will always be derived, based on scan/assessment dates, not visit dates.
Tumour assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied:

Date of progression will be determined, based on the earliest of the dates of the 
component that triggered the progression. 

When censoring a participant for PFS, the participant will be censored at the latest of 
the dates contributing to a particular overall visit assessment.
Kaplan-Meier plots will be provided.
27.4.5.5
Overall Survival (OS)
Overall survival is defined as the time from first dose until date of death from any cause. 
Participants who have not died by the analysis data cut-off date will be censored at their 
last date known to be alive before the cut-off date. Participants known to be alive or dead 
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lost to follow-up will be censored at the date of the participant is last known to have been 
alive. KM curves and estimates may be presented, if appropriate.
27.4.6
Pharmacokinetics
Pharmacokinetic results are a secondary objective for Part A.
Plasma concentrations of AZD4573 plus acalabrutinib and its metabolite ACP-5862 will 
be summarised by nominal sample time. Plasma concentrations and derived PK 
parameters will be summarised by treatment period. Plasma concentrations and the 
derived PK parameters at each time point will be summarised according to treatment by 
the following summary statistics:

The geometric mean (gmean)

Coefficient of variation (CV)

Gmean ± standard deviation

Arithmetic mean calculated using untransformed data

Standard deviation calculated using untransformed data

Minimum

Median

Maximum

Number of observations
The PK data for AZD4573, acalabrutinib and its metabolite ACP-5862 will also be 
displayed graphically. Displays will include plasma concentration participant profiles (on 
the linear and log-scale) versus time and gmean concentration (± standard deviation) 
versus time, stratified by dose.
Scatter plots of PK parameters versus dose, or log-dose, will also be considered to assess 
dose proportionality.
Derived PK parameters to be determined include Cmax, AUC0-t, AUClast, AUC0-inf, 
tmax, and t1/2.
Additional PK parameters may be determined.
27.5
Safety Review Committee – Module 2
An SRC, which includes the principal investigators, is tasked with the review of the 
available safety data (AEs and available pharmacokinetics/pharmacodynamics [PKPD] 


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data) for AZD4573 alone or in combination with acalabrutinib. All decisions made by the 
SRC will be documented in writing in the form of meeting minutes.
The SRC will meet during Module 2, Part A after the first 6 participants have completed 
Period 1, Cycle 1, and again after the first 6 participants entering Period 2 have 
completed Cycle 1. The AZD4573 monotherapy RP2D established in DLBCL (12 mg 
once weekly; study D8230C00001) will be evaluated in MCL participants (Period 1), and 
safety and tolerability compared with the known safety profile in DLBCL participants to 
confirm the RP2D in the MCL population. The AZD4573 + acalabrutinib combination 
RP2D established in participants with DLBCL from Module 1 will be evaluated in MCL 
participants (Period 2) after receiving AZD4573 monotherapy RP2D in Period 1.
A proposed interpretation of the dose confirmation of the AZD4573 monotherapy RP2D 
and assessment of the AZD4573 + acalabrutinib RP2D safety data will be presented to 
the SRC, who will provide their recommendations on the continued development of 
AZD4573 monotherapy and/or in combination with acalabrutinib in MCL participants. 
This process will be further described in the SRC Charter.
The SRC will continue to monitor safety and tolerability data for all participants in Part A 
as described in the SRC Charter.
Please refer to Appendix A 5 and the SRC Charter for further information on the SRC.
The decisions and decision-making of the SRC will be documented and provided to the 
investigators.


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28
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29
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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


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documents] and will notify the IRB/IEC, if appropriate according to local 
requirements.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the AstraZeneca Study Team with 
sufficient, accurate financial information as requested to allow the AstraZeneca Study 
Team 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 one year after 
completion of the study.
A 3
Informed Consent Process

The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised representative will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study centre.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorised person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
To participate in the optional Genomics Initiative component of the study the participant 
should sign and date the consent form for the main study and, as applicable, a separate 
consent form for the Genomics Initiative components of the study.
A 4
Data Protection

Participants will be assigned a unique identifier by the Sponsor. Any participant 
records or datasets that are transferred to the Sponsor will contain the identifier only; 


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participant names or any information which would make the participant identifiable 
will not be transferred.

The participant must be informed that his/her personal study related data will be used 
by the Sponsor in accordance with local data protection law. The level of disclosure 
and use of their data must also be explained to the participant in the informed 
consent. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from Regulatory 
Authorities.
A 5
Committees Structure
The detailed remit and functioning of the SRC will be defined in the SRC Charter.
The SRC Charter for this study will define the exact membership and who should be 
present for decisions to be made.
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 trial will be available on http://astrazenecaclinicaltrials.com
and http://www.clinicaltrials.gov, as will the summary of the main study results when 
they are available. The clinical study and/or summary of main study results may also be 
available on other websites according to the regulations of the countries in which the 
study is conducted. 
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.

The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF.

The Investigator must permit study related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.


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
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 Organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorised site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for 15 years after study completion unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site.

Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The Investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available.

Source data may include, but are not limited to: medical history and physical 
examination notes, hospital discharge summary, autopsy report (when available), 
results of relevant diagnostic tests completed.

All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study are defined as source documents. Source 
data are contained in source documents (original records or certified copies).


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
A digital copy of all imaging scans should be stored as source documents.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants in the first module.
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 participants by the Investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the investigators, the IRBs/IECs, the Regulatory Authorities, and any CROs used in the 
study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments.

The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicentre studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement.


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
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
A 11
Study Protocol Requirements During the 2019-Novel Corona 
Virus Outbreak (COVID-19)
Benefit/risk pertaining to conduct of trial during COVID-19 pandemic
Respiratory viral infections pose a particular threat to patients with haematological 
malignancies due to their increased tendency in this population to progress to severe 
lower respiratory tract infections (LRTIs) (Martino et al 2003, Dignan et al 2016) and 
their association with bacterial/fungal superinfections (Hermann et al 2017). In the case 
of COVID-19, it is not yet clear whether cancer patients have a higher risk of COVID-19 
or of more severe outcomes (Liang et al 2020, Xia et al 2020). It is known, however, that 
cancer patients are more likely to have factors that predispose them to a poor prognosis 
with COVID-19, such as advanced age, hypertension, and diabetes (Zhou et al 2020). 
Additionally, cancer patients may have an increased risk of exposure to the virus due to 
hospital visits for treatment, as was reported in a retrospective cohort study of 28 
COVID-19-infected cancer patients from 3 hospitals in Wuhan, China, in which a third of 
patients (28.6%; N = 8) were suspected to have acquired the infection by hospital-
associated transmission (Zhang et al 2020). In terms of mortality risk of COVID-19 in 
patients with haematological malignancy, data are limited but preliminary experience 
from Italy suggests that rates may be as high as 20% (von Lilienfeld-Toal et al 2020).
This trial will enrol participants with selected haematological malignancies who have 
relapsed after, or are refractory to prior standard therapy, and for whom there is no other 
standard therapy available. The prognosis for these patients is poor: for example, the 
median OS for patients with r/r DLBCL proposed to be enrolled in Module 1 is 
approximately 6 months (Crump et al 2017). These patients are also at increased risk of 
disease-related cytopenias and severe opportunistic infections (Safdar and Armstrong 
2001). Thus, although there may be risks to patients associated with increased 
opportunity for exposure to SARS-CoV-2 during trial visits, this is offset by the benefit 
that patients may receive by potential control of their disease.
In accordance with FDA and European Medicines Agency (EMA) guidelines (EMA-
CTFG-EC 2020; FDA 2021), a risk assessment will be conducted in collaboration with 
investigators for each site and participant prior to site initiation/participant enrolment and 
on an ongoing basis throughout the trial to assess whether additional measures may be 
necessary to ensure participant safety and data validity. Measures may include 
postponement of study start on a global, country or site level or suspension of recruitment 
of participants in locations with an increased risk of COVID-19 related disruption. Given 


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the proposed dosing regimen for AZD4573 requiring weekly administration in a hospital 
setting there is limited opportunity to reduce participant contact with sites; however, 
additional guidance on alternative means of obtaining reconsent to avoid unnecessary 
study visits is provided below (as a supplement to the standard consent procedures in 
Appendix A 3). Any deviations to the protocol necessary to safeguard participant safety 
or data validity as a result of COVID-19 related disruption will be recorded and any 
permanent changes requiring an amendment to the protocol will be communicated to 
Regulatory Authorities and IRBs / ECs in line with relevant local guidance and 
procedures (see Appendix A 1).
AstraZeneca recommends administering non-live inactivated vaccines 72 hours prior to 
administration of the first dose of any IP to avoid biases in the interpretation of safety 
data due to the potential overlap of vaccine-related AEs with IP AEs.
Potential Changes to Informed Consent during the COVID-19 outbreak
General Principles

The rights, safety, and wellbeing of the trial participants are the most important 
considerations and should prevail over interests of science and society. All informed 
consent activities must follow ICH GCP, the CSP, and local laws, regulations and 
guidance. Prospective protocol waivers with respect to enrolment remain 
unacceptable. Participants should not be included in studies without written informed 
consent according to national laws and regulations and proper eligibility assessment.

The reconsent process described in this appendix must be adopted only at 
sites/countries affected by the COVID-19 outbreak where reaching the site means 
placing the trial participant under unnecessary risk. The described process does not 
overrule local laws, regulations and guidance; where differences arise, the latter must 
be followed.

If the need for re-consenting trial participants arises, visiting the Investigator sites for 
the sole purpose of obtaining reconsent should be avoided.

Any validated and secure electronic system already used in the trial for obtaining 
informed consent can be used as per usual practice and if in compliance with local 
regulations.
Process for reconsent of trial participants at sites affected by the COVID-19 
outbreak
Before reconsent is obtained, the approved updated participant information sheet and 
consent form should be provided to trial participants by email. If the trial participant is 
not able to receive e-mails, courier or mail should be used.


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
Verbal consent via phone or teleconference is allowed.

If possible, verbal consent should be supplemented with email confirmation. The 
Investigator should emphasize that trial participants should only use email to confirm 
their ICF consent and that the participant should not include any sensitive personal 
identifier (eg, date of birth, social security number etc.) or medical information 
including AEs.

Please note: Trial participants should not sign the document at home after giving 
verbal consent. The phone call or teleconference should be informative. The 
document will be signed and filed with the participant’s source data once the trial 
participant is able to attend the site. Under no circumstances should the trial 
participant scan and send the document back via email.

Verbal consent and print-out of the email confirmation (if available and once 
possible) must be documented by the Investigator or delegate (if applicable) in 
the trial participant’s medical records:

Documentation should include details on when the contact took place, the reason 
why the trial participant could not reach the site, any important details of the 
consenting call/concerns raised, any questions raised (especially on safety 
measures) by the trial participant and that these were answered satisfactorily by 
the site consenting party.

At the earliest possible occasion, consent must be documented via standard consent 
process. This would not apply if the trial participant is lost to follow-up, dies or study 
ends before the COVID-19 outbreak is over. In this case the reason why the trial 
participant did not sign the document in person has to be documented in the trial 
participant’s medical records.
Courier Use
A courier may be used

when participants do not have access to email.

to deliver study drug to the participant’s home.

to pick up biological samples from the participant’s home.
References
Crump et al 2017
Crump M, Neelapu SS, Farooq U, Van den Neste E, Kuruvilla J, Westin J, et al. 
Outcomes in refractory diffuse large B-cell lymphoma: results from the international 
SCHOLAR-1 study. Blood. 2017;130(16):1800–08.


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Dignan et al 2016
Dignan FL, Clark A, Aitken C, Gilleece M, Jayakar V, Krishnamurthy P, et al. 
BCSH/BSBMT/UK clinical virology network guideline: diagnosis and management of 
common respiratory viral infections in patients undergoing treatment for haematological 
malignancies or stem cell transplantation. Br J Haematol. 2016;173(3):380-93.
EMA-CTFG-EC 2020
European Medicines Agency (EMA), Clinical Trials Facilitation and Coordination Group 
(CTFG), European Commission (EC). Guidance on the management of clinical trials 
during the COVID-19 (coronavirus) pandemic, Version 2, 27 March 2020. 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. Accessed 16 April 2020.
FDA 2021
US Food and Drug Administration (FDA). Guidance on conduct of clinical trials of 
medical products during COVID-19 public health emergency, March 2020 (updated 
January 2021). https://www.fda.gov/media/136238/download. Accessed 11 June 2021.
Hermann et al 2017
Hermann B, Lehners N, Brodhun M, Boden K, Hochhaus A, Kochanek M, et al. 
Influenza virus infections in patients with malignancies - characteristics and outcome of 
the season 2014/15. A survey conducted by the Infectious Diseases Working Party 
(AGIHO) of the German Society of Haematology and Medical Oncology (DGHO). Eur J 
Clin Microbiol Infect Dis. 2017;36(3):565-73.
Liang et al 2020
Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 
infection: a nationwide analysis in China. Lancet Oncol. 2020;21(3):335-7.
Martino et al 2003
Martino R, Rámila E, Rabella N, Muñoz JM, Peyret M, Portos JM, et al. Respiratory 
virus infections in adults with hematologic malignancies: a prospective study. Clin Infect 
Dis. 2003;36(1):1-8.
Safdar and Armstrong 2001
Safdar A, Armstrong D. Infectious morbidity in critically ill patients with cancer. Crit 
Care Clin. 2001;17(3):531-70.
von Lilienfeld-Toal et al 2020
von Lilienfeld-Toal M, Vehreschild JJ, Cornely O, Pagano L, Compagno F, EHA 
Infectious Disease Scientific Working Group, et al. Frequently asked questions regarding 
SARS-CoV2 in cancer patients: recommendations for clinicians caring for patients with 


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malignant diseases. 25 March 2020. https://ehaweb.org/assets/Uploads/01-EHA-SWB-
Infect-Manuscript-FAQ-COVID19-25032020.pdf. Accessed 16 April 2020.
Xia et al 2020
Xia Y, Jin R, Zhao J, Li W, Shen H. Risk of COVID-19 for patients with cancer. Lancet 
Oncol. 2020;21(4):e180.
Zhang et al 2020
Zhang L, Zhu F, Xie L, Wang C, Wang J, Chen R, et al. Clinical characteristics of 
COVID-19-infected cancer patients: a retrospective case study in three hospitals within 
Wuhan, China. Ann Oncol. 2020; 26. pii: S0923-7534(20)36383-3.
Zhou et al 2020
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for 
mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort 
study. Lancet. 2020;395(10229):1054-62.


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Appendix B
Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An adverse event (AE) is the development of any untoward medical occurrence in a 
patient or clinical study participant administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavourable and unintended sign (eg, an abnormal laboratory finding), symptom (for 
example nausea, chest pain), or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, 
including run-in or washout periods, even if no study treatment has been administered.
B 2
Definitions of Serious Adverse Event
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity. 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the participant or may require 
medical treatment to prevent one of the outcomes listed above.
Adverse Events 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 IP under study and is not the development of new or 
progression of existing metastasis to the tumour under study). Malignant tumours that –
as part of normal, if rare, progression – undergo transformation (eg, Richter's 
transformation of B-cell CLL into DLBCL) should not be considered a new malignant 
tumour.
Life-threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE 
as it occurred, or it is suspected that use or continued use of the product would result in 
the participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a 
more severe form it might have caused death (eg, hepatitis that resolved without hepatic 
failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the 
reasons for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or 
surgical operations planned before or during a study are not considered AEs if the illness 
or disease existed before the participant was enrolled in the study, provided that it did not 
deteriorate in an unexpected way during the study.
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is 
serious in situations where important medical events may not be immediately life-
threatening or result in death, hospitalisation, disability or incapacity but may jeopardise 
the participant or may require medical treatment to prevent one or more outcomes listed 
in the definition of serious. These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; 
medical judgement must be used.

Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion) 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 latest version 
will be utilised for all events with an assigned CTCAE grading, with the exception of 
TLS which will use both CTCAE grade and Howard modification of Cairo-Bishop 
criteria (see Appendix F). For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate and severe events 
into CTCAE grades should be used. A copy of the CTCAE can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.


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
Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

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 drug that either causes harm to 
the participant or has the potential to cause harm to the participant.
A medication error is not lack of efficacy of the drug, but rather a human or process 
related failure while the drug is in control of the study-site staff or participant.
Medication error includes situations where an error:

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion


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
Dispensing error eg, medication prepared incorrectly, even if it was not actually 
given to the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet

Drug not stored as instructed eg, kept in the fridge when it should be at room 
temperature

Wrong participant received the medication (excluding Interactive Voice Response 
System [IVRS]/Interactive Web Response System [IWRS] errors)

Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which lead to one of 
the above listed events that would otherwise have been a medication error

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or 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 life cycle.
The Investigator at each centre keeps full traceability of collected biological samples 
from the participants while in storage at the centre until shipment or disposal (where 
appropriate) and records relevant processing information related to the samples while 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.
C 2
Withdrawal of Informed Consent for Donated biological 
samples 
If a participant withdraws consent to the use of donated biological samples, the samples 
will be disposed of/destroyed/repatriated, and the action documented. If samples are 
already analysed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation 
should be considered in relation to the withdrawal processes outlined in the informed 
consent.
The Investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples 
is highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.

Ensures that the participant and AstraZeneca are informed about the sample disposal.


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


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Appendix D
Optional Genomics Initiative Saliva Sample
D 1
Use/Analysis of DNA

AstraZeneca intends to collect and store DNA for genetic research to explore how 
genetic variations may affect clinical parameters, risk and prognosis of diseases, and 
the response to medications. This genetic research may lead to better understanding 
of diseases, better diagnosis of diseases or other improvements in health care and to 
the discovery of new diagnostics, treatments or medications. Therefore, where local 
regulations and IRB/IEC allow, a saliva sample will be collected for DNA analysis 
from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome.

The results of genetic analyses may be reported in a separate study summary.

The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.

The samples will be retained while research on AZD4573 continues but no longer 
than 15 years or other period as per local requirements.
D 2
Genetic Research Plan and Procedures
Selection of genetic research population

All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss 
of benefit. The participant will not be excluded from any aspect of the main study.
Inclusion criteria
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and provide informed consent 
for the Genomics Initiative sampling and analyses.
Exclusion criteria

Exclusion from this genetic research may be for any of the exclusion criteria 
specified in the main study or any of the following:

Previous allogeneic bone marrow transplant.

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection.

Healthy Volunteers and paediatric patient samples will not be collected for the 
Genomics Initiative.


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Withdrawal of consent for genetic research

Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 
withdrawal will not prejudice further treatment. Procedures for withdrawal are 
outlined in Section 7.2 of the main Clinical Study Protocol.
Collection of samples for genetic research

The saliva sample for this genetic research will be obtained from the patients before 
the first dose of IP. Although DNA is stable, early sample collection is preferred to 
avoid introducing bias through excluding participants who may withdraw due to an 
AE. If for any reason the sample is not drawn before the first dose of IP, it may be 
taken at any visit until the last study visit. Only one sample should be collected per 
participant for genetics during the study.
Coding and storage of DNA samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a 
maximum of 15 years, from the date of last participant last visit, after which they 
will be destroyed. DNA is a finite resource that is used up during analyses. Samples 
will be stored and used until no further analyses are possible or the maximum storage 
time has been reached.

An additional second code (DNA number) will be assigned to the sample either 
before or at the time of DNA extraction replacing the information on the sample 
tube. Thereafter, the sample will be identifiable only by the second, unique number. 
This number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated organization. No personal 
details identifying the individual will be available to any person (AstraZeneca 
employee or designated organizations working with the DNA).

The link between the participant enrolment number and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca 
or designated organizations. The link will be used to identify the relevant DNA 
samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent.


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Ethical and regulatory requirements

The principles for ethical and regulatory requirements for the study, including this 
genetics research component, are outlined in Appendix A.
Informed consent

The genetic component of this study is optional, and the participant may participate 
in other components of the main study without participating in this genetic 
component. To participate in the genetic component of the study the participant must 
sign and date both the consent form for the main study and the addendum for the
Genomics Initiative component of the study. Copies of both signed and dated 
consent forms must be given to the participant and the original filed at the study 
centre. The principal Investigator(s) is responsible for ensuring that consent is given 
freely and that the participant understands that they may freely withdrawal from the 
genetic aspect of the study at any time.
Participant data protection

AstraZeneca will not provide individual genotype results to participants, any 
insurance company, any employer, their family members, or general physician unless 
required to do so by law.

Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, 
certain individuals might see both the genetic data and the personal identifiers of a 
participant. For example, in the case of a medical emergency, an AstraZeneca 
Physician or an Investigator might know a participant’s identity and also have access 
to his or her genetic data. Regulatory authorities may require access to the relevant 
files, though the participant’s medical information and the genetic files would remain 
physically separate.
Data management

Any genetic data generated in this study will be stored at a secure system at 
AstraZeneca and/or designated organizations to analyse the samples.

AstraZeneca and its designated organizations may share summary results (such as 
genetic differences from groups of individuals with a disease) from this genetic 
research with other researchers, such as hospitals, academic organizations or health 
insurance companies. This can be done by placing the results in scientific databases, 
where they can be combined with the results of similar studies to learn even more 
about health and disease. The researchers can only use this information for health-


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related research purposes. Researchers may see summary results, but they will not be 
able to see individual participant data or any personal identifiers.

Some or all of the clinical datasets from the main study may be merged with the 
genetic data in a suitable secure environment separate from the clinical database.

The results of the Genomics Initiative research will be reported separately and will 
not form part of the Clinical Study Report.


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


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Hy’s Law (HL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other 
than the IMP, can be found to explain the combination of increases, eg, elevated ALP 
indicating cholestasis, viral hepatitis, another drug.
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, 
on the same day) the elevation in TBL, but there is no specified timeframe within which 
the elevations in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria 
in isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
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 (Medical Monitor)

Determine whether the participant meets PHL criteria (see Section E 1 Definitions 
within this appendix for definition) by reviewing laboratory reports from all previous 
visits

Promptly enter the laboratory data into the laboratory eCRF
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria Not Met
If the participant does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.


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E 4.2
Potential Hy’s Law Criteria Met
If the participant does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (see Section E 6)

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the Investigator will report the case as an 
SAE; serious criteria ‘Important Medical Event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting.
o
Events that meet PHL criteria will be reported as an SAE with the reported 
term “Potential Hy’s Law” ONLY if:

The ALT and bilirubin elevations did not improve by Day 3 from Start 
of Infusion (SOI) or resolve back to baseline by Day 5, and/or

INR ≥1.5 x ULN (or an absolute increase of 0.3 x baseline if elevated at 
baseline) of any duration at the time of ALT elevation, and/or

Was accompanied by clinical symptoms of liver impairment including 
fatigue, nausea, vomiting, abdominal pain, and/or

Required hospitalization for monitoring or treatment, or was considered 
clinically relevant by the investigator
o
Events that meet PHL criteria but do not fulfil the above characteristics will 
be reported as a SAE with the investigator-reporter term (such as AST/ALT 
elevations, bilirubin elevation, transaminase elevation, etc.) per the 
investigator’s discretion.

Of note, all cases that meet the standard PHL criteria must be reported. The above
characteristics are only to guide which reported term to use for these cases.

The Study Physician contacts the Investigator, to provide guidance, discuss and agree 
an approach for the study participants’ follow-up (including any further laboratory 
testing) and the continuous review of data

Subsequent to this contact the Investigator will:

Monitor the participant until liver biochemistry parameters and appropriate 
clinical symptoms and signs return to normal or baseline levels, or as long as 
medically indicated. Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.

Complete Liver/PHL eCRF modules/forms as information becomes available.


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E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are 
met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria, to ensure timely analysis and 
SUSAR reporting to Health Authorities in an expedited manner. The AstraZeneca Global 
Clinical Lead or equivalent and Global Safety Physician will also be involved in this 
review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL
elevations, a determination of whether the alternative explanation is an AE will be made 
and subsequently whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF.

If the alternative explanation is an AE/SAE: update the previously submitted PHL 
SAE and AE eCRFs accordingly with the new information (reassessing event term; 
causality and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no alternative explanation for the ALT or AST and TBL 
elevations:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply.

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, 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:


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
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 participants with liver metastases who meet PHL criteria on 
study treatment, having previously met PHL criteria at a study visit prior to starting study 
treatment.
At the first on-study treatment occurrence of PHL criteria being met the Investigator will 
determine if there has been a significant change in the participants’ condition# compared 
with the last visit where PHL criteria were met#

If there is no significant change no action is required

If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Section E 4.2
E 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant meets PHL criteria on study treatment and 
has already met PHL criteria at a previous on study treatment visit (Section E 6).
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) 
of PHL is based on the nature of the alternative cause identified for the previous 
occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria 
being met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study eg, chronic or progressing malignant disease, 
severe infection or liver disease? 
If No: follow the process described in Section E 4.2 for reporting PHL as an SAE


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If Yes: Determine if there has been a significant change in the participant’s condition#
compared with when PHL criteria were previously met

If there is no significant change no action is required

If there is a significant change follow the process described in Section E 4.2 for 
reporting PHL as an SAE


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E 8
Laboratory Tests
Proposed laboratory assessments to be performed as judged by the investigator
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV
HBsAg
IgM and IgG anti-HBc
HBV DNQa
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)c
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrinc
Transferrin saturation
a
HBV DNA is only recommended when IgG anti-HBc is positive
b
HCV RNA is only recommended when IgG anti-HCV is positive or inconclusive 
c
CD-transferrin and Transferrin are not available in China. Study teams should amend this list 
accordingly
E 9
References
Aithal et al, 2011
Aithal GP, Watkins PB, Andrade RJ, Larrey M, Molokhia M, Takikawa H, et al. Case 
definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol 
Ther. 89(6):806-15.


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FDA Guidance for Industry, July 2009
FDA Guidance for Industry (July 2009) Drug-induced liver injury: premarketing clinical 
evaluation. https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/drug-induced-liver-injury-premarketing-clinical-evaluation. Accessed 06 
April 2021.


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Appendix F
Cairo-Bishop Tumour Lysis Syndrome Definition and 
Grading Criteria (Howard Modification)
Laboratory tumour lysis syndrome (TLS) is defined as a level above or below normal, as 
defined below, for any 2 or more serum values of uric acid, potassium, phosphate, and 
calcium within 3 day before or 7 day after the initiation of anti-cancer therapy. This 
assessment assumes that a participant has or will receive adequate hydration and a 
hypouricemic agent(s).
Cairo-Bishop Definition of Laboratory Tumour Lysis Syndrome (Howard 
Modification)
Element 
Value
Uric Acid 
≥476 µmol/L (8 mg/dL)
Potassium
≥6.0 mmol/L (6 mg/L)
Inorganic phosphorus
≥1.45 mmol/L (4.5 mg/dL)
Calcium
≤1.75 mmol/L (7.0 mg/dL)
Howard et al 2011
Cairo-Bishop Definition of Clinical Tumour Lysis Syndrome 
Clinical tumour lysis syndrome (TLS) assumes the laboratory evidence of metabolic 
changes and significant clinical toxicity that requires clinical intervention. Clinical TLS is 
defined as the presence of laboratory TLS and any 1 or more of the below-mentioned 
criteria. Maximal clinical TLS manifestation (renal, cardiac, neuro) defines the grade.
1
Creatinine ≥1.5 × ULN (age > 12 years or age adjusted)
2
Cardiac arrhythmia/sudden death
3
Seizure
Cairo-Bishop Clinical Tumour Lysis Syndrome Grading Criteria
Grade
Complication
0
1
2
3
4
5
Creatinine*,†
< 1.5 × 
ULN
1.5 × ULN
>1.5 – 3.0 × 
ULN
> 3.0 – 6.0 × 
ULN
> 6.0 × ULN
Death


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Grade
Complication
0
1
2
3
4
5
Cardiac 
Arrhythmia*
None
Intervention 
not 
indicated
Nonurgent 
medical 
intervention 
indicated
Symptomatic 
and 
incompletely 
controlled 
medically or 
controlled 
with devise 
(eg, 
defibrillator) 
Life-
threatening 
(eg, 
arrhythmia 
associated 
with CHF, 
hypotension, 
syncope, 
shock)
Death
Seizure*
None
None
One brief, 
generalised 
seizure; 
seizure(s) well 
controlled by 
anticonvulsants 
or infrequent 
focal motor 
seizures not 
interfering with 
ADL
Seizure in 
which 
consciousness 
is altered; 
poorly 
controlled 
seizure 
disorder; with 
breakthrough 
generalised 
seizures 
despite 
medical 
intervention 
Seizure of 
any kind 
which are 
prolonged, 
repetitive or 
difficult to 
control (eg, 
status 
epilepticus, 
intractable 
epilepsy)
Death
ADL = activities of daily living; CHF = congestive heart failure; CTLS = clinical tumour lysis syndrome; 
LTLS = laboratory tumour lysis syndrome; ULN = upper limit of normal
Clinical tumour lysis syndrome (CTLS) requires one or more clinical manifestations along with criteria for 
LTLS. Maximal CTLS manifestation (renal, cardiac, neuro) defines the grade.
*Not directly or probably attributable to therapeutic agent (eg, rise in creatinine after amphotericin 
administration).
†If no institutional ULN is specified, age/sex ULN creatinine may be defined as 105.6 μmol/L for female 
participants ≥16 years of age and 114.4 μmol/L for male participants ≥16 years of age. 
Modified from Cairo and Bishop 2004.


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Appendix G
Strong Inhibitors and Inducers of CYP3A
Avoid co-administration of these agents with acalabrutinib, if possible. If not possible to 
avoid, monitor for toxicity (with inhibitors of CYP3A) and potential reduction in efficacy 
(with CYP3A inducers).
Strong Inhibitors of CYP3Aa
Strong Inducers of CYP3Ae
boceprevir
apalutamide
cobicistatb
carbamazepinef
clarithromycinb
enzalutamide
danoprevir and ritonavirc
mitotane
elvitegravir and ritonavirc
phenytoinf
grapefruit juiced
rifampinf
idelalisib
St John's wortf
indinavir and ritonavirc
itraconazoleb
ketoconazole
lopinavir and ritonavirb,c
paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir)c
nefazodone
nelfinavir
posaconazole
ritonavirb,c
saquinavir and ritonavirc
telaprevir
tipranavir and ritonavirc
telithromycin
troleandomycin
voriconazole
a
A strong inhibitor for CYP3A is defined as an inhibitor that increases the area under the 
concentration-time curve (AUC) of a substrate for CYP3A by ≥5-fold.
b
In vivo inhibitor of P-glycoprotein.
c
Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical 
practice. Caution should be used when extrapolating the observed effect of ritonavir alone to the 
effect of combination regimens on CYP3A activities.
d
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” 
when a certain preparation was used (eg, high dose, double strength) or as a “moderate CYP3A 
inhibitor” when another preparation was used (eg, low-dose, single strength).
e
A strong inducer for CYP3A is defined as an inducer that results in ≥80% decrease in the AUC of 
a substrate for CYP3A.


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f
In vivo inducer of P-glycoprotein.
Note: The list of drugs in this table is not exhaustive. Any questions about drugs not on this list should be 
addressed to the Medical Monitor of the protocol.
Source: FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors, and Inducers. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteraction
sLabeling/ucm093664.htm#inVivo (Accessed 05 April 2020).


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


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schedule of assessments for the relevant module must be undertaken to confirm eligibility 
using the same randomisation number as for the participant.
H 3
Home or Remote Visit to Replace On-site Visit (where 
applicable)
A qualified health care professional (HCP) from the study site or third-party verification 
(TPV) service will visit the participant’s home / or other remote location as per local 
standard operating procedures (SOPs), as applicable. Supplies will be provided for a safe 
and efficient visit. The qualified HCP will be expected to collect information per the 
clinical study protocol (CSP).
H 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the participants 
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced 
by a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine 
contact with the participants will allow adverse events and concomitant medication to be 
reported and documented.
H 5
At-home or Remote Location IP Administration Instructions
If a site visit is not possible, at-home or remote location administration of IP may be 
performed by a qualified HCP, provided this is acceptable within local 
regulation/guidance. The option of at-home or remote location IP administration ensures 
participants safety in cases of a pandemic where participants may be at increased risk by 
traveling to the site/clinic. This will also minimise interruption of IP administration 
during other study disruptions, eg, site closures due to natural disaster. 
H 5.1
At-home or Remote Location IP Administration by the Participant 
or His/Her Caregiver
Prior to at-home or remote location IP administration the Investigator must assess the 
participant or his/her caregiver to determine whether they are appropriate for at-home or 
remote location administration of IP. Once the participant or his/her caregiver is deemed 
appropriate for at-home or remote location administration, he/she must receive 
appropriate training. All necessary supplies and instructions for administration and 
documentation of IP administration will be provided. More information related to the 
visit can be obtained via a telemedicine or home / remote visit.


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H 6
Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home / remote visits will be captured by the 
qualified HCP from the study site or TPV service.


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Appendix I
References
Armitage et al 2004
Armitage JO, Vose JM, Weisenburger DD. Towards understanding the peripheral T-cell 
lymphomas. Ann Oncol. 2004;15(10):1447-9.
Bellei et al 2017
Bellei M, Sabattini E, Pesce EA, Ko YH, Kim WS, Cabrera ME, et al. Pitfalls and major 
issues in the histologic diagnosis of peripheral T-cell lymphomas: results of the central 
review of 573 cases from the T-cell Project, an international, cooperative study. Hematol 
Oncol. 2017;35(4):630-6.
Boiko et al 2020
Boiko S, Proia TA, San Martin M, Gregory G, Wu MM, Aryal NK et al. Targeting Bfl-1 
via acute CDK9 inhibition overcomes intrinsic BH3 mimetic resistance in lymphomas. 
Blood. 2021;137(21);2947-57.
Bray et al 2018
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer 
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 
cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
Cairo and Bishop 2004
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and 
classification. Br J Haematol 2004;127(1):3-11.
Cancer Stat Facts: Hodgkin Lymphoma.
Cancer Stat Facts: Hodgkin Lymphoma. SEER NCI. Available at: 
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Appendix J
Abbreviations
Abbreviation or 
special term
Explanation
ABC
Activated B-cell
AE
Adverse event 
AESI
Adverse event of special interest
ALC
Absolute lymphocyte count
ALL
Acute lymphocytic leukaemia
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myeloid leukaemia
ANC
Absolute neutrophil count
Anti-HBc
Hepatitis B core antibody
aPTT
Partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BCL2
B-cell Lymphoma-2
BCL-XL
B-cell lymphoma extra large
BCR
B-cell receptor
BR
Bendamustine and rituximab
BTK
Bruton’s tyrosine kinase
CBC
Complete blood count
CD
Carbohydrate deficient
CDK9
Cyclin-dependent kinase 9
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CLL
Chronic lymphocytic leukaemia
Cmax
Maximum concentration
CMML
Chronic myelomonocytic leukaemia
CMV
Cytomegalovirus


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Abbreviation or 
special term
Explanation
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatinine phosphokinase
CR
Complete response / Complete remission
CRO
Contract research organisation
CRR
Complete response rate
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTD
Carboxyl-terminal domain
CTFG
Clinical Trials Facilitation and Coordination Group
CYP
Cytochrome P450
DILI
Drug-Induced Liver Injury
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose-limiting toxicity
DoR
Duration of response
DSIF
5,6-dichloro-1-β-D-ribofuranosylbenzimidazole sensitivity 
inducing factor
DSUR
Development Safety Update Report
DU
Dose is unsafe
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Case Report Form (electronic/paper)
EDC
Electronic data capture
EMA
European Medicines Agency
ESMO
European Society for Medical Oncology
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose


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Abbreviation or 
special term
Explanation
FFPE
Formalin-fixed paraffin embedded
FTIH
First-time-in-human
GCB
Germinal centre B-cell
GCP
Good Clinical Practice
G-CSF
Granulocyte-colony-stimulating factor
GGT
Gamma-glutamyl transferase
GLDH
Glutamic dehydrogenase
GLP
Good Laboratory Practice
gmean
Geometric mean
HBV
Hepatitis B virus 
HCP
Health care professional
HCV
Hepatitis C virus
hERG
Human Ether-à-go-go-Related Gene
HGBCL
High-grade B-cell lymphoma
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HL
Hy’s Law
HR
Hazard ratio
IATA
International Airline Transportation
IC50
Half maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Committee on Harmonisation
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
INR
International Normalised Ratio
IP
Investigational product
IR
Idelalisib and rituximab
IRB
Institutional Review Board
IRC
Independent Review Committee
IV
Intravenous


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Abbreviation or 
special term
Explanation
IVRS
Interactive Voice Response Systems
iwCLL
International Workshop on Chronic Lymphocytic Leukemia
IWRS
Interactive Web Response System
KM
Kaplan-Meier
LDH
Lactate dehydrogenase
LCT
Liver chemistry test
LRTI
Lower respiratory tract infection
LTFU
Long-term follow-up
LVEF
Left ventricular ejection fraction
MALT
Mucosa-associated lymphoid tissue
MATE
Multi-antimicrobial extrusion
MCL
Myeloid Cell Leukaemia
MDS
Myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
MM
Multiple myeloma
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
mTPI-2
modified toxicity probability interval
MUGA
Multigated acquisition scan
MYC
Myelocytomatosis
MZL
Marginal zone lymphoma
NCCN
National Comprehensive Cancer Network
NELF
Negative elongation factor
NHL
Non-Hodgkin lymphoma
NK
Natural killer
OAE
Other significant adverse event
OAT
Organic anion transporter
OATP
Organic anion transporting polypeptide
ORR
Objective response rate
CCI
CCI


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Abbreviation or 
special term
Explanation
OS
Overall survival
PCR
Polymerase chain reaction
PD
Progressive disease
PET
Positron-emission tomography
PFS
Progression-free survival
PHL
Potential Hy’s Law
PK
Pharmacokinetics
PKPD
Pharmacokinetic-pharmacodynamic
PMBCL
Primary mediastinal B-cell lymphoma
PML
Progressive Multifocal Leukoencephalopathy
PR
Partial response / Partial remission
PT
Prothrombin time
P-TEFb
Positive transcription elongation factor b
pSer2RNAP2
Phosphorylation levels of Serine 2(Ser2) found in the carboxyl-
terminus (CTD) of RNA polymerase II (RNAP2)
QT
ECG interval measured from the onset of the QRS complex to 
the end of the T-wave
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected using Fridericia’s formula (QTcF)
RCHOP
Rituximab and chemotherapy combination therapy
RNAP2
RNA polymerase II
r/r
Relapsed/refractory
RP2D
Recommended Phase II dose
SAE
Serious adverse event (see definition in Appendix B)
SAP
Statistical Analysis Plan
SCT
Stem cell transplantation
SD
Stable disease
Ser2
Serine 2
SFU
Safety follow-up
CCI
CCI


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Abbreviation or 
special term
Explanation
SLL
Small lymphocytic lymphoma
SoA
Schedule of Activities
SoC
Standard of care
SRC
Safety Review Committee
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TLS
Tumour lysis syndrome
TPV
Third-party verification
TSH
Thyroid-stimulating hormone
TTNT
Time to next treatment
TTR
Time to response
ULN
Upper limit of normal


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Appendix K
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 1 [03 July 2020]
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:
This protocol amendment incorporates changes requested by the FDA arising from review of 
version 1 of the protocol.
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Core protocol
5.1 Inclusion Criteria -
Core
Removal of serum creatinine from 
Table 2 (Criteria for Adequate 
Organ Function); update of 
calculated creatinine clearance 
from ≥50 mL/minute to 
≥60 mL/minute; inclusion 
criterion 8 amended to specify 
that participants should be able to 
swallow capsules intact without 
difficulty.
Amended in response to 
FDA request.
Substantial
Module 1
13.1 Overall design
Statement added to clarify that no 
further intra-patient dose 
escalation (other than the ramp up 
to the assigned target dose level) 
will be allowed.
Clarification as per FDA 
request.
Non-substantial
13.3 Justification for 
Dose
Information regarding TLS events 
and DLTs from Study 
D8230C00001 (Phase I AZD4573 
monotherapy) updated in line 
with most recent information 
from ongoing FTIH study.
Updated in line with 
response to FDA request.
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Confirmation added that the 
planned starting dose regimen for 
the AZD4573/acalabrutinib 
combination is 9 mg AZD4573 
once weekly, following SRC 
declaration that AZD4573 12 mg 
once weekly is a tolerated dose.
Updated in line with 
response to FDA request.
Substantial
14.1 Inclusion Criteria
Wording for inclusion criterion 2 
clarified.
Inclusion criterion 4 amended to 
state participants must have failed 
at least 2 prior therapies instead 
of 1.
Amended in response to 
FDA request.
Substantial
14.2 Exclusion Criteria
Addition of 2 exclusion criteria 
regarding participants on 
anticoagulant therapy due to risk 
of bleeding as a potential 
overlapping toxicity with 
AZD4573 and acalabrutinib.
Updated in line with
response to FDA request. 
Substantial
15.2 Starting Dose, 
Dose-Escalation 
Scheme, and Stopping 
Criteria
Amended to add additional safety 
monitoring after the 
DLT-assessment period and 
potential stopping criteria.
Amended in response to 
FDA request.
Substantial
15.3 Definition of 
Dose-limiting Toxicity 
(DLT)
DLT criteria timing updated to 
include within 72 hours of onset 
of toxicity, for consistency with 
the threshold for duration of 
non-haematologic toxicities 
≥Grade 3.
Updated in line with 
response to FDA request.
Substantial
DLT criteria for febrile 
neutropenia and 
thrombocytopenia updated.
Updated in line with 
response to FDA request.
Substantial
Definition of isolated changes in 
GGT in DLT criteria exclusions 
updated to clarify that this 
exception only applies to 
genuinely isolated elevations of 
GGT.
Exclusions pertaining to TLS 
removed.
Amended in response to 
FDA request.
Substantial
15.11.2 Prohibited 
Concomitant Therapy
Inclusion of warfarin or 
equivalent vitamin K antagonists 
Amended in response to 
FDA request.
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
as a prohibited therapy due to risk 
of bleeding as a potential 
overlapping toxicity with 
AZD4573 and acalabrutinib.
17.1.9.6 Haemorrhage
Addition of requirement that 
acalabrutinib treatment must be 
discontinued if participants 
require either a vitamin K 
antagonist or combined 
administration of antiplatelet and 
therapeutic anticoagulation while 
on study, due to risk of bleeding 
as a potential overlapping toxicity 
with AZD4573 and acalabrutinib.
Amended in response to 
FDA request.
Substantial
18.6 Safety Review 
Committee
Amended to add additional safety 
monitoring and potential stopping 
criteria.
Amended in response to 
FDA request.
Substantial
Amendment 2 21 Jul 2021
This amendment is considered to be substantial based on 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
This protocol amendment expands the disease population in Module 1 to include participants with r/r 
MZL, and adds the new Module 2.
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-Substantial
1.1 Synopsis, 6 Study 
Intervention - Core
Synopsis updated to 
reflect the amended text 
in the body text for Core 
and Module 1, and the 
addition of Module 2
Recruitment of 
participants with r/r MZL 
added to Module 1
Expansion of disease 
population in Module 1
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-Substantial
1.1 Synopsis, Module 2 
(United States) – NEW, 
Sections 19 through 27
Module 2 – Part A: 
AZD4573 monotherapy 
window followed by 
combination therapy with 
acalabrutinib. Part B 
study design to be 
determined from 
emerging Part A data
Additional Module
Substantial
2.2.6 Clinical Experience 
with AZD4573
Study data for ongoing 
FTIH study updated, 
including data in Table 1
To align with updated IB and 
emerging data from ongoing 
FTIH study
Non-substantial
2.3.1 Risk Assessment, 
4.1 Overall Design, 
8.2.10 Reporting of SAEs, 
10.2 SoAs – Module 1
Requirement for 
overnight hospitalisation 
amended
Based on emerging data from 
ongoing FTIH study
Substantial
3 Objectives and Endpoints, 
10.2 SoAs – Module 1, 12 
Objectives and Endpoints –
Module 1, 17 Study 
Assessments and Procedures 
– Module 1, and 17.9 
Exploratory Whole Blood 
Analysis Samples – NEW, 
17.10.4.1 
 Sample for 
 Isolation
Exploratory 
 
sample collection added, 
including 
 sample 
 
 
exploratory 
objectives/endpoints for 
 
 updated
 
 
 
 
 
Substantial
3 Objectives and Endpoints, 
5.1 Inclusion Criteria - Core, 
10.2, SoAs – Module 1 17.11 
Optional Genomics Initiative 
Sample, and Appendix D 2 
Genetic Research Plan and 
Procedures
Genomic initiative tissue 
source changed from 
blood to saliva
A saliva sample is more 
appropriate for this participant 
population
Non-substantial
3 Objectives and Endpoints 
and 4.1 Overall Design
Allowance for dose 
confirmation instead of 
dose setting added
For some new disease 
populations, dose 
confirmation is needed rather 
than dose setting
Non-substantial
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-Substantial
4.1 Overall Design, 6 Study 
Intervention - Core, 10.1 
Schema, 11.2 Acalabrutinib 
Background, 11.3.1 Risk 
Assessment, 13.1 Overall 
Design, 13.2.2  MZL 
Participants - NEW, and 14.1 
Inclusion Criteria
Module 1 description 
amended to include r/r 
MZL participants
To recruit a more inclusive 
and diverse real-world 
participant population while 
maintaining safeguards for 
participant safety
Substantial
4.1 Overall Design
Clarification that the SRC 
will review PK data when 
available
PK data may not always be 
available at the time of SRC 
meetings
Non-substantial
2.2.6 Clinical Experience 
With AZD4573
Study data for ongoing 
FTIH study updated
Emerging data from ongoing 
FTIH study
Non-substantial
5.1 Inclusion Criteria – Core
Inclusion criterion #5: 
lipase and amylase 
criteria were updated
The potential risk of 
pancreatic injury is based on 
preclinical data only. There 
are no emergent significant 
clinical data to support the 
risk of pancreatic injury, 
therefore the thresholds for 
lipase and amylase values 
were revised to be more 
inclusive
Non-substantial
6.1.1 Investigational 
Products, 17.1.6 Clinical 
Safety Laboratory 
Assessments, and 17.1.10.9 
Liver Chemistry Test 
Abnormalities and the Risk 
of Liver Injury
LCT requirements for 
participants with elevated 
transaminases updated
Liver  chemistry values  
(AST, ALT, bilirubin) were 
updated to be aligned with the 
latest international guidance 
by DILI experts
Non-substantial
6.11 Prior/Concomitant 
Therapy, 15.11.3 AZD4573 
and Concomitant Therapy, 
and Appendix A 11 Study 
Protocol Requirements 
During the 2019-Novel 
Corona Virus Outbreak 
(COVID-19)
Recommendation 
regarding administration 
of non-live inactivated 
vaccines added
To avoid biases in safety data 
due to potential 
vaccine-related AEs
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-Substantial
6.12 Dose Modification
Dose modification 
clarified that for AEs 
possibly related to 
AZD4573, study drug 
may be temporarily or 
permanently stopped, or 
reduced
Clarification of dose 
modification options
Non-substantial
8.2.1 Time Period and 
Frequency for Collecting AE 
and SAE Information
Aligned timing for AE 
collection with timing for 
SAEs
To correct for AE collection 
starting at informed consent
Non-substantial
8.2.8 New Cancers - NEW
New Cancers section 
added
Company instructions for 
safety reporting
Non-substantial
8.2.9 Handling of Deaths -
NEW
Handling of Deaths 
section added
Company instructions for 
safety reporting
Non-substantial
13.1 Overall Design
Data cut-off for the 
primary analysis for each 
expansion subgroup 
changed from after all 
participants have had the 
opportunity to be 
followed for at least 
12 months to at least 
6 months
Based on providing sufficient 
opportunity to respond to 
study treatment for the 
primary endpoint of ORR, and 
on expected PFS in the current 
target population, data cut-off 
for primary analysis after all 
participants have had the 
opportunity to be followed for 
at least 6 months is considered 
to best serve the objectives of 
the study
Substantial
11.1 Study Rationale –
Module 1, 13.1 Overall 
Design, 14.1 Inclusion
Criteria, 17.10.1 Collection 
of Archival Tumour 
Samples, 23.1 Inclusion 
Criteria, and 26.10.1 
Collection of Archival 
Tumour Samples
Made clear that 
participants will be 
enrolled based on 
pathology report
Actual tumour samples will 
not be available at Screening
Non-substantial
17.1.1 Enrolment and 
Screening
Tobacco use will no 
longer be collected
New corporate policy
Non-substantial
17.2.1 Adverse Events of 
Special Interest for 
Acalabrutinib - NEW
AESIs for acalabrutinib 
added
To align with updated 
acalabrutinib IB v 10
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-Substantial
17.4.2
The disease assessment 
schedule for CT and PET 
updated to include 
mandatory scheduled 
PET scans post-baseline
Per the requirements of 
Lugano 2014 Response 
Criteria
Substantial
Appendix E 4.2 Potential 
Hy’s Law Criteria Met, 
Appendix E 5 Review and 
Assessment of Potential Hy’s 
Law Cases, Appendix E 8 
Laboratory Tests
Appendix E 6 Actions 
Required When Potential 
Hy’s Law Criteria are Met 
Before and After Starting 
Study Treatment - NEW
Information regarding 
Hy’s Law updated
Clarification
Non-substantial
Appendix H Changes 
Related to Mitigation of 
Study Disruptions Due to 
Cases of Civil Crisis, Natural 
Disaster, or Public Health 
Crisis - NEW
Changes Related to 
Mitigation of Study 
Disruptions Due to Cases 
of Civil Crisis, Natural 
Disaster, or Public Health 
Crisis section added
Due to COVID-19 pandemic
Non-substantial
Appendix J - NEW
Protocol amendment 
history section added
Previous amendment 
summary moved from cover 
pages, per template
Non-substantial
General
Possible reporting of 
exploratory analyses in 
the CSR removed 
throughout the document
No plans for exploratory 
analyses prior to submission 
of the CSR
Non-substantial
TLS monitoring will use 
the Howard modification 
of Cairo-Bishop criteria –
change made throughout 
the document
Refined version of the criteria
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-Substantial
1.1, 2.1, 2.2.4, 2.3.1, 3, 4.3.2, 
5.1, 5.2, 5.3.1, 6.2, 6.9, 6.11, 
8.2.2, 8.2.5, 8.2.6, 8.2.10, 
8.2.12, 8.3, 10.2, 11.1, 
11.2.1, 11.3, 14, 14.3.1 –
NEW, 15.2, 15.3, 15.10, 
15.11.1, 15.11.2, 15.12.1, 
17.1, 17.4.3, 17.4.4, 17.6, 
17.7, 17.8, 17.10, 18.2, 18.3, 
18.4.4, 18.4.5, 18.6, 28, 
Appendix A 9, 
Appendix A 11, 
Appendix B 2, Appendix F, 
and Appendix I
Updates or new 
information added 
throughout the document 
for consistency across 
sections, updates for 
clarity, and edits made 
based on completeness of 
information which are not 
considered significant
Minor, therefore have not 
been summarised
Non-substantial
Minor editorial and 
document formatting 
revisions
Minor, therefore have not 
been summarised
Non-substantial
Amendment 3, 01 August 2022
This amendment is considered to be substantial based on 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
This protocol amendment changes to allow up to approximately 21 patients (dose-limiting toxicity 
evaluable) per dose level in the backfill of Module 1 part A to make the study more available for the 
all-comer diffuse large B-cell lymphoma population and reduces the amount of assessments from 
Cycle 9 onwards. Furthermore, updates are made to secure consistency within the protocol, correct 
errors, and provide clarifications.


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-Substantial
Schedule of Activities-
Module 1 
Table 4 Part A-Dose setting 
Cohorts
Table 5 Part B-Expansion
Schedule of Activities-
Module 2 
Table 23 Part A, Period 1
Table 24 Part A, Period 2
And body text throughout the 
document
Updates 
added throughout the SoA 
tables and footnotes to 
reflect the instructions 
given in the in-text 
Sections of the protocol, 
for consistency with the 
instructions given in the 
footnotes, to clarify 
ambiguous wording, to 
clarify definitions, and to 
correct typing errors.
Clarification and consistency
Non-substantial
Section 1.1 Synopsis
Section 13.1 Overall Design 
(Module 1)
Module 1 Part A, clarified 
to allow up to 
approximately 21 patients 
to be included.
Clarification
Non-substantial
Section 4.1 Overall Design 
(Core)
Section 15.2 Starting Dose, 
Dose-Escalation Scheme, 
and Stopping Criteria
Literature reference to 
Goy et al removed
Correction of an error
Non-substantial
Section 5.2 Exclusion 
Criteria-Core
Reduced the CAR-T 
exclusion criterion to 
within 60 days prior to 
first dose of study drug
To make the study available to 
more patients, increasing the 
population of R/R DLBCL 
patients who progressed after 
prior CAR-T treatment
Substantial
Section 5.2 Exclusion 
Criteria-Core
Removed neutropenia 
from Exclusion 
Criterion 2, as this was an 
error
Correction of error
Non-Substantial
Section 8.2.2 Follow-up of 
AEs and SAEs
Added that “Detailed 
information on the event 
(symptoms and signs, 
work-up done)” will be 
collected following SAE
Clarification
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-Substantial
Section 1.1 Synopsis
Section 13.1 Overall Design 
(Module 1)
Section 18.2 Sample Size 
Determination
Figure 4 Module 1 Overall 
Study Design
Module 1 part B, changed 
so that any safe dose level 
can be backfilled up to 
approximately 21 patients 
instead of 12.
To make study available to 
all-comer DLBCL population
Substantial
Section13.1, Table 8 Dosing 
Schedule- Module 1
Clarified the DLT-
assessment period in 
footnote
Clarification
Non-substantial
Section 14.1 Inclusion 
Criteria (Module 1)
Included instructions for 
how to handle 
participants who do not 
have a viable biopsy.
To make the study available to 
more patients who accept to 
undergo all biopsy 
assessments required per 
protocol
Non-substantial
Section 14.2 Exclusion 
Criteria (Module 1)
Removed exclusion 
criterion for BTK 
inhibitors.
Prior BTK inhibitor 
treatments do not preclude 
potential efficacy of the 
AZD4573 + acalabrutinib 
combination. Hence, such 
patients shall not be excluded 
from the study.
Substantial
Section 14.2 Exclusion 
Criteria (Module 1)
Section 1.1 Synopsis
Clarified the use of 
anticoagulants
Clarification
Non-substantial
Dose Modification
Section 15.12
Section 24.9
Clarified wording for 
maximal drug 
interruption for related 
toxicity
Clarification
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-Substantial
Schedule of Activities-
Module 1 
Table 4
Table 5
Schedule of Activities-
Module 2
Table 23
Table 24
Study Assessments and 
Procedures (Module 1)
Section 17.1 Enrolment and 
Screening
Study Assessments and 
Procedures (Module 2)
Section 26.1 Safety 
Assessments
Change to have less 
frequent assessments 
starting Cycle 9 instead of 
Cycle 13
To reduce burden for the 
patient
Substantial
Section 17.4.1 and Section 
26.4.1
Lugano Modification of Ann 
Arbor Staging System 
Table 17
Table 35
Reinstated Ann Arbor 
staging system tables to 
this protocol version 
Tables were previously in 
Protocol Amendment 1; they 
were unintentionally deleted 
when Amendment 2 was 
published. Reinstated in this 
protocol version. 
Non-substantial
Lugano Response Criteria for 
NHL
Table 18
Table 36
Added footnote to define 
Deauville score for 
complete metabolic 
response
Clarification 
Non-substantial
Table 4
Table 5
Table 23
Table 24
And body text throughout the 
document
Timing of 
Lipase/Amylase, urine 
samples, cardiac troponin 
and 
T4/cortisol/ACTH/TSH 
samples aligned with 
haematology and 
chemistry samples
Simplification, alignment of 
timepoints, less impact on 
patient
Non-substantial
Section 17.7.1 Collection of 
Samples (Part A and Part B)
Section 26.7.1 Collection of 
Samples
Pharmacodynamic 
samples will be whole 
blood, 
 
Correction of an error
Non-substantial
CCI


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-Substantial
Mandatory TLS Prophylaxis 
Guidance 
Table 16
Table 34
Changed dose of 
allopurinol to once daily
Correction, based on local 
standard of care many 
investigators consider 300 mg 
twice daily to be too high dose
Non-substantial
Survival Follow-up 
Section 17.1.9.3
Section 26.1.9.3
Added clarification of 
how the survival 
follow-up should be 
performed.
Clarification
Non-substantial
Section 17.4.2, Table 19
Footnote that was 
included in error removed
Correction of an error
Non-substantial
Section 19 and throughout 
the document
Removed mention that 
Module 2 part of the 
study is for US only.
To make the study available 
for patients in selected 
countries
Non-substantial
Section 26.6
Pharmacokinetics
Part A, Periods 1 and 2 
were split into separate 
descriptions
Clarification
Non-substantial
Section 26.8 Exploratory 
 
Samples (Module 2)
Table 24 Schedule of 
Activities-Module 2, Part A, 
Period 2
Removed 
 
in 
Module 2 Part 2 
Simplification
Non-substantial
Appendix E Actions 
Required in Cases of 
Increases in Liver 
Biochemistry and Evaluation 
of Hy’s Law
Updated PHL process
Adapt the PHL reporting 
process to reflect the current 
experience of the AZD4573 
liver safety profile.
Substantial
Appendix E 8, Laboratory 
Tests
Updated title in the table 
in E8 laboratory tests
This Section was for a central 
lab receiving chemistry tests 
and is not applicable to this 
study
Non-substantial
Abbreviations: ACTH = adrenocorticotropic hormone; BTK = Bruton’s tyrosine kinase; CDK9 = cyclin-
dependent kinase 9; DLBCL = diffuse large B-cell lymphoma; DLT = dose-limiting toxicity; NHL = non-
Hodgkin lymphoma; PHL = potential Hy’s law; PMBC = Peripheral blood mononuclear cell; SAE = serious 
adverse event; T4 = thyroxine;TSH = thyroid-stimulating hormone.
CCI
CCI


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d8230c00002-csp-v5
Document Title:
D8230C00002 Clinical Study Protocol version 5
Document ID:
Doc ID-004236033
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
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Meaning of Signature
06-Jun-2023 03:37 UTC
Content Approval
05-Jun-2023 11:25 UTC
Author Approval
05-Jun-2023 20:44 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
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