Conditions: Urinary Bladder Neoplasms Colorectal Cancer Carcinoma, Non-Small-Cell Lung
Keywords: AZD8853 Monoclonal antibody First-in-Human Non-Small Cell Lung Cancer Colorectal cancer Bladder cancer Urinary Bladder Neoplasms Growth Differentiation Factor-15 (GDF-15) CD8-Positive T-Lymphocytes Urothelial Carcinoma CD8 ⁸⁹Zr-Df-IAB22M2C PET Imaging CD8 + T cells Zirconium-89 crefmirlimab berdoxam
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 17
Healthy volunteers: no

Brief summary:
A Phase I/IIa First-in-human, Open-label Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of AZD8853 in Participants with Selected Advanced/Metastatic Solid Tumours.

Detailed description:
This study is evaluating the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AZD8853 in participants with advanced, unresectable or metastatic Non-Small Cell Lung Cancer (NSCLC), Microsatellite Stable Colorectal Cancer (MSS-CRC), Urothelial Carcinoma (UC).

This is a modular study, that includes a master protocol and Substudies.

Substudy 1 will be conducted in 3 parts - Part A: Dose escalation, Part B: Safety expansion and exploratory CD8+ T cell radiopharmaceutical tracer with PET imaging, and Part C: Efficacy expansion.

Arms:
arm 1: * Part A: AZD8853 monotherapy dose escalation
* Part B1 and Part B2: AZD8853 monotherapy safety expansion at dose levels and indications determined to be safe in Part A
* Part C1 and Part C2: AZD8853 monotherapy safety and preliminary efficacy expansion at dose levels and indications determined to be safe in Parts A and B arm 2: Sub-set of participants from Parts B1 and B2 will also receive investigational CD8+ T cell targeted radioactive tracer, Zirconium-89 crefmirlimab berdoxam with PET scans

Interventions: intervention 1: AZD8853 intervention 2: Zirconium-89 crefmirlimab berdoxam
Intervention descriptions: intervention 1: Monotherapy given until progressive disease or upon meeting other discontinuation criteria. intervention 2: CD8+ T cell tracer for positron emission tomography (PET) at two time points in addition to monotherapy AZD8853

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol 
Study Intervention
AZD8853
Study Code
D9450C00001
Version
3.0
Date
11 Apr 2022
A Phase I/IIa First-in-human, Open-label Study to Evaluate the 
Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary 
Efficacy of AZD8853 in Participants with Selected 
Advanced/Metastatic Solid Tumours
Sponsor Name: AstraZeneca
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s): 
IND number: 157890
EudraCT number: 2021-005438-41
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: D9450C00001
Amendment Number: 2
Study Intervention: AZD8853
Study Phase: I/IIa 


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Short Title: A First-in-human Study to Evaluate the Safety and Tolerability of AZD8853 in 
Participants with Selected Advanced/Metastatic Solid Tumours
Study Physician Name and Contact Information will be provided separately
International Co-ordinating Investigator:
Yale Cancer Center
333 Cedar Street
WWW 211
New Haven, CT 06510
United States
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
11-Apr-2022
Amendment 1
03-Dec-2021
Original Protocol
15-Oct-2021
The summary of changes for Amendment 2 is provided below. Refer to Appendix K for a 
summary of the previous amendments.
Amendment 2 11 April 2022
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of European Union. 
Overall Rationale for the Amendment:
The primary reasons for this protocol amendment were to update the definition of study 
population and the removal of prospective GDF15 testing/pre-screening. In addition, to 
implement changes based on template requirements and other updates to aid sense and flow of 
the document.
Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Section 1.1 (Synopsis; 
Key objectives and 
Endpoints Applicable 
to all Substudies) & 
Section 3 (Objectives 
and Endpoints)
Updated secondary 
efficacy endpoint 
description for change 
in ctDNA levels 
between baseline and 
post-treatment.
Clarification of secondary 
efficacy endpoint description 
for change in ctDNA levels 
from baseline to between 
baseline and post-treatment.
Non-substantial
Section 1.1 (Synopsis; 
Overall Design) & 
Section 10.4.1 
(Substudy 1 Design)
Updated the definition 
for selected 
advanced/metastatic 
solid tumours from 
second to fourth line 
setting to second or 
later line setting of 
unresectable, locally 
advanced (Stage III) or 
metastatic (Stage IV) 
NSCLC that have 
progressed on anti-
PD-1/PD-L1 inhibitors 
Criteria adjusted for clarity, 
consistency, and to relax the 
criteria considering the study 
phase and population.
Substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
with or without 
platinum-containing 
chemotherapy.
Synopsis 1.2 (Schema, 
Figure 2) & Section 
10.1.1 (Schema, 
Figure 3)
Removal of description 
requiring selection of 
participants with high 
GDF15 levels.
New data shows that up to 
% of the study participants 
may have high GDF15 levels 
(above the current cut off); in 
addition, the removal of the 
GDF15 cut off level does not 
have any impact on 
participant safety.
Substantial
Section 1.1 (Synopsis; 
Overall Design; 
Table 2) & Section 
10.4.1 (Substudy 1 
Design)
Updated the number of 
participants required 
for Part B1 and B2 to 
“approximately” 
10 MSS-CRC and 
“approximately” 
10 NSCLC participants 
for PD cohort and “up 
to” 10 participants for 
CD8+ PET cohort.
Clarification on the number of 
participants required for Part 
B1 and B2.
Non-substantial
Main study
Section 2.1 (Study 
Rationale)
Removal of description 
requiring selection of 
participants with high 
GDF15 levels. 
New data shows that up to 
% of the study participants 
may have high GDF15 levels 
(above the current cut off); in 
addition, the removal of the 
GDF15 cut off level does not
have any impact on 
participant safety.
Substantial
Section 2.2.1 (Tumour 
Selection Type)
Updated text to include 
information from 
ongoing trials 
suggesting 
% of 
pre-treated patients in 
these indications have 
 GFD15 
levels.
Clarification and further 
information regarding 
background to tumour 
selection.
Non-substantial
Section 4.2 (Scientific 
Rationale for Study 
Design), Section 5.1 
(Inclusion Criteria), old 
section 5.4 (Pre-Screen 
and Screen Failures), 
Removal of description 
requiring pre-screening 
for GDF15 levels.
New data shows that up to 
% of the study participants 
may have 
 GDF15 levels 
(above the current cut off); in 
addition, the removal of the 
GDF15 cut off level does not 
Substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Section 6.3 (Measures 
to Minimise Bias: 
Randomization and 
Blinding), Section 6.5 
(Concomitant 
Therapy), and Section 
8 (Study Assessments 
and Procedures)
have any impact on 
participant safety.
Section 4.4 (End of 
Study Definition)
Deletion of definition 
for completion of 
study.
The study design does not 
allow participants to be 
considered completed.
Non-substantial
Section 5.1 (Inclusion 
Criteria)
Criterion 8, addition of 
the Cockcroft-Gault 
formula for calculating 
creatinine clearance.
Since creatinine clearance is 
included as an inclusion 
criterion, its calculation needs 
to be standardized for 
collection in eCRF. 
Non-substantial
Section 5.2 (Exclusion 
Criteria)
Criterion 10, updated 
to exclude body weight 
loss > 10% within 
30 days of screening.
Clarification of language 
regarding inclusion of 
participants with body weight 
loss.
Non-substantial
Criterion 20, deletion 
of old bullet a) related 
to previous suspected 
or confirmed 
COVID-19 diagnosis.
Clarification of language 
regarding inclusion of 
participants with prior 
COVID-19.
Non-substantial
Criterion 20, updates 
made to old bullet b) 
now a) in relation to 
COVID-19 cases prior 
to Cycle 1 Day 1.
Clarification of language 
regarding inclusion of 
participants with prior 
COVID-19.
Non-substantial
Section 5.3.2 (Activity)
Text updated to clarify 
that strenuous exercise 
is not allowed 48 hours 
prior to each GDF15 
blood collection.
Clarification that this 
restriction applies only to 
visits with GDF15 blood 
collection.
Non-substantial
Section 6.5 
(Concomitant Therapy)
Update to Table 8 for 
prohibited concurrent 
chemotherapy during 
the study.
Clarification that concurrent 
use of hormones for 
non-cancer-related conditions 
and local treatment of isolated 
lesions may be acceptable 
upon consultation with study 
physician.
Non-substantial


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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Update to Table 8 for 
prohibited metformin 
use during the study.
Based on available research 
data, 
 
 
 
 
 
Substantial
Section 6.5.1 (Rescue 
Medicine) & Section 
10.6.6 (Rescue 
Medication)
Deletion of this 
template section for 
rescue medicine.
Rescue medicine is not 
specified for this study.
Substantial
Section 8.1 (Efficacy 
Assessments, Skeletal 
Muscle Index)
Updated text for CT or 
MRI scans that will be 
obtained for SMI 
assessment.
Clarification that CT or MRI 
scans for SMI assessment will 
be obtained using the same 
modality and timepoints as 
the disease assessment scans.
Non-substantial
Section 8.2.1 (Physical 
Examinations)
Text has been added to 
categorise participants 
appetite as poor, 
average, or good and 
change in appetite as 
worse, about the same, 
or improved.
Clarification of data to be 
collected in eCRF.
Non-substantial
Section 8.2.5 (Clinical 
Safety Laboratory 
Assessments)
Deletion of time of 
collection from text.
Clarification of local 
laboratory assessment needs.
Non-substantial
Table 10, deletion of 
carbonate and 
phosphate from 
clinical chemistry 
variable list. The 
addition of lactate 
dehydrogenase.
Clarifications of local 
laboratory assessment needs.
Non-substantial
Table 10 addition of a 
footnote microscopy.
Clarification that it is 
investigator discretion for 
microscopy for abnormal 
dipstick results.
Non-substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Section 8.3.1 (Time 
Period and Frequency 
for Collecting AE and 
SAE Information)
Addition of text for 
collection of any SAE, 
including death, at any 
time during survival 
follow-up that is 
suspected to have a 
causal relationship to 
study intervention.
Clarifications of local 
laboratory assessment needs.
Non-substantial
Section 8.3.9 (Disease 
Under Study)
This section is deleted.
To prevent duplication and 
aid clarity, AEs reporting for 
disease under study is already 
covered in Section 8.3.5. 
Non-substantial
Section 8.4 (Overdose)
Updated time window 
for reporting relevant 
information to 
AstraZeneca Patient 
Safety within 1 to 
5 days for overdose 
associated SAEs.
Clarification of time window 
to between 1 and 5 days from 
1 or 5 days.
Non-substantial
Section 9.6 (Safety 
Review Committee)
Updated text for SRC 
required data, 
confirming that every 
effort is to be made to 
provide available PK 
data for SRC meetings.
Clarification that PK data is 
not a requirement for SRC 
meetings but every effort 
should be made to provide 
available PK data.
Non-substantial
Substudy 1
Section 10.1.2 
(Schedule of Activities, 
Table 12)
Removal of 
pre-screening for 
GDF15 levels ≥
 
pg/mL.
New data shows that up to 
% of the study participants 
may have 
 GDF15 levels 
(above the current cut off); in 
addition, the removal of the 
GDF15 cut off level does not 
have any impact on 
participant safety.
Substantial
Assignment of 
participant 
identification number, 
metformin use history, 
and demographic 
information moved to 
screening.
Updated as required following 
the removal of pre-screening 
visit.
Non-substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Addition of Part A/C 
 
and Part B mandatory 
paired biopsy at 
screening. Addition of 
new footnote e stating 
that if they are taken 
during screening they 
will not need to be 
taken for Cycle 1 
Day 1 pre-dose.
Clarification of the time 
window for collection of 
paired biopsies.
Non-substantial
Updated footnote b to 
include CT or MRI 
scans for SMI 
assessment.
Updated for consistency with 
updates in Section 8.1.
Non-substantial
Deletion of old 
footnote e)
To prevent repetition, the 
detailed description of 
archival tissue block 
collection is only included in 
Section 10.8.6.2.
Non-substantial
Addition to footnote f) 
stating that the if 
participants hold or 
discontinue treatment 
prior to Day 29, they 
should still perform 
PET scan if they are
able.
Clarification of collection 
requirements.
Non-substantial
Section 10.1.2 
(Schedule of Activities, 
Table 13)
Included new footnote 
a confirming safety 
assessments are 
relative to most recent 
dosing.
Clarification of collection 
requirements.
Non-substantial
Updated time windows 
for disease assessments 
to include ±1D for V4 to 
V8, and ±3D for V12 and 
V13+.
Added ±1 and ±3 day windows 
to be consistent with prior 
collection timepoints.
Non-substantial
Updated time window 
for disease assessment 
at V8/V9 and V12.
Clarification of time window 
for disease assessment. 
Non-substantial
Updated footnote d 
(now e) to include CT 
Updated for consistency with 
updates in Section 8.1.
Non-substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Section 10.5 
(Substudy 1 
Population)
Removal of screening 
description from 
informed consent 
signing.
Clarification of informed 
consent to be signed.
Substantial
Section 10.5.1
(Substudy 1 Inclusion 
Criteria)
Update to criterion 2 
for tumour-specific 
requirements in 
NSCLC, MSS-CRC, 
and UC.
Improve clarity of criteria and 
to improve enrolment.
Substantial
Deletion of old 
criterion 3 for centrally 
confirmed 
pre-treatment GDF15 
levels ≥ 
 pg/mL.
New data shows that up to 
% of the study participants 
may have 
 GDF15 levels 
(above the current cut off); in 
addition, the removal of the 
GDF15 cut off level does not 
have any impact on 
participant safety.
Non-substantial
Addition of new 
criterion 3 confirming 
that participation in 
this trial is determined 
to be the best option 
for next treatment 
option based on prior 
response to standard of 
care.
Clarification of criteria 
considering the study phase.
Non-substantial
Updated criterion 4 to 
reduce the detail and 
refer to Section 
10.8.6.2 and laboratory 
manual.
To prevent repetition, the 
detailed description of 
archival tissue block 
collection is only included in 
Section 10.8.6.2.
Non-substantial
Section 10.6.6.1.1. 
(Starting Dose)
Updated text to 
remove “single 
sentinel” from starting 
dose description.
Clarification of starting dose 
and process for dosing of 
participants in the first cohort.
Non-substantial
Section 10.6.10
(Definition of DLT 
Evaluable Participant)
Updated text to state 
that participants who 
do not remain in the 
Clarification of definition of 
DLT evaluable participant.
Non-substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
study up to the DLT 
evaluation period will 
be considered non-
evaluable for DLT 
assessment.
Section 10.8 (Substudy 
1 Study Assessments 
and Procedures), 
Section 10.8.5.3 
(GDF15 Assay for 
Prospective Testing)
Removal of description 
requiring pre-screening 
for GDF15 levels.
New data shows that up to 
% of the study participants 
may have 
 GDF15 levels 
(above the current cut off); in 
addition, the removal of the 
GDF15 cut off level does not 
have any impact on 
participant safety.
Substantial
Section 10.8.6.1 (Fresh 
Tumour Biopsy)
Addition of text 
confirming that 
screening and 
on-treatment biopsies 
should be taken from 
the same lesion.
Clarification of sampling 
process for biopsies.
Non-substantial
Section 10.8.6.1.2 
(Optional Fresh Paired 
Tumour Biopsies)
Updated to state that if 
 
 
 
, every effort 
should be made to 
collect while on 
treatment.
Clarification regarding missed 
second biopsy and that for the 
CD8+ PET cohort, the first 
and second biopsy should be 
taken within 
 hours after 
the respective first and second 
CD8+ PET scans.
Non-substantial
Section 10.8.6.2 
(Mandatory Archival 
Tumour Samples)
Updates made to the 
requirement of archival 
tumour tissue, number 
of slides/sections, and 
reference to laboratory 
manual for process, 
storage and shipment.
Clarification to confirm all the 
required details in one 
location. 
Non-substantial
Appendix A3 
(Informed Consent 
Process)
Text updated to 
confirm that separate 
Part B ICFs will be 
needed for sites in the 
CD8+ PET part of the 
study.
Clarification made to avoid 
confusion in terms of when a 
separate ICF is required for 
CD8+ PET part of study.
Non-substantial
Appendix E3 
(Identification of 
Deletion of process for 
central laboratory.
Hy’s law assessments will be 
done locally and not via 
central laboratory.
Non-substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-
substantial
Potential Hy’s Law 
Cases)
Appendix E8 
(Laboratory Tests)
Table E8 header 
updated to “Local 
Laboratory Tests”
Hy’s law assessments will be 
done locally and not via 
central laboratory.
Non-substantial
Appendix K (Protocol 
Amendment History)
Addition of this 
appendix.
Included as per template 
guidance.
Non-substantial
Throughout
Minor administrative 
changes.
Revisions made to correct 
errors in format, typography, 
or language.
Non-substantial


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS .................................................................................................... 13
1
PROTOCOL SUMMARY ................................................................................ 19
1.1
Synopsis ........................................................................................................... 19
1.2
Schema............................................................................................................. 26
1.3
Schedule of Activities ....................................................................................... 28
2
INTRODUCTION............................................................................................ 29
2.1
Study Rationale ................................................................................................ 29
2.2
Background ...................................................................................................... 30
2.2.1
Tumour Type Selection..................................................................................... 30
2.3
Benefit/Risk Assessment................................................................................... 31
2.3.1
Risk Assessment ............................................................................................... 31
2.3.2
Benefit Assessment........................................................................................... 34
2.3.3
Overall Benefit/Risk Conclusion....................................................................... 35
2.3.4
Benefit/Risk Pertaining to Study Conduct During the COVID-19 Pandemic ..... 35
3
OBJECTIVES AND ENDPOINTS................................................................... 37
4
STUDY DESIGN ............................................................................................. 38
4.1
Overall Design.................................................................................................. 38
4.1.1
Master Protocol Structure ................................................................................. 38
4.1.2
Substudy Naming Conventions ......................................................................... 38
4.1.3
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 39
4.2
Scientific Rationale for Study Design ............................................................... 39
4.3
Justification for Dose........................................................................................ 40
4.4
End of Study Definition.................................................................................... 40
4.4.1
Study Stopping Criteria..................................................................................... 40
5
STUDY POPULATION.................................................................................... 42
5.1
Inclusion Criteria .............................................................................................. 42
5.2
Exclusion Criteria ............................................................................................. 43
5.3
Lifestyle Considerations ................................................................................... 46
5.3.1
Contraception ................................................................................................... 46
5.3.2
Activity............................................................................................................. 47
5.4
Screen Failures ................................................................................................. 48
6
STUDY INTERVENTION ............................................................................... 49
6.1
Study Intervention(s) Administered................................................................... 49
6.1.1
Investigational Medicinal Product – AZD8853 ................................................. 49
6.1.1.1
Identity of Investigational Medicinal Product.................................................... 49


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6.2
Preparation/Handling/Storage/Accountability ................................................... 49
6.2.1
Investigational Medicinal Product Inspection.................................................... 50
6.2.2
AZD8853 Preparation and Administration ........................................................ 50
6.2.3
Treatment Administration ................................................................................. 51
6.2.4
Monitoring of Dose Administration................................................................... 52
6.2.5
Reporting Product Complaints .......................................................................... 52
6.2.6
Additional Study Drugs .................................................................................... 52
6.2.7
Labelling .......................................................................................................... 52
6.2.8
Storage ............................................................................................................. 53
6.2.9
Treatment Compliance...................................................................................... 53
6.2.10
Accountability .................................................................................................. 53
6.3
Measures to Minimise Bias: Randomization and Blinding ................................ 53
6.4
Study Intervention Compliance......................................................................... 53
6.5
Concomitant Therapy........................................................................................ 54
6.6
Dose Modification ............................................................................................ 56
6.7
Intervention after the End of the Study.............................................................. 57
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 58
7.1
Discontinuation of Study Intervention............................................................... 58
7.1.1
Temporary Discontinuation............................................................................... 59
7.2
Participant Withdrawal from the Study.............................................................. 59
7.3
Lost to Follow-Up............................................................................................. 60
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 61
8.1
Efficacy Assessments........................................................................................ 61
8.2
Safety Assessments........................................................................................... 63
8.2.1
Physical Examinations...................................................................................... 63
8.2.2
ECOG Performance Status................................................................................ 63
8.2.3
Vital Signs ........................................................................................................ 64
8.2.4
Electrocardiograms........................................................................................... 64
8.2.5
Clinical Safety Laboratory Assessments............................................................ 65
8.2.6
30-Day Follow-up Visit .................................................................................... 66
8.2.7
90-Day Follow-up Visit .................................................................................... 67
8.2.8
Survival Follow-up ........................................................................................... 67
8.3
Adverse Events and Serious Adverse Events..................................................... 67
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 67
8.3.2
Follow-up of AEs and SAEs ............................................................................. 67
8.3.3
Causality Collection.......................................................................................... 68
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 69
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 69
8.3.6
Adverse Events of Special Interest.................................................................... 69
8.3.7
Hy’s Law.......................................................................................................... 71
8.3.8
Disease Progression.......................................................................................... 71
8.3.9
Reporting of Serious Adverse Events ................................................................ 71


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8.3.10
Pregnancy......................................................................................................... 72
8.3.10.1
Maternal Exposure............................................................................................ 72
8.3.10.2
Paternal Exposure............................................................................................. 73
8.3.11
New Cancers..................................................................................................... 73
8.3.12
Deaths .............................................................................................................. 73
8.3.13
Medication Error............................................................................................... 74
8.4
Overdose .......................................................................................................... 74
8.5
Human Biological Samples............................................................................... 75
8.5.1
Pharmacokinetics.............................................................................................. 75
8.5.1.1
Determination of Drug Concentration ............................................................... 76
8.5.2
Immunogenicity Assessments ........................................................................... 76
8.5.3
Pharmacodynamics........................................................................................... 76
8.6
............................................................. 76
8.7
................................................................ 76
8.8
...................................... 77
9
STATISTICAL CONSIDERATIONS................................................................ 78
9.1
Statistical Hypotheses....................................................................................... 78
9.2
Sample Size Determination............................................................................... 78
9.3
Populations for Analyses................................................................................... 78
9.4
Statistical Analyses ........................................................................................... 79
9.4.1
General Considerations..................................................................................... 79
9.4.2
Safety Analyses ................................................................................................ 79
9.4.3
Efficacy Analyses ............................................................................................. 80
9.4.4
Other Analyses.................................................................................................. 82
9.4.4.1
Immunogenicity, Pharmacokinetics and Pharmacodynamics ............................. 82
9.5
Interim Analyses............................................................................................... 83
9.6
Safety Review Committee................................................................................. 83
10
SUBSTUDY 1.................................................................................................. 84
10.1
Substudy 1 Summary........................................................................................ 84
10.1.1
Schema............................................................................................................. 84
10.1.2
Schedule of Activities ....................................................................................... 85
10.2
Substudy 1 Introduction.................................................................................... 96
10.3
Substudy 1 Objectives and Endpoints ............................................................... 96
10.4
Substudy 1 Study Design .................................................................................. 97
10.4.1
Substudy 1 Design............................................................................................ 97
10.4.2
Substudy 1 Justification for Dose...................................................................... 99
10.4.3
End of Substudy 1 Definition.......................................................................... 100
10.5
Substudy 1 Population .................................................................................... 100
10.5.1
Substudy 1 Inclusion Criteria.......................................................................... 100
10.5.2
Substudy 1 Exclusion Criteria......................................................................... 102
10.6
Substudy 1 Study Intervention ........................................................................ 103
10.6.1
Study Intervention(s) Administered................................................................. 103
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10.9.4.1
General Considerations................................................................................... 119
10.9.4.2
Efficacy Analyses ........................................................................................... 119
10.9.4.3
Safety Analyses .............................................................................................. 120
10.9.4.4
Other Analyses................................................................................................ 120
10.9.5
Interim Analyses............................................................................................. 120
11
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 122
12
REFERENCES............................................................................................... 172
LIST OF FIGURES
Figure 1
AZD8853 Phase I/IIa Study in Selected Advanced/Metastatic Solid 
Tumours .................................................................................................. 26
Figure 2
Substudy 1 Schema: AZD8853 Monotherapy in Participants with 
NSCLC, MSS-CRC and UC .................................................................... 27
Figure 3
Substudy 1 Schema: AZD8853 Monotherapy in Participants with 
NSCLC, MSS-CRC and UC .................................................................... 84
Figure 4
CD8+ PET and Biopsy Timelines .......................................................... 162
LIST OF TABLES
Table 1
Objectives and Endpoints (All Substudies) .............................................. 21
Table 2
Description of Study Parts ....................................................................... 22
Table 3
Risk Assessment...................................................................................... 32
Table 4
Objectives and Endpoints......................................................................... 37
Table 5
Substudy Naming Conventions................................................................ 38
Table 6
Criteria for Adequate Organ and Marrow Function .................................. 43
Table 7
Highly Effective Methods of Contraception (< 1% Failure Rate) ............. 47
Table 8
Prohibited Concomitant Medications ....................................................... 55
Table 9
Permitted Concomitant Medications ........................................................ 56
Table 10
Laboratory Safety Variables..................................................................... 66
Table 11
Populations for Analyses ......................................................................... 78
Table 12
Schedule of Activities - Screening ........................................................... 85
Table 13
Schedule of Activities – Study Visits ....................................................... 88
Table 14
Schedule of Activities – End of Treatment............................................... 94
Table 15
Substudy 1 Objectives and Endpoints ...................................................... 96


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Table 16
mTPI-2 Decision Rules.......................................................................... 106
Table 17
Sampling Schedule for Electrocardiograms............................................ 112
Table 18
Sampling Schedule for PK Samples....................................................... 112
Table 19
Sampling Schedule for ADA Samples.................................................... 113
Table 20
Sampling Schedule for GDF15 Target Engagement Samples ................. 114
Table 21
Populations for Analyses ....................................................................... 119
Table 22
Details of Analyses................................................................................ 119
Table 23
Summary of Imaging Modalities for Tumour Assessment...................... 145
Table 24
RECIST v1.1 Evaluation of Target Lesions ........................................... 153
Table 25
RECIST 1.1 Evaluation of Non-Target Lesions ..................................... 154
Table 26
RECIST v1.1 Overall Visit Response..................................................... 155
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 122
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 128
Appendix C
Handling of Human Biological Samples ................................................ 133
Appendix D
..................................................... 135
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 138
Appendix F
Guidelines For Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours).. 145
Appendix G
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 157
Appendix H
National Institute of Allergy and Infectious Disease and Food Allergy 
and Anaphylaxis Network guidance for anaphylaxis diagnosis............... 159
Appendix I
CD8+ PET Imaging ............................................................................... 160
Appendix J
Abbreviations ........................................................................................ 165
Appendix K
Protocol Amendment History................................................................. 170
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title:
A Phase I/IIa First-in-human, Open-label Study to Evaluate the Safety, Pharmacokinetics, 
Pharmacodynamics, and Preliminary Efficacy of AZD8853 in Participants with Selected 
Advanced/Metastatic Solid Tumours.
Short Title:
A First-in-human Study to Evaluate the Safety and Tolerability of AZD8853 in Participants 
with Selected Advanced/Metastatic Solid Tumours.
Rationale:
Chemotherapy and radiotherapy have historically been used for the treatment of patients with 
advanced/metastatic cancers; however, these strategies are usually not effective in controlling 
disease in the long term. Disease aggression is in part driven by the tumour immune 
microenvironment (TME) and in recent years there has been a focus on targeting different 
aspects of the TME to inhibit pro-tumourigenic immunosuppression and promote anti-tumour 
inflammatory responses. Therapeutics that target the programmed cell death-1 
(PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint pathway have seen 
significant success in a number of solid tumour types by reversing cluster of differentiation 
(CD)8+ T cell exhaustion and driving a cytotoxic response. A caveat of this approach is that 
only a subset of participants will demonstrate long-term disease control, and so it is imperative
to identify additional pathways for therapeutic development to promote anti-tumour immune 
response.
Growth differentiation factor 15 (GDF15), a transforming growth factor beta (TGF-)
superfamily cytokine, has been shown to affect the TME and is associated with a poor 
prognosis in a number of solid tumour types.
 
 
 As an antagonist to GDF15, 
the monoclonal antibody AZD8853 neutralizes the effects of GDF15 in preclinical tumour 
models. Effectively targeting GDF15 culminates in an enhanced cytotoxic anti-tumour 
immune response and reverses immunosuppression in the TME.
This study is primarily designed to evaluate the safety and tolerability of AZD8853. The study 
will include several "Substudies", the first of which will evaluate AZD8853 as monotherapy at 
increasing doses in participants with selected advanced/metastatic solid tumours who have 
elevated serum GDF15 levels and who have progressed or are refractory to at least one line of 
standard systemic therapy. This first Substudy will also characterise the pharmacokinetics 
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(PK) and immunogenicity of AZD8853 and explore potential biological activity by assessing 
pharmacodynamic (PD) biomarkers and anti-tumour activity. 
 
. The results from this study will guide future Substudies 
with AZD8853, which have yet to be defined. 
AZD8853 is currently being developed as monotherapy but may be investigated in 
combination with other approved anti-cancer agents and/or investigational agents for greater 
efficacy in future Substudies, based upon emerging data. These combination Substudies may 
be added once a recommended Phase 2 dose (RP2D) for monotherapy has been defined based 
on emerging supportive preclinical and/or clinical data and scientific rationale in the first 
Substudy.
The overarching primary hypothesis for this study is that AZD8853 will demonstrate an 
acceptable safety, PK and PD profile, and evidence of preliminary efficacy in participants with 
selected advanced/metastatic solid tumours.
Key Objectives and Endpoints Applicable to all Substudies
The objectives and endpoints that are common for all Substudies are listed in Table 1. See the 
individual Substudies in the clinical study protocol for the objectives and endpoints specific to 
each of the Substudies.
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Substudy 1
Substudy 1 will be a first time in human (FTiH), open-label, multicentre study, in which 
AZD8853 will be evaluated as monotherapy for safety, PK, PD, and preliminary efficacy in 
participants with selected advanced/metastatic solid tumours defined as:

Second or later line setting of unresectable, locally advanced (Stage III) or metastatic 
(Stage IV) non-small-cell lung cancer (NSCLC) that have progressed on anti-PD-1/PD-
L1 inhibitors with or without platinum-containing chemotherapy.

Third or later line setting of Stage IV microsatellite stable-colorectal cancer (MSS-CRC)
that have progressed on prior standard of care treatment.

Second or later line setting of Stage IV urothelial carcinoma (UC) that have progressed on
prior treatment with platinum and/or checkpoint inhibitors (CPI).
Substudy 1 will comprise 3 main parts (A, B and C), as shown in Table 2:
Table 2
Description of Study Parts
Study Part
Description
Number of Participants Planned
Part A (AZD8853) Dose Escalation
Part A: Dose Escalation
•
Dose escalation of AZD8853 in 
participants with selected 
advanced/metastatic solid tumours
•
Up to 45 participants 
(assuming up to 5 dosing 
cohorts and 3-9 participants 
per cohort).
•
.
Part B (AZD8853) PD/MoA Expansion
Part B1 (Biopsy and CD8+ 
PET)
•
PD cohort at alternative dose
•
Up to approximately 
20 participants
(approximately 
10 MSS-CRC and 
approximately 10 NSCLC
participants). 
•
Mandatory biopsies.
•
CD8+ PET
•
Up to 10 participants (a 
subset of the 20 participants 
above).
Part B2 (Biopsy and CD8+ 
PET)
•
PD cohort at MTD/HPDD
•
Up to approximately 
20 participants
(approximately 
10 MSS-CRC and 
approximately 10 NSCLC 
participants). 
•
Mandatory biopsies.
•
CD8+ PET
•
Up to 10 participants (a 
subset of the 20 participants 
above).
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Study Part
Description
Number of Participants Planned
Part C (AZD8853) Efficacy Expansion*
Part C1
•
First indication at MTD/HPDD
Up to 40 participants.
.
Part C2
•
Second indication at MTD/HPDD 
or
•
First indication at alternative dose
Up to 40 participants.
.
Abbreviations: CD8 = cluster of differentiation 8; HPDD = highest protocol-defined dose; MoA = mechanism of 
action; MTD = maximum tolerated dose; MSS-CRC = microsatellite stable-colorectal cancer; 
NSCLC = non-small-cell lung cancer; PD = pharmacodynamics; PET = positron emission tomography.
* If the RP2D cannot be adequately determined from Part B and additional data (eg, efficacy) is required to guide 
RP2D determination, then 2 dose levels in one indication will be investigated. If the RP2D is determined at the 
end of Part B, RP2D will be evaluated in 2 indications.
Disclosure Statement:
Substudy 1
This is a multi-part, open-label, dose escalation, PD/mechanism of action (MoA) expansion,
and efficacy expansion Substudy.
Number of Participants:
Substudy 1
Across all parts of Substudy 1 up to a total of 165 eligible participants may be enrolled and 
treated with AZD8853, consisting of up to 45 participants in Part A, up to 40 participants in 
Part B and up to 80 participants in Part C.
Intervention Groups and Duration:
Refer to the relevant Substudy for details.
Safety Review Committee: Yes
A safety review committee (SRC) will be responsible for making dose escalation or dose 
de-escalation decisions and recommendations regarding further conduct of the study, during 
all phases of the study. The SRC will provide ongoing safety surveillance of the study, with 
regularly scheduled reviews of safety and other relevant data to monitor the ongoing safety 
profile of the study intervention. 
Statistical Methods
Safety
Dose escalation will follow the modified toxicity probability interval (mTPI-2) algorithm and 
will be based on the dose limiting toxicity (DLT) evaluable population (all enrolled 
participants who complete the DLT evaluation period of 21 days after receiving at least 75%
of the first infusion of study intervention, or who experience any DLT). Safety and tolerability 
will be assessed in terms of DLTs, adverse events (AEs), serious AEs (SAEs), vital signs, 
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clinical chemistry/haematology parameters, dose interruptions/discontinuations, and 
electrocardiogram (ECG) data. These variables will be collected for all participants. All safety 
analyses will be performed on the Safety Population (all participants who receive at least 
one dose of study intervention) and will be summarised using descriptive statistics. Adverse 
events will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) and graded according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) v5.0.
Efficacy
The efficacy endpoints for tumour response (objective response rate [ORR], disease control 
rate [DCR] at 15 weeks, duration of response [DoR], and percentage change in tumour size)
will be summarised for the Response Evaluable Population (all dosed participants who have
measurable disease at baseline) using Response Evaluation Criteria in Solid Tumours
(RECIST) v1.1 by Investigator assessment. The efficacy endpoints of progression-free 
survival (PFS) and overall survival (OS) will be summarised based on the Safety Population. 
The RECIST tumour response data will be used to programmatically determine each 
participant’s visit response and to derive the endpoints of ORR, DoR, DCR at 15 weeks, 
percentage change in tumour size, and PFS. Endpoints will be summarised using descriptive 
statistics and Kaplan Meier methods as appropriate.
Additionally, the percentage change in circulating tumour deoxyribonucleic acid (ctDNA)
from pre-treatment (baseline) to each post baseline timepoint as well as the maximum change 
will be summarised using descriptive statistics on the Safety Population. 
Pharmacokinetics
The PK analysis of the serum data for AZD8853 will be performed using the PK Population 
(all participants who receive at least one dose of study intervention with at least one reportable 
concentration). The actual sampling times will be used in the parameter calculations and the 
PK parameters will be derived using standard non-compartmental methods, if the data 
permits. It is anticipated that maximum concentration (Cmax), area under the curve (AUC), 
and other PK parameters will be calculated if the data allows. 
Relevant descriptive statistics will be used to summarise PK parameters and concentrations.
Immunogenicity
Immunogenicity results will be analysed descriptively on the Immunogenicity Population (all 
participants who receive at least one dose of study intervention with at least one reportable 
immunogenicity measurement) by summarising the number and percentage of participants 
who develop detectable anti-drug antibodies (ADAs) against AZD8853 at protocol-specified 
timepoints. The immunogenicity titre may be reported for samples confirmed positive for the 
presence of ADAs. The effect of immunogenicity on PK, efficacy, and safety may be 


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evaluated, if the data allow.
Depending on the extent of any impact, summaries of data relating to participants diagnosed 
with coronavirus disease 2019 (COVID-19), any impact of COVID-19 on study conduct (in 
particular missed visits, delayed or discontinued study treatment, and other protocol 
deviations) may be generated.
Further details of all analyses will be provided in a separate statistical analysis plan.
Interim analyses will be conducted separately for each Substudy and are described in the 
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1.2
Schema
Please see the individual schema for each study Substudy within the respective Clinical Study 
Protocol section.
Figure 1
AZD8853 Phase I/IIa Study in Selected Advanced/Metastatic Solid 
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1.3
Schedule of Activities
Please see the individual schedule of activities for each study Substudy within the respective 
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2
INTRODUCTION
AZD8853 is a humanized IgG1 mAb with an 
 
. AZD8853 specifically binds to and neutralizes GDF15, a TGF-β 
superfamily cytokine that is overexpressed in certain solid malignant tumours. GDF15
functions to regulate inflammation and has an immunosuppressive effect on T cells, DCs and 
myeloid-derived cell subsets. Neutralizing GDF15 leads to increased T cell proliferation and 
DC activation, thereby enhancing the immune response.
2.1
Study Rationale
Chemotherapy and radiotherapy have historically been used for the treatment of patients with 
advanced/metastatic cancers; however, these strategies are usually not effective in controlling 
disease in the long term. Disease aggression is in part driven by the TME and in recent years 
there has been a focus on targeting different aspects of the TME to inhibit pro-tumourigenic 
immunosuppression and promote anti-tumour inflammatory responses. Therapeutics that 
target the PD-1/PD-L1 immune checkpoint pathway have seen significant success in a number 
of solid tumour types by reversing CD8+ T cell exhaustion and driving a cytotoxic response. 
A caveat of this approach is that only a subset of participants will demonstrate long-term 
disease control, and so it is imperative to identify additional pathways for therapeutic 
development to promote anti-tumour immune response.
GDF15, a TGF-β superfamily cytokine, has been shown to affect the TME and is associated 
with a poor prognosis in a number of solid tumour types (Wischhusen et al, 2020; Liu et al, 
2016; Mehta et al, 2014; Mehta et al, 2015; Traeger et al, 2019). High expression of GDF15 in 
the TME has been shown to lead to decreased DC activation, decreased cytotoxic CD8+ T cell 
infiltration and increased CD4+ Treg expansion (Wischhusen et al, 2020; Wang et al, 2021; 
Roth et al, 2010). As an antagonist to GDF15, the monoclonal antibody AZD8853 neutralizes 
the effects of GDF15 in preclinical tumour models. Effectively targeting GDF15 culminates in 
an enhanced cytotoxic anti-tumour immune response and reverses immunosuppression in the 
TME.
Substudy 1 of this study is primarily designed to evaluate the safety and tolerability of 
AZD8853 as monotherapy at increasing doses in participants with selected 
advanced/metastatic solid tumours who have elevated serum GDF15 levels and who have 
progressed or are refractory to at least one line of standard systemic therapy. Substudy 1 will 
also characterise the PK and immunogenicity of AZD8853 and explore potential biological 
activity by assessing PD biomarkers and anti-tumour activity. 
 
. The results from this Substudy will guide future clinical 
studies with AZD8853.
AZD8853 is currently being developed as monotherapy, but may be investigated in 
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combination with other anti-cancer agents or other types of agents for greater efficacy in the 
future. New Substudies for combination treatments may be added once monotherapy RP2D 
has been defined based on emerging supportive preclinical and/or clinical data and scientific 
rationale.
The overarching primary hypothesis for this study is that AZD8853 will demonstrate an 
acceptable safety, PK, and PD profile, and evidence of potential efficacy in participants with 
selected advanced/metastatic solid tumours.
2.2
Background
The TME plays an important role in tumourigenesis and overall disease aggression and thus 
has been targeted by many immune therapies. Patient prognosis is affected by both the extent 
of immune cell infiltration and how inflammatory or immune-suppressed these immune cells 
are (Tang et al, 2021; Waldman et al, 2020). To date, the most successful immunotherapies 
have focused on modulating cytotoxic T cell responses. However, tumour progression is
controlled by several immune cell types and soluble factors that can be released by both 
tumour and non-tumour cells and research endeavours have sought to identify novel 
therapeutics that can target multiple aspects of the TME. 
GDF15 has been linked to the development of cancers (Wischhusen et al, 2020; Bauskin et al, 
2006). High levels of GDF15 alter the TME toward an immunosuppressive, 
tumour-“promoting” microenvironment. 
 
 
(unpublished AstraZeneca clinical trial analyses). 
 
 
Preclinical in vivo research has shown that anti-GDF15 treatment causes infiltration of T cells 
and activation of DCs, leading to an anti-tumour response in anti-PD-L1 resistant models. 
This suggests that anti-GDF15 may provide an alternative therapy for patients whose tumours
have previously failed to respond to anti-PD-L1 therapy. Since anti-GDF15 is hypothesised to 
have the dual effect of recruiting T cells to the TME and alleviating immune suppression, this 
novel therapeutic is expected to remodel the TME and, therefore, improve the anti-tumour
immune response in patients who have a TME that is either poorly infiltrated with T cells or 
highly immunosuppressive.
2.2.1
Tumour Type Selection
In cancer, elevated serum GDF15 levels have been reported in many solid malignancies, 
including colon (Mehta et al, 2015), lung (Liu et al, 2016) and bladder cancer (Traeger et al, 
2019). According to unpublished work conducted by AstraZeneca with 
 
 
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 Similarly, higher levels of GDF15 were found in NSCLC samples, where high serum 
levels correlated with fewer cytotoxic CD8+ T cells and reduced DC gene expression 
signatures. Lastly, the correlation was also found in bladder cancer samples, where high 
GDF15 levels correlated with low CD8+ T cell numbers (IHC) and low cytotoxic activity and
NK cell gene expression signatures. Furthermore, emerging data from ongoing clinical trials 
conducted by AstraZeneca suggest that 
% of pre-treated patients in these indications 
have elevated GDF15 levels (>
 pg/mL). Lastly, in all of these tumour types elevated 
GDF15 levels have been correlated with poor outcomes (Mehta et al, 2015; Liu et al, 2016; 
Traeger et al, 2019).
2.3
Benefit/Risk Assessment
Detailed information about the known and anticipated benefits and potential risks of 
AZD8853 are found in the IB.
2.3.1
Risk Assessment
This is the FTiH trial for AZD8853; no clinical data are available and there are no identified 
risks at this time. The study will be performed in accordance with ethical principles that have 
their origin in the Declaration of Helsinki and are consistent with ICH/GCP requirements, and 
applicable regulatory requirements.
Preclinical Work
The initial single dose (intravenous) PK and PD non-GLP study was performed in male 
cynomolgus monkeys where animals were dosed mg/kg, 
 mg/kg, or 
 mg/kg followed 
by a 4-week recovery period. Single doses were well tolerated with no adverse clinical 
reactions or clinical pathology observed; specifically, there were no changes to coagulation, 
complement, or immune subsets.
A 3-month GLP toxicology study was performed in cynomolgus monkeys with an 8-week 
recovery period. Both male and female monkeys were dosed 
mg/kg, 
mg/kg, or 
mg/kg AZD8853 by weekly intravenous (15 min) infusion for 14 administrations. There 
were no AZD8853-related changes in body weight, or neurological, ECG, respiratory or BP 
examinations. There were no changes in clinical pathology (haematology, clinical chemistry, 
urinalysis or cytokine analysis), nor immunophenotyping. No AZD8853-related organ weight 
changes were noted. Minimal to slight vascular/perivascular inflammatory changes were noted 
in the kidney, heart, and gall bladder of an individual animal administered the 
 dose of 
mg/kg which is suggestive of secondary immune complex formation related vascular 
injury. There were no histopathological changes observed in the remaining 5 animals at the 
 dose of 
mg/kg or the 
 dose of 
 mg/kg, respectively. Refer to the IB for 
detailed information about the GLP toxicology studies.
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Potential Risks
Based upon the GLP toxicology studies to date, there are no identified risks for AZD8853. 
The potential risks for AZD8853 include 
 
 
 
 
. These risks are based on animal data, including 
 mice models,
described in the literature. Immune complex disease is a potential risk based on preclinical 
findings in the GLP toxicology study. Additional potential risks include 
 
, which can occur after infusions with mAbs. The 
TMG are provided as a separate document. The risk assessment for AZD8853 is provided in 
Table 3.
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2.3.2
Benefit Assessment
In nonclinical pharmacology studies, AZD8853 was able to 
 
. In 
addition, AZD8853 was able to
 
 
 
Overall, the 
preclinical data from both in vitro and in vivo models suggest that AZD8853 has the potential 
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to induce clinical response in participants with selected advanced/metastatic cancers.
2.3.3
Overall Benefit/Risk Conclusion
There remains an unmet need for improved therapies for patients with advanced/metastatic 
solid tumours. The design of this current study aims to minimize potential risks to participants 
based on the inclusion and exclusion criteria, restrictions on concomitant medication during 
the study, continuous safety monitoring (including review of all available safety, PK, and 
other relevant data by the SRC), and TMGs. The potential risks are designated AESIs and 
hence are subject to intensive safety monitoring. Thus, the benefit/risk assessment for this 
Phase I/IIa study appears acceptable based upon the poor outcomes for this patient population 
and the strength of the scientific hypothesis under evaluation. 
More detailed information about the known and anticipated benefits and potential risks of 
AZD8853 may be found in the IB.
2.3.4
Benefit/Risk Pertaining to Study Conduct During the COVID-19 
Pandemic
Cancer patients have an increased risk of exposure to SARS-CoV-2 due to frequent hospital or
clinic visits for treatment and monitoring. A retrospective cohort study of 
28 COVID-19-infected cancer participants from 3 hospitals in Wuhan, China, reported that a 
 of participants
%; N = ) were suspected to have acquired the infection by 
hospital-associated transmission (Yu et al, 2020; Zhang et al, 2020). Participants with cancer 
may have a higher risk of a poorer outcome if infected with SARS-CoV-2 than individuals 
without cancer but current evidence appears insufficient to support a conclusive association 
between cancer in general and COVID-19 (Xia et al, 2020).
This study will enrol participants with selected advanced/metastatic solid tumours. 
Participants in this study will receive AZD8853 treatment that leads to inhibition of GDF15 as 
part of the treatment strategy. Overall, the intervention received and procedures during the 
course of this study are considered to have low risk for increasing susceptibility to 
SARS-CoV-2 infection.
Furthermore, at this stage of disease, participants would typically have frequent 
healthcare-related visits, irrespective of participation in a clinical study. Therefore, it is 
anticipated that participation in this clinical study should not significantly increase a 
participant’s risk of exposure to COVID-19.
Novel treatment options are needed to improve the long-term prognosis for participants with
advanced/metastatic solid cancer tumours, which are associated with chemoresistance, 
extremely poor prognosis, and a high risk of developing cancer-related death. AZD8853 could 
be a potential treatment option in this patient population with high unmet medical need. The 
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scheduled safety assessment visits that are considered in excess of standard-of-care are 
intended to monitor the participants involved in the study. Thus, although there may be 
increased risk to participants by exposure to COVID-19 during study visits, this is offset by 
the benefit of participating in a clinical trial.
In accordance with EMA and FDA guidelines (EMA-CTFG-EC, 2021; 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 study to
assess whether additional measures may be necessary to ensure participant safety and data
validity. Measures may include postponement of study start on a global, country, or site level
or suspension of recruitment of participants in locations with an increased risk of COVID-19
related disruption.
If there is a need to reconsent study participants for the implementation of new urgent changes
in study conduct, additional guidance on alternative means of obtaining reconsent to avoid
unnecessary study visits is provided in Appendix A. Any deviations to the CSP 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 CSP will be 
communicated to regulatory authorities and IRBs/IECs in line with relevant local guidance 
and procedures.




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4
STUDY DESIGN
4.1
Overall Design
4.1.1
Master Protocol Structure
The overall study design will include a Master Protocol with Substudies. Information relating 
to the overall study, including study objectives, rationale, master inclusion and exclusion 
criteria, safety assessments, and AE reporting can be found in the Master Protocol
(ie, Sections 1-9). In addition to the Master Protocol, individual “Substudies” will contain 
elements specific to each individual Substudy. Substudy 1 as described below, includes both a 
dose escalation and 2 expansions for monotherapy. The content of additional Substudies has
not yet been defined and will be further added based on emerging supportive preclinical data.
The information in this Master Protocol cannot be superseded by information in the 
Substudies. Any change to the study master elements (ie, this Master Protocol) or Substudies
will be submitted to Regulatory Authorities and ethics committees according to the local 
legislation/requirements.
Study drug-specific information including doses and justifications, toxicity management, dose 
modifications and concomitant medications can be found in the relevant Substudy(ies).
4.1.2
Substudy Naming Conventions
Initially, the study will consist of one Substudy (Substudy 1) evaluating the safety, PK, PD,
and preliminary efficacy of AZD8853 as monotherapy in participants with selected 
advanced/metastatic solid tumours. Additional Substudies may be added by substantial 
amendment evaluating AZD8853 in different combination cohorts. These different 
combination cohorts will be determined by emerging preclinical data using combinations of 
approved therapies and/or investigational agents which have established safety data in 
humans.
Table 5
Substudy Naming Conventions
Substudy
Tumour Type
Intervention
Substudy 1 – Monotherapy Escalation and Expansion 
NSCLC
MSS-CRC
UC
AZD8853
Potential combination therapy Substudies a
Substudy X – AZD8853 + [combination treatment #1]
TBD
AZD8853 +
[combination treatment #1]
Substudy Y – AZD8853 + [combination treatment #2]
TBD
AZD8853 +
[combination treatment #2]
a
Anticipated combination cohort Substudies will be numbered per the order added to the study protocol 
(Substudy 2, Substudy 3, etc).


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Abbreviations: MSS-CRC = microsatellite stable-colorectal cancer; NSCLC = non-small-cell lung cancer; 
TBD = to be decided; UC = urothelial carcinoma.
4.1.3
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis 
(eg, during quarantines and resulting site closures, regional travel restrictions, and 
considerations if site personnel or study participants become infected with SARS-CoV-2 or 
similar pandemic infection) which would prevent the conduct of study-related activities at 
study sites, thereby compromising the study site staff or the participant’s ability to conduct the 
study. The Investigator or designee should contact the study Sponsor to discuss whether the 
mitigation plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimise risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options:

Obtaining reconsent for the mitigation procedures (note, in the case of verbal reconsent, 
the ICF should be signed at the participant’s next contact with the study site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed for previously screened participants. 
The Investigator should confirm this with the designated study physician.

Home or remote visit: Performed by a site qualified HCP or HCP provided by a TPV.

Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix G.
4.2
Scientific Rationale for Study Design
This is a FTiH study primarily designed to evaluate the safety and tolerability of AZD8853 at 
increasing doses in participants with selected metastatic/advanced solid tumour and for whom 
no standard-of-care exists. The study will also characterise the PK of AZD8853 and explore 
potential biological activity by assessing PD and 
 and anti-tumour 
activity. The results from this study will form the basis for decisions for future studies. The 
ability to acquire appropriate consent to collect biological samples is of utmost importance in 
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order to establish an archive and allow future meta-analysis of data derived from a number of 
studies with AZD8853.
The Master Protocol with Substudy structure allows for the optimization of both dose and 
schedule of AZD8853 as monotherapy and in combination with anti-cancer agents, including 
intensive safety monitoring followed by expansion cohorts in specific indications. In addition, 
the Master Protocol with Substudy structure allows flexibility to open and close different 
AZD8853 combinations at a different pace based on emerging data. This allows for a more 
fluid development of AZD8853 in combinations and indications with the greatest potential to 
benefit participants.
Key aspects of the study, such as starting dose of AZD8853 in Substudy 1, the dose escalation, 
stopping criteria, cohort sizes, and study endpoints are based upon accepted methodology for 
Phase I/II oncology studies.
4.3
Justification for Dose
Information on dose justification is provided in the respective Substudies.
4.4
End of Study Definition
The end of the study is defined as 18 months after the last enrolled participant received his/her 
last dose of study intervention or when the Sponsor stops the study, whichever occurs first.
4.4.1
Study Stopping Criteria
AstraZeneca reserves the right to temporarily suspend or permanently terminate this study or 
components of the study at any time. The reasons for temporarily suspending or permanently 
terminating the study may include, but are not limited to the following:

Fatal event deemed related to study therapy (probable or certain causality after full 
etiological work-up). This will also result in a comprehensive review of safety.

Unexpected and life-threatening events deemed related to study therapy.

Sponsor decision that the study participants are placed at undue safety risk.

Participant enrolment is unsatisfactory.

Noncompliance that might significantly jeopardize the validity or integrity of the study.

Sponsor decision to terminate development of the study intervention.
If AstraZeneca determines that temporary suspension or permanent termination of the study or 
components of the study is required, AstraZeneca will discuss the reasons for taking such 
action with all participating Investigators. When feasible, AstraZeneca will provide advance 
notice to all participating Investigators of the impending action.


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If the study or components of the study are suspended or terminated for safety reasons, 
AstraZeneca will promptly inform all Investigators and/or institutions conducting the study. 
AstraZeneca will also promptly inform the relevant regulatory authorities of the 
suspension/termination along with the reasons for such action. Where required by applicable 
regulations, the Investigator must inform the IRB/IEC promptly and provide the reason(s) for 
the suspension/termination. If the study or components of the study is suspended for safety 
reasons and it is deemed appropriate by AstraZeneca to resume the study or components of the 
study, approval from the relevant regulatory authorities (and IRBs/IECs when applicable) will 
be obtained prior to resuming the study.


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5
STUDY POPULATION
All criteria and considerations listed in this section are for the master study design and apply 
to all Substudies of the study. Additional Substudy-specific criteria and considerations are 
listed in the study population section of the relevant Substudy.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
The below are the master inclusion criteria for all Substudies of the study; all participants 
must meet the criteria described in the relevant Substudy in addition to those described below. 
Where Substudy-specific criteria are more stringent than master study criteria, the 
Substudy-specific criteria take precedent.
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
1. Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
2. Provision of signed and dated, written informed consent prior to any mandatory 
study-specific procedures, sampling, and analyses.
3. Provision of signed and dated written 
 Information informed 
consent prior to collection of samples for 
 that supports the 
.
Age
4. Participant must be at least 18 years of age inclusive, at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
5. Have a life expectancy of ≥ 12 weeks.
6. Participants must have at least one lesion, that qualifies as a RECIST v1.1 TL at baseline. 
Tumour assessment by CT scan or MRI must be performed within 28 days prior to 
treatment.
a) A previously irradiated lesion can be considered a TL if the lesion is well defined, 
measurable per RECIST v1.1, and has clearly progressed during or after most recent 
therapy.
b) Participants undergoing paired tumour biopsies must have additional NTLs that can 
be biopsied at acceptable risk as judged by the Investigator or if no other lesion is 
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deemed suitable for biopsy, then a RECIST v1.1 TL used for biopsy must be ≥ 2 cm 
in longest diameter (Please see requirements outlined in Appendix F).
7. ECOG performance status of 0 to 1 with no deterioration over the previous 2 weeks.
8. Adequate organ and bone marrow function measured within 14 days prior to first dose as 
defined in Table 6.
Note that one rescreen is permitted for participants if required, in line with Section 5.4. 
Table 6
Criteria for Adequate Organ and Marrow Function
Parameter
Value
Haematological
Haemoglobin
≥ 9.0 g/dL (5.59 mmol/L) with no blood transfusions 
(packed red blood cells) in the past 28 days.
Absolute neutrophil count
≥ 1.5 × 109/L (1,500 per mm3)
Platelet count
≥ 100 × 109/L (100,000 per mm3) with no platelet 
transfusions in the past 10 days.
Hepatic
Total bilirubin
≤ 1.5 × ULN in the absence of Gilbert’s syndrome
≤ 3 × ULN if the participant has Gilbert’s syndrome
Alanine transaminase and 
aspartate transaminase
≤ 3.0 × ULN.
≤ 5 × ULN in case of liver metastasis.
Renal
Calculated creatinine 
clearance a
≥50 mL/minute2 (≥45 mL/minute2 for urothelial 
carcinoma participants).
a
As determined by Cockcroft-Gault (using actual body weight):
Males:
Creatinine CL =
Weight (kg) x (140 – Age)
(mL/min)
72 x Serum creatinine (mg/dL)
Females:
Creatinine CL =
Weight (kg) x (140 – Age) x 0.85
(mL/min)
72 x Serum creatinine (mg/dL)
Abbreviations: ULN = upper limit of normal. 
5.2
Exclusion Criteria
The below are the master exclusion criteria for all Substudies of the study; all participants 
must meet the criteria described in the relevant Substudy in addition to those described below. 
Where Substudy-specific criteria are more stringent than master study criteria, the 
Substudy-specific criteria take precedent. 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Participants with a history of thromboembolic events within 6 months of Cycle 1 Day 1
unless they received adequate treatment. Please discuss with the Study Physician to 
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2. Unresolved toxicities of ≥ Grade 2 (CTCAE v5.0) from prior therapy (excluding vitiligo, 
alopecia, endocrine disorders that are controlled with replacement hormone therapy, 
asymptomatic laboratory abnormalities). Participants with ≥Grade 2 neuropathy will be 
evaluated on a case-by-case basis after consultation with the Study Physician.
3. Symptomatic CNS metastasis or leptomeningeal disease.
4. Ongoing or an active infection, including tuberculosis (clinical evaluation that includes 
clinical history, physical examination and radiographic findings, and tuberculosis testing 
in line with local practice), hepatitis B (known positive HBsAg result), hepatitis C, or HIV 
(positive HIV 1/2 antibodies). 
5. Participants with a past or resolved HBV infection (defined as the presence of anti-HBc 
and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible 
only if polymerase chain reaction is negative for HCV RNA.
6. Uncontrolled intercurrent illness, including but not limited to, symptomatic congestive 
heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac 
arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions 
associated with diarrhoea, or psychiatric illness/social situations that would limit 
compliance with study requirement, substantially increase risk of incurring AEs or 
compromise the ability of the participant to give written informed consent.
7. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: 
(a) Participants with vitiligo or alopecia.
(b) Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement.
(c) Any chronic skin condition that does not require systemic therapy.
(d) Participants without active disease in the last 5 years may be included but only after 
consultation with the Study Physician.
(e) Participants with celiac disease controlled by diet alone.
8. Other invasive malignancy within 2 years except for non-invasive malignancies.
9. Known allergy or hypersensitivity to IMP formulations, imaging agents (per Investigator’s 
discretion; if the participant can receive steroids and is stable prior to imaging), or any of 
the study intervention excipients.
10. Body weight loss > 10% within 30 days of screening visit.
11. Type 2 diabetes managed by metformin (please refer to Table 8).


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Prior/Concomitant Therapy
12. Current or prior use of immunosuppressive medication within 14 days before the first 
dose of study intervention is excluded. The following are exceptions to this criterion:
a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intraarticular 
injection).
b) Systemic corticosteroids at physiological doses not to exceed 10 mg/day of 
prednisone or its equivalent or 2 mg/day of dexamethasone or equivalent for 
participants with CNS metastases. Participants with brain metastases unless treated, 
asymptomatic, stable, and not requiring continuous corticosteroids at a dose of 
> 10 mg prednisone/day or equivalent for at least 4 weeks prior to start of study.
c) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
13. Prior therapy targeting GDF15 or GRFAL.
14. Any concurrent chemotherapy, IMP, biologic, or hormonal therapy for cancer treatment. 
Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone 
replacement therapy) is acceptable.
Prior/Concurrent Clinical Study Experience
15. Enrolment into another interventional clinical trial where:
a) Study intervention was administered within 28 days, or 5 half-lives of the previous 
intervention, whichever is shorter, prior to the first dose of AZD8853.
b) Concurrent enrolment in another clinical study unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an interventional 
study.
Other Exclusions 
16. History of organ transplant.
17. Receipt of live attenuated vaccine within 30 days prior to the first dose of study 
intervention. Note: Participants, if enrolled, should not receive live vaccine while 
receiving study intervention and up to 30 days after the last dose of study intervention.
18. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of study intervention or anticipation of the need for major surgical procedure during 
the course of the study. Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
19. Mean QTcF ≥ 470 ms calculated from 3 ECGs (within 5 minutes).
20. COVID-19:
a) Negative COVID-19 test is required for participants who have clinical signs and 
symptoms consistent with COVID-19 (eg, fever, dry cough, dyspnoea, sore throat, 


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fatigue, loss of sense of smell or taste). If the participant tests positive for COVID-19, 
a subsequent negative test result and symptom resolution are required before Cycle 1 
Day 1.
b) COVID-19 vaccination should not be given for 72 hours prior to administration of the 
first dose of AZD8853 or during the DLT period.
21. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site).
22. Female participants who are pregnant or breastfeeding, or male or female participants of 
reproductive potential who are not willing to employ effective birth control from screening 
to 3 months after the last dose of AZD8853 (Section 5.3).
23. Judgment by the Investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.
5.3
Lifestyle Considerations
5.3.1
Contraception
The following restrictions apply while the participant is receiving study treatment and for the 
specified times before and after:

Female participants of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least one highly effective method of contraception (see Table 7) 
from the time of screening and must agree to continue using such precautions for 
3 months after the last dose of AZD8853. Male partners of a female participant must use 
male condom plus spermicide throughout this period. Cessation of birth control after this 
point should be discussed with a responsible physician. Female participants should refrain 
from breastfeeding throughout this period. In addition, female participants must refrain 
from egg donation while on study and for 3 months after the final dose of AZD8853.

Non-sterilized male participants who are sexually active with a female partner of 
childbearing potential must use male condom plus spermicide from screening through 
3 months after the last dose of study drug. Male participants should refrain from sperm 
donation for 3 months after the last dose of AZD8853. Female partners of a male 
participant must use a highly effective method of contraception throughout this period.

Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral tubal ligation, salpingectomy, bilateral oophorectomy, or complete 
hysterectomy) or post-menopausal (defined as 12 months with no menses without an 
alternative medical cause).

Acceptable non-hormonal birth control methods include:
a) Total/True abstinence: When the participant refrains from any form of sexual 
intercourse and this is in line with their usual and/or preferred lifestyle; this must 


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continue for the total duration of the study and for at least 3 months after the last dose 
of study drug. Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods, or declaration of abstinence solely for the duration of a study) 
and withdrawal are not acceptable methods of contraception.
b) Vasectomized sexual partner PLUS male condom. With participant assurance that 
partner received post-vasectomy confirmation of azoospermia.
c) Tubal occlusion PLUS male condom.
d) Intrauterine device PLUS male condom. Coils must be copper-banded.
e) Highly effective methods of contraception are described in Table 7. A highly effective 
method of contraception is defined as one that results in a low failure rate (ie, less 
than 1% per year) when used consistently and correctly. Note that some contraception 
methods are not considered highly effective (eg, male or female condom with or 
without spermicide; female cap, diaphragm, or sponge with or without spermicide; 
non-copper containing intrauterine device; progestogen only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action 
[excluding Cerazette/desogestrel, which is considered highly effective]; and triphasic 
combined oral contraceptive pills).
Table 7
Highly Effective Methods of Contraception (< 1% Failure Rate)
Barrier/Intrauterine Methods
Hormonal Methods
•
Copper T intrauterine device
•
Levonorgestrel-releasing 
intrauterine system (eg,
Mirena®)a
•
Implants: Etonogestrel-releasing implants (eg, Implanon® or 
Norplant®).
•
Intravaginal Devices: Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®).
•
Injection: Medroxyprogesterone injection (eg, Depo-Provera®).
•
Combined Pill: Normal and low dose combined oral contraceptive 
pill.
•
Patch: Norelgestromin/ethinylestradiol-releasing transdermal 
system (eg, Ortho Evra®).
•
Minipill: 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.
5.3.2
Activity
Participants will abstain from strenuous exercise for 48 hours before each GDF15 blood 
collection timepoint. Participants may participate in light recreational activities during the 
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5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study and do not receive study treatment. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the CONSORT publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, any SAE and medications administered for a given SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Each participant may undergo only one rescreen in the study. Rescreened 
participants should be assigned the same participant number as for the initial screening. 
Rescreening should be documented so that its effect on study results, if any, can be assessed. 
Individuals who fail screening should have the reason recorded in the eCRF to indicate them 
as screen failures.


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6
STUDY INTERVENTION
Study intervention is defined as any IMP(s), marketed product(s) or placebo intended to be 
administered to or medical device(s) utilised by a study participant according to the study 
protocol. Additional details can be found in the Handling Instructions.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Medicinal Product – AZD8853
Intervention name
AZD8853
Type 
Biologic
Dose formulation
Concentrate for solution for infusion 
mg/mL
AZD8853 in 
mM 
, 
mM 
, 
% (w/v) 
, 
pH 
Unit dose strength
 mg/vial (
 mg/mL)
Minimum dosage level
Maximum dosage level
300 mg
3000 mg
Route of administration
i.v. infusion
Use
Experimental
IMP or NIMP
IMP
Sourcing
Provided centrally by the Sponsor
Packaging and labelling
Study intervention will be provided in vials in a carton. 
Each vial and carton will be labelled in accordance with 
country regulatory requirements.
Abbreviations: IMP = investigational medicinal product; i.v. = intravenous; NIMP = non-investigational 
medicinal product.
6.1.1.1
Identity of Investigational Medicinal Product
The IMP kit has a unique number that is printed on all labels within the kit (ie, the outer carton 
label and the label of each container within the carton). Each carton and vial are labelled with 
the same unique sequence number range.
6.2
Preparation/Handling/Storage/Accountability
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention. 
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3. 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.
4. 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).
6.2.1
Investigational Medicinal Product Inspection
Each vial selected for dose preparation should be inspected. 
AZD8853 will be supplied by AstraZeneca as a
 
and 
administered via i.v. infusion.
If any defects are noted with the IMP(s), the Investigator and site monitor should be notified 
immediately. Refer to the Product Complaint section (Section 6.2.5) for further instructions.
6.2.2
AZD8853 Preparation and Administration
The dose of AZD8853 for administration must be prepared by the Investigator’s or site’s 
designated IMP manager using aseptic technique.
Total time from needle puncture of the AZD8853 vial to the start of administration should not 
exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature 
If the final product is stored at both refrigerated and ambient temperatures, the total time must 
not exceed 24 hours. No incompatibilities between AZD8853 and polyolefin i.v. bags have 
been observed for i.v. administration. 
Doses of AZD8853 will be administered using an i.v. bag containing 
, with a 
final AZD8853 concentration ranging from 
mg/mL and delivered through an i.v.
administration set with a 
-μm filter. Add required volume of AZD8853 for dose 
level (using calculation below) to the i.v. bag. 
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The volume of AZD8853 (in mL) to add to the i.v. bag is calculated as follows:
 	
 	 () = 
	  ()
50 /
where 50 mg/mL is the nominal AZD8853 drug product concentration.
The i.v. bag size should be ≤ 
 mL and be selected such that the final concentration is 
within 
 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in 
the bag.
Standard infusion time for AZD8853 is 1 hour; however, if there are interruptions during 
infusion, the total allowed infusion time should not exceed 4 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
Flush the i.v. line with a volume of i.v. diluent equal to the priming volume of the infusion set 
used after the contents of the i.v. bag are fully administered or complete the infusion according 
to institutional policy to ensure the full dose is administered.
If either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials. AZD8853 does not contain preservatives, and any unused portion 
must be discarded.
6.2.3
Treatment Administration
No premedication for the prevention of IRRs prior to the first infusion of AZD8853 is 
permitted (ie, primary prophylaxis). Any planned premedication with acetaminophen 
(paracetamol), histamine (H1 and H2)-receptor antagonists, with subsequent infusions of 
AZD8853 following an IRR (ie, secondary prophylaxis) is permitted. Steroids should not be 
used as routine premedication for Grade 1 or 2 IRRs. If more than one participant during the 
course of the study develops a Grade ≥ 3 IRR during the first infusion, the SRC may 
recommend premedication for all subsequent participants to be implemented for the first 
infusion as follows: paracetamol/acetaminophen (500 to 1000 mg orally) and 
diphenhydramine (25 to 50 mg orally or i.v.; or an alternative antihistamine at an adequate 
dose), should be administered approximately 30 minutes prior to infusion with AZD8853. For
additional premedication guidelines for the prevention of IRR, refer to Section 6.5.
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6.2.4
Monitoring of Dose Administration
Participants will be monitored during and after infusion of AZD8853. Vital signs will be 
measured according to the schedules described in Section 8.2.3. In the event of an IRR, or any 
other AE, see TMGs for toxicity management and dose modification.
As with any biological product, allergic reactions to dose administration are possible. 
Therefore, appropriate drugs and medical equipment to treat acute anaphylactic reactions must 
be immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. 
The Investigator’s or site’s designated IMP manager is required to maintain accurate IMP
accountability records. Upon completion of the study, copies of IMP accountability records 
will be returned to AstraZeneca. All unused IMPs will be returned to an AstraZeneca 
authorized depot or disposed of upon authorization by AstraZeneca according to the 
investigational site policy.
6.2.5
Reporting Product Complaints
Any defects with the IMP must be reported immediately to the Sponsor Product Complaint 
Department by the site with further notification to the site monitor. All defects will be
communicated to the Sponsor and investigated further with the Product Complaint 
Department. During the investigation of the product complaint, all IMP must be stored at 
labelled conditions unless otherwise instructed.
Contact information for reporting product complaints:
Email: productcomplaints@astrazeneca.com
Phone: +1-301-398-2105
Mail:
AstraZeneca
Attn: Product Complaint Department
One MedImmune Way,
Gaithersburg, MD USA 20878
6.2.6
Additional Study Drugs
Provided in respective Substudy.
6.2.7
Labelling
Labels for the IMP will be prepared in accordance with good manufacturing practice and local 
regulatory guidelines. Label text will be translated into local languages, as required.


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6.2.8
Storage
AZD8853 vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. All IMPs 
should be kept in a secure and dry place. Drug product should be kept in original packaging 
until use to prevent prolonged light exposure.
6.2.9
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor compliance.
Details of treatment with IMPs for each participant will be recorded in the eCRF.
6.2.10
Accountability
The Investigator’s or site’s designated IMP manager is required to maintain accurate IMP
accountability records. Upon completion of the study, copies of IMP accountability records 
will be returned to the Sponsor. All unused IMP will be returned to a Sponsor-authorized 
depot or disposed of upon authorization by the Sponsor.
6.3
Measures to Minimise Bias: Randomization and Blinding
This is an open-label study; no blinding is required. Each potential participant is assigned a 
unique participant identification number at the screening visit after signing consent. Once a 
participant is assigned a unique identification number, it cannot be reused for another 
participant. Study intervention will be dispensed at the study visits summarised in the relevant 
Substudy. Returned study intervention should not be re-dispensed to the participants.
If an unscheduled assessment is performed, and the participant has not progressed, every 
attempt should be made to perform the subsequent assessments at their scheduled visits. This 
schedule is to be followed to minimise any unintentional bias caused by some participants
being assessed at a different frequency than other participants. 
6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date, and time, 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.
A record of the volume of AZD8853 infusion administered to 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.
Deviations from the prescribed dosage regimen should be recorded in the eCRF. The 


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Investigational Product Storage Manager is responsible for managing the study intervention 
from receipt by the study site until the destruction or return of all unused study intervention.
6.5
Concomitant Therapy
Any medication or vaccine (including OTC or prescription medicines, vitamins, and/or herbal 
supplements) that the participant is receiving at the time of screening or receives during the 
study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including route of administration, dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
Participants must be instructed not to take any medications, including OTC products, herbal or 
natural remedies, vitamins and supplements, without first consulting with the Investigator. 
Authorised/approved COVID-19 vaccines can be given to participants enrolled in this study as 
long as these do not represent a prohibited concomitant medication. Investigators should 
follow the CSP, their local prescribing information, and policies when considering if 
vaccination against COVID-19 is appropriate for their participants enrolled in an AstraZeneca 
clinical study. COVID-19 vaccination should not be given for 72 hours prior to administration 
of the first dose of AZD8853 or during the DLT period.
For any authorised/approved COVID-19 vaccine, specific considerations should be given to 
the relevant labelling information (ie, “Indications,” “Contraindications,” “Warnings and 
Precautions,” “Adverse Reactions”) on its use in this study. In any case, COVID-19 
vaccination details must be captured in the eCRF as concomitant medication, and adverse 
reactions reported.
Prohibited concomitant therapies are listed in Table 8 and permitted concomitant therapies are 
listed in Table 9. Concomitant medication additional to those listed in Table 8 may be 
considered on a case-by-case basis by the Investigator in consultation with the Study 
Physician if required. 


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Table 8
Prohibited Concomitant Medications
Prohibited Medication/Class of Drug
Usage
Any investigational therapy including anti-cancer 
therapy other than those under investigation in this 
study
Should not be given concomitantly while the 
participants are on study intervention
mAbs against CTLA-4, PD-1, or PD-L1 other than 
those under investigation in this study
Should not be given concomitantly while the 
participants are on study intervention
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal therapy for 
cancer treatment other than those under investigation 
in this study
Should not be given concomitantly while the 
participants are on study intervention, unless specified 
in a Substudy. (Concurrent use of hormones for 
non-cancer-related conditions [eg, insulin for diabetes 
and hormone replacement therapy] is acceptable. 
Local treatment of isolated lesions for palliative intent 
may be acceptable [eg, by local surgery or 
radiotherapy]) upon consultation with study physician.
Live attenuated vaccines
Should not be given through 30 days after the last 
dose of study intervention 
Immunosuppressive medications including, but not 
limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumour necrosis 
factor-α blockers
Should not be given concomitantly or used for 
premedication prior to the immunotherapy infusions. 
The following are allowed exceptions:
•
Use of immunosuppressive medications for the 
management of study intervention-related AEs
•
Short-term premedication for participants
receiving combination agent where the 
prescribing information for the agent requires the 
use of steroids for documented hypersensitivity 
reactions
•
Use in participants with contrast allergies
•
In addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy related events 
experienced by the participant (eg, chronic obstructive 
pulmonary disease, radiation, nausea, etc)
Metformin
Metformin has been shown to induce GDF15 gene 
expression, thereby elevating circulating GDF15 
levels significantly. One study showed that a one-time 
dose of metformin increased mean circulating GDF15 
levels about 2.5-fold (Coll et al, 2020). To prevent 
falsely high GDF15 level results, participants must not 
take metformin for at least 72 hours prior to the 
screening GDF15 blood sample and should be 
switched to an acceptable alternative; the participant
must demonstrate controlled diabetes mellitus on this 


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Table 8
Prohibited Concomitant Medications
Prohibited Medication/Class of Drug
Usage
alternative at least 7 days prior to starting the study 
intervention on Cycle 1 Day 1.
Herbal and natural remedies
Should not be given concomitantly unless agreed by 
the Sponsor
Abbreviations: AE = adverse event; CTLA-4 = cytotoxic T-lymphocyte associated antigen; 
PD-1 = programmed cell death-1; PD-L1 = programmed cell death ligand-1.
Table 9
Permitted Concomitant Medications
Supportive Medication/Class of Drug
Usage
Premedication for management of diarrhoea, nausea, 
and vomiting
Permitted after but not before the first dose of study 
intervention
Blood transfusions
Permitted at any time during the study
Erythropoietin
Prophylactic erythropoietin should not be started 
during Cycle 1 of the study but may be started during 
Cycle 2 and after. Participants already receiving 
erythropoietin at the time of screening may continue 
it provided they have been receiving it for more than 
one month at the time study treatment has started.
G-CSF
G-CSF should not be used prophylactically during 
Cycle 1, but may be considered after Cycle 1 
Megestrol acetate
Permitted for appetite stimulation
Bisphosphonates, and denosumab
Permitted for treatment of bone metastases
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed in Table 8
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management [including 
palliative radiotherapy to non-target lesions, etc])
Should be used, when necessary, for all participants
Inactivated viruses, such as those in the influenza 
vaccine, and COVID-19 vaccine
Permitted. COVID-19 vaccination should not be 
given for 72 hours prior to administration of the first 
dose of AZD8853 or during the DLT period.
Abbreviations: DLT = dose limiting toxicity; G-CSF = granulocyte colony stimulating factor, 
COVID-19 = coronavirus disease 2019.
6.6
Dose Modification
If, in the opinion of the Investigator, a participant experiences a clinically significant and/or 


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unacceptable adverse reaction, then the dose may be temporarily or permanently halted. 
Supportive therapy will be administered as required. Relevant reporting and discussion with 
the Study Physician will take place before resumption of dosing.
See the relevant Substudy for details on dose modification.
6.7
Intervention after the End of the Study
No intervention is planned after the end of the study. However, provisions will be in place for 
participants still enrolled at the end of the study to continue to receive study intervention if, in 
the opinion of the Investigator, they are continuing to receive benefit from treatment. Such 
participants will continue to be monitored for all SAEs up to 90 days after the last dose of 
study intervention, or until commencing new anti-cancer therapy, whichever is sooner.
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, participants currently receiving treatment with study intervention may 
be transitioned to such a study, and the current study would reach its end. The roll-over or 
safety extension study would ensure treatment continuation with visits and assessments per its 
protocol. Any participant who would be proposed to move to such a study would be asked to 
sign a new ICF.


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7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for safety to the end of the 90-day follow-up period 
(Section 8.2.7), or withdrawal of consent or starting another anti-cancer therapy, whichever is 
earlier. Participants will be evaluated for efficacy until documented disease progression or 
withdrawal of consent, whichever is earlier. Participants will be followed for subsequent 
anti-cancer therapy until withdrawal of consent or death, whichever is earlier. See the relevant
Substudy SoA for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed.
Note that discontinuation from study intervention is NOT the same as a withdrawal from the 
study.
The participant should continue attending subsequent study visits and data collection should 
continue according to the CSP. If the participant does not agree to continue in-person study 
visits, a modified follow-up must be arranged to ensure the collection of endpoints and safety 
information. This could be a telephone contact with the participant for the follow-up visit, a 
contact with a relative or treating physician, or information from medical records. The 
approach taken should be recorded in the medical records. A participant who agrees to 
modified follow-up is not considered to have withdrawn consent or to have withdrawn from 
the study.
Participants may be discontinued from study intervention in the following situations:

Objective disease progression assessed by Investigator (a confirmatory scan for disease 
progression is up to the Investigator’s discretion).
Note: If the participant has been discontinued from the AZD8853 intervention before 
disease progression, it is required for disease assessment to continue (see the relevant 
Substudy SoA), until documented disease progression.

Adverse event as defined in Section 8.3.

Participant or Investigator decision. The participant is free to discontinue treatment at any 
time, without prejudice to further treatment. When the reason does not impact safety, the 
Study Physician together with the Investigator will consider the risk/benefit to the 
participant of stopping treatment. 

Pregnancy (see Section 8.3.10).

Non-compliance with the CSP (Investigator or participant).


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
Participant incorrectly initiated on study treatment.

Unexpected, significant, or unacceptable risk to the participants enrolled in the study.

Sponsor termination of study for reasons including but not limited to unfavourable 
risk/benefit or change in drug development plan.
7.1.1
Temporary Discontinuation
Applicable criteria and procedures for stopping and re-starting study intervention will be 
defined in individual Substudies.
7.2
Participant Withdrawal from the Study
All participants will be followed until either death, lost to follow-up, or withdrawal of consent, 
or end of study whichever occurs first.

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon.

A participant who considers withdrawing from the study must be informed by the 
Investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).

If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation. The 
Investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team. Please refer to Appendix C for further details.
Participants who are withdrawn from the study but are evaluable per the definition in the 
Populations for Analyses section of the relevant Substudy will not be replaced. 
In addition, participants will be withdrawn from the study in the event that the Sponsor
terminates this study.


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7.3
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and,
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 described in
Appendix A.


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8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA for the relevant Substudy. 
Protocol waivers or exemptions are not allowed for any of the Substudies.

Immediate safety concerns should be discussed with the Study Physician 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 meet the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
8.1
Efficacy Assessments
RECIST v1.1 guidelines for measurable, non-measurable, TLs and NTLs, and the objective 
tumour response criteria are presented in Appendix F of this CSP. Tumour assessments will be 
based on RECIST v1.1 (Eisenhauer et al, 2009) and will be performed according to the 
schedule presented in each Substudy.
Standard radiographic imaging using RECIST is used to assess both response (in participants 
with measurable disease) and progression. An ORR as per RECIST v1.1 criteria requires 
confirmation of PR and CR and must occur no fewer than 4 weeks after initial documentation 
of PR or CR. Disease progression will be defined as per RECIST v1.1; however, if the 
participant is clinically stable, a confirmatory scan for progression is left up to the discretion 
of the Investigator.
Tumour assessments use images from CT (preferred) or MRI, with i.v. contrast, of the chest, 
abdomen, and pelvis, and should additionally investigate areas that may be involved based on 
signs and symptoms of individual participants, collected during screening/baseline and at 
regular (follow-up) intervals during study intervention. Brain scans (MRI preferred) are 
mandatory at screening/baseline for all NSCLC participants in this study, participants with 
known brain metastasis, and as clinically indicated for other participants. Post-baseline MRI 
of the brain will only have to be performed in participants with brain metastases at baseline, 
while participants without brain metastases do not need additional brain scans for subsequent 
tumour assessments unless clinically indicated. The imaging modality used for baseline 


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tumour assessment should be kept the same consistently at each subsequent follow-up 
assessment throughout the study if possible. It is important to follow the tumour assessment 
schedule as closely as possible (refer to the SoA in the respective Substudy) relative to dose of 
study intervention. 
Screening/baseline imaging should be performed no more than 28 days before start of study 
intervention and ideally should be performed as close as possible to and prior to the start of 
study intervention. Scans obtained as part of standard clinical practice, prior to informed 
consent, but within the 28-day period are acceptable. Tumour assessments should be 
performed per the SoA in the respective Substudy until objective disease progression as 
defined by RECIST v1.1 (refer to Appendix F) and assessed by the Investigator, or withdrawal 
of consent. Response (CR or PR) should be confirmed by a repeat, consecutive scan at least 
4 weeks after the first documentation of response.
If the Investigator is in doubt as to whether progression has occurred, particularly with 
response to NTLs or the appearance of a new lesion, it is advisable to continue treatment until 
the Investigator reassesses the participant’s status at the next scheduled assessment 
(confirmation), or sooner if clinically indicated. Scans confirming progression should not be 
conducted within 1 week after a progression biopsy to allow for reduction in inflammation.
If scans are performed outside of scheduled visit window and the participant has not 
progressed, every attempt should be made to perform the subsequent scans at their scheduled 
visits whilst the participant remains on study treatment. If the participant interrupts treatment 
or incurs a treatment delay, scans should continue to occur at the protocol-defined frequency. 
It is important to follow the SoA as closely as possible.
Tumour markers will not be used for tumour response assessments as per RECIST v1.1. 
Tumour markers should be obtained as per standard-of-care.
Storage of Scans
Sites will be required to store electronic copies of all scans (CT, or other scans for efficacy,
and PET scans), and the Sponsor will arrange for centralized storage of all imaging data. All 
imaging assessments, including unscheduled visit scans, will be collected on an ongoing basis,
and sent to the Sponsor or designee for storage. The centralized storage of imaging data would 
allow independent centralized third party blinded review of disease assessments. In this 
regard, and at the discretion of the Sponsor, an independent central review of all scans used in 
the assessment of tumours by RECIST v1.1 may be conducted. Guidelines for imaging 
collection and storage will be provided in a separate document.


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Skeletal Muscle Index
To study the effects of AZD8853 on cancer cachexia, SMI will also be collected in this study. 
To collect this information, participants should have CT or MRI scan with slices at T12 or L3 
(Yang et al, 2021,Wang et al, 2020, Rybar et al, 2016). These should be obtained using the 
same modality and at the same timepoint as the disease assessment scans.
8.2
Safety Assessments
Planned timepoints for all safety assessments are provided in the respective Substudy SoA and 
are detailed below.
8.2.1
Physical Examinations
Physical examination will be performed at timepoints as specified in the respective Substudy
SoA.

Demographics will be performed at the screening visit. 

A full physical examination should be completed at screening, other SoA specific study 
visits and EOT and will include, at a minimum: the general appearance of the participant, 
and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal system, lymphatic system, and nervous system. Height will be assessed 
at screening only. 

Investigators should pay special attention to clinical signs related to previous serious 
illnesses and new or worsening abnormalities that may qualify as AEs. Investigators must 
ask about participant’s appetite (poor, average, or good) at every physical examination
and should ask about changes in appetite (worse, about the same, or improved) since the 
last assessment for all physical examinations after screening.

A standard medical, medication, and surgical history including smoking history (smoking 
pack-years) will be obtained with review of the selection criteria with the participant.
8.2.2
ECOG Performance Status
Performance status will be assessed at timepoints as specified in the respective Substudy SoA 
according to ECOG criteria as follows:

0 = Fully active, able to carry out all pre-disease activities without restrictions.

1 = Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature 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.


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
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 = Dead
8.2.3
Vital Signs
Vital signs measurements (body temperature, BP, heart [pulse] rate, respiration rate, and body 
weight) will be performed at timelines specified in the respective Substudy SoA.

Blood pressure and pulse/heart rate measurements will be assessed in supine position with 
a completely automated device. Manual techniques will be used only if an automated 
device is not available.

Blood pressure, respiratory rate, and pulse measurements should be preceded by at least 
10 minutes of rest for the participant in a quiet setting.

Vital signs are to be taken before any blood collection. 

Body temperature will be taken prior to all infusions (within 2 hours before start of the 
infusion).

Body weight is only required pre-dose.
8.2.4
Electrocardiograms
Electrocardiograms will be performed at timepoints specified in the respective Substudy SoA.
Local 12-lead digital ECGs will be obtained after the participant has been resting semi-supine 
for at least 10 minutes. Triplicate ECGs will be collected within a 5-minute period. All ECGs 
should be recorded with the participant in supine position.
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, the Investigator should contact the Study Physician.
The ECG parameters to be determined will include (but will not be limited to) the following: 

Heart rate

RR interval: duration in msec between 2 R peaks of 2 consecutive QRS complexes

PR interval: duration in msec from the beginning of wave P to onset of ventricular 
depolarisation (Q and R)

QRS interval: duration in msec of the QRS complex

QT interval: duration in msec from the beginning of Q wave to the end of the T-wave


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
QTcF: QT[msec]/RR[sec]1/3
Any abnormal finding in the ECG tracing will be evaluated by the Investigator and will be 
specifically documented and registered in the eCRF. Throughout the study, clinically relevant 
new findings or worsening of a pre-existing finding in the ECGs (parameters or abnormal 
findings in the tracing) must be considered an AE and must be recorded in the AE eCRF.
8.2.5
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
virology, and urinalysis will be taken at the timepoints indicated in the respective Substudy
SoA.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date of collection and results (values, units, and reference ranges) will be 
recorded on the appropriate eCRF.
The analysis of safety samples will be performed at a local laboratory at or near to the 
Investigator site. Sample tubes and sample sizes may vary depending on laboratory method 
used and routine practice at the site.
For all participants, results of safety laboratory testing (haematology, coagulation and clinical 
chemistry at a minimum) must be available within 24 hours prior to dosing and must be 
reviewed by the Investigator prior to administration of AZD8853. Samples can be collected 
the day before AZD8853 administration. If clinically indicated, additional clinical laboratory 
tests and evaluations may be performed by the Investigator and these need to be entered into 
the eCRF. 
The laboratory variables to be measured for haematology, clinical chemistry, urinalysis, 
coagulation, virology, and pregnancy testing are listed in Table 10.


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Table 10
Laboratory Safety Variables
Haematology (whole blood)
Clinical Chemistry (serum or plasma)
B-Hb
S/P-Creatinine
S/P-Chloride
B-WBC count with differential
S/P-Bilirubin total
S/P-Magnesium
B-Platelet count
S/P-Direct and indirect bilirubin S/P-Phosphorus
B-Haematocrit
S/P-Alkaline phosphatase
S/P-Cholesterol
B-Absolute neutrophil count
S/P-Aspartate transaminase
S/P-Amylase
B-Absolute lymphocyte count
S/P-Alanine transaminase
S/P-Lipase
S/P-Albumin
S/P-TSH
Urinalysis (dipstick)
S/P-Free T3
S/P-Free T4
Colour and appearance
S/P-Potassium
S/P-Bicarbonate
U-
Hb/Erythrocytes/Blood 
U-
Protein/Albumin
S/P-Calcium, total
S/P-Total protein
U-Glucose
U-pH
S/P-Sodium
S/P-Blood urea nitrogen
U-Specific gravity
U-Ketones
S/P-Creatine phosphokinase
S/P-Glucose (fasting preferred)
U-Microscopy including WBC/high-power 
field, RBC/high-power field a
S/P-HbA1c
S/P-Triglycerides
S/P-lactate dehydrogenase
Coagulation
INR
PT
aPTT, absolute or relative
D-Dimer
Fibrinogen
Virology
Hepatitis B virus core antibodies
Hepatitis A serology
Hepatitis C serology
HIV-1 and 2 antibodies
Hepatitis B virus surface antigen
Pregnancy Test (women of childbearing potential only)
β-hCG
a
Microscopy should be performed at Investigator’s discretion for abnormal dipstick.
Abbreviations: aPTT = activated partial thromboplastin time; B = blood; Hb = haemoglobin; 
HbA1c = haemoglobin A1c; hCG = human chorionic gonadotropin; HIV = human immunodeficiency viruses; 
INR = international normalised ratio; P = plasma; PT = prothrombin time; RBC = red blood cells; S = serum; 
TSH = thyroid-stimulating hormone; T3 = triiodothyronine; T4 = thyroxine; U = urinalysis; WBC = white blood 
cells.
8.2.6
30-Day Follow-up Visit
A follow-up visit will be performed 30 (± 7) days from the EOT visit (see the SoA for the 
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8.2.7
90-Day Follow-up Visit
A follow-up visit will be performed 90 (± 7) days from the time that all study intervention is 
permanently discontinued (see the SoA for the relevant Substudy). Assessment of disease 
progression (CT or MRI) will not be performed at this visit if previously confirmed disease 
progression has been documented.
8.2.8
Survival Follow-up
All participants will be followed for survival until death, lost to follow-up, withdrawal of 
consent, or end of study whichever occurs first. Participants will be followed for survival by 
telephone calls, email, or clinic visits approximately every 12 weeks. 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 intervention or study procedures.
8.3
Adverse Events and Serious Adverse Events
The Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorised representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
AEs/SAEs will be collected from the time of signature of the screening ICF throughout the 
treatment period and including the follow-up period of 90 days (± 7 days) after last dose of 
study intervention.
If the Investigator becomes aware of any SAE, including death, at any time during survival 
follow-up, with a suspected causal relationship to the study intervention, the Investigator shall 
report the SAE in the eCRF.
If the Investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the Investigator shall, without undue delay, report the SAE to the Sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 


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eCRF. These AEs must still be reported to the Sponsor and records must be kept with the 
participant’s record. 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 and time when the AE started and stopped

CTCAE grade/changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the study intervention(s) (yes or no)

Action taken with regard to study intervention(s)

AE caused participant’s withdrawal from study (yes or no)

Outcome, including administration of any treatment
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of SAE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
8.3.3
Causality Collection
The Investigator should assess causal relationship between study intervention 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 IMP?’
For SAEs, causal relationship should also be assessed for all other study medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.


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A guide to the interpretation of the causality question is found in Appendix B to the CSP.
8.3.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’ or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5
Adverse Events Based on Examinations and Tests
The results from the CSP mandated laboratory tests and vital signs will be summarised in the 
CSR. 
Deterioration as compared to baseline in protocol-mandated physical examinations, laboratory 
values, vital signs, ECGs should therefore only be reported as AEs if they fulfil any of the 
SAE criteria, are the reason for discontinuation of treatment with the study intervention or are 
considered to be clinically relevant as judged by the Investigator (which may include but not 
limited to consideration as to whether treatment or non-planned visits were required or other 
action was taken with the study intervention, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to disease progression.
8.3.6
Adverse Events of Special Interest
An AESI is an AE of scientific and medical interest specific to understanding of a study 
intervention and may require close monitoring and rapid communication to AstraZeneca by 
the Investigator. An AESI may be serious or non-serious. The reporting of AESIs allows 
ongoing surveillance of these events to characterise and understand them in association with 


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the use of a study intervention. 
Adverse events of special interest will be recorded in the eCRF using a recognised medical 
term or diagnosis that accurately reflects the event. Adverse events will be assessed by the 
Investigator for severity, relationship to the study intervention, possible aetiologies, and 
whether the event meets criteria for an SAE and therefore requires immediate notification to 
AstraZeneca. If an AE evolves into a condition that meets the regulatory definition of 
“serious,” it will be reported as described in Section 8.3.9.
Based on the available preclinical data, review of the cumulative literature, and biological 
plausibility, the following events are considered to be AESIs:

 





Other AEs which are considered to be AESIs with AZD8853 include, but are not limited to:




The immune system can respond to foreign protein, even to humanised mAb by producing
human-anti-human antibodies, which may result in formation of immune complexes and their
deposition in blood vessels, joints, and glomeruli causing symptomatic disease (eg,
). Participants will be monitored clinically and for
the presence of ADAs. Participants who experience an AE suspected to be immune complex
related will discontinue study intervention. Immune complex disease will be managed in 
accordance with standard-of-care.

. 
have some common manifestations and may be difficult to distinguish from each other. 
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are commonly observed during or shortly after the first time of 
exposure to therapeutic mAbs delivered through i.v. infusion. These reactions are less 
common following subsequent exposures. Unlike 
, 
 is a rare event, usually 
occurring after subsequent exposure to an antigen, and it is most commonly accompanied by 
. The Investigator is advised to carefully 
examine symptoms of adverse reactions observed during or shortly after exposure to 
AZD8853 and consider the above-mentioned facts prior to making a final diagnosis. Reactions 
occurring at the time of or shortly after subsequent infusions of study intervention are to be 
judged by the Investigator at his/her own discretion. For the Investigator’s convenience and to 
facilitate consistency in judgements, a copy of the
 
is 
provided in Appendix H. Refer to TMGs for management of participants with 
 
(including 
) and 
. In the event of an 
, the site should document
which medications have been infused at the time of onset of the 
 in addition to signs and
symptoms.
8.3.7
Hy’s Law
Cases where a participant has elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may need 
to be reported as SAEs. Please refer to Appendix E for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
8.3.8
Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the study intervention 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 AEs during the study.
8.3.9
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
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days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day ie, immediately but no later than 24 hours of when he or she becomes 
aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the Investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
For further guidance on the definition of a SAE, see Appendix B.
The reference document for definition of expectedness/listedness is the IB for AZD8853.
8.3.10
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the participant has received any study intervention.
If a pregnancy is reported, the Investigator should inform AstraZeneca within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.10.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
anomalies/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly/birth defect) should be followed up and documented even if the 
participant was discontinued from the study.
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informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.9) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.3.10.2
Paternal Exposure 
Male participants should refrain from fathering a child or donating sperm during the study and 
3 months following the last dose (see inclusion criteria, Section 5.1).
Pregnancy of the participant’s partners is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly), occurring from the date of the first dose until 3 months after the 
last dose should, if possible, be followed up and documented in the Pregnancy Report Form. 
Consent from the partner must be obtained before the Pregnancy Report Form is completed.
If a pregnancy occurs in a participant’s partner within the timeframe specified above, then 
Investigators or other site personnel will inform the appropriate Sponsor representative 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The same timelines apply when outcome information is available.
8.3.11
New Cancers
The development of a new cancer should be regarded as an SAE. New primary cancers are 
those that are not the primary reason for the administration of the study intervention and have 
been identified after the participant’s inclusion in this study. They do not include metastases of 
the original cancer.
8.3.12
Deaths
All deaths that occur during the study intervention period, or within the protocol-defined 
follow-up period after the administration of the last dose of study intervention, must be 
reported as follows:

Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the eCRF. It 
should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported as an SAE within 24 hours. It should also be 
documented in the eCRF. The report should contain a comment regarding the 


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co-involvement of progressive disease, if appropriate, and should assign main and 
contributory causes of death.

Death with an unknown cause should always be reported as an SAE. It should also be 
documented in the eCRF. A post-mortem may be helpful in the assessment of the cause of 
death, and if performed, a copy of the post-mortem results should be forwarded to 
AstraZeneca Patient Safety or its representative within the usual time frames.

Deaths occurring after the protocol-defined safety follow-up period (90 days) after the 
administration of the last dose of study intervention should be documented in the eCRF. If 
the death occurred as a result of an event that started after the defined safety follow-up 
period and the event is considered to be due to a late-onset toxicity to study intervention, 
then it should also be reported as an SAE.
8.3.13
Medication Error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.9) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 4.
8.4
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.

An overdose without associated symptoms is only reported on the Overdose eCRF 
Module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, the Investigator
or other site personnel inform appropriate AstraZeneca representatives immediately, but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 


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relevant information is provided to the AstraZeneca Patient Safety data entry site within 
24 hours for overdoses associated with an SAE (see Section 8.3.9) and within 30 days for all 
other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific laboratory manual. Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality. For further details on Handling of Human 
Biological Samples see Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 

Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses.
−
Pharmacokinetic samples may be disposed of or anonymised. Additional analyses 
may be conducted on the anonymised, PK samples to further evaluate and validate 
the analytical method. Any results from such analyses may be reported separately 
from the CSR.

Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years following issue of the CSR. Additional use includes but is not 
limited to further characterisation of any ADAs, confirmation and/or requalification of the 
assay as well as additional assay development work. The results from future analysis will 
not be reported in the CSR.
8.5.1
Pharmacokinetics

Serum samples will be collected for measurement of serum concentrations of AZD8853
as specified in the SoA of relevant Substudies. 

Samples may be collected at additional timepoints during the study if warranted and 
agreed upon between the Investigator and the Sponsor, eg, for safety reasons. The timing 
of sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring. 

Serum samples will be used to analyse the PK of AZD8853. Samples collected for 
analyses of AZD8853 serum concentration may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study.

Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual. 


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Refer to relevant Substudy for the sampling schedule for PK samples.
8.5.1.1
Determination of Drug Concentration
Samples for determination of drug concentration in serum will be assayed by bioanalytical test 
sites operated by or on behalf of AstraZeneca, using an appropriately validated bioanalytical 
method. Full details of the analytical method used will be described in a separate bioanalytical 
report.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Samples for determination of ADA in serum will be assayed by bioanalytical test sites 
operated by or on behalf of AstraZeneca, using an appropriately validated bioanalytical 
method. Tiered analyses will be performed to include screening, confirmatory, and titre assay 
components. Full details of the methods used will be described in a separate report. ADA 
samples may also be further tested for characterization of the ADA response, including 
possible assessment of neutralising antibody. Samples will be collected, labelled, stored, and 
shipped as detailed in the Laboratory Manual.
Refer to relevant Substudy for the sampling schedule for ADA samples.
8.5.3
Pharmacodynamics
Refer to relevant Substudy for information on pharmacodynamics.
8.6
Refer to relevant Substudy for information on 
.
8.7
 Initiative Sample
Collection of 
 is also part of this study as 
specified in the SoA and is subject to agreement in the ICF addendum. 
Blood sample for
 will be collected from participants who have consented to 
participate in the 
 of the study. Participation is optional. 
Participants who do not wish to participate in the 
 may still participate in the 
study.
See Appendix D for information regarding the 
. Details on 
processes for collection and shipment and destruction of these samples can be found either in
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the appendices or in the Laboratory Manual. 
For storage and destruction of 
 see Appendix D.
8.8
Participants will be given the option to complete a 
 after consenting to the main 
study to collect 
 
 The goals of 
this 
 research are to
 
 
. Certain main study data not related to disease or treatment, 
such as demographics, informed consent review metrics, etc., may be re-used from the EDC 
and/or eConsent platform. This 
 does not collect clinical data about the 
participant's disease, symptoms, treatment effect or adverse events. Therefore, data from this 
 will not be reported in the CSR. The data will be anonymized and 
aggregated and may be published in an academic journal or presented at scientific meetings. 
No individual, identifying, protected health information will be included in any publications 
or presentations. 
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9
STATISTICAL CONSIDERATIONS
The statistical analyses will be performed by AstraZeneca or a CRO under the direction of the 
Early Biometrics Oncology, AstraZeneca. A comprehensive SAP will be prepared.
9.1
Statistical Hypotheses
Refer to the relevant Substudy for information.
9.2
Sample Size Determination
Refer to the relevant Substudy for information.
9.3
Populations for Analyses
For purposes of analysis, the study populations are defined as provided in Table 11. For all 
efficacy analyses, and for baseline and demography, participants will be classified according 
to the dose they were assigned to (ie, the planned treatment).
Table 11
Populations for Analyses
Population/Analysis Set
Description
Endpoint/Output
Enrolled
All participants who sign the ICF.
Disposition
Safety
All participants who receive at least one dose of 
study intervention.
Exposure
Safety endpoints
PFS
OS
ctDNA
DLT Evaluable
Enrolled participants who complete the DLT 
evaluation period (defined as 21 days after 
receiving the first infusion of study intervention
and has completed safety evaluation requirements) 
with at least 75% dosing or who experience any 
DLT.
DLT
Response Evaluable
All dosed participants who have measurable 
disease at baseline.
ORR
DoR
DCR
Tumour size
Pharmacokinetics 
All participants who receive at least one dose of 
study intervention with at least one reportable 
concentration.
PK concentrations
PK parameters
Immunogenicity
All participants who receive at least one dose of 
study intervention with at least one reportable 
immunogenicity measurement.
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Abbreviations: ctDNA = circulating tumour deoxyribonucleic acid; DCR = disease control rate; DLT = dose 
limiting toxicity; DoR = duration of response; ICF = informed consent form; PFS = Progression Free Survival;
PK = pharmacokinetics; OS = overall survival; ORR = objective response rate.
9.4
Statistical Analyses
The SAP will be finalised prior to database lock and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section only 
includes the planned statistical analyses for the master objectives.
Refer to the relevant Substudy for more information on the statistical analyses for 
Substudy-specific objectives.
9.4.1
General Considerations
Descriptive statistics will be used for all variables. Continuous variables will be summarised 
by the number of observations, mean, standard deviation, median, minimum, and maximum. 
Categorical variables will be summarised by frequency counts and percentages for each 
category. Unless otherwise stated, percentages will be calculated based on the population total.
Time to event variables will be presented using the Kaplan-Meier methodology, including 
median time calculated from the Kaplan-Meier curves.
In general, the last observed measurement prior to first dose of study intervention will be 
considered the baseline measurement.
Depending on the extent of any impact, summaries of data relating to participants diagnosed 
with COVID-19, any impact of COVID-19 on study conduct (in particular missed visits, 
delayed or discontinued study treatment, and other protocol deviations) may be generated. 
More details will be provided in the SAP.
9.4.2
Safety Analyses
Safety and tolerability will be assessed in terms of DLTs, AEs/SAEs, ECOG status, vital signs, 
clinical chemistry/haematology parameters, dose interruptions/discontinuations and ECG data.
These variables will be collected for all participants. All safety analyses will be performed on 
the Safety Population, except for the evaluation of DLTs that will be performed on the DLT 
Evaluable Population. Additional subgroup analysis of safety may be performed, as specified 
in the SAP.
Medical Dictionary for Regulatory Activities will be used to code AEs. Adverse events will be 
graded according to the NCI CTCAE v5.0. The number of participants in each dose cohort 
(Part A) and each expansion (Parts B and C) experiencing each AE will be summarised by 
MedDRA SOC and preferred term. The number and percentage of participants with AEs in 


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different categories (eg, causally related, CTCAE Grade ≥3, etc) will be summarised by dose 
regimen; events in each category will be further summarised by MedDRA SOC and preferred 
term. Serious adverse events will be summarised separately, if a sufficient number occurs.
Adverse event summary tables will include only treatment-emergent AEs. Adverse events will 
be defined as treatment-emergent if they have an onset or worsen (by Investigator report of a 
change in intensity) during the study treatment or the safety follow-up period (defined as 
90 days after last dose of study treatment) but prior to subsequent anti-cancer therapy. Adverse 
events occurring outside this period will only be listed.
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. Based on
the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered OAEs and reported as 
such in the CSR. A similar review of laboratory/vital signs (pulse and BP)/ECG data will be 
performed for identification of OAEs. Examples of these could be marked haematological and 
other laboratory abnormalities, and certain events that lead to intervention (other than those 
already classified as serious), dose reduction, or significant additional treatment.
Duration of exposure will be summarised.
All safety data including clinical chemistry, haematology, coagulation, urinalysis, vital signs, 
and ECG data will be listed individually by participant and appropriately summarised. For all 
laboratory variables that 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 appropriate. Dose-limiting toxicities will be displayed in a 
listing.
9.4.3
Efficacy Analyses
The efficacy endpoints for tumour response (ORR, DCR at 15 weeks, DoR, and percentage 
change in tumour size) will be summarised for the Response Evaluable Population using 
RECIST v1.1 by Investigator assessment. The efficacy endpoints of PFS and OS will be 
summarised on the Safety Population.
Additional subgroup analysis of efficacy may be performed as specified in the SAP.
The RECIST tumour response data will be used to programmatically determine each 
participant’s visit response and derive the endpoints ORR, DoR, DCR at 15 weeks, percentage 
change in tumour size, and PFS. 


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Best Overall Response
The BoR is calculated based on the overall visit responses from each RECIST assessment. It 
is the best response a participant has following start of treatment but prior to starting any 
subsequent cancer therapy and up to and including RECIST progression or the last evaluable 
assessment in the absence of RECIST progression. Categorisation of BoR will be based on 
RECIST using the following response categories: CR, PR, SD, progressive disease, and NE. 
Objective Response Rate
The ORR is defined as the percentage of participants with a confirmed CR or PR, with the 
denominator defined as the number of participants in the Response Evaluable Population. 
Objective response rate and its 90% CIs (Clopper Pearson method; Clopper et al, 1934) will 
be summarised.
Duration of Response
The DoR is defined as the time from the date of first documented response (which is 
subsequently confirmed) until the date of documented progression or death in the absence of 
disease progression. The time of the initial response will be defined as the latest of the dates 
contributing towards the first visit that was CR or PR that was subsequently confirmed. 
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 RECIST assessment.
It will be summarised using descriptive statistics and Kaplan-Meier plots, where there are 
sufficient numbers of responders.
Disease Control Rate at 15 Weeks 
The DCR at 15 weeks is defined as the percentage of participants who have a BoR of CR or 
PR in the first 16 weeks (to allow for late assessment within the assessment window) or who 
have SD for at least 14 weeks after the start of treatment (to allow for early assessment within 
the assessment window). The DCR and its 90% CIs (Clopper Pearson method; Clopper et al, 
1934) will be summarised.
Percentage Change in Tumour Size
The percentage change in TL tumour size from baseline will be summarised using descriptive 
statistics by timepoint. Best percentage change will also be summarised.
Waterfall plots showing the percentage change at 15 weeks and the best percentage change 
from baseline in sum of the diameters of TLs will be produced. Spider plots showing the 
percentage change from baseline in tumour size for each participant over time will be 
produced.


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Progression-free Survival
The PFS is defined as the time from the start of study intervention until the date of objective 
disease progression or death (by any cause in the absence of progression), regardless of 
whether the participant withdraws from study intervention 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 
RECIST assessment.
The PFS time will always be derived, based on scan/assessment dates, not visit dates.
The RECIST 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 participants for PFS, the participant will be censored at the latest of the 
dates contributing to a particular overall visit assessment.
Progression-free survival will be summarised descriptively, and Kaplan-Meier plots will be 
provided.
Overall Survival
Overall survival is defined as the time from the start of treatment until death due to any cause. 
Any participant not known to have died at the time of analysis will be censored based on the 
last recorded date on which the participant was known to be alive.
Overall survival will be summarised descriptively, and Kaplan-Meier plots will be provided.
Change in ctDNA
Percentage change in ctDNA from baseline to each post baseline timepoint as well as the 
maximum change will be analysed descriptively on the Safety Population.
9.4.4
Other Analyses 
9.4.4.1
Immunogenicity, Pharmacokinetics and Pharmacodynamics
The PK analysis of the serum data for AZD8853 will be performed on the PK Population. The 
actual sampling times will be used in the parameter calculations and the PK parameters will be 
derived using standard non-compartmental methods, if the data permits. It is anticipated that 
Cmax, AUC, and other PK parameters will be calculated if the data allows. 
Relevant descriptive statistics will be used to summarise PK parameters and concentrations. In 
addition, population PK modelling may be conducted and reported separately.


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Immunogenicity results will be analysed descriptively on the Immunogenicity Population by 
summarising the number and percentage of participants who develop detectable ADAs against 
AZD8853 at protocol-specified timepoints. The immunogenicity titre may be reported for 
samples confirmed positive for the presence of ADAs. The effect of immunogenicity on PK, 
efficacy, and safety may be evaluated, if the data allow. 
Refer to the relevant Substudy for information on PD analyses. Further details on the analysis 
of immunogenicity, PK and PD will be provided in the SAP.
9.5
Interim Analyses 
Interim analyses will be conducted separately for each Substudy and are described in the 
relevant Substudy.
9.6
Safety Review Committee
A study-specific SRC will be responsible for making dose-escalation or dose de-escalation 
decisions and recommendations regarding further conduct of the study, during all parts of the 
study. The SRC will provide ongoing safety surveillance of the study, with regularly 
scheduled reviews of safety and other relevant data to monitor the ongoing safety profile of 
the study intervention. 
The SRC may also meet to review data at other timepoints (eg, in response to AEs assessed as 
medically relevant by the Study Physician). The SRC will review the totality of the AE, SAE, 
and laboratory safety data from a minimum of 3 participants who have completed the 21-day 
DLT period, and all relevant available data, including PK, prior to adjudicating on 
dose‑escalation/de-escalation decisions based on the dose-escalation rules. For each dose 
cohort, every effort will be made to have all available PK data to the SRC at the time of the 
dose escalation decision. All decisions by the SRC will be documented and shared with all 
participating sites in writing. The SRC will be composed of Sponsor representatives and 
Investigators. The composition and procedures of the SRC will be fully described in the SRC 
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10.1.2
Schedule of Activities
Table 12
Schedule of Activities - Screening
Study Period
Screening
Details in Section
Visit Number
V1
Procedure/Study Day
Days -28 to -1 a
Screening informed consent (Main Study)
X
10.5,
Appendix A 3
Assignment of participant identification number (PID / E-Code) in IRT
X
6.3
Metformin Use History, including date of last dose
X
5.2, Table 8
X
8.8
Confirm eligibility for enrolment in Main Study 
X
10.5.1; 10.5.2
Medical and Disease History
Demographics
X
8.2.1
Medical/surgical history, including smoking history
X
8.2.1
Disease history and characteristics, including biomarkers and 
X
8.2.1
Prior cancer treatment, including surgeries, radiotherapy, and systemic therapy
X
8.2.1
Disease Assessments
Disease assessment by RECIST v1.1 and SMI assessment b
X c
10.8.1
CT or MRI, Brain (Required for NSCLC participants, participants with known brain metastasis, and as 
clinically indicated for other participants)
X c
10.8.1
Study Procedures and Examinations
Physical examination, including assessment of appetite 
X
8.2.1
ECOG performance status
X
8.2.2
Vital signs, including weight
X
8.2.3
Height
X
8.2.1
Local 12-lead ECG (triplicate)
X
8.2.4
Assessment of AEs/SAEs
X
8.3
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Study Period
Screening
Details in Section
Visit Number
V1
Procedure/Study Day
Days -28 to -1 a
Concomitant medications
X
6.5
Safety Laboratories
Clinical chemistry
X
8.2.5
HbA1c
X
8.2.5
Thyroid function tests (TSH, free T4, free T3)
X
8.2.5
Haematology
X
8.2.5
Urinalysis
X
8.2.5
Serum pregnancy test (WOCBP)
X
8.2.5
Coagulation parameters (PT/aPTT/INR/d-dimer/fibrinogen)
X
8.2.5
Virology (Hepatitis A, B, and C, HIV-1 and HIV-2) d
X
8.2.5
Biomarker Evaluations
 
X
10.8.6.2
Part A/C: 
e
X
10.8.6.1.2
Part B: Mandatory paired biopsy e
X
10.8.6.1.1
Serum for GDF15 target engagement
X
10.8.5.3.1
Whole blood for 
 (refrigerated)
X
10.8.6.4
Whole blood for flow cytometry
X
10.8.6.5
Whole blood for 
X
10.8.6.3
X
10.8.6.7
X
10.8.6.7
Plasma for circulating tumour DNA
X
10.8.6.6
Part B only: CD8+ PET (select and validated sites only)
CD8+ PET tracer administration
X f
Appendix I
Whole body PET scan
X f
Appendix I
a
The screening period may last no longer than 28 days from Cycle 1 Day 1. 
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b
To include CT or MRI slices through T12 and L3.
c
Previous scans for baseline disease and brain imaging that were performed within 4 weeks of dosing and meet the protocol requirements do not need to be repeated.
d
Participants with active hepatitis A, active hepatitis B, or active hepatitis C are excluded; however, participants who have chronic hepatitis B or hepatitis C receiving 
suppressive antiviral therapy are allowed to be enrolled if ALT is normal and viral load is controlled. Controlled hepatitis B viral load is defined as serum hepatitis B virus 
DNA < 2000 IU/mL by PCR. Controlled hepatitis C viral load is defined as undetectable hepatitis C RNA by PCR either spontaneously or in response to a successful prior 
course of anti-hepatitis C therapy. NOTE: Participants with controlled hepatitis B viral load must remain on antiviral therapy, per institutional practice, to ensure adequate 
viral suppression during the study treatment and follow-up period.
e
Fresh paired biopsy samples will be taken as specified in all mandatory paired biopsy cohorts in Parts B but are optional for all other participants. 
 
. If they are taken during screening they will not need to be taken for Cycle 1 
Day 1 pre-dose.
f
Whole body PET imaging to occur before the initial dosing of study intervention (≤ 14 day) on Cycle 1 Day 1. Imaging to be done only after the participant’s eligibility for 
the study has been confirmed. PET imaging must be before pre-treatment biopsy. CD8+ PET Tracer [89Zirconium (Zr)-deferoxamine (Df)-crefmirlimab] to be ordered at 
least 72 hours before administration and PET imaging appointments should be booked accordingly. Tracer to be administered preferably 24 (±3) hours but not more than 
72 hours prior to whole body PET imaging. The duration between administration of the tracer and the PET scan should be the same at screening and at Day 29. If a 
participant holds or discontinues study treatment prior to Day 29, if able, the participant should still perform the PET scan as scheduled.
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; CD8 = cluster of differentiation 8; CT = computed 
tomography; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; GDF15 = growth differentiation factor 15; 
HbA1c = haemoglobin A1c; HIV = human immunodeficiency virus; IRT = interactive response technology system; INR = international normalised ratio; MRI = magnetic 
resonance imaging; NSCLC = non-small-cell lung carcinoma; 
 cell; PET = positron emission tomography; PT = prothrombin time; 
PID = participant identification number; RECIST = response evaluation criteria in solid tumours; RNA = ribonucleic acid; SAE = serious adverse event; T3 = triiodothyronine; 
T4 = thyroxine; TSH = thyroid-stimulating hormone; V = visit; WOCBP = woman of childbearing potential.
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Table 13
Schedule of Activities – Study Visits
Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13-Vn
Details
in
Section
Procedure/Study 
Day
D1
Pre-
Dose
D1
Post-
Dose
D2
D8
D15
D22
D29
D36
D43
D64
D85
D106
D127+
Q3W
Week
1
1
1
2
3
4
5
6
7
10
13
16
19+
Cycle Number 
and
Cycle Day a
C1D1
b
C1D1
C1D2
C1D8
(±1D)
C1D15
(±1D)
C2D1
(±1D)
C2D8
(±1D)
C2
D15
(±1D)
C3D1
(±3D)
C4D1
(±3D)
C5D1
(±3D)
C6D1
(±3D)
C7D1-CnD1
(±3D)
Eligibility
Confirm 
eligibility for 
enrolment in Main 
Study
X
10.5.1; 
10.5.2
Study Procedures and Examinations
Physical 
examination, 
including appetite 
assessment
X
X
X
X
X c
X c
X
X
X
X
X
8.2.1
Local 12-lead 
ECG
X
X
X
X
X
Q12W
10.8.2.1
Table 17
Vital signs, 
including body 
weight
X
X d
X
X
X
X c
X c
X
X
X
X
X
8.2.3
ECOG 
Performance 
Status
X
X
X
X
X c
X c
X
X
X
X
X
8.2.2
Assessment of 
AEs/SAEs
X
X
X
X
X
X
X c
X c
X
X
X
X
X
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Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13-Vn
Details
in
Section
Procedure/Study 
Day
D1
Pre-
Dose
D1
Post-
Dose
D2
D8
D15
D22
D29
D36
D43
D64
D85
D106
D127+
Q3W
Week
1
1
1
2
3
4
5
6
7
10
13
16
19+
Cycle Number 
and
Cycle Day a
C1D1
b
C1D1
C1D2
C1D8
(±1D)
C1D15
(±1D)
C2D1
(±1D)
C2D8
(±1D)
C2
D15
(±1D)
C3D1
(±3D)
C4D1
(±3D)
C5D1
(±3D)
C6D1
(±3D)
C7D1-CnD1
(±3D)
Concomitant 
medications
X
X
X
X
X
X c
X c
X
X
X
X
X
6.5
Disease Assessments
Disease 
assessment by 
RECIST v1.1 and 
SMI assessment e
X
W6 D1-D7
X f
W15
D1-D7
W24±6D then 
Q9W±6D until 
W52, then 
Q12W±6D
10.8.1
CT or MRI, Brain 
(required for 
participants with 
known brain 
metastasis and as 
clinically 
indicated for other 
participants)
X
W6 D1-D7
X f
W15
D1-D7
W24±6D then 
Q9W±6D until 
W52, then 
Q12W±6D
10.8.1
Safety Laboratories
Clinical chemistry
b
X
X
X
X
X
X
X
X
X
8.2.5
HbA1c
X
X
Q12W
8.2.5
Thyroid function 
(TSH, free T4, 
free T3) b, i
X
X
X
X
X
X
X
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Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13-Vn
Details
in
Section
Procedure/Study 
Day
D1
Pre-
Dose
D1
Post-
Dose
D2
D8
D15
D22
D29
D36
D43
D64
D85
D106
D127+
Q3W
Week
1
1
1
2
3
4
5
6
7
10
13
16
19+
Cycle Number 
and
Cycle Day a
C1D1
b
C1D1
C1D2
C1D8
(±1D)
C1D15
(±1D)
C2D1
(±1D)
C2D8
(±1D)
C2
D15
(±1D)
C3D1
(±3D)
C4D1
(±3D)
C5D1
(±3D)
C6D1
(±3D)
C7D1-CnD1
(±3D)
Haematology b
X
X
X
X
X
X
X
X
X
8.2.5
Urinalysis b
X
X
X
X
X
X
X
8.2.5
Pregnancy test 
(WOCBP Only) j
X
X
X
X
X
X
X
8.2.5
Coagulation 
parameters 
(PT/aPTT/INR/d-
Dimer/fibrinogen)
b
X
X
X
X
X
X
X
X
X
8.2.5
Virology 
(Hepatitis B 
and C) k
X
Q12W
8.2.5
Biomarker Evaluations g
Part A/C: 
 
X l
X m
X m
10.8.6.1.2
Part B: Mandatory 
paired biopsy
X l
X m
X m
10.8.6.1.1
Serum for GDF15 
target engagement
X
X
X
X
X
X
X n
X
X
X
X
10.8.5.3.1, 
Table 20
Whole blood for 
 
(refrigerated)
X
X n
On 
progression
10.8.6.4
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Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13-Vn
Details
in
Section
Procedure/Study 
Day
D1
Pre-
Dose
D1
Post-
Dose
D2
D8
D15
D22
D29
D36
D43
D64
D85
D106
D127+
Q3W
Week
1
1
1
2
3
4
5
6
7
10
13
16
19+
Cycle Number 
and
Cycle Day a
C1D1
b
C1D1
C1D2
C1D8
(±1D)
C1D15
(±1D)
C2D1
(±1D)
C2D8
(±1D)
C2
D15
(±1D)
C3D1
(±3D)
C4D1
(±3D)
C5D1
(±3D)
C6D1
(±3D)
C7D1-CnD1
(±3D)
Whole blood for 
flow cytometry
X
X
X
X n
X
X
X
On 
progression
10.8.6.5
 
 
X
X
X
X n
X
On 
progression
10.8.6.3
 
X
X
X
X n
X
X
X
On 
progression
10.8.6.7
 
X
X
X
X n
X
X
X
On 
progression
10.8.6.7
Plasma for 
circulating tumour 
DNA
X
X
X
X n
X
X
X
On 
progression
10.8.6.6
 
 
h
X
8.7
PK and Immunogenicity
Part A: AZD8853 
PK
X
X
X
X
X
X
X n
X
X
X
X
10.8.5.1; 
Table 18
All Parts: 
AZD8853 ADA
X g
X g
X g
X g
X g Q12W
10.8.5.2; 
Table 19
Part B: AZD8853 
PK
X
X
X
X
X
X
X
X
X
X
10.8.5.1; 
Table 18
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Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13-Vn
Details
in
Section
Procedure/Study 
Day
D1
Pre-
Dose
D1
Post-
Dose
D2
D8
D15
D22
D29
D36
D43
D64
D85
D106
D127+
Q3W
Week
1
1
1
2
3
4
5
6
7
10
13
16
19+
Cycle Number 
and
Cycle Day a
C1D1
b
C1D1
C1D2
C1D8
(±1D)
C1D15
(±1D)
C2D1
(±1D)
C2D8
(±1D)
C2
D15
(±1D)
C3D1
(±3D)
C4D1
(±3D)
C5D1
(±3D)
C6D1
(±3D)
C7D1-CnD1
(±3D)
Part C: AZD8853 
PK
X
X
X
X
X
X
X
10.8.5.1; 
Table 18
Study Treatment Administration
AZD8853 
administration 
(Q3W)
X
X
X
X
X
X
Q3W
6.1
Part B only: CD8+ PET (select and validated sites only)
CD8+ PET Tracer 
Administration
X o
Appendix
I
Whole body PET 
scan
X o
Appendix
I
a
Any timing of safety assessment visit is relative to the day of most recent dosing (Day 1 of the latest cycle).
b
If screening assessments have been performed within the 72 hours prior to Day 1, then the assessment does not need to be performed pre-dose on Day 1. All safety laboratory 
results must be reviewed by the Investigator or physician designee prior to administration of the scheduled dose of study intervention. Pregnancy testing for WOCBP is 
required on all days of dosing.
c
For Part A only.
d
Weight on Day 1 post-dose is not needed.
e
To include CT or MRI slices through T12 and L3. Any timing of tumour assessment visit is relative to Cycle 1 Day 1.
f
Disease assessment should be performed on the week prior to next assessment cycle, always prior to dosing.
g
All collections must be pre-dose unless specified otherwise.
h
Sample can be taken at any point during study.
i
Free T4 and T3 measured if TSH is abnormal or if clinical suspicion of an AE related to the endocrine system.
j
A urine or serum pregnancy test is acceptable; if urine test is equivocal or positive then serum β-hCG testing should be performed for confirmation.
k
Required for participants with a history of hepatitis B or hepatitis C.


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l
Fresh paired biopsy samples will be taken as specified in all mandatory paired biopsy cohorts in Parts B but are optional for all other participants. 
 
. If they are taken during screening they will not need to be taken for Cycle 1 
Day 1 pre-dose.
m
The second paired biopsy sample should be collected on Cycle 2 Day 8 (±  days relative to Cycle 2 Day 8). For participants who are in the CD8+ PET cohort, the first and 
second biopsy should be taken within 
 hours after the first and second CD8+ PET scan, respectively. This second biopsy must still be collected if not done within the 
time windows described. 
n
To be taken at time of second paired biopsy.
o
Whole body PET imaging to occur before the initial dosing of study intervention (≤ 14 day) on Cycle 1 Day 1. Imaging to be done only after the participant’s eligibility for 
the study has been confirmed. PET imaging must be before pre-treatment biopsy. CD8+ PET Tracer [89Zirconium (Zr)-deferoxamine (Df)-crefmirlimab] to be ordered at 
least 72 hours before administration and PET imaging appointments should be booked accordingly. Tracer to be administered preferably 24 (±3) hours but not more than 
72 hours prior to whole body PET imaging. The duration between administration of the tracer and the PET scan should be the same at screening and at Day 29. If a 
participant holds or discontinues treatment prior to Day 29, if able, the participant should still have the PET scan as scheduled.
Abbreviations: ADA = antidrug antibody; AE = adverse event; CR = complete response; CT= computed tomography; D = Day; DNA= deoxyribonucleic acid; 
ECG = electrocardiogram; ECOG = eastern cooperative oncology group; EOT = end of treatment; GDF15 = growth differentiation factor 15; HbA1c = haemoglobin A1c; 
MRI = magnetic resonance imaging; n = visit number; NSCLC = non-small-cell lung cancer; 
; PK = pharmacokinetic; PR = partial 
response; Q3W = every 3 weeks; Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; Q26W = every 26 weeks; RNA = ribonucleic acid; RECIST = response 
evaluation criteria in solid tumours; SAE = serious adverse event; SD = stable disease; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; V = visit; 
WOCBP = woman of childbearing potential.
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Table 14
Schedule of Activities – End of Treatment
Study Period
EOT
Follow-up Post EOT
LTFU
Details in 
Section
Procedure/Study Day
Day 30
(± 7 days)
Day 90
(± 7 days)
Q12W Post 
Day 90 Visit
Post EOT
Post Last Dose
Study Procedures and Examinations
Physical examination, including appetite assessment
X
X
X
8.2.1
ECOG performance status
X
X
X
8.2.2
Local 12-lead ECG (triplicate) 
X
8.2.4
Vital signs, including body weight
X
X
X
8.2.3
Assessment of AEs/SAEs
X
X
X
8.3
Concomitant medications
X
X
X
6.5
Disease Assessments
Disease assessment by RECIST v1.1 and SMI assessment a
X b
X c
X c
10.8.1
CT or MRI, brain (Required for participants with known brain metastasis and 
as clinically indicated for other participants)
X b
X c
X c
10.8.1
Safety Laboratories
Clinical chemistry
X
X
8.2.5
Haematology
X
X
8.2.5
HbA1c
X
X
8.2.5
Thyroid function tests (TSH, free T4, free T3) d
X
X
8.2.5
Urinalysis
X
X
8.2.5
Coagulation parameters (PT/aPTT/INR/d-Dimer/Fibrinogen)
X
X
8.2.5
Pregnancy test (WOCBP) e
X
X
X
8.2.5
Virology (Hepatitis B and C) f
X
8.2.5
Biomarker Evaluations
Collect on 
progression
10.8.6.1.3
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Study Period
EOT
Follow-up Post EOT
LTFU
Details in 
Section
Procedure/Study Day
Day 30
(± 7 days)
Day 90
(± 7 days)
Q12W Post 
Day 90 Visit
Post EOT
Post Last Dose
Serum for GDF15 target engagement
X
X
X
10.8.5.3.1
Whole blood for 
 (refrigerated)
X
X
X
10.8.6.4
Whole blood for flow cytometry
X
X
X
10.8.6.5
X
X
X
10.8.6.3
X
X
X
10.8.6.7
X
X
X
10.8.6.7
Plasma for circulating tumour DNA
X
X
X
10.8.6.6
PK and Immunogenicity
Parts A, B and C: AZD8853 PK
X
10.8.5.1
Table 18
AZD8853 ADA
X
X
X
10.8.5.2
Table 19
EOT and Follow-up Assessment
Subsequent anti-cancer therapy
X
X
X
X
8.2.8
Survival status (by telephone, email, or clinic visit)
X
X
X 
X
8.2.8
a
To include CT or MRI slices through T12 and L3.
b
If CT or MRI scan for disease assessment is performed ≤ 14 days prior to the EOT visit, it will not be required at EOT visit.
c
Will not be performed if previously confirmed disease progression has been documented.
d
Free T4 and T3 measured if TSH is abnormal or if clinical suspicion of an AE related to the endocrine system.
e
A urine or serum pregnancy test is acceptable; if urine test is equivocal or positive then serum β-hCG testing should be performed for confirmation.
f
Required for participants with a history of hepatitis B or hepatitis C.
Abbreviations: ADA = antidrug antibody; AE = adverse event; aPTT = activated partial thromboplastin time; CT = computerized tomography; DNA = deoxyribonucleic acid; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; GDF15 = growth differentiation factor 15; INR = international normalised 
ratio; LTFU = long Term Follow-up; MRI = magnetic resonance imaging; NSCLC = non-small-cell lung cancer; 
; 
PK = pharmacokinetics; PT = prothrombin time; Q12W = every 12 weeks; RNA = ribonucleic acid; RECIST = Response Evaluation Criteria in Solid Tumours; SAE = serious 
adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = woman of childbearing potential.
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Participants will be followed until either death, loss to follow-up, withdrawal of consent or 
end of study. This Substudy of the study will comprise of 3 main parts (Figure 3), as follows:
Part A: Dose Escalation
The dose-escalation part of the study may enrol up to 45 participants (assuming up to 5 dosing 
cohorts and 3-9 participants per cohort) with selected advanced/metastatic solid tumours 
(NSCLC, MSS-CRC and UC). AZD8853 will be administered as monotherapy at the selected 
dose by i.v. infusion on a Q3W schedule. All participants will be treated until progressive 
disease, unacceptable toxicity, or withdrawal of consent.
See Section 10.6.6.1 for the starting dose, dose escalation and stopping criteria.
Part B: PD/MoA Expansion
Dose levels that are deemed safe in Part A of the study and have shown preliminary evidence 
of circulating free GDF15 reduction can be expanded in this PD/MoA expansion part of the 
study which will enrol up to approximately 20 participants with NSCLC and 20 participants 
with MSS-CRC advanced/metastatic solid tumours into 2 dose expansions (Part B1 and 
Part B2; approximately 10 NSCLC and 10 MSS-CRC participants in each part).
See Section 10.6.7 for details on PD/MoA expansion.
Mandatory archival, pre- and on-treatment tumour biopsies, serum GDF15 samples, and other 
samples including PK for each participant will be required at pre-specified timepoints. 
Pre- and on-treatment CD8+ PET imaging will be performed to assess PD response. Up to
10 participants in Part B1 and up to 10 participants in Part B2 will be enrolled with evaluable 
data from paired biopsies. Data from Part A and Part B of this Substudy of the study will 
inform tumour types and dose levels most suitable to progress onto an efficacy expansion part.
The RP2D will be defined based on an updated PK/PD and safety analysis using data 
generated from both Part A and Part B of the study.
Cluster of Differentiation (CD)8+ Positron Emission Tomography (PET) Imaging 
In Part B of the study, selected sites will use CD8+ PET imaging in combination with 
mandatory paired biopsies to monitor changes in CD8 T cell infiltration following treatment,
to evaluate the correlation between the CD8 immune infiltrate present by IHC of biopsies with 
in vivo CD8 T cell localization by PET imaging using a 89Zirconium (Zr)-deferoxamine (Df)-
crefmirlimab. 
Selected sites will recruit approximately up to 20 participants combined in Parts B1 and B2, 
across MSS-CRC and NSCLC study participants. These selected sites should prioritize 
recruitment to the CD8+ PET cohort of Part B prior to enrolling to non-CD8+ PET slots.
For further details on the CD8+ PET imaging, refer to Appendix I. 


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Part C: Efficacy Expansion
The efficacy expansion parts of the study will enrol up to approximately 40 participants in 
each expansion (Part C1 and Part C2). Relevant participants from Part B will count towards 
Part C efficacy expansions. These expansions may open either in parallel or sequentially at the 
Sponsor’s discretion.
See Section 10.6.7 for details on efficacy expansion.
Mandatory pre- and on-treatment serum GDF15 samples and other samples including PK will 
be required. Archival of FFPE tissue is mandatory for all participants. Fresh pre- and 
on-treatment biopsies at pre-specified timepoints are 
 in this part of the study.
10.4.2
Substudy 1 Justification for Dose
A starting dose of 300 mg is proposed for AZD8853. The selection of the dose was based on 
the observed toxicology data from the cynomolgus monkey and a population PK model.
The HNSTD in non-human primate was estimated to be 
 mg/kg following 
 weekly 
doses with no toxicity concerns. Following AZD8853 administration, 100% reduction in 
serum GDF15 was observed with no apparent toxicity in animals. No changes in 
immunophenotyping and cytokine amounts were seen in the cynomolgus toxicology study. 
The observed Cmax and AUC(0-168) at 
 mg/kg in cynomolgus monkey was 
 µg/mL
and 
 µg*h/mL. Based on FDA Guidance for Industry: S9 Nonclinical Evaluation for 
anti-cancer Pharmaceuticals a starting dose was calculated. 
 of the HNSTD was 
mg/m2, or a human equivalent dose of 
 mg/kg. For a 
 kg patient, this would equate 
to a 
 mg dose. An additional safety margin of 
-fold was applied to allow for a starting 
dose of 300 mg.
A population PK model was developed based on available PK and GDF15 data from 
cynomolgus monkeys. An allometric scaling, with an exponent of 0.85 for clearances and 1 
for volume of distributions was applied to translate relevant PK parameters from animals to 
humans. A target turnover model was used to predict the percentage decrease in free GDF15 
in serum (Lowe et al, 2009; Davda et al, 2010). At the proposed starting dose of 300 mg, the
predicted Cmax and AUC(0-168hr) in human were 
µg/mL and 
µg*hr/mL. Therefore a 
-fold safety margin on Cmax and 
-fold safety margin on AUC(0-168hr) is predicted. 
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At the proposed starting dose of 300 mg the model predicted a reduction of GDF15 at Cmax 
and Ctrough of
% and 
% respectively. Doses of 1000 and 3000 mg are expected to reduce 
free GDF15 levels by 
% and 
%, respectively at Ctrough. A dose of 3000 mg is expected to 
have 
-fold safety margins on Cmax and 
-fold safety margins on AUC(0-168hr). Although a 
relatively high suppression of GDF15 is expected at Cmax, the levels of GDF15 are expected 
to recover rapidly given the fast turnover of GDF15 in humans (3 hours [Xiong et al, 2017], or 
24 minutes from cynomolgus monkeys). In addition, AZD8853 is not a T cell agonist or an 
innate immune agonist and GDF15 suppression is not expected to cause cascading 
immune-stimulatory effects. A cytokine release assay was not conducted as GDF15 is a 
soluble factor and is not expected to cause cross-linking of immune cells. No changes in 
immunophenotyping or cytokine analysis were seen during the 3-month cynomolgus 
toxicology study [Three Month Intravenous Toxicity Study Two Month Assessment of 
Recovery in the Cynomolgus Monkey (8447292)]. 
Overall given that AZD8853 has a clear safety profile in toxicological studies, relatively high 
safety margins based on both absolute dose and predicted human exposure and is not expected 
to cause cascading immune-stimulatory effects, a 300 mg dose is proposed as a first-in-human 
dose.
10.4.3
End of Substudy 1 Definition
The end of Substudy 1 is defined as the last scheduled visit or contact of the last participant 
enrolled in the Substudy.
10.5
Substudy 1 Population
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Main Consent
Informed consent must be obtained prior to any study specific assessments. After the 
participant signs the ICF, a participant enrolment number will be assigned.
Based on study design as outlined in Section 10.4.1, participants will be enrolled in the study. 
The main ICF for participants in this Substudy will include consent (mandatory and optional) 
for all biomarker samples as outlined in the SoA (Table 12, Table 13, and Table 14).
10.5.1
Substudy 1 Inclusion Criteria
In addition to the master study inclusion criteria listed in Section 5.1, participants are eligible 
to be included in this Substudy only if the further Substudy 1 criteria below also apply:
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1
Histologically or cytologically documented unresectable, locally advanced (Stage III) or 
metastatic (Stage IV) NSCLC, metastatic (Stage IV) MSS-CRC or metastatic (Stage IV) 
UC.
2
Participants must meet all of the tumour-specific criteria below, with documented 
progression from previous therapy at study entry. Interval progression between 2 lines of 
therapy defines separate lines of therapy. Both standard and investigational treatments will 
count as lines of therapy when determining eligibility.
(a) Participants with NSCLC must:
i.
Have received at least one prior line of systemic therapy in the 
advanced/metastatic setting.
ii.
Have received at least one prior line of therapy which contained an anti-PD-
1/PD-L1 agent, with or without platinum-based chemotherapy.
iii.
Have documented test results for:
•
Sensitizing EGFR mutations and ALK fusions/rearrangements
•
Other genomic alterations which are part of a local standard of care and for 
which a locally approved standard of care targeted therapy exists (such as 
ROS proto-oncogene 1 [ROS1] fusions/rearrangements, neurotrophic receptor 
tyrosine kinase (NTRK) fusions, RET fusions/rearrangements, MET exon 14 
skipping mutations, BRAF V600E mutation, etc.). 
iv.
Have received targeted therapy according to the identified genomic alteration. 
Targeted therapy is not mandatory if it is not in the local standard of care, or if it 
is refused by the participant or contraindicated.
v.
For Parts B and C: PD/MoA and Efficacy Expansions:
No sensitizing EGFR mutations or ALK fusions/rearrangements (documented 
test result is mandatory).
(b) Participants with MSS-CRC:
i.
Must have documented MSS by local testing (genetic analysis or 
immunohistochemistry).
ii.
Must have received at least 2 prior lines of systemic therapy for 
advanced/metastatic disease.
•
Prior systemic therapies must include fluoropyrimidines, irinotecan and 
oxaliplatin, unless refused or contraindicated. Participants may or may not 
have received a vascular endothelial growth factor (VEGF) agent 
(eg, bevacizumab), a BRAF inhibitor and an EGFR therapy (eg, cetuximab or 
panitumumab), according to local standard or care.
iii.
Participants who have withdrawn from standard treatment due to unacceptable 
toxicity warranting discontinuation of treatment and precluding retreatment with 
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iv.
Participants who had received adjuvant chemotherapy and had recurrence during 
or within 6 months of completion of the adjuvant chemotherapy are allowed to 
count the adjuvant therapy as one prior line of chemotherapy.
(c) Participants with UC must:
i.
Have histological confirmation of unresectable, locally advanced or metastatic
UC (including any of the following: renal pelvis, ureters, urinary bladder, and/or 
urethra). Histological confirmation at initial diagnosis is acceptable. Participants 
must have received at least one prior line of systemic therapy including prior 
platinum-containing regimen and/or a checkpoint inhibitor therapy with 
anti-PD-1 or anti-PD-L1.
3
Participation in a clinical trial is determined to be the best option for next treatment based 
on prior response and/ or tolerability to standard of care in the opinion of the Investigator. 
4
Participants must provide archival tumour tissue (FFPE block or unstained slides if a block 
cannot be provisioned). Refer to Section 10.8.6.2 and the Laboratory Manual for 
additional details.
Part B only:
5
All participants must be willing to provide mandatory paired biopsies (pre and 
on-treatment biopsies). The biopsied lesion must be distinct from any lesion used in the 
RECIST v1.1 evaluation.
6
CD8+ PET Cohort Only: Participants must have at least one non-liver lesion, suitable for 
PET imaging and be willing to be assessed with CD8+ PET imaging at screening 
(pre-treatment) and designated on treatment timepoints.
10.5.2
Substudy 1 Exclusion Criteria 
In addition to the master study exclusion criteria listed in Section 5.2, participants are 
excluded from this Substudy if any of the further Substudy 1 criteria below also apply:
1. Participants who have received prior immunotherapy with anti-PD-1, anti-PD-L1, or 
anti-CTLA-4:
a) Must not have experienced a toxicity that led to permanent discontinuation of prior 
immunotherapy.
b) All AEs while receiving prior immunotherapy must have completely resolved or 
resolved to baseline prior to screening for this study.
c) Must not have experienced a ≥ Grade 3 imAE or a neurologic or ocular imAE of any 
grade while receiving prior immunotherapy. Note: Participants with an endocrine AE 
of ≤ Grade 2 are permitted to enrol if they are stably maintained on appropriate 
replacement therapy and are asymptomatic.


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d) Must not have required the use of additional immunosuppression other than 
corticosteroids for the management of an AE, not have experienced recurrence of an 
AE if re-challenged, and not currently require maintenance doses of > 10 mg 
prednisone or equivalent per day.
2. Participants with spinal cord compression or history of leptomeningeal carcinomatosis.
3. Participants with brain metastases unless treated, asymptomatic, stable, and not requiring 
continuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for at least 
4 weeks prior to the start of the study.
4.
):
Exclusion criteria for participation in the 
 component of the 
study include:
a)
.
b)
 
.
10.6
Substudy 1 Study Intervention
10.6.1
Study Intervention(s) Administered
10.6.1.1
Investigational Products
Please refer to Section 6.1 for AZD8853 details.
10.6.1.2
Investigational Imaging Agent
Imaging sites will be provided with an investigational imaging agent (Part B only), an 
anti-CD8 minibody (Mb) (Crefmirlimab) conjugated with Df and radiolabelled with Zr-89 
(89Zr-Df-crefmirlimab), for participants in the CD8+ PET imaging cohorts (see Appendix I for 
more details).
10.6.2
Preparation/Handling/Storage/Accountability
Please refer to Section 6.2 for details on preparation/handling/storage/accountability of study 
intervention.
10.6.3
Measures to Minimise Bias: Randomization and Blinding
Please refer to Section 6.3 for details on randomisation and blinding.
10.6.4
Study Intervention Compliance
Please refer to Section 6.4 for details on study intervention compliance.
10.6.5
Concomitant Therapy
Please refer to Section 6.5 for details on concomitant therapy.
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10.6.6
Dose Modification
Discontinuation or withholding of study intervention will be implemented to manage potential 
immune-related and non-immune mediated AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v5.0. Dose reductions are not permitted. For any ≥ Grade 3 
AE that does not meet criteria for treatment discontinuation and whose causal relationship is 
attributable to the IMP, a single scheduled dose of IMP may be skipped (maximum of 
2 non-consecutive doses) to permit resolution and the next dose will be administered on the 
next scheduled date. Omitted doses will not be administered at a later date. If the toxicity does 
not resolve to ≤Grade 1 or baseline by the time of the next scheduled dose after skipping one
dose of IMP (ie, a total of 2 consecutive doses are skipped), the participant will be 
permanently discontinued from treatment.
Potential risks for AZD8853 are expected to be similar to those of other human monoclonal 
immunoglobulins, and include immune-mediated and non-immune-mediated risks. The 
overall dose modifications, are given below:

Grade 1
No dose modification.

Grade 2
Hold study intervention until resolution to Grade ≤ 1 or baseline.
-
If toxicity worsens, then treat as Grade 3 or Grade 4.
-
Study intervention can be resumed once event stabilises to Grade ≤ 1.
-
Consider whether study intervention should be permanently discontinued in Grade 2 
events with high likelihood for morbidity and/or mortality when they do not rapidly 
improve to Grade < 1 upon treatment.

Grade 3
Hold study intervention (see rules for Grade 2 events), or permanently 
discontinue as per AZD8853 TMG.

Grade 4
Permanently discontinue study intervention.
For detailed guidelines on management of toxicities and dose modifications (temporary or 
permanent discontinuation only) refer to AZD8853 TMGs provided to the sites as a separate 
document.
10.6.6.1
Starting Dose, Dose Escalation Scheme and Stopping Criteria
10.6.6.1.1 Starting Dose
The initial dose level of 300 mg is based upon findings from the 3-month GLP toxicology 
study in cynomolgus monkeys and predictions around GDF15 suppression (see Section
10.4.2). The first participant in Cohort 1 must complete 1 week on study post the AZD8853
administration (Cycle 1 Day 1) without any DLTs before additional participants may be
enrolled into the first cohort. A waiting period between additional participants in the cohort is 
not required. 


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10.6.6.1.2 Safety Review Committee
Please refer to Section 9.6 for details on the SRC. 
10.6.6.1.3 Escalation Cohorts
Dose escalation will follow the mTPI-2 algorithm (Guo et al, 2017) as described below. Dose
escalation cohorts will initially enrol 3 to 5 participants per cohort (to ensure at least 
3 evaluable participants for dose-escalation decisions). A minimum of 3 participants must 
complete the DLT-evaluation period before making an escalation decision. A maximum of 
9 participants may be enrolled in each dose-escalation cohort.
1. The MTD will be determined based on assessment of DLT according to the mTPI-2 
algorithm (see Table 16). 
2. A minimum of 3 DLT-evaluable participants are required in each dose level unless 
unacceptable toxicity is encountered in the first 2 participants prior to enrolment of the 
third participant, which would require dose de-escalation per the mTPI-2 design. For a 
dose level that has fewer than 3 participants who are DLT-evaluable, participants will be 
replaced.
3. If a de-escalation decision is made, choice of de-escalation to the previous main dose level 
or an intermediate dose level below will be at the discretion of the SRC. In the eventuality 
that a decision is made to de-escalate back to a dose escalation level that was previously
deemed safe, in which additional participants (Part B1) have since been enrolled at that 
dose level, these participants will now be included in further dose-escalation decisions 
following mTPI-2 rules.
4. If a stay (“S”) decision is made, additional participants will be enrolled up to a maximum 
of 9 participants for a given dose level (typically in groups of 2 to 4 participants).
5. After the sentinel dosing of the first participant in the initial cohort, participants 2 and 3 
dosing will be staggered such that administration of the first dose is separated by at least 
48-hours before the next participant is dosed. In subsequent cohorts, a 48-hour separation 
in first dosing between participants is required for the first 3 participants in each cohort. 
Provided there are no serious or unexplained safety issues after the first 3 participants, as 
determined by the respective treating physician, participants may be enrolled concurrently 
or sequentially for the remainder of the cohort with the Sponsor’s agreement. 
Intra-participant dose escalation will not be allowed.
6. At the discretion of the Sponsor, dose escalation may be stopped before an MTD is 
reached. In this case, the doses for evaluation in the dose-expansion parts (Part B and 
Part C) may be chosen based on an assessment of available PK, PD, safety, or efficacy 
data.
7. The MTD will be determined by isotonic regression analysis applied to DLT rates 
observed during dose escalation using the mTPI-2 method (Guo et al, 2017).


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The mTPI-2 employs a simple beta-binomial Bayesian model. Decision rules are based on 
calculating the UPM of three intervals corresponding to underdosing, proper dosing, and 
overdosing in terms of toxicity. The underdosing interval corresponds to a dose escalation, 
overdosing interval corresponds to a dose de-escalation, and proper dosing interval 
corresponds to staying at the current dose. Given an interval and a probability distribution, the 
UPM of that interval is defined as the probability of the interval divided by the length of the 
interval. The mTPI-2 design calculates the UPMs for the multiple equal toxicity intervals, and 
the one with the largest UPM implies the corresponding dose-finding decision. The design for 
the dose-escalation part of the Substudy 1 uses a target DLT rate of 
% and an equivalence 
interval of (
%, 
%) for dose-escalation/de-escalation decisions as well as MTD 
determination. A dose level will be considered unsafe, with no additional participants enrolled 
at that dose level, if it has an estimated 95% or more probability of exceeding the target DLT 
rate of 
% (ie, P [DLT > 
% data] > 95%) with at least 3 DLT-evaluable participants treated 
and evaluated at that dose level. In Table 16 dose escalation/de-escalation decision rules are 
computed based on the above information. 
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Dose-escalation decisions guided by the mTPI-2 design with the targeted DLT rate =
 and the equivalence 
interval (EI) = (
). The table lists the decisions for up to 9 participants treated at a given dose. The 
column in this table represents the number of participants enrolled at the dose, and the row represents the number 
of DLTs at the same dose. The dose-escalation decisions are as follows: E: Escalate to the next higher dose; S: 
Stay at the current dose; D: De-escalate to the previous lower dose; DU: De-escalate to the previous lower dose 
and marking the current dose and its higher doses as unacceptably toxic so that they will never be used again in 
the remainder of the trial. 
10.6.7
Dose Expansion
Part B
The 2 dose expansion levels will be chosen based on peripheral target engagement and 
non-overlapping PK in order to evaluate intra-tumoural PD activity and help determine the 
RP2D. One dose expansion level will be the MTD/HPDD and one dose expansion level will 
be lower than the MTD/HPDD. Each dose level will enrol approximately 20 participants with 
NSCLC or MSS-CRC (enrolling approximately 10 participants in each tumour type). 
Expansions may open either in parallel or sequentially at Sponsor’s discretion. Expansions 
may start before the MTD/HPDD has been determined.
Part C
The two efficacy expansions will be determined based on emerging data from Part A and/or 
Part B and may include two indications at a single dose level or one indication at two dose 
levels. If the RP2D cannot be adequately determined from Part B and additional data (eg,
efficacy) is required to guide RP2D determination, then two dose levels in one indication will 
be investigated. If the RP2D is determined at the end of Part B, RP2D will be evaluated in 
two indications. Each efficacy expansion will enrol up to approximately 40 participants which 
may include up to 10 participants from the relevant Part B expansion. An interim analysis will 
take place after 20 participants (further details in Section 10.9.5).
10.6.7.1
Treatment Allocation in Dose Expansion Phase
Participants will not be randomised in this study; however, IxRS will be used in all parts of the 
study to ensure participants receive their allocated medication.
10.6.8
Definition of DLT
Dose limiting toxicity includes event(s) which happen during the 21 days of Cycle 1 of Part A
and represent ≥Grade 3 toxicity, as defined below, which is not clearly attributable to the 
disease under investigation, other concomitant medications, disease-related processes under 
investigation, or another non-drug-related aetiology, with modifications or exceptions noted 
below. 
The DLT evaluation period is from the first exposure of AZD8853 until the end of Cycle 1, 
which is 21 days. All DLTs must be documented as AEs, graded according to 
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NCI CTCAE v5.0 and need to be followed until improvement to CTCAE Grade < 1. A 
minimum of at least 3 DLT-evaluable participants are required for the SRC to hold a 
dose-escalation vote.
An AE not listed below, or an AE meeting the DLT criteria below but occurring outside of the 
DLT period may be defined as a DLT-like event after consultation with the Sponsor and 
Investigators based on the emerging safety profile.
The following toxicities constitute a DLT:

Any death not clearly due to the underlying disease or extraneous causes.

Grade 4 adverse events of immune nature (imAE).

Any ≥Grade 3 non-infectious pneumonitis regardless of duration; diagnosis should 
include clinical evaluation, monitoring of oxygenation using pulse oximetry (resting and 
exertion), laboratory workup and high-resolution CT scan.

Any ≥Grade 3 non-infectious colitis irrespective of duration after confirmation by 
colonoscopy and histopathology.

Any Grade 3 imAE, including rash, pruritus, or diarrhoea (NOTE: this excludes colitis or 
pneumonitis, as these AEs are already defined above), that does not downgrade to 
Grade ≤ 2 within 7 days after onset of the event despite maximal supportive care 
including systemic corticosteroids.

Liver transaminase elevation:
i.
Criteria for all participants except participants with elevated transaminases 
(ALT/AST) at baseline/screening due to liver metastasis:

Isolated liver transaminase elevation > 5 × but ≤ 8 × ULN that does not 
downgrade to AST/ALT ≤ 3 x ULN within 14 days after onset with 
optimal medical management.

Isolated liver transaminase elevation > 8 × ULN regardless of duration 
or reversibility.

Any increase in AST or ALT > 3 × ULN and concurrent increase in 
TBL ≥ 2 × ULN, regardless of duration or reversibility, where no other 
reason, other than the study intervention, can be found to explain the 
combination of increases.
ii.
Criteria for participants with elevated transaminases (ALT/AST) at 
baseline/screening due to liver metastasis (inclusion criterion 8):

Isolated liver transaminase elevation > 2 × but ≤ 5 × baseline that does 
not downgrade to < 2 × baseline or less within 14 days after onset with
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
Isolated liver transaminase elevation > 5 × baseline regardless of 
duration or reversibility.

Any increase in AST or ALT > 3 × baseline and concurrent increase in 
TBL ≥ 2 × ULN regardless of duration or reversibility, where no other 
reason, other than the study intervention, can be found to explain the 
combination of increases.

Grade 3 nausea, vomiting, or diarrhoea that does not resolve to Grade ≤ 1 within 3 days of 
initiation of maximal supportive care.

Neutropenia:
i.
≥Grade 3 febrile neutropenia regardless of duration ruling out the cause of fever 
due to non-infections events.
ii.
≥Grade 3 neutropenia, without associated fever or systemic infection, which 
does not improve by at least one grade within 5 days of onset.

Anaemia:
i.
Grade 4 anaemia regardless of duration.
ii.
Grade 3 anaemia that requires more than one transfusion of > 2 units of red 
blood cell.

Thrombocytopenia:
i.
≥Grade 4 thrombocytopenia lasting > 7 days.
ii.
≥Grade 3 thrombocytopenia, regardless of duration, associated with 
haemorrhage.

Thrombocytopenia in presence of anticoagulation therapy:
i.
Thrombocytopenia below Grade 3 lasting for 7 days, without additional risk 
factors. 

Any ≥Grade 3 neurotoxicity (to include but not limited to limbic encephalitis, autonomic 
neuropathy, including peripheral neuromotor syndromes such as myasthenia gravis and 
Guillain-Barré) regardless of duration.

Any ≥Grade 3 cardiotoxicity (to include but not limited to arrhythmias, myocarditis with 
cardiomyopathy, ventricular dysfunction) regardless of duration.

Any ≥Grade 3 ocular toxicity (including but not limited to iritis, uveitis, significant 
vision changes) regardless of duration.

Any other pre-existing toxicity that has worsened as compared to baseline that is 
clinically significant and unacceptable, does not respond to supportive care, results in a 
disruption of dosing schedule of more than 21 days or is judged to be a DLT by the SRC.
The DLT definition excludes the following conditions:


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
Grade ≥ 3 fatigue lasting ≤ 7 days.

Concurrent vitiligo or alopecia of any grade.

Grade 3 or Grade 4 lymphopenia, unless associated with infection.

Grade 3 or higher amylase or lipase that is not associated with symptoms or clinical 
manifestations of pancreatitis, irrespective of duration.

Grade 3 or higher electrolyte abnormality that lasts up to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
interventions.
10.6.9
Definition of maximum tolerated dose
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 decision table. With this constraint, the 
MTD will be determined as the dose level with the DLT estimate closest to the target toxicity 
level of 
%.
In the case of dose levels with estimated toxicity of equal distance (tied dose levels) from the 
target toxicity of 
%, the following approach will be used (Ji et al, 2010): among all tied 
dose levels the highest dose level with target toxicity 
% will be selected, unless all tied 
dose levels have estimated toxicity 
%, in which case the lowest dose level will be 
selected.
10.6.10
Definition of DLT Evaluable Participant
For decisions on dose escalation, an evaluable participant is defined as a participant who has 
received AZD8853 and either:

Has received at least 75% of the AZD8853 infusion and has completed safety evaluation 
requirements during the DLT evaluation period of 21 days in Cycle 1. Participants who 
do not remain in the study up to this time for reasons other than DLT will be considered 
non-evaluable for DLT assessment.
OR

Has experienced a DLT during the DLT evaluation period.
Non-evaluable participants in the dose-escalation cohorts will be replaced in the same dose 
cohort if needed to ensure a minimum of 3 DLT-evaluable participants.
10.6.11
Intervention after the End of the Study
Please refer to Section 6.7 for details on intervention after the end of the study.
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10.7
Substudy 1 Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
10.7.1
Discontinuation of Study Intervention
Please refer to Section 7.1 for details on discontinuation of study intervention.
10.7.2
Participant Withdrawal from the Study
Any participant in Part A that is withdrawn and is not evaluable will be replaced to ensure a 
minimum number of 3 DLT-evaluable participants.
10.7.3
Lost to Follow-up
Please refer to Section 7.3 for lost to follow-up.
10.8
Substudy 1 Study Assessments and Procedures
In addition to the master study assessment and procedures listed in Section 8, the below 
Substudy specific assessments and procedures also apply. 

Approximately 86 mL of blood will be required for all screening tests which will be 
conducted during the 28-day screening period. Approximately 210 mL of blood 
(including 
) will be collected between Days 1 and 21 
of study intervention in Part A and Part B whereas during the same time period 
approximately 189 mL of blood (including 
) will be 
collected in Part C. No more than approximately 144 mL of blood will be drawn during 
any cycle or individual study visit after Cycle 1. The total volume to be collected will 
depend on the number of doses administered and the length of follow-up.

All efficacy assessments should continue until progression; however, if the participant is 
clinically stable then a confirmatory scan for progression could be performed per 
Investigator’s discretion, and assessments should also be performed when a participant’s 
study intervention has been stopped.
10.8.1
Efficacy Assessments
Please refer to Section 8.1 for the efficacy assessments
10.8.2
Safety Assessments
Details of all safety assessments are provided in Section 8.2, for the planned timepoints for the 
safety assessments refer to SoA (Table 12, Table 13, and Table 14).
10.8.2.1
Electrocardiograms
Please refer to Section 8.2.4 for details of ECGs. Table 17 provides the Substudy-specific 
sampling schedule of electrocardiograms.
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Table 17
Sampling Schedule for Electrocardiograms
Cycle
Day
Sampling Time
Sampling Window
Parts A, B and C
1
1
Pre-dose
-2 hrs
1
0 hrs post EoI
+15 min
2
1
Pre-dose
-2 hrs
3
1
Pre-dose
-2 hrs
7-n
1
Pre-dose Q12W
-2 hrs
EOT
N/A
Up to 14 days post EOT
Abbreviation: EoI = end of infusion; EOT =end of treatment; hrs = hours; min = minutes; N/A = not applicable
10.8.3
Adverse Events and Serious Adverse Events
For details on AEs and SAEs, refer to Section 8.3.
10.8.4
Overdose
Please refer to Section 8.4 for details on overdose.
10.8.5
Human Biological Samples
10.8.5.1
Pharmacokinetics
Please refer to Section 8.5.1 for details of PK. Table 18 provides the Substudy-specific 
sampling schedule for the PK samples.
Table 18
Sampling Schedule for PK Samples
Cycle
Day
Sampling Time
Sampling PK Window
Part A
1
1
Pre-dose
-2 hrs
1
0 hrs post EoI
+5 min
1
15 min post EoI
±5 min
1
2 hrs post EoI
±5 min
1
6 hrs post EoI
±5 min
2
24 hrs post EoI
±5 min
8
168 hrs post EoI
±5 min
15
336 hrs post EoI
±5 min
2, 3, 4, 5, and 6
1
Pre-dose
-2 hrs
2, 3, 4, 5, and 6
1
0 hrs post EoI 
+5 min
2a
8
168 hrs post EoI
±5 min


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Cycle
Day
Sampling Time
Sampling PK Window
EOT
N/A
90 days post EOT
±7 days
Part B
1
1
Pre-dose
-2 hrs
1
0 hrs post EoI 
+5 min
1
15 min post EoI
±5 min
1
2 hrs post EoI
±5 min
1
6 hrs post EoI
±5 min
2
24 hrs post EoI
±5 min
8
168 hrs post EoI
±5 min
15
336 hrs post EoI
±5 min
2,3,4,5, and 6
1
Pre-dose
-2 hrs
EOT
N/A
90 days post EOT
±7 days
Part C
1
1
Pre-dose
-2 hrs
1
0 hrs post EoI 
+5 min
2,3,4,5, and 6
1
Pre-dose
-2 hrs
EOT
N/A
90 days post EOT
±7 days
a
Taken at time of second paired biopsy
Abbreviation: EoI = end of infusion; EOT = end of treatment; hrs = hours; min = minutes; N/A = not applicable
10.8.5.2
Immunogenicity Assessments
Please refer to Section 8.5.2 for details of immunogenicity assessments. Table 19 provides the 
Substudy-specific sampling schedule for the ADA samples.
Table 19
Sampling Schedule for ADA Samples
Cycle
Day
Sampling Time
Sampling ADA Window
Parts A, B and C
1
1
Pre-dose
-2 hrs
2
1
Pre-dose
-2 hrs
3
1
Pre-dose
-2 hrs
5
1
Pre-dose
-2 hrs
7-n
1
Pre-dose Q12W
-2 hrs
EOT
N/A
Up to 14 days post EOT
EOT
N/A
30 days post EOT
±7 days
EOT
N/A
90 days post EOT
±7 days
Abbreviation: EOT = end of treatment; hrs = hours; N/A = not applicable; Q12W = every 12 weeks


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10.8.5.3
Pharmacodynamics
Blood samples will be collected at specific timepoints mentioned in the SoA (Table 12, 
Table 13, and Table 14).
Further details on sample processing, handling and shipment will be provided in the 
Laboratory Manual.
For storage, re-use, and destruction of pharmacodynamic samples see Appendix C. 
10.8.5.3.1 GDF15 Assay for Target Engagement
As specified in the SoA for study visits (Table 12 and Table 13) and per the additional 
timepoints denoted in Table 20, samples for determination of free GDF15 in serum will be 
assayed by bioanalytical test sites operated by or on behalf of AstraZeneca, using an 
appropriately validated bioanalytical method. Full details of the method to be used will be 
described in a separate bioanalytical report.
Table 20
Sampling Schedule for GDF15 Target Engagement Samples
Cycle
Day
Sampling Time
Sampling PD Window
1
1
Pre-dose
-2 hrs
1
0 hrs post EoI
+5 min
1
15 min post EoI 
±5 min
1
2 hrs post EoI
±5 min
1
6 hrs post EoI
±5 min
2
24 hrs post EoI
±5 min
8
168 hrs post EoI
±5 min
15
336 hrs post EoI
±5 min
2, 3, 4, 5, and 6
1
Pre-dose
-2 hrs
2, 3, 4, 5, and 6
1
0 hrs post EoI 
+5 min
2a
8
168 hrs post EoI
±5 min
EOT
N/A
Up to 14 days post EOT
EOT
N/A
30 days post EOT
±7 days
EOT
N/A
90 days post EOT
±7 days
a
Taken at time of second paired biopsy
Abbreviations: EoI = end of infusion; EOT = end of treatment; hrs = hours; min = minutes; N/A = not applicable


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10.8.6
10.8.6.1
Fresh Tumour Biopsy
Fresh tumour biopsy samples (both mandatory and 
) will be collected for participants 
enrolled in both the dose-escalation part (Part A) and the expansion parts (Part B and Part C). 
For mandatory and 
 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 (details in the Laboratory Manual). If clinically feasible, at each fresh 
tumour sample timepoint, participants will undergo 4 core image-guided needle biopsies. 
Details for fresh tumour sample collection, processing, storage, and shipment are provided in 
the Laboratory Manual. Per institutional practice, image-guided fresh core needle 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. Collection of tumour cells from fluid such as ascites or pleural effusion is not
permitted. Fine-needle aspirate specimens are not acceptable. For fresh tumour biopsies, the 
tumour lesion should not be used as a RECIST target lesion, unless this is the only soft tissue 
lesion. If a RECIST v1.1 TL is used for biopsy, the lesion must be ≥ 2 cm in the longest 
diameter and must be biopsied at least 2 weeks prior to baseline RECIST assessment. Sites 
should confirm adequacy of tumour biopsy material at the time of the procedure. The 
screening and on-treatment biopsy should be taken where possible from the same lesion to 
ensure consistency and reduce variability of the sample. Biopsies should not be taken from 
previously irradiated sites unless the lesions were progressing after radiation. Bone biopsies 
are not permitted.
All tumour biopsies will be collected, stored, and shipped as detailed in the Laboratory 
Manual.
10.8.6.1.1 Mandatory Fresh Paired Biopsies
Up to 40 participants in Part B will be required to provide tumour samples. These participants 
will be required (mandatory) to undergo a tumour biopsy pre-treatment and during treatment 
as described below. 

Cycle 1 Day 1 (≤ 14 days, must be before the initial dosing of study intervention) 

Cycle 2 Day 8 (± 5 days, must be after CD8+ PET imaging if participant is in the CD8+ 
PET cohort).

Informed consent must be obtained from any participant who agrees to provide tissue for 
mandatory tumour tissue sample testing.
10.8.6.1.2
.
 
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. 
 
.
 
 
 
 
 
 
10.8.6.1.3
 
 
 
 
 
 
10.8.6.2
Mandatory Archival Tumour Samples
Sites must provision archival tumour tissue (FFPE blocks), with sufficient material to produce
approximately 40 slides. Provision of archival FFPE blocks is preferred, but if an archival 
block is not available, then approximately 40 unstained slides must be provided from another 
biopsy. Associated pathology report(s) for biopsy samples must be provided at screening for 
all participants. Central confirmation of the number of slides available is not required prior to 
participant dosing. However, sites should ensure that the archival block or other tissue sample 
has sufficient material, to the best of their knowledge, to produce the required number of 
slides. In the event that less than approximately 40 sections are thought to be available, then 
the CRA or Sponsor representative should be contacted. Please refer to the Laboratory Manual 
for details of acceptable sample types, processing, storage, and shipment of tissue samples.
10.8.6.3
 
 
 
 
 
 
 
 
 
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10.8.6.4
Whole blood samples will be collected from all participants as described in the SoA, for 
preparation of 
 and are mandatory. A variety of assays include, but are not limited to, 
 
 
10.8.6.5
Whole Blood for Flow Cytometry
Whole blood samples will be collected from all participants as described in the SoA, for flow 
cytometry-based immunophenotyping of circulating lymphocytes and are mandatory. 
Populations to be assessed may include, but are not limited to: T cell subsets, B cell subsets, 
natural killer cells, DCs, and myeloid-derived suppressor cells. Markers will also be used to 
investigate the expression of immune checkpoint molecules and activation and proliferation 
status of immune cells.
10.8.6.6
Circulating Tumour DNA
Whole blood to extract plasma will be collected from all participants as described in the SoA, 
for, but not limited to, ctDNA analysis and is mandatory. The ctDNA samples will be analysed 
longitudinally for secondary and 
, and to 
 in 
 and 
.
10.8.6.7
Whole Blood for 
Whole blood to extract 
 will be collected from all participants as described 
in the SoA, for analysis of 
 and is 
mandatory. 
 
 
 
10.8.6.8
 Research
Already collected samples may be analysed on 
 thought to play a role in 
 
 to AZD8853.
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For storage, re-use and destruction of biomarker samples see Section 8.5 and Appendix C. 
10.8.6.9
 Future Scientific Research
Already collected samples may be analysed to support research beyond AZD8853 and is 
pursuant to agreement to a separate 
 for future scientific research. Future 
research is important to advance science and public health. At present, however, it is not 
possible to foresee all details of future scientific research projects. These future scientific 
research projects are beyond the scope of the clinical study.
10.8.7
Please refer to Master Protocol Section 8.7 for details on the 
 
10.8.8
Health Economics and Participant eConsent Opinions
Please refer to Section 8.8.
10.9
Substudy 1 Statistical Considerations
Statistical considerations as described in Section 9 will be followed in the analysis of 
Substudy 1, unless specifically stated in this section. Substudy-specific considerations are 
described in this section.
10.9.1
Statistical Hypotheses
Not applicable. 
10.9.2
Sample Size Determination
For dose escalation (Part A) cohorts of 3 to 9 evaluable participants will be enrolled. The total 
number of participants will depend on the number of non-evaluable participants and the 
number of dose escalations necessary in order to declare MTD/RP2D. It is anticipated that 
approximately up to 5 dose-escalation cohorts of up to 9 evaluable participants may be 
included resulting in an overall total of up to approximately 45 participants.
Dose escalation using mTPI-2 is visualised in Table 16.
In the PD/MoA expansions (Part B1 and B2) up to 10 participants may be enrolled in each of 
2 dose levels and 2 indications (NSCLC and MSS-CRC) for a total of approximately 
40 participants. It is estimated that this will provide at least 7 participants per indication and 
dose level with evaluable paired biopsies for PD assessment.
In the efficacy expansions (Part C1 and C2) up to 40 participants in each expansion will be 
enrolled for a total of 80 participants. This will be an additional 30 participants per expansion 
since 10 relevant participants may be included from the associated PD/MoA expansion. With 
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Clopper et al, 1934) 
 
Across all parts of the study up to a total of 165 participants may be enrolled and treated with 
AZD8853 (145 participants if 20 participants from Part B are included in Part C). Additional 
participants may be required if additional expansions or dosing schedules are explored.
10.9.3
Population for Analyses
In addition, to the populations for analyses mentioned in Section 9.3, the definition of 
Substudy 1 specific populations for analyses is provided in Table 21. 
Table 21
Populations for Analyses
Population/Analysis set
Description
Endpoint/Output
PD
All participants who receive at least one dose of study 
intervention with baseline measurement and at least 
one reportable pharmacodynamic measurement.
PD endpoints
Abbreviation: PD = pharmacodynamics
10.9.4
Statistical Analyses
10.9.4.1
General Considerations
Data will be presented by dose cohort (Part A) and dose expansion (Part B and Part C); no 
direct statistical comparisons will be made between any cohorts or expansions.
Table 22 details which data will be analysed at each timepoint.
Table 22
Details of Analyses 
Analysis
Trigger
Data Type Included
Interim for efficacy expansions 
(Parts C1 and C2)
After the 20th participant in each 
expansion had the opportunity for 
2 on-treatment RECIST 
assessments or has discontinued or 
withdrawn from treatment
Efficacy
Safety
Primary analysis
At completion of each part 
(analysis will be conducted 
separately for each part)
All data
10.9.4.2
Efficacy Analyses
Please refer to Section 9.4.3 for efficacy analyses. 
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10.9.4.3
Safety Analyses
Please refer to Section 9.4.2 for safety analyses.
10.9.4.4
Other Analyses
10.9.4.4.1 Pharmacodynamics
The secondary PD endpoint of change in circulating GDF15 serum levels from pre-treatment 
(baseline) to each post baseline timepoint as well as the maximum change will be summarised 
using descriptive statistics on actual and percent change. 
The secondary endpoint of change in CD8 tumour infiltration by IHC between the 
pre-treatment and on-treatment biopsy will be summarised using descriptive statistics for 
those participants with paired biopsies.
In general, PD variables based on 
 and fresh biopsy samples will be 
summarized using descriptive statistics on the PD Population. Summaries of change from 
baseline and percent change from baseline will be also be presented for PD variables as 
appropriate. Such summaries may be reported separately from the main CSR. Summaries and 
analyses for 
 may be reported outside the CSR in a separate report. 
Descriptive statistics will be the primary method for the biomarker analyses. Depending on 
the nature of the data, geometric mean and other appropriate statistical summaries might be 
used as well.
Analyses of PK/PD may include, but are not limited to, 
 
. Other 
 
. Where relevant, 
data collected from this study may be combined with other data from other studies for 
modelling purposes. All analysis results may be reported separately from the CSR.
Refer to Section 9.4.4.1 for information on PK and immunogenicity analyses. Further details 
on the analysis of immunogenicity, pharmacokinetics and pharmacodynamics will be provided 
in the SAP.
10.9.5
Interim Analyses
In the efficacy expansions (Part C1 and Part C2) an interim analysis will be performed after 
the 20th participant in each expansion has had the opportunity for 2 on-treatment RECIST 
assessments or has discontinued or withdrawn from treatment. Enrolment will continue while 
this analysis is ongoing. The analysis will provide tolerability and safety data and will also 
provide a reasonable chance to determine if there is a lack of efficacy. 
 
 
 
 
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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
i.
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
ii.
Applicable ICH GCP Guidelines
iii.
Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (eg,
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO, but the accountability remains with AstraZeneca.

The Investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations
Regulatory Reporting Requirements for Serious Adverse Events

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 utilizing medical devices Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
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-
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations

An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB or state other documents and will notify the 
IRB/IEC, if appropriate according to local requirements.
A 2
Financial Disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate Regulatory Authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process

The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.
-
Sites participating in the CD8+ PET imaging portion of the study will be provided 
with separate Part B ICFs.

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 
requirements, where applicable, and the IRB/IEC or study centre.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 28 days from the previous ICF signature date.
The ICF will contain a separate section that addresses and documents the collection and use of 


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any mandatory and/or optional human biological samples. The Investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period.
A 4
Data Protection

Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from Regulatory 
Authorities.
A 5
Committees Structure
No Data Monitoring Committee will be used in this study; however, a SRC will closely 
monitor participant safety on an ongoing basis. The SRC Members will include the following:

Principal Investigator, or delegate, who will chair the committee

Study Chair (if not Principal Investigator)

Principal Investigator or delegate from investigational site

AstraZeneca Medical Science Director or delegate

AstraZeneca Global Safety Physician, or delegate
The Sponsor or CRO Study Physician, or delegate, should always be present at the SRC.
The AstraZeneca Clinical Pharmacology Scientist, Study Statistician, Patient Safety Scientist, 
Study Leader and other AstraZeneca and non-AstraZeneca technical experts may also be 
invited as appropriate. The SRC Remit document for this study will define the exact 
membership and who will be present for decisions to be made.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 


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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 main study is
conducted.
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on the 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.

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, CRO).

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.


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
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study are defined as source documents. Source data 
are contained in source documents (original records or certified copies). 

A digital copy of all imaging scans should be stored as source documents.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first act of recruitment is the first site open and will be the study start date.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the Investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the Regulatory Authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.


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


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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An 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 is an AE occurring during any study period (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-participant hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above.
Adverse events 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 hospitalization, may be assessed as non-serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy.


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The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 
is being treated by the investigational medicinal product under study and is not the 
development of new or progression of existing metastasis to the tumour under study). 
Malignant tumours that – as part of normal, if rare, progression – undergo transformation 
(eg, Richter’s transformation of B-cell chronic lymphocytic leukaemia into diffuse large 
B-cell lymphoma) should not be considered a new malignant tumour.
Life-threatening
‘Life-threatening’ means that the 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 i.v. hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse


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Intensity Rating Scale:
The grading scales found in the revised NCI CTCAE v5.0 will be utilised for all events with 
an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate and severe events into 
CTCAE grades should be used. A copy of the CTCAE can be downloaded from the Cancer 
Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable version of 
CTCAE should be described clearly.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

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.


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The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error:

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IRT]/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTMS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTMS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg, forgot to take medication


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
Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard-of-care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.


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


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
Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the 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 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association 
(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
D 1

AstraZeneca intends to collect and store 
 
 
 
 

 
 

The results of 
 may be reported in a separate study summary.

The Sponsor will store the 
 in a secure storage space with adequate 
measures to protect confidentiality.
D 2
 Plan and Procedures
Selection of 
 Population

All participants will be asked to participate in this 
. 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 
, participants must fulfil all of the inclusion criteria 
described in the main body of the Master CSP and: Provide informed consent for the 
(refer to Section 5.1).
Exclusion Criteria

Exclusion from this 
 may be for any of the exclusion criteria specified in 
the main study (refer Section 5.2)
Withdrawal of Consent for 

Participants may withdraw from this 
 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 Master CSP.
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Collection of Samples for 

The blood sample for this 
 will be obtained from the participants at the 
visit specified in the relevant Substudy SoA. Although 
 is stable, early sample 
collection is preferred to avoid introducing bias through excluding participants who may 
withdraw due to an AE. If for any reason the sample is not drawn at the planned visit, it 
may be taken at any visit until the last study visit. Only one sample should be collected 
per participant for 
during the study.
Coding and Storage of 
 Samples

The processes adopted for the coding and storage of samples for 
 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. 
is a finite resource that is used up during analyses. Samples will be stored and used 
until no further analyses are possible or the maximum storage time has been reached.

An additional second code will be assigned to the sample either before or at the time of 
 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 
 laboratories, or at the 
designated organisation. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organisations working with the 
).

The link between the participant enrolment/randomisation code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organisations. The link will be used to identify the relevant 
 samples for analysis, facilitate correlation of 
 with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent.
Ethical and Regulatory Requirements

The principles for ethical and regulatory requirements for the study, including this 
 component, are outlined in Appendix A.
Informed Consent

The 
 of this study is 
, and the participant may participate in 
other components of the main study without participating in this 
. To 
participate in the 
 of the study the participant must sign and date both 
the consent form for the main study and the addendum for the 
 
 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 
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responsible for ensuring that consent is given freely, and that the participant understands 
that they may freely withdrawal from the 
 of the study at any time.
Participant Data Protection

AstraZeneca will not provide individual 
 results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law.

Extra precautions are taken to preserve confidentiality and prevent 
 being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the 
 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 
 
. Regulatory Authorities may require access to the relevant files, though the 
participant’s medical information and the 
 would remain physically separate.
Data Management

Any 
 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 organisations may share summary results (such as 
 
) from this 
 with 
other researchers, such as hospitals, academic organisations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results, but they will not be able to see 
individual participant data or any personal identifiers. 

Some or all of the clinical datasets from the main study may be merged with the 
 
 in a suitable secure environment separate from the clinical database.
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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and 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 Substudy in the CSP.
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 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 all local 
laboratory evaluations even if collected outside of the study visits; for example, PHL criteria 
could be met by an elevated ALT from a central laboratory and/or elevated TBL from a local 
laboratory. 
The Investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. 
Hy’s Law criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than DILI caused by the IMP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law
Aspartate transaminase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point during 
the study following the start of study medication irrespective of an increase in ALP.
Hy’s Law
Aspartate transaminase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other 
reason, other than the IMP, can be found to explain the combination of increases, eg, elevated 
ALP indicating cholestasis, viral hepatitis, another drug. 


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any 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:

Determine whether the participant meets PHL criteria (see Section E 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not Met
If the participant does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria. 

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
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 


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
Within one day of PHL criteria being met, the Investigator will report the case as an SAE 
of PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting IMP, the Investigator is not 
required to submit a PHL SAE unless there is a significant change# in the participant’s 
condition

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 the three Liver eCRF Modules as information becomes available.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days from 
date PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global 
Safety Physician will also be involved in this review together with other subject matter experts 
as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
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


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


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
If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Section E 4.2.
E 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on-study treatment visit (Section E 6).
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found 
to be the disease under study eg, chronic or progressing malignant disease, severe 
infection or liver disease?
If No: follow the process described in Section E 4.2 for reporting PHL as an SAE
If Yes: Determine if there has been a significant change in the participant’s condition#
compared with when PHL criteria were previously met

If there is no significant change no action is required

If there is a significant change follow the process described in Section E 4.2 for reporting 
PHL as an SAE
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.


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E 8
Laboratory Tests
Local Laboratory Tests
Additional standard chemistry and coagulation tests
Gamma-glutamyltransferase
Lactate dehydrogenase
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
HBsAg
IgM and IgG anti-HBc 
HBV DNA a
IgG anti-HCV
HCV RNA b
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-cytomegalovirus
IgM & IgG anti-herpes simplex virus
IgM & IgG anti- anti-Epstein-Barr virus
Alcoholic hepatitis
CD-transferrin c
Autoimmune hepatitis
ANA
Anti-LKM
ASMA
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin c
Transferrin saturation
a
HBV DNA is only recommended when IgG anti-HBc is positive
b
HCV RNA is only recommended when IgG anti-HCV is positive or inconclusive 
c
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly
Abbreviations: ANA = antinuclear antibody; ASMA = anti-Smooth Muscle Ab; CD = carbohydrate deficient 
transferrin; DNA = deoxyribonucleic acid; HAV = hepatitis A virus; HBc = hepatitis B core; HBV = hepatitis B 
virus; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HEV = hepatitis E virus; 
IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international normalised ratio; 
LKM = Liver/Kidney Microsomal Ab; RNA = ribonucleic acid
E 9
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.


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


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Appendix F
Guidelines For Evaluation of Objective Tumour Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours)
Introduction
This appendix details the implementation of RECIST v1.1 guidelines (Eisenhauer et al, 2009).
Investigator assessments will use the RECIST v1.1 guidelines described in this appendix.
Imaging modalities and acquisition specifications for RECIST v1.1
A summary of the imaging modalities that can be used for tumour assessment TLs, NTLs, and 
NLs is provided in Table 23.
Table 23
Summary of Imaging Modalities for Tumour Assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
FDG-PET/CT
Abbreviations: CT = Computed tomography; FDG-PET/CT = 18F-Fluoro-deoxyglucose positron emission 
tomography/CT; MRI = Magnetic resonance imaging.
CT and MRI 
Computed tomography with i.v. contrast is the preferred imaging modality (although MRI 
with i.v. contrast is acceptable if CT is contraindicated) to generate reproducible anatomical 
images for tumour assessments (ie, for measurement of TLs, assessment of NTLs, and 
identification of NLs). It is essential that the same correct imaging modality, image acquisition 
parameters (eg, anatomic coverage, imaging sequences, etc.), imaging facility, tumour
assessor (eg, radiologist), and method of tumour assessment (eg, RECIST v1.1) are used 
consistently for each participant throughout the study. The use of the same scanner for serial 
scans is recommended, if possible. It is important to follow the image collection/tumour
assessment schedule as closely as possible (refer to the Schedules of Activities [SoAs; 
Table 12, Table 13, and Table 14]), and this on-study imaging schedule MUST be followed 
regardless of any delays in dosing or missed imaging visits. If an unscheduled assessment is 
performed (eg, to investigate clinical signs/symptoms of progression) and the participant has 
not progressed, every attempt should be made to perform the subsequent scan acquisitions at 
the next scheduled imaging visit.
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 


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scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artifacts (eg, heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence. In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumour evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the 
chest-abdomen (-pelvis). Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual participants. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a NL representing 
disease progression, careful consideration should be given to the extent of imaging coverage 
at baseline and at subsequent follow-up timepoints. This will enable better consistency not 
only of tumour measurements but also identification of new disease.
Required anatomical regions to be imaged for assessment of tumour burden (TLs and/or 
NTLs) at baseline and follow-up visits vary according to the study, and these timepoints are 
specified in the SoAs (Table 12, Table 13, and Table 14). Examples include the following:

Intravenous contrast-enhanced CT of chest-abdomen (including the entire liver and both 
adrenal glands) (-pelvis)

Non-contrast CT of chest and i.v. contrast-enhanced abdomen (including the entire liver 
and both adrenal glands) (-pelvis)

Intravenous contrast-enhanced CT or MRI of the head and neck

Intravenous contrast-enhanced MRI (preferred) or CT of the brain
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order 
of preference, with additional options (2 to 4) for consideration when participants have 
sensitivity to i.v. contrast or have compromised renal function:
1
Chest-abdomen (-pelvis) CT with i.v. CT contrast (most preferred)
2
Chest CT without i.v.-contrast + abdomen (-pelvis) MRI with i.v. MRI contrast, if CT i.v.
contrast (iodine based) is medically contraindicated at any time during the study


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3
Chest-abdomen (-pelvis) CT without i.v. contrast, if both i.v. CT and MRI contrast are 
medically contraindicated, or the participant has compromised renal function
4
Chest-abdomen (-pelvis) MRI with i.v. MRI contrast, if CT cannot be performed at any 
time during the study
b. IV contrast administration: Optimal visualization and measurement of metastases in solid 
tumours require consistent administration (dose and rate) of i.v. contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumour
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given participant. Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen and pelvis.
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤5-mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses > 5 mm. If this 
occurs, the minimum size of measurable lesions at baseline should be twice the slice thickness 
of the baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study.
Chest X-Ray
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that 
a higher resolution modality, such as CT, be used to confirm the presence of NLs.
Plain X-Ray
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions.
Isotopic Bone Scan
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray).
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 


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equivocal hot-spot on a bone scan that cannot be verified with correlative imaging (CT, MRI, 
or X-ray) of the same anatomical region shall not be the only trigger for a progressive disease 
assessment at that timepoint.
FDG-PET/CT
18F-Fluoro-deoxyglucose positron emission tomography/CT scans may be used as a method 
for identifying new extrahepatic lesions (but not intrahepatic lesions) for RECIST v1.1 
assessments according to the following algorithm: NLs will be recorded where there is 
positive FDG uptake1 not present on baseline or prior FDG-PET/CT scan or in a location 
corresponding to a NL on a companion CT/MRI collected close in time to the FDG-PET/CT 
scan. The PET portion of the PET/CT introduces additional data that may bias an Investigator 
if it is not routinely or serially performed. Therefore, if there is no baseline or prior 
FDG-PET/CT scan available for comparison, and no evidence of NLs on companion CT/MRI 
scans, then follow-up CT/MRI assessments should continue as per the regular imaging 
schedule to verify the unequivocal presence of NLs.
At present, low-dose or attenuation correction CT portions of a combined FDG-PET/CT scan 
are of limited use in anatomically based efficacy assessments, and it is therefore suggested 
that they should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumour
measurements by RECIST v1.1. In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with i.v.
contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used 
for RECIST v1.1 tumour assessments. Caution that this is not recommended because the PET 
portion of the CT introduces additional (PET) data that may bias an Investigator if it is not 
routinely or serially performed.
Ultrasound 
Ultrasound examination will not be used for RECIST v1.1 assessment of tumours as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumour size. Tumours identified by ultrasound 
                                               
1
A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that 
of the surrounding tissue or liver is observed.


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will need to be assessed by correlative CT or MRI anatomical scan.
Other Tumour Assessments
Clinical Examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST v1.1 assessments. Tumours identified by clinical examination will 
need to be assessed by correlative CT or MRI anatomical scans.
Endoscopy and Laparoscopy 
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour assessment.
Histology and Cytology
Histology or tumour markers on tumour biopsy samples will not be used as part of the tumour
response assessment as per RECIST v1.1.
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumour response assessment as per RECIST v1.1.
Furthermore, an overall assessment of complete response (all other disease disappears/reverts 
to normal) would be changed to partial response if an effusion remains present radiologically.


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Measurability of Tumour Lesions at Baseline
RECIST 1.1 Measurable Lesions at Baseline:
A tumour lesion that can be accurately measured at baseline as ≥10 mm in the longest 
diameter for non-nodal lesions or ≥15 mm in short axis2 diameter for lymph node lesions with 
i.v. contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements.
Please see additional RECIST v1.1 guidance below on measurability of intrahepatic 
hepatocellular carcinoma lesions and porta hepatis lymph nodes.
Non-measurable Lesions at Baseline:

Truly non-measurable lesions include the following:
−
Bone lesions (see exception below for soft tissue component)
−
Leptomeningeal disease
−
Ascites, pleural effusion, or pericardial effusion
−
Inflammatory breast disease
−
Lymphangitic involvement of skin or lung

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥10-mm to < 15-mm short axis diameter at baseline3)

Previously irradiated lesions4

Brain metastasis
                                               
2
The short axis is defined as the longest in-plane axis perpendicular to the long axis.
3
Lymph nodes with < 10-mm short axis diameter are considered non-pathological and should not be 
recorded or followed as NTLs.
4
Localized post-radiation changes that affect lesion size may occur. Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and as NTL at baseline and followed up as 
part of the NTL assessment.


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Special Considerations Regarding Lesion Measurability at Baseline:

Bone lesions
−
Bone scan, PET scan, or plain X-ray are not considered adequate imaging 
techniques to measure bone lesions; however, these techniques can be used to 
confirm the presence or disappearance of bone lesions.
−
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.
−
Blastic lesions are considered non-measurable.

Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the criteria for measurability from a radiological point of view, but if 
non-cystic lesions are present in the same participant, these should be selected over cystic 
lesions as TLs.
RECIST v1.1 TL Selection at Baseline:
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TLs at baseline. Target lesions should be selected on the basis of their 
size (longest diameter for non-nodal lesions or short axis diameter for nodal lesions), but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement, in which circumstance the next largest lesion that can be measured reproducibly 
should be selected.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands), 
a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
organ.
The site and location of each TL should be documented, as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimeters. At baseline, the sum of the diameters for all TLs will be calculated 
and reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all 
TLs will be calculated and reported as the follow-up sum of diameters.
Special cases for TL assessment at baseline:

For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter.


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
When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non-nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter.

Tumour lesions selected for fresh screening biopsy should not be selected as TLs, unless 
imaging occurred at least approximately 2 weeks after biopsy, allowing time for healing.

If the CT/MRI slice thickness used is > 5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a NL.
RECIST 1.1 NTL Selection at Baseline:
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up.
Evaluation of Tumour Response and Progression
RECIST v1.1 TL Assessment at Follow-up
This section defines the criteria used to determine objective tumour visit response for 
RECIST v1.1-defined TLs. The imaging modality, location, and scan date of each TL 
identified previously at baseline should be documented at follow-up visits with the long axis 
diameter for non-nodal lesions or short axis diameter for lymph node lesions. All 
measurements should be recorded in millimeters. The sum of the diameters for all TLs at each 
follow-up visit will be compared to the baseline sum of diameters (for response or stable 
disease) or to the smallest prior (nadir) sum of diameters (for progression).
Special cases for TL assessment at follow-up:

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.

If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded.

If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the vector of the longest diameter of the coalesced mass should be used to 
determine the perpendicular vector for the maximal short axis diameter.


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
If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. The choice of “Too large to measure” in the case report form will 
trigger an overall visit response of progressive disease.

When a TL has had any intervention (eg, definitive radiotherapy, embolization, surgery, 
transarterial chemoembolization, etc.) during the study, the size of the TL should still be 
provided where possible and the intervention recorded in the RECIST v1.1 case report 
form for the current imaging visit and all subsequent visits. If a TL has been completely 
removed (surgery) or disappears, the longest diameter should be recorded as 0 mm.
Table 24
RECIST v1.1 Evaluation of Target Lesions
CR
Disappearance of all TLs since baseline. Any pathological lymph nodes 
selected as TLs must have a reduction in short axis diameter to 
< 10 mm.
PR
At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters.
SD
Neither sufficient decrease in the sum of diameters to qualify for PR nor 
sufficient increase to qualify for progressive disease.
Progressive Disease
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir)—This includes 
the baseline sum if that is the smallest on study. In addition to the 
relative increase of 20%, the sum must demonstrate an absolute increase 
of at least 5 mm from nadir.
NE
Only relevant if any of the TLs at follow-up were not assessed or not 
evaluable (eg, missing anatomy) or had a lesion intervention at this 
visit. Note: If the sum of diameters meets the progressive disease 
criteria, progressive disease overrides not evaluable as a TL response.
NA
Only relevant if no TLs present at baseline.
Abbreviations: CR = complete response; NA = not applicable; NE = not evaluable; PR = partial response; 
SD = stable disease; TL = target lesion.
RECIST v1.1 NTL Assessment at Follow-up
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. At each visit, an overall assessment of the NTL response should be 
recorded by the Investigator.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or 


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partial response in TLs, the overall tumour burden has increased sufficiently to merit 
unequivocal progression by NTLs. A modest ‘increase’ in the size of one or more NTLs is 
usually not sufficient to qualify for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare.
Table 25
RECIST 1.1 Evaluation of Non-Target Lesions
CR
Disappearance of all NTLs since baseline. All lymph nodes must be 
non-pathological in size (< 10 mm short axis).
Non-CR/non-progressive disease
Persistence of one or more NTLs.
Progression of disease
Unequivocal progression of existing NTLs. Unequivocal progression 
may be due to an important progression in 1 lesion only or in several 
lesions. In all cases, the progression MUST be clinically significant for 
the physician to consider changing (or stopping) therapy.
NE
Only relevant when one or some of the NTLs were not assessed and, in 
the Investigator’s opinion, they are not able to provide an evaluable 
overall NTL assessment at this visit.
Note: For participants without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression criteria 
have not been met.
NA
Only relevant if no NTLs present at baseline
Abbreviations: CR = Complete response; NA = Not applicable; NE = Not evaluable; NTL = Non-target lesion; 
TL = Target lesion.
RECIST v1.1 NL Identification at Follow-up
Details, including the imaging modality, the date of scan, and the location of any NLs will also 
be recorded in the case report form. The presence of one or more NLs is assessed as 
progression. The finding of a NL should be unequivocal, ie, not attributable to differences in 
scanning technique, change in imaging modality, or findings thought to represent something 
other than tumour. If a NL is equivocal, for example because of its small size, the treatment 
and tumour assessments should be continued until the previously (pre-existing) new lesion has 
been assessed as unequivocal at a follow-up visit, and then the progression date should be 
declared using the date of the initial scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression.
RECIST v1.1 Evaluation of Overall Visit Response at Follow-Up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 26.


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Table 26
RECIST v1.1 Overall Visit Response
Target Lesions
Non-Target Lesions
New Lesions
Overall Visit Response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non-CR/Non-progressive 
disease
No
PR
CR
NE
No 
PR
PR
Non-progressive disease or 
NE or NA
No
PR
SD 
Non-progressive disease or 
NE or NA
No
SD
NA
Non-CR/Non-progressive 
disease
No
SD (non-CR/non-progressive 
disease)
NE
Non-progressive disease or 
NE
No
NE
NA
NE
No
NE
NA
NA
No
NED
Progressive disease
Any
Yes or No
Progressive disease
Any
Progressive disease
Yes or No
Progressive disease
Any
Any
Yes
Progressive disease
Abbreviation: CR = complete response; NA = not applicable; NE = not evaluable; NED = no evidence of 
diseases; PR = partial response; SD = stable disease; TL = target lesion.
a
Non-CR/Non-progressive disease for Overall Response if only non-target lesions (no TLs) are present at 
baseline.
Note: An overall assessment of Complete Response (all other disease disappears/reverts to normal) would be
changed to Partial Response if ascites remains present radiologically.
The following overall visit responses are possible depending on the extent of tumour disease 
at baseline:

For participants with TLs (at baseline): CR, PR, SD, progression of disease, or NE

For participants with NTLs only (at baseline): CR, Non-CR/Non-progressive disease, 
progressive disease, or NE

For participants with no disease at baseline: no evidence of disease (available as an option 
in the electronic case report form), progressive disease, or NE


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Evaluation of Scans Subsequent to RECIST v1.1-defined Progression
A follow-up scan is left up to the Investigator’s discretion but, if performed, should be at least 
4 weeks after a RECIST v1.1-defined radiological progression and no later than the next 
regularly scheduled imaging visit. The follow-up scans provide additional information to the 
Investigator for patient management and further treatment decisions, and since the published 
RECIST v1.1 criteria (Eisenhauer et al, 2009) do not provide guidance on how to assess scans 
acquired after RECIST v1.1-defined progressive disease, supplemental instructions for 
Investigators on how to evaluate these follow-up scans are provided below. If the follow-up 
scan acquired after a RECIST v1.1 progressive disease scan meets any of the following 
criteria, it will be assigned an overall visit response of progressive disease, and if the scan 
does not meet any of these 4 criteria, the timepoint assessment will be non-progressive disease
(ie, CR, PR, SD, or NE).

≥20% increase and at least a 5-mm increase in the sum diameters of TLs compared with 
the nadir sum of diameters at 2 consecutive visits, and a further increase of ≥5 mm in the 
sum of diameters at the follow-up timepoint compared with the immediate prior timepoint

significant progression (worsening) of NTLs at the follow-up scan timepoint compared 
with the immediate prior timepoint

significant progression (worsening) of previously new lesions (pre-existing new lesions) 
at the follow-up scan timepoint compared with the immediate prior timepoint

additional unequivocal brand-new lesions at the follow-up scan timepoint
Central Imaging
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed iCRO for quality control, storage, and potentially for BICR. Digital 
copies of all original scans should be stored at the Investigator site as source documents.
Electronic image transfer from the sites to the iCRO is strongly encouraged. A BICR of 
images will be performed at the discretion of AstraZeneca. Results of these independent 
reviews will not be communicated to Investigators, and results of Investigator tumour
assessments will not be shared with the central reviewers. The management of participants
will be based in part upon the results of the tumour assessments conducted by the Investigator.
Further details of the BICR will be documented in an Independent Review Charter.


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Appendix G
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 AstraZeneca Study Physician.
G 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 G 2 to G 5. 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. 
G 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 IMP. If this 
delay is outside the screening window specified in schedule of assessments the participant will 
need to be rescreened to reconfirm eligibility before commencing study procedures. This will 
provide another opportunity to re-screen a participant in addition to that detailed in 
Section 5.4. The procedures detailed in the SoA must be undertaken to confirm eligibility 
using the same randomization number as for the participant.


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G 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service will visit the participants home/or other 
remote location as per local standard operating procedures, as applicable. Supplies will be 
provided for a safe and efficient visit. The qualified HCP will be expected to collect 
information per the CSP.
G 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 AEs and concomitant medication, to be reported and 
documented.
G 5
Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site or TPV service.


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Appendix H
National Institute of Allergy and Infectious Disease and Food 
Allergy and Anaphylaxis Network guidance for anaphylaxis 
diagnosis
The National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis 
Network define anaphylaxis as a serious allergic reaction that is rapid in onset and may cause 
death. They recognize 3 categories of anaphylaxis, with criteria designated to capture from 
80% of cases (category 1) to > 95% of all cases of anaphylaxis (for all 3 categories).

Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING:
(a) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
(b) Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence)

Two or more of the following that occur rapidly after exposure to a likely allergen for that 
participant (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
(b) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)

Reduced BP after exposure to known allergen for that participant (minutes to several 
hours):
(a) Infants and children: low systolic BP (age-specific) or greater than 30% decrease in 
systolic BP
(b) Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that 
person’s baseline


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I 2
Introduction
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parameters, slice thickness and other parameters as well as instructions for how to submit 
images for review (Note: Important for the sites to follow the instruction in Imaging Manual).
I 5
Schema
Figure 4 illustrates CD8+ PET and mandatory biopsies timelines in Part B1 and Part B2: 
AZD8853 Expansion.
I 6
Benefit-Risk Assessment with 89Zr-Df-Crefmirlimab (CD8+ PET 
Tracer)
The safety monitoring practices employed in the main protocol (Section 8.2, Section 8.3) are 
adequate to protect the participant safety for this part of the study. Preclinical data, both 
in vivo and in vitro have demonstrated that 89Zr-Df-crefmirlimab had no measurable effect on 
T cell proliferation, activation or cytokine release. An imaging investigating the use of 
89Zr-Df-crefmirlimab as a non-interventional or a treatment modality is not likely to improve 
response to treatment. However, should CD8+ PET imaging show a direct correlation to TIL 
recruitment to the TME, future cancer patients may be spared from painful invasive biopsies. 
Moreover, a positive correlation to clinical outcome could, in the future, potentially allow 
more rapid assessment of whether patients are responding to therapy and allow physicians to 
make decisions earlier about continuing or switching therapies for their participants. 
Potential risks include infusion site reactions (eg, redness, itching and pain), allergic reaction 
(including anaphylaxis), renal failure, hepatic failure, arthritis, and/or hypotension. 
For information on all identified and potential risks of crefmirlimab refer to the current 
version of the 89Zr-Df-crefmirlimab IB.
I 7
Study Population
Parts B1 and B2 of the study have no additional inclusion/exclusion criteria for CD8+ PET
imaging compared to the overall study, except known allergies to CD8+ PET tracer. For 
further details on the study population refer to Section 10.5.
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I 8
Investigational Imaging Agent
For participants enrolled in Parts B1 and B2 for CD8+ PET imaging, an investigational 
imaging agent will be utilized, an anti-CD8 minibody (crefmirlimab), conjugated with Df and 
radiolabelled with 89Zr (89Zr-Df-crefmirlimab): 

Pharmacological Class: A biological PET radioligand for detecting CD8+ T cells

Dosage Formulation: 
 
 
 
 
 

Route of Administration: i.v. infusion, between 5 to 10 minutes.
I 8.1
Investigational Product Storage
The dose will be delivered by a central manufacturing facility to the investigational site’s 
radio pharmacy or Nuclear Medicine Department. Each shipment of 89Zr-Df-crefmirlimab will 
arrive in a thermally controlled shipping system. Investigational product is stored in a secure 
refrigerator at 2°C to 8°C, housed inside a sealed lead pot until one hour before the time of 
infusion. The dose of 89Zr-Df-crefmirlimab should be dispensed and administered by the 
expiration time listed on the label.
I 8.2
Investigational Product Handling
The 89Zr-Df-crefmirlimab dose will be measured by the qualified personnel in a dose 
calibrator prior to dispensing. Then the syringe will be placed in a shielded carrier along with 
a designated i.v. infusion pump for radioactive infusion and administration. After the dose 
administration, the qualified personnel will return the syringe for residual measurement by the 
nuclear pharmacist at the site. Measured radioactivity values and times of measurement will 
be documented, as well as the total injected volume.
I 8.3
Treatment Administration
The dose of 89Zr-Df-crefmirlimab should be removed from the secure refrigerator 1 hour 
before the time of infusion in order for the dose to come to room temperature. A single dose of 
the investigational imaging agent, 89Zr-Df-crefmirlimab [
mL] will 
be drawn up into a syringe according to the site’s schedule of procedures. Site personnel will 
label the syringe with the completed investigational imaging agent label and log the dose in 
the radio pharmacy standard drug use logs.
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For further information see the 89Zr-Df-crefmirlimab Imaging Manual.
I 9
Statistical Considerations
The sample size for CD8+ PET imaging is not based on statistical power calculations. It was 
determined by practical considerations and to provide data to enable the relationship between 
CD8+ PET imaging and the paired biopsy data to be explored, taking into account dropouts. 
Up to approximately 20 participants enrolled into Part B of the study will participate in CD8+ 
PET imaging. 
To meet objectives of CD8+ PET imaging, the following endpoint will be evaluated:

Standardized uptake value quantitative measures of tumour lesions (biopsied and non-
biopsied) and reference tissues; SUV values will be calculated at and between 
timepoints.
Positron emission tomography data are converted to lean body mass SUVs, using the 
participant’s height, weight, and injected activity. 
Descriptive statistics will be used to describe the SUV measurements of tissues of interest 
(eg, tumour, lymph node). Categorical data will be summarized by counts and percentages. 
Continuous variables will be summarized by mean, median, standard deviation, minimum, and 
maximum. 
The relationship between SUV measurements of tissue and 
 or 
IHC of innate, and adaptive immune cells/factors from tumour biopsies from the main 
protocol will be explored. 
Efficacy endpoints from the main protocol (ORR, DoR, PFS, and OS, where possible) will be 
assessed in relation to SUV measurements. 
Any results from such analyses may be reported separately from the CSR.
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Appendix J
Abbreviations 
Abbreviation or special term
Explanation
ADA
Anti-drug antibody 
AE
Adverse event
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase gene
ALP
Alkaline phosphatase
ALT
Alanine transaminase
aPTT
Activated partial thromboplastin time
AST
Aspartate transaminase
AUC
Area under the curve
BICR
Blinded Independent Central Review
BMI
Body mass index
BoR
Best overall response
BP
Blood pressure
CAP
College of American Pathologists
CD4
Cluster of differentiation 4
CD8
Cluster of differentiation 8
CFR
Code of Federal Regulations
CI
Confidence interval
CLIA
Clinical laboratory improvement amendments
Cmax
Maximum concentration
CNS
Central nervous system
CONSORT
Consolidated standards of reporting trials
COVID-19
Coronavirus disease 2019
CPI
Checkpoint inhibitors
CR
Complete response
CRC
Colorectal cancer
CRO
Contract research organisation
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common terminology criteria for adverse events
ctDNA
Circulating tumour deoxyribonucleic acid
CTLA-4
cytotoxic T-lymphocyte associated protein 4
DC
Dendritic cells


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Abbreviation or special term
Explanation
DCR
Disease control rate
DCO
Data cut-off
Df
Deferoxamine
DILI
Drug induced liver injury
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DoR
Duration of response
ECG
Electrocardiogram
eCRF
Electronic case report form
ECOG
Eastern cooperative oncology group
EDC
Electronic data collection
EGFR
Estimated glomerular filtration rate
EMA
European medicines agency
EoI
End of infusion
EOT
End of treatment
FDA
Food and drug administration
FDG
18F-Fluoro-deoxyglucose
Fc
Fragment crystallizable
FFPE
Formalin-fixed paraffin-embedded
FTiH
First time in human
GCP
Good clinical practice
G-CSF
Granulocyte colony stimulating factor
GDF15
Growth differentiation factor 15
GLP
Good laboratory practice
GRFAL
Glial cell line-derived neurotrophic factor (GDNF) family receptor α-
like
HAV
Hepatitis A virus
Hb
Haemoglobin
HbA1c
Haemoglobin A1c
HBc
Hepatitis B core
HBV
Hepatitis B virus
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCP
Health care professional
HCV
Hepatitis C virus


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Abbreviation or special term
Explanation
HEV
Hepatitis E virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency viruses
HL
Hy’s Law
HNSTD
Highest non-severely toxic dose
HPDD
Highest protocol defined dose
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICD
Immune complex disease
ICF
Informed consent form
ICH
International Council for Harmonisation
iCRO
Imaging Contract Research Organisation
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IHC
Immunohistochemistry
imAE
Immune mediated adverse event
IMP
Investigational medicinal product
INR
International normalised ratio
IRB
Institutional Review Board
IRR
Infusion related reactions
IxRS
Interactive voice/web response system
IRT/RTSM
Interactive Response Technology System/Randomisation and Trial 
Supply Management
i.v.
Intravenous
LTFU
Long term follow-up
mAb
Monoclonal antibody
MedDRA
Medical dictionary for regulatory activities
MoA
Mechanism of action
MSS
Microsatellite stable
MTD
Maximum tolerated dose
MRI
Magnetic resonance imaging
mTPI
Modified toxicity probability interval
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Abbreviation or special term
Explanation
NASH
Non-alcoholic steatohepatitis
NCI
National Cancer Institute
NE
Not evaluable
NIMP
Non-investigational medicinal product
NK
Natural killer 
NL
New lesion
NSCLC
Non-small-cell lung cancer
NTL
Non-target lesions
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall Survival
OTC
Over-the-counter
PD
Pharmacodynamics
PD-1
Programmed cell death-1
PD-L1
Programmed death-ligand 1
PEF
Peak expiratory flow
PET
Positron emission tomography
PFS
Progression free survival
PHL
Potential Hy’s Law
PK
Pharmacokinetics
PR
Partial response
PT
Prothrombin time
Q3W
Every 3 weeks
Q9W
Every 9 weeks
Q12W
Every 12 weeks
Q26W
Every 26 weeks
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBC
Red blood cells
RECIST
Response evaluation criteria in solid tumours
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 dose
RT-qPCR
Reverse transcription-quantitative polymerase chain reaction
SAE
Serious adverse event 
SAP
Statistical analysis plan
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Abbreviation or special term
Explanation
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
Stable disease
SMI
Skeletal muscle index
SoA
Schedule of activities
SOC
System organ class
SRC
Safety review committee
SUV
Standardised uptake value
T3
Triiodothyronine
T4
Thyroxine
TBD
To be decided
TBL
Total bilirubin
TGF-β
Transforming growth factor beta
Th1
T helper type 1 cells
TIL
Tumour infiltrating lymphocyte
TL
Target lesion
TME
Tumour immune microenvironment
TMG
Toxicity management guidelines
TPV
Third party vendor
Treg
Regulatory T cells
TSH
Thyroid-stimulating hormone
UC
Urothelial carcinoma
ULN
Upper limit of normal
UPM
Unit probability mass
WBC
White blood cells
WOCBP
Women of childbearing potential
w/v
% weight per volume
Zr
Zirconium


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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 29 November 2021
Overall Rationale for the Amendment:
This amendment is considered to be a global substantial amendment based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
European Union. 
This protocol amendment incorporates changes requested by the United States Food and Drug 
Administration (FDA).
A high-level description of the changes is provided in the table below.
Section(s)
Description of Change
Title
Title updated to remove “Modular” language
Entire Protocol
•
References to “Core Protocol” changed to “Master Protocol” 
throughout the entire document
•
References to “Module 1” or “Module #” changed throughout 
the entire document to “Substudy 1” or “Substudy #”
•
Updated urothelial bladder cancer (UBC) to urothelial 
carcinoma (UC) throughout for consistency
•
Updates made for clarity and consistency, including the 
correction of grammar and/or spelling.
Sections 1 to 9
Changed from “Core Protocol” sections to “Master Protocol” sections
Sections 1.1, 4.1.1, 4.1.2
Addition of clarified study design details 
Sections 1.2, 10.1.1
Study schema in Figure 3 (Section 10.1.1), which provides details on 
Substudies, copied to Section 1.1 (Figure 2) 
Section 2.3.1
Sentence added to clarify that the TMG is provided as a separate 
document.
Section 4.4.1
Study Stopping Criteria updated to require halting enrolment in the 
event of unacceptable toxicity
Section 10
Changed from “Module 1” to “Substudy 1”
Section 10.8
Blood volumes updated.
Sections 10.1.2, Table 13; 10.8.5.1
Table 18
Additional pharmacokinetic (PK) timepoints added for Substudy 1 
Parts B and C
Sections 10.1.2 Table 13; 10.8.2.1
Table 17
Table added to clarify electrocardiogram collection timepoints
Section 10.1.2 Table 13
Correction of footnotes for clarity
Sections 10.4.1, 10.6.7
Clarified Recommended Phase 2 dose (RP2D) will be defined in 
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Section(s)
Description of Change
Section 10.5.1
Growth differentiation factor 15 (GDF15) cut off of ≥ 
pg/mL 
specified
Section 10.6.8
•
Clarified language regarding relatedness of adverse events in the 
Dose limiting toxicity (DLT) definition
•
Removed DLT exception for Grade ≥3 endocrine disorders
•
Separated exception to DLT criteria for elevated amylase / 
lipase and electrolyte abnormalities
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12
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Clinical Study Protocol – Addendum – Global No. 2
Study Intervention
AZD8853
Study Code
D9450C00001
Addendum Version
2.0
Date
24 June 2022
Global Addendum No. 2
A Phase I/IIa First-in-human, Open-label Study to Evaluate the
Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary
Efficacy of AZD8853 in Participants with Selected
Advanced/Metastatic Solid Tumours
Sponsor Name: AstraZeneca
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s): 
IND number: 157890
EudraCT number: 2021-005438-41
Protocol Number: D9450C00001
Corresponding Protocol Versions:
Amendment 2.0, v3.0 (11 April 2022)
Amendment 1.0, v2.0 (03 December 2021)


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1.
DOCUMENT HISTORY
DOCUMENT HISTORY
Document
Date
Global Addendum 2 (v2.0)
24 June 2022
Protocol Amendment 2 (v3.0)
11 April 2022
Global Addendum 1 (v1.0)
30 Mar 2022
Protocol Amendment 1 (v2.0)
03 Dec 2021
Overall Rationale for the Addendum:
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 European Union.
The primary reason for this addendum is to implement a washout period for prior radiotherapy 
and standard of care treatment. This addendum should be implemented immediately due to 
possible patient safety implications, regardless of current approved protocol version. 
These changes will be incorporated in the next global protocol amendment. 
Section # and Name
Description of Change with Reason
5.1 Inclusion Criteria –
Prior / Concomitant 
Therapy
Add 2 new criteria: 

Wide-field radiotherapy must be completed at least 28 days 
before the first dose of study intervention. However, limited-
field, palliative radiotherapy may be administered up to 7 days 
before the first dose of study intervention. 

Systemic standard of care (SOC) therapy must be completed at 
least 28 days, or 5-half-lives of the SOC therapy, whichever is 
shorter, prior to the first dose of study intervention. 
While the protocol has other defined washout periods, there is not a clear 
washout for radiotherapy and standard of care therapies. Clear washout 
periods are necessary for patient safety, and for supporting a clear safety 
profile. 


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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
Study Code
D9450C00001 (AZD8853)
Edition Number
3.0
Date
28-Jun-2023
A Phase I/IIa First-in-human, Open-label Study to Evaluate the 
Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary 
Efficacy of AZD8853 in Participants with Selected 
Advanced/Metastatic Solid Tumours


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TABLE OF CONTENTS
TITLE PAGE................................................................................................................1
TABLE OF CONTENTS..............................................................................................2
LIST OF ABBREVIATIONS .......................................................................................5
AMENDMENT HISTORY...........................................................................................9
1
INTRODUCTION....................................................................................20
2
CHANGES TO PROTOCOL PLANNED ANALYSES............................20
3
DATA ANALYSIS CONSIDERATIONS ................................................21
3.1
Timing of Analyses...................................................................................21
3.1.1
Substudy 1................................................................................................21
3.2
Analysis Populations.................................................................................22
3.3
General Considerations.............................................................................24
3.3.1
General Study Level Definitions ...............................................................24
3.3.2
Visit Window ...........................................................................................25
3.3.3
Handling of Unscheduled Visits................................................................26
3.3.4
Multiplicity/Multiple Comparisons ...........................................................27
3.3.5
Handling of Protocol Deviations in Study Analysis...................................27
3.3.6
Missing Dates...........................................................................................27
3.3.7
Sample Size..............................................................................................29
3.3.7.1
Dose escalation: mTPI-2...........................................................................29
3.3.7.2
Dose Expansion........................................................................................30
4
STATISTICAL ANALYSIS.....................................................................31
4.1
Study Population.......................................................................................31
4.1.1
Participant Disposition and Completion Status..........................................31
4.1.1.1
Definitions and Derivations ......................................................................31
4.1.1.2
Presentation ..............................................................................................31
4.1.2
Analysis Sets ............................................................................................32
4.1.2.1
Definitions and Derivations ......................................................................32
4.1.2.2
Presentation ..............................................................................................32
4.1.3
Protocol Deviations...................................................................................32
4.1.3.1
Definitions and Derivations ......................................................................32
4.1.3.2
Presentation ..............................................................................................32
4.1.4
Demographics...........................................................................................33
4.1.4.1
Definitions and Derivations ......................................................................33
4.1.4.2
Presentation ..............................................................................................33
4.1.5
Baseline Characteristics ............................................................................34
4.1.5.1
Definitions and Derivations ......................................................................34
4.1.5.2
Presentation ..............................................................................................34
4.1.6
Disease Characteristics .............................................................................34
4.1.6.1
Definitions and Derivations ......................................................................34
4.1.6.2
Presentation ..............................................................................................35
4.1.7
Medical History and Concomitant Disease................................................35


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4.1.7.1
Definitions and Derivations ......................................................................35
4.1.7.2
Presentation ..............................................................................................36
4.1.8
Prior and Concomitant Medications ..........................................................37
4.1.8.1
Definitions and Derivations ......................................................................37
4.1.8.2
Presentation ..............................................................................................37
4.2
Endpoint Analyses....................................................................................38
4.2.1
Safety .......................................................................................................42
4.2.1.1
Exposure...................................................................................................42
4.2.1.2
Adverse Events.........................................................................................43
4.2.1.3
Clinical Laboratory, Blood Sample ...........................................................47
4.2.1.4
Clinical Laboratory, Urinalysis .................................................................49
4.2.1.5
Other Laboratory Evaluations ...................................................................49
4.2.1.6
Vital Signs................................................................................................49
4.2.1.7
Electrocardiogram.....................................................................................50
4.2.1.8
Other Safety Assessments.........................................................................52
4.2.2
Secondary Endpoint: Objective Response Rate .........................................53
4.2.2.1
Definition .................................................................................................53
4.2.2.2
Derivations ...............................................................................................54
4.2.2.3
Handling of dropouts and missing data .....................................................54
4.2.2.4
Primary Analysis of Secondary Endpoint..................................................54
4.2.2.5
Sensitivity Analyses of the Secondary Endpoint........................................54
4.2.2.6
Subgroup Analyses ...................................................................................54
4.2.3
Best Overall response ...............................................................................54
4.2.3.1
Definition .................................................................................................54
4.2.3.2
Derivations ...............................................................................................54
4.2.3.3
Handling of dropouts and missing data .....................................................55
4.2.3.4
Primary Analysis of Secondary Endpoint..................................................55
4.2.3.5
Sensitivity Analyses..................................................................................55
4.2.3.6
Subgroup Analyses ...................................................................................55
4.2.4
Secondary Endpoint: Disease Control Rate at Study Week 15...................55
4.2.4.1
Definition .................................................................................................55
4.2.4.2
Derivations ...............................................................................................55
4.2.4.3
Primary Analysis of Secondary Endpoint..................................................56
4.2.5
Secondary Endpoint: Duration of Response ..............................................56
4.2.5.1
Definition .................................................................................................56
4.2.5.2
Derivations ...............................................................................................56
4.2.5.3
Handling of dropouts and missing data .....................................................56
4.2.5.4
Primary Analysis of Secondary Endpoint..................................................57
4.2.5.5
Sensitivity Analyses of the Secondary Endpoint........................................57
4.2.5.6
Subgroup Analyses ...................................................................................57
4.2.6
Secondary Endpoint: Progression Free Survival........................................57
4.2.6.1
Definition .................................................................................................57
4.2.6.2
Derivations ...............................................................................................57
4.2.6.3
Handling of dropouts and Missing Data ....................................................61
4.2.6.4
Analysis of the Secondary Endpoint..........................................................61
4.2.7
Secondary Endpoint: Change in Target Lesion Tumour Size.....................61


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4.2.7.1
Definition .................................................................................................61
4.2.7.2
Derivations ...............................................................................................62
4.2.7.3
Primary Analysis of Secondary Endpoint..................................................63
4.2.8
Secondary Endpoint: Overall Survival ......................................................64
4.2.8.1
Definition .................................................................................................64
4.2.8.2
Derivations ...............................................................................................64
4.2.8.3
Handling of dropouts and missing data .....................................................65
4.2.8.4
Primary Analysis of Secondary Endpoint..................................................65
4.2.8.5
Sensitivity Analyses of the secondary endpoint.........................................66
4.2.8.6
Supplementary Analyses of the secondary endpoint..................................66
4.2.8.7
Subgroup analyses ....................................................................................66
4.2.9
Secondary Endpoint: Changes in ctDNA from baseline.............................66
4.2.9.1
Definition and Derivations........................................................................66
4.2.9.2
Derivations ...............................................................................................66
4.2.9.3
Primary Analysis of Secondary Endpoint..................................................66
4.2.10
Secondary Endpoint: Change in circulating GDF15 serum levels 
(Applicable for Substudy 1: Part A and Part B only) .................................66
4.2.10.1
Definition and Derivations........................................................................66
4.2.10.2
Primary Analysis of Secondary Endpoint..................................................66
4.2.11
Secondary Endpoint: Change in CD8 tumour infiltration by IHC using 
baseline and on treatment samples (Applicable for Substudy 1: Part A and B 
only).........................................................................................................67
4.2.11.1
Definition and Derivations........................................................................67
4.2.11.2
Primary Analysis of Secondary Endpoint..................................................67
4.2.12
Pharmacokinetics......................................................................................67
4.2.13
Immunogenicity........................................................................................73
5
INTERIM ANALYSIS .............................................................................74
6
REFERENCES.........................................................................................74
7
APPENDICES..........................................................................................74
7.1
Appendix A RECIST................................................................................74
7.2
Appendix B PK Parameter Derivation.......................................................82


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LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ADA
Anti-Drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
AJCC
American Joint Committee on Cancer
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Curve 
BMI
Body Mass Index 
BOR
Best Overall Response
BSR
Baseline Scaled Ratio
CCr
Creatinine Clearance Rate
CD8
Cluster of differentiation 8
CI 
Confidence Interval
CL
Clearance
CL/F
Apparent Clearance
CPQP
Clinical Pharmacology and Quantitative Pharmacology
CPS
Clinical Pharmacology Scientist
CR
Complete Response
CRF
Case Report Forms
CSP/PROTOCOL
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computerised Tomography 
CTAE
Cancer Institute Common Terminology Criteria for Adverse Events 
ctDNA
Circulating Tumour Deoxyribonucleic Acid
CV
Coefficient of Variation 
DBL
Data Base Lock
DCO
Data Cut Off
DCR
Disease Control Rate
DLT
Dose-Limiting Toxicity
DMPK
Clinical Pharmacology & Drug Metabolism and Pharmacokinetics 
DNA
Deoxyribonucleic acid
DoR
Duration of Response


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DU 
De-escalate to the previous lower dose and the current dose is never used again due 
to unacceptable toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
F
Absolute bioavailability
FAS
Full Analysis Set
Frel
Relative bioavailability
gCV
Geometric Coefficient of Variance (%)
GFR
Glomerular Filtration Rate
gmean
Geometric mean
HPDD
Highest protocol defined dose 
ICD
Immune complex disease
ICF
Informed Consent Form
IHC
Immunohistochemistry
IP
Investigational Product
IPD
Important Protocol Deviation
iRECIST
Immune response evaluation criteria in solid tumours
IRR
Infusion related reactions
ITT
Intention to treat
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum 
Max
Maximum
MoA
Mechanism of Action
MRI
Magnetic Resonance Imaging 
MSS-CRC
Microsatellite Stable-Colorectal Cancer 
MTD
Maximum Tolerated Dose
mTPI-2
Modified Toxicity Probability Interval-2
NC
Not Calculable
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NE
Non-evaluable
NED
No Evidence of Disease
NQ
Non-Quantifiable
CCI
CCI
CCI


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NR
Not Reportable
NS
No Sample
NSCLC 
Non-Small-Cell Lung Cancer 
NTL
Non-Target Lesion
OAE
Other significant Adverse Events
OR
Objective Response
ORR
Objective Response Rate
OS
Overall Survival
PAVA
Pool Adjacent Violators Algorithm
PD
Pharmacodynamics 
PFS
Progression-Free Survival
PK
Pharmacokinetics
PR
Partial Response
PDAP
Protocol Deviation Assessment Plan
PDT
Protocol Deviation Tool
PT
Preferred Term
QTcF
Fridericia’s correction
Rac
Accumulation Ratio
Rac
Accumulation Ratio
RECIST v1.1
Response Evaluation Criteria in Solid Tumours version 1.1
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 dose
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease
SMI
Skeletal Muscle Index
SOC
System Organ Class
Std Dev
Standard Deviation
SUV
Standardised uptake value
TCP
Temporal Change Parameter
TEAE
Treatment-Emergent Adverse Events
TFL
Tables, Figures, Listings
TL
Target Lesion
TNM
Tumour, Nodes, and Metastases
UC
Urothelial carcinoma
ULN
Upper Limit of Normal range


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WHODrug
World Health Organisation Drug Dictionary


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AMENDMENT HISTORY


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CATEGORY
Change 
refers to:
Date
Description of change
In line with CSP?
Rationale
N/A
18/08/2022
Initial approved SAP
N/A
N/A
Version 2.0
04/01/2023

Section 2 – Changes to protocol planned 
analyses: 
-
The following bullet point has been added to 
section 2: “At the completion of Substudy 1 
Part A, all appropriate data will be presented 
to answer the primary analysis endpoint 
which will evaluate Dose Limiting 
Toxicities (DLTs) and determine the MTD. 
This deviates from the protocol which 
suggests all data will be presented. 
Presenting data only applicable to the 
primary endpoint of Part A, ensures the 
question is sufficiently answered in a timely 
manner, and prevents other data not needed 
for this endpoint being analyzed too early 
and too often during the study which could 
have a detrimental affect trial integrity.”
No (Planned change).
Added further clarification to 
what will be presented in the 
Primary analysis of Part A. 


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
Section 3.1: 
-
The following text has been added to 
paragraph 1 “Participants who have 
completed study may have their data frozen 
once their data is clean”.
-
Added clarification that data (from previous 
Substudies) will not be re-analysed at the 
completion of all Substudies.  
-
Final analysis definition has been amended 
slightly in section 3.1 to include ‘End of 
study will be based on the last sub-study 
open’.
All changes are in line 
with the CSP. 
Add further clarification to 
the timing of analysis 

Section 3.1.1: Added in the primary analyses to 
be conducted at the completion of each Part in 
Substudy 1 (as per Table 22 Protocol version 3). 
This also includes additional information on data 
cut-offs and data lock. Table 1 has also been 
updated for this information.
To add in the primary 
analyses after Part A of 
Substudy 1

Section 3.2 - Table 2: 
-
Removed immunogenicity listings from 
Table (included in Version 1.0 in error).
Immunogenicity included in 
error; it is already being 
presented in Safety analysis 
set.
-
Referenced additional information on DLT 
analysis set as added in the exposure section 
4.2.1.1.
Additional guidance 
provided on how to derive 
DLT analysis set


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
Section 3.3.2: Additional information has been 
added regarding visit windows and missing visit 
dates: “In the scenario that a complete visit date 
falls into the same visit as one that has been 
assigned due to missing data, the visit with the 
complete date is summarised”
Added to further clarify how 
this data would be handled.

Section 3.3.5: Added that protocol deviations 
will be reviewed before the end of database lock 
and prior to the data cut-off for any primary 
analyses 
Protocol deviations need to 
also be reviewed prior to 
primary analyses (I.e. 
Substudy 1, Part A) where a 
data cut-off is used.


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
Section 3.3.6: Additional information has been 
added into the ‘Missing dates’ section. This 
provides more specific information about the 
date that should be imputed: 

For the imputation of missing AE and 
concomitant medication end dates, where the 
date is completely missing, additional 
information has been added to the following text: 
“Or if it started on or after first dose date then 
impute a date that is after the last dose of study 
drug date'. Added e.g., the day after.”

Additional information added to clarify the 
imputation of data where a participant is known 
to have died: "If a participant is known to have 
died where only a partial death date is available, 
then the date of death is imputed according to the 
rules for imputing AE start dates unless this date 
is before the last date the patient is known to be 
alive from the database" - Added 'In this 
scenario, the day after the last known alive date 
should be imputed.'

Section 3.3.6: Additional information has been 
added into the ‘Missing dates’ section with 
reference to subsequent cancer therapy. This 
allows a more conservative approach to the 
imputation of subsequent therapy start date, 
which means more AEs will be treatment 
emergent: 
-
“Missing day - impute the last day of the 
month unless both the month and the year 
are the same as the last dose date or the 
primary analysis DCO date then impute the 
Added to further clarify how 
this data would be handled.


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last dose date +1 day or the primary analysis 
DCO date. 
-
Missing day and month - impute 31st
December unless the year is the same as the 
last dose date or the primary analysis DCO 
date then impute the last dose date + 1 day 
or the primary analysis DCO date. 
-
Impute last IP dose date + 1 day 
-
Imputed start date should be no earlier than 
the last IP dose.”

Section 4.1.1.2
-
Added participants who completed treatment 
into ‘participant demographics’ table as 
discussed in TFL CRM. 
-
Removed covid pandemic text. This will be 
replaced with “Global/ country situation” as 
we collect information in the CRF on this 
rather than COVID-19.
Added to bring summarises 
in line with the data we 
collect in the CRF
Section 4.1.3.2:

Protocol deviations, presentation. Changed IPDs 
relating to ‘Global\ country situation’ to IPDs 
relating to COVID-19, as PDs are reviewed and 
those relating to COVID-19 are indicated only.

Number and percentage of participants with each 
IPD is presented for each category; At least 1 
IPD, at least 1 Covid-19 related IPD, at least 1 
IPD excluding COVID-19 related IPDs.
Added to bring summarises 
in line with what is collected.


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
Section 4.1.4 – Demographics presentation –
Removed ‘suspected’ COVID-19 from the 
description, as we do not collect suspected 
COVID-19. Demographic data will only be 
presented for participants who have confirmed 
COVID-19 (if data allows).
Added to bring summarises 
in line with what is collected.

Section 4.1.6.1 – Disease characteristics: 
-
Definition and derivations. Correction made 
to an error in the derivation of ‘Time since 
last cancer therapy’ and ‘Time since most 
recent date of progression’ as these should 
be derived in days rather than years. 
-
removed AJCC at study entry as we only 
collect this information at diagnosis
-
Added the number of metastatic sites, to 
present within the demographics section. 
Correction of derivation.
Added to bring summarises 
in line with what is collected.
As requested from the Part A 
TLF CRM. 

Section 4.2: Text prior to Table 3 has been 
reworded slightly so the grammar makes more 
sense.
Correction of grammar.

Section 4.2.1.2 – Amended text so AEs >=Grade 
3 are presented, rather than Grade 3 and 4.

Section 4.2.1.6 – Vital signs – Reference ranges 
need to be presented for vital signs. These have 
been added in Table 6 using the cleaning alert 
ranges from the medical monitoring report. 
As requested from the Part A 
TLF CRM. 
Added so reference ranges 
for vital signs can be 
presented in the TLFs. 

Section 4.2.8.2 – Secondary endpoint overall 
survival, derivations: Added 'Physical 
examination, ECOG and ECG dates' into the list 
of dates to use for last known alive date.
Added to bring summarises 
in line with what is collected.


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
Section 4.2.3.2 - Best Overall Response 
Derivation:
-
Updated the derivation for patients who dies 
with no evaluable RECIST assessments as 
per guidance given in AZ SAP Template: 
AZ SAP guidance is the following:” XX 
weeks is defined as within 2 visits of 
baseline, plus [e.g. 1] week to allow for a 
late assessment within the protocol visit 
window.” This was incorrectly included as 
10 weeks in version 1 but should be 16 
weeks (6 weeks + 9 weeks + 1 week) as per 
guidance. 
-
Updated the derivation for stable disease. 
The current definition incorrectly allows for 
an early assessment within the assessment 
window, which is not specified in the 
protocol for assessments done at week 6, 
meaning a cut-off of 5 weeks is incorrectly 
being used rather than 6 weeks. As per the 
protocol, SD should only be reported if more 
than 6 weeks after first dose. 

Section 4.2.4.1 – Disease control rate at week 15 
-
Definition: Definition of disease control as a 
BOR of SD (without subsequent cancer 
therapy) has changed from being maintained 
from 14 weeks to 15 weeks from first IP, as 
a 1-week early assessment is not allowed in 
the protocol.
Removed “confirmed PR or CR or >16 weeks from first 
IP”. Followed AZ early oncology template: “Disease 
control is defined as a BOR of confirmed CR or PR or 
Correction of derivation and 
definition.


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having SD (without subsequent cancer therapy) 
maintained for ≥ 15 weeks from first IP.”

Section 4.2.6.2 – Progression Free Survival 
Derivation: Updated the derivation for 
calculating two missed visits when considering 
RECIST assessment at Week 6 and Week 15. As 
per the protocol, these two visits do not allow for 
early assessments, which was incorrectly 
considered in SAP Version 1.0. 

Section 4.2.7.2: Change in Target Lesion 
Derivation: As per the protocol, we do not allow 
for an early assessment of RECIST at Week 6 or 
Week 15 assessments, therefore the +/- has been 
removed, allowing for late assessments only: 
“RECIST v1.1 scan performed within W6(D1-
D7), W15(D1-D7).”  

‘RECIST’ updated to ‘RECIST v1.1’ throughout.

Sub-study and Substudies changed to Substudy 
and Substudies respectively throughout. 
Clarify the version of 
RECIST we use throughout.
Ensure consistency 
throughout the SAP.


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Version 3.0
28/06/2023
The RECIST timepoints are incorrectly defined in the 
SAP, the study weeks does not equal the time following 
first IP, for example, the first RECIST assessment is 
expected at study week 6, which is 5 weeks following first 
IP rather than 6 weeks following first IP which was 
incorrectly being used in the SAP. 

Section 4.2.3.2 - Best Overall Response 
Derivation:
o
Updated the derivation for patients who 
dies with no evaluable RECIST 
assessments. The current definition 
incorrectly defines the first assessment 
timepoint at 6 weeks after 1st IP dose 
instead of 5 weeks
o
Updated the derivation for stable 
disease. The current definition 
incorrectly defines the first assessment 
timepoint at 6 weeks after 1st IP dose 
instead of 5 weeks. 

Section 4.2.4 – Disease control at Study week 15:
o
Disease control rate updated to be at 
study week 15 (14 weeks after first IP)., 
rather than at 15 weeks.

Section 4.2.6.2 – Progression Free Survival 
Derivation:
o
Updated the definition of two missing 
consecutive visits, based on the correct 
RECIST timepoints. 

Section 4.2.7.2 – Change in Target Lesion 
Tumour Size Derivation:

Clarified it is Study week 15, rather than week 15 
throughout.
All changes are in line 
with the CSP.
Correction of RECIST time 
windowing as per protocol.


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
Section 4.1.4 – Demographics:
o
Further detail added about Nicotine 
summarises and the derivation of 
number of pack years. 

Section 4.1.6 – Disease Characteristics
o
Time since most recent date of 
progression derived in days, but label 
says “months”. Text has been updated 
so it also says days

Section 4.2.1.7 – ECG: 
o
Added normal reference ranges into the 
SAP for ECG variables.

Section 4.2.1.3 - Clinical Laboratory, Blood 
Sample
o
Included definition for clinically 
significant on-treatment values worse 
than baseline. 

Section 4.2.1.4 - Clinical Laboratory, Urinalysis:
o
Included definition for clinically 
significant on-treatment values worse 
than baseline.  

Section 4.2.1.1 -Exposure: 
o
Total duration of safety follow-up 
derivation and summary has been 
removed.
Added to further clarify how 
this data will be derived and 
handled. 
Updated to be consistent with 
the definition.
ECG variables required for 
derivations in the TLF 
Outputs.
Added clarification on 
definition.
Does not follow AZ TLF 
standards.


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1
INTRODUCTION
This document describes the statistical analysis methodology for protocol D9450C00001 
supporting the Clinical Study Report (CSR). This is a first-in-human Phase 1/2a, multicenter, 
open-label, dose escalation and dose expansion study to evaluate the safety, tolerability, 
preliminary anti-tumour activity, pharmacokinetics (PK), pharmacodynamics (PD) and 
immunogenicity of AZD8853 in patients with selected advanced/metastatic solid tumour. 
The reader is referred to version 3.0 (dated 11 Apr 2022) of the Clinical Study Protocol (CSP) 
and the electronic Case Report Form (eCRF) for details of objectives, study design, study 
conduct and data collection. The Statistical Analysis Plan (SAP) should be read in 
conjunction with the CSP.
The study currently includes 1 “Substudy”, which has 3 parts: Part A (dose escalation), Part 
B (Pharmacodynamics [PD]/ Mechanism Of Action [MoA] Expansion) and Part C (Efficacy 
Expansion). Part B includes Part B1, in which up to approximately 20 participants 
(approximately 10 Microsatellite Stable-Colorectal Cancer (MSS-CRC) participants and 
approximately 10 Non-Small-Cell Lung Cancer (NSCLC) participants) receive an alternative 
dose of Investigational Product (IP), and part B2 in which, up to approximately 20 
participants (approximately 10 MSS-CRC and approximately 10 NSCLC participant) receive 
an IP at Maximum Tolerated Dose (MTD)/Highest Protocol Defined Dose (HPDD). In 
addition, up to approximately 20 participants who consent in part B1 or Part B2 of the study 
may also participate in cluster of differentiation (CD)8+ positron emission tomography (PET) 
imaging, which has additional endpoints. Part C includes Part C1, in which up to 40 
participants (first indication) received IP at MTD/HPDD, and Part C2, in which up to 40 
participants (first indication) received IP at an alternative dose, or up to 40 participants 
(second indication) received IP at MTD/HPDD.
Further combination Substudies may be added into the CSP once a Recommended Phase 2 
Dose (RP2D) for monotherapy has been identified. The SAP will be updated accordingly if 
further Substudies are added. Each section of the SAP describes the general analysis 
applicable to all Substudies and parts. Substudy specific analysis will be described under the 
relevant subheading.
2
CHANGES TO PROTOCOL PLANNED ANALYSES
The following changes have been applied to this version of the SAP and are pending update 
in the protocol: 

The end of study definition in CSP section 4.4 will change from last IP dose to first IP 
dose, “The end of study is defined as 18 months after the last enrolled participant 
received his/her first dose of study IP or when the sponsor stops the study, whichever 
occurs first.”


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
The definition of screen failures, in CSP section 5.4, will change in the protocol. Screen 
failures are patients who have been enrolled but failed to meet the study 
inclusion/exclusion criteria.

At the completion of Substudy 1 Part A, all appropriate data will be presented to answer 
the primary analysis endpoint which will evaluate Dose Limiting Toxicities (DLTs) and 
determine the MTD. This deviates from the protocol which suggests all data will be 
presented. Presenting data only applicable to the primary endpoint of Part A, ensures the 
question is sufficiently answered in a timely manner, and prevents other data not needed 
for this endpoint being analyzed too early and too often during the study which could 
have a detrimental affect trial integrity. 
3
DATA ANALYSIS CONSIDERATIONS
3.1
Timing of Analyses
Participant data will be locked prior to the final analysis of each Substudy, and outputs will 
be produced and reported in a CSR. Participants who have completed study may have their 
data frozen once their data is clean. Further details are provided under each study subsection.
Data will be hard locked once all Substudies are completed, and data will be presented per 
Substudy (and part if applicable) within a CSR, using the Data cut-off (DCO) of the primary 
analysis within each Substudy. Analyses already completed within previous Substudies will 
not be re-run at the hard lock. Additional information on how the data will be presented for 
each Substudy is provided in the corresponding sections of the SAP.
The final analysis of the study is planned 18 months after the last enrolled participant received 
his/her first dose of study IP or when the Sponsor stops the study, whichever occurs first. End 
of study will be based on the last Substudy open.
Further details on the analyses planned are provided in Table 1. 
3.1.1
Substudy 1
For Substudy 1, data is presented separately for part A, B and C. For part A data is presented 
by dose level and overall. For part B, data is presented in separate tables by tumour type, by 
dose level and overall. For part C, data is presented in separate tables for indication by dose 
level (as applicable at the time).  No direct statistical comparisons will be made between any 
cohorts or expansions. 
One interim analysis is planned for Part C in this Substudy. Recruitment will not be paused 
while the participants required for the interim analysis are being evaluated. 


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At the completion of each part within Substudy 1, a primary analysis will be conducted 
(analysis will be conducted separately for each part). 
Table 1: Timing of analysis
Analysis
Trigger
Data Type Included
Final analysis 
The end of the study is defined as 18 
months after the last enrolled participant 
received his/her first dose of study IP or 
when the Sponsor stops the study, 
whichever occurs first.
All data*
Substudy 1
Interim for efficacy expansions 
(Parts C1 and C2)
After the 20th participant in each 
expansion had the opportunity for 2 on-
treatment RECIST assessments 
Efficacy (RECIST v1.1 
ORR, DoR, DCR at 15 
weeks, PFS, OS and 
tumour size)
Safety
Primary analysis
At completion of each part (primary 
analysis is conducted separately for each 
part):
All appropriate data
DCR = disease control rate; DoR = duration of response; IP = Investigational Product; ORR = objective 
response rate; OS= Overall Survival; RECIST = Response Evaluation Criteria in Solid Tumours v1.1; PFS = 
Progression Free Survival. 
*Data will be presented by part at the final analysis of the Substudy, except for safety analyses, which will be 
presented by part and for Part A + Part B if same patients and same dose (See section 4.2).
3.2
Analysis Populations
All participants who receive any amount of IP are included in the Safety analysis set.  For 
the safety and PK analyses, participants are classified according to the IP starting dose. For 
all efficacy analyses, and for baseline and demography, participants are classified according 
to the dose they were assigned to (i.e., the planned IP dose level).
The following populations are defined in Table 2.
Table 2: Populations for Analysis
Population/Analysis set
Description
Endpoint/Output
Enrolled
All participants who sign the ICF
Disposition
Safety
All participants who receive any 
amount of IP.
Baseline and demographics
Exposure
Safety endpoints
PK concentrations listings  


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Population/Analysis set
Description
Endpoint/Output
PK parameters listings
Immunogenicity listings
PFS
OS
ctDNA
DLT Evaluable
Enrolled participants who complete 
the DLT evaluation period (defined as 
21 days after receiving the first 
infusion of IP) with at least 75% 
dosing* and have completed safety 
evaluation requirements during the 
DLT evaluation period, as defined in 
the CSP
OR
Patients who experience any DLT 
during the DLT evaluation period.
DLT
Response Evaluable
All dosed participants who have 
measurable disease at baseline.
ORR
DoR
BoR
DCR at 15 weeks
Percentage change in tumour size
Pharmacokinetics 
All participants who receive at least 
one dose of IP with at least one 
reportable concentration. **
PK concentrations
PK parameters 
Immunogenicity
All participants who receive at least 
one dose of IP who have a non-
missing baseline ADA result and at 
least 1 non-missing post-baseline 
ADA result
Incidence of ADA
ADA titer
Substudy 1 Population
Interim Response Evaluable 
(Interim – Expansion only) 
All dosed participants who had 
measurable disease at baseline and 
have had the opportunity for 2 on-
treatment RECIST assessments (16 
weeks, 6+9 weeks + 1 week window) 
or have had 2 on schedule tumour 
assessments.
ORR at interim 
DoR 
BoR at interim 
Tumour size
Pharmacodynamics 
All participants who receive at least 
one dose of IP with baseline 
measurement and at least one 
Change in circulating GDF15 
serum levels (applicable for Part 
A and Part B only). 


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Population/Analysis set
Description
Endpoint/Output
reportable pharmacodynamic 
measurement.
Change in CD8 tumour 
infiltration by IHC using baseline 
and on treatment samples 
(applicable to Part B only).
ADA=Anti-Drug Antibody; BoR=Best Overall Response; CD8=cluster of differentiation 8; 
ctDNA=circulating tumour deoxyribonucleic acid; DCR=disease control rate; DLT=dose limiting toxicity; 
DoR=duration of response; FAS = Full analysis set; ICF= informed consent form; IP= Investigational 
product; ITT=Intention to treat; PET=positron emission tomography; PFS=Progression Free Survival; 
PK=pharmacokinetics; PD=pharmacodynamics; OS= overall survival; ORR= objective response rate; 
RECIST = Response Evaluation Criteria in Solid Tumours v1.1.
*Please refer to section 4.2.1.1 for the derivation of percentage of dosing. 
** Individual PK concentration and parameter data for any participants who are excluded from the descriptive 
summary tables, figures and/or inferential statistical analyses are included in the listings and are flagged with 
an appropriate footnote.
3.3
General Considerations
Data for Substudy 1 is presented separately for part A, B and C. For part A data is presented 
by dose level and overall. For part B, data is presented in separate tables for tumour type, and 
by dose level and overall (in each column of the tables). For part C, data is presented in 
separate tables for indication or by dose level (as applicable at the time).  
3.3.1
General Study Level Definitions
The general principles described below are followed throughout the study:

Continuous endpoints are summarised by the number of observations, mean, standard 
deviation (Std Dev), median, upper, and lower quartiles (as applicable), minimum, 
and maximum. For data that requires log-transformation, it is more appropriate to 
present geometric mean, Coefficient of Variation (CV), median, minimum, and 
maximum. Categorical endpoints are summarised by frequency counts and 
percentages for each category.  

If data are available for less than three participants, no summary statistics other than 
minimum, maximum, and number of observations are presented.

Unless otherwise stated, percentages are calculated out of the analysis set total 
(excluding efficacy and exposure) and for dose cohort by time point and tumour type 
as appropriate.

For continuous data, descriptive summary statistics (mean, median, Std Dev, standard 
error, Confidence Intervals [CIs]) are rounded to one additional decimal place 
compared to the original data. Minimum and maximum are displayed with the same 
accuracy as the original data.

For categorical data, percentages are rounded to 1 decimal place.

SAS® version 9.4 (as a minimum) is used for all analyses.


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
Baseline is the last non-missing value obtained prior to the first dose/administration 
of any IP and any information taken after first dose/administration of IP is regarded 
as post-baseline information. If two visits are equally eligible to assess participant 
status at baseline (e.g., screening and baseline assessments both on the same date prior 
to first dose/administration with no washout or other intervention in the screening 
period), the average is taken as the baseline value.  For non-numeric laboratory tests 
(i.e., some of the urinalysis parameters) where taking an average is not possible then 
the best value is taken as baseline as this is the most conservative. In the scenario 
where there are two assessments on Day 1 prior to first dose, one with time recorded 
and the other without time recorded, the one with time recorded is selected as 
baseline. Where safety data are summarised over time, study day is calculated in 
relation to date of first treatment.  For assessments on the day of first dose where time 
is not captured, a nominal pre-dose indicator, if available, serves as sufficient 
evidence that the assessment occurred prior to first dose. Assessments on the day of 
the first dose where neither time nor a nominal pre-dose indicator are captured is 
considered prior to the first dose if such procedures are required by the protocol to be 
conducted before the first dose. If no value exists before the first dose/administration, 
then the baseline value is treated as missing. 

In all summaries, change from baseline endpoints are calculated as the post treatment 
value minus the value at baseline. The percentage change from baseline is calculated 
as (post-baseline value - baseline value) / baseline value × 100. For any endpoint 
subjected to log transformation, the change from baseline calculated and summarised 
on the log scale are back-transformed and presented as a ‘baseline scaled ratio’ (BSR). 
Percentage change is then calculated as (BSR - 1) × 100.

Unless stated otherwise, two-sided CIs are produced at 90%. 

For the purposes of summarizing safety data assessed at visits, in addition to baseline 
data, only on treatment data is included in the summary tables. On treatment data is 
defined as data after the first dose of investigational product (IP) and with assessment 
date up to and including the date of last IP + 97 days (to consider the ±7 days visit 
window for the post-treatment follow-up visit planned 90 days after the last dose), 
and prior to the start of any subsequent cancer therapy.
3.3.2
Visit Window
For safety, time windows are defined for any presentations that summarize values by visit.  
The following conventions apply:

The time windows are exhaustive so that data recorded at any timepoint has the 
potential to be summarised. Inclusion within the time window is based on the actual 
date and not the intended date of the visit.

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
The window for the visits’ following baseline is 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 is Day 2). If an even number of days exists between two 
consecutive visits, then the upper limit is taken as the midpoint value minus 1 day.
Substudy 1: 
The first 11 visit windows for data between scheduled assessments in this study are:
-
Day 2, visit window 2-4
-
Day 8, visit window 5-11
-
Day 15, visit window 12-18
-
Day 22, visit window 19-25
-
Day 29, visit window 26-32
-
Day 36, visit window 33-39
-
Day 43, visit window 40-52
-
Day 64, visit window 53-73
-
Day 85, visit window 74-94
-
Day 106, visit window 95-115
-
Day 127, visit window 115-136

Visit windowing are done separately for each assessment based on the schedule of 
events specific to that assessment

Should visit date be missing (due to partial or missing dates), then visits are assigned 
to the nominal visit at which that assessment was recorded, and no windowing is 
performed.

For visit-based summaries, if there is more than one value per participant within a 
time window then the closest value to the scheduled visit date is summarised, or the 
earlier, in the event the values are equidistant from the nominal visit date. In the 
scenario that a complete visit date falls into the same visit as one that has been 
assigned due to missing data, the visit with the complete date is summarised. The 
listings highlight the value for the participant 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.  

For summaries at a participant level, all values are included, regardless of whether 
they appear in a corresponding visit-based summary, when deriving a participant 
level statistic such as a maximum.
3.3.3
Handling of Unscheduled Visits 
See Section 3.3.2.


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3.3.4
Multiplicity/Multiple Comparisons
Not Applicable.
3.3.5
Handling of Protocol Deviations in Study Analysis
The definitions of study specific Important Protocol Deviations (IPDs) are provided in the 
Protocol Deviation Assessment Plan (PDAP). IPDs identified as liable to influence statistical 
analysis may include, but are not limited to the following types of deviations:

Participants who deviate from the core entry criteria as per CSP (e.g., Inclusion, 
exclusion, and discontinuation criteria), and participants who deviate from Substudy 
specific entry criteria as per CSP.

Participants who received prohibited medications or therapies. 

Participants where the administration or dosing of IP is not per CSP.

Procedure/ tests that are outside of required timeframes or not performed as specified 
in the CSP and are required for trial endpoints.
IPDs are tracked throughout the conduct of the study and reviewed by the study team with 
the frequency specified in the PDAP. Protocol deviations are evaluated on a case-by-case 
basis.
None of the deviations lead to the participant being excluded from any analysis sets described 
in the SAP, unless otherwise specified in the PDAP. If a deviation is serious enough to have 
a potential impact on the primary analysis, sensitivity analyses may be performed. The need 
for such a sensitivity analysis is decided during the data review meeting and before the Data-
Base Lock (DBL). A list of all protocol deviations is reviewed and all decisions regarding 
how to handle these deviations are documented by the study team physician, clinical 
pharmacology scientist (CPS) and statistician prior to DBL and prior to the data cut-off for 
any primary analyses, in the Protocol Deviation Tool (PDT).
3.3.6
Missing Dates
When partial dates exist in the data there are some general conventions for when the month 
or day are missing. These are described in the PhUSE guidance on partial dates, which are 
outlined here.
If the whole date is missing, it is more difficult to follow a general principle, and these are 
reviewed within the study and decided on how to be handled. General guidance for 
completely missing dates is provided below, but the guidance is assessed as necessary within 
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Generally, the imputation of dates is used to decide if an observation is treatment emergent 
for adverse events (AEs) or concomitant medications. The imputed dates should not be used 
to calculate durations, where the results would be less accurate.
The following are the guidelines used when partial dates are detected in the study:

For missing diagnostic dates (e.g., disease diagnosis) if day and/or month are missing use 
01 and/or Jan. If year is missing, put the complete date to missing.

For missing AE and concomitant medication start dates (with the exception of subsequent 
cancer therapy), the following is applied:
a.
Missing day - impute the 1st of the month unless month is the same as month of 
the first dose of IP then impute first IP dose date.
b. Missing day and month - impute 1st January unless year is the same as first IP 
dose date then impute first IP dose date.
c.
Completely missing - impute first IP dose date unless the end date suggests it 
could have started prior to this in which case impute the 1st of January of the same 
year as the end date.
d. Imputed start date should be no later than the end date.

For missing AE and concomitant medication end dates, the following is applied:
a.
Missing day - impute the last day of the month unless both the month and the 
year are the same as the last dose date or the primary analysis DCO date then 
impute the last dose date or the primary analysis DCO date. 
b. Missing day and month - impute 31st December unless the year is the same as 
the last dose date or the primary analysis DCO date then impute the last dose 
date or the primary analysis DCO date. 
c.
Completely Missing – need to look at whether the AE/medication is still 
ongoing before imputing a date and when it started in relation to IP. If the 
ongoing flag is missing, then assume that AE is still present / medication is 
still being taken (i.e., do not impute a date). If the AE/medication has stopped 
and start date is prior to first dose date, then impute first dose date. Or if it 
started on or after first dose date then impute a date that is after the last dose 
of study drug date (e.g the day after).

For missing subsequent therapy start dates, the following is applied:


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a.
Missing day - impute the last day of the month unless both the month and the 
year are the same as the last dose date or the primary analysis DCO date then 
impute the last dose date +1 day or the primary analysis DCO date. 
b. Missing day and month - impute 31st December unless the year is the same as 
the last dose date or the primary analysis DCO date then impute the last dose 
date + 1 day or the primary analysis DCO date. 
c.
Completely Missing – Impute last IP dose date + 1 day 
d. Imputed start date should be no earlier than the last IP dose.

Flags are retained in the database indicating where any programmatic imputation has been 
applied, and in such cases for AEs and concomitant medications, any durations would 
not be calculated.

If a participant is known to have died where only a partial death date is available, then 
the date of death is imputed according to the rules for imputing AE start dates unless this 
date is before the last date the patient is known to be alive from the database. In this 
scenario, the day after the last known alive date should be imputed. (See section 4.2.8.3  
for further details).  
3.3.7
Sample Size
Substudy 1
Across all parts of the study up to a total of 165 participants may be enrolled and treated with 
AZD8853 (145 participants if 20 participants from Part B are included in Part C). 
3.3.7.1
Dose escalation: mTPI-2
Part A: Substudy 1
The Modified Toxicity Probability Interval-2 (mTPI-2) employs a simple beta-binomial 
Bayesian model (Guo et al 2017). The posterior density of the toxicity probability is divided 
into multiple intervals with equal length. These intervals are categorized as underdosing 
(below), proper dosing (equivalent), and overdosing (above) in terms of target toxicity. The 
underdosing interval corresponds to a dose escalation, overdosing corresponds to a dose 
de-escalation, and proper dosing corresponds to staying at the current dose. The design for 
the dose-escalation phase of the study uses a target Dose Limiting Toxicity (DLT) rate of 
% and an equivalence interval 
 for dose-escalation/de-escalation decisions as 
well as MTD determination. A dose level is considered unsafe, with no additional participants 
enrolled at that dose level, if it has an estimated 95% or more probability of exceeding the 
target DLT rate of 
% (i.e., P [DLT > 
% | data] ≥ 95%).
CCI
CCI
CCI
CCI


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For specific dose escalation rules, refer to CSP Section 10.6.6.1.3.
For dose escalation (Part A) cohorts of at least 3 and up to 9 evaluable participants are 
required for each dose cohort (unless unacceptable toxicity is seen before 3 evaluable 
participants). The total number of participants will depend on the number of non-evaluable 
participants and the number of dose escalations necessary in order to declare MTD/RP2D. 
More patients may also need to be enrolled to a dose level if toxicity is observed. It is 
anticipated that approximately up to 5 dose-escalation cohorts of up to 9 evaluable 
participants may be included resulting in an overall total of up to approximately 45 
participants.
The dosing cohorts are grouped depending on the starting dose they are planned. The starting 
dose for this study is 300 mg with the maximum dose set at 3000 mg.
3.3.7.2
Dose Expansion 
Part B: Substudy 1 
In the PD/MoA expansions (Part B1 and B2) up to approximately 10 participants may be 
enrolled in each of 2 dose levels and 2 indications (Non-Small-Cell Lung Cancer [NSCLC] 
and Microsatellite Stable-Colorectal Cancer [MSS-CRC]) for a total of approximately 40 
participants. It is thought that approximately 20 participants enrolled in part B of the study 
will participate in CD8+ PET imaging.
Part C: Sub Study 1
At least 40 participants will be enrolled in each efficacy expansion (part C1 and C2) for a 
total of 80 participants. This will be an additional 30 participants per expansion since 10 
relevant participants may be included from the associated PD/MoA expansion. The sample 
size has been determined to provide sufficient precision for the estimation of ORR.  With 40 
participants in each expansion, 
 
 CI. CIs are constructed around the response rates observed in 
each population using the Clopper-Pearson method (Clopper and Pearson 1934) to enable 
decisions to be made about the likely success of future studies in each of the populations. For 
example:
CCI
CCI


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4
STATISTICAL ANALYSIS
This section provides information on definitions, derivation, and analysis/data presentation 
per domain.
4.1
Study Population
The domain study population covers participant disposition, analysis sets, protocol 
deviations, demographics, baseline characteristics medical history, prior and concomitant 
medication.
4.1.1
Participant Disposition and Completion Status
4.1.1.1
Definitions and Derivations
Participants screened is defined as informed consent received. Further details are provided in 
CSP Section 10.5. Participants are followed until either death, lost to follow up or withdrawal 
of consent or end of study. Participants who permanently discontinue from study intervention 
remain in the study follow up until death or withdrawal of consent. Further information is 
defined in CSP section 7.1.
Completion of study is defined in CSP Section 4.4 as 18 months after the last enrolled 
participant received his/her first dose of IP or when the sponsor stops the study, whichever 
occurs first.
4.1.1.2
Presentation
Participant disposition including screen failures and reason for screen failure are summarised 
and listed based on all participants screened (i.e., informed consent received) by the current 
relevant tables, figures, listings (TFL) standards. 
The number and percentage of participants for the following are summarised if applicable:

Participants screened.

Screen failures.

Participants assigned to treatment.

Participants assigned to treatment, but who were not treated.

Participants who started treatment.

Participants ongoing treatment at DCO.

Participants who discontinued treatment, and reason if applicable.


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
Participants ongoing study at DCO.

Participants who withdrew from study and reason if applicable.

Participants who completed study
Summaries on disposition due to global/country situation are added to the disposition table 
if applicable. The number and percentage of participants for the following summaries are 
added if applicable:

Participants who discontinued treatment due to global/country situation.

Participants who withdrew from study due to global/country situation.
Data for each Substudy will be presented as per Section 3.3.
4.1.2
Analysis Sets
4.1.2.1
Definitions and Derivations
For the definitions of each analysis set, refer to section 3.2.
4.1.2.2
Presentation
Data for each Substudy will be presented as per Section 3.3.
Any exclusions from analysis sets are listed.
4.1.3
Protocol Deviations
4.1.3.1
Definitions and Derivations
The examples of the categories are shown in Section 3.3.5.
4.1.3.2
Presentation
The incidence of IPDs is summarised by deviation categories on the safety analysis set by 
deviation category. The number and percentage of participants in the following categories 
are summarised:

Number of participants with at least 1 IPD.

Number of participants with at least 1 COVID-19 related IPD.

Number of participants with at least 1 IPD, excluding COVID-19 related IPDs.
For each summary above, the number and percentage of participants with each IPD is also 
presented.


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A listing is provided with the important protocol deviation details. IPDs resulting from 
coronavirus disease 2019 (COVID-19) circumstances are also included, if any.
Data for each Substudy will be presented as per Section 3.3.
4.1.4
Demographics
4.1.4.1
Definitions and Derivations
Age (years) is grouped accordingly in the following categories: < 65, ≥ 65 years. Each race 
category counts participants who selected only that category. 
Number of nicotine pack years is derived as the following: 
If nicotine substance use is collected daily:
Number of Nicotine pack years= 
Number of nicotine packs per day * Number of years the patient has smoked
If nicotine substance use is collected weekly: 
Number of Nicotine pack years=
( Number of nicotine packs per week /7 ) * Number of years the patient has smoked
4.1.4.2
Presentation
Demographics for Substudy 1 are summarised and listed based on the safety analysis set as 
defined by the current relevant TFL standards. 
The following are summarised: 

Age (years) 

Age group 

Sex 

Race 

Ethnicity
Participant recruitment per country and site is summarised by the safety population.
Participant’s substance (nicotine) use, frequency of substance use and number of pack year, 
is also summarised in a separate table for the safety population.


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If data allows (i.e., there are more than 5 participants with this data), demographic 
characteristics in participants with confirmed COVID-19 infection are summarised, 
otherwise only listings for these participants are provided.
Data for each Substudy will be presented as per Section 3.3.
4.1.5
Baseline Characteristics
4.1.5.1
Definitions and Derivations
Body mass index (BMI) is calculated as: 
BMI(kg/m2 )= weight (kg)
(height (m))2
4.1.5.2
Presentation
Baseline characteristics are listed and summarised for the safety analysis set.
The following are summarised: 

height (cm)

weight (kg) 

BMI (kg/m² )
Data for each Substudy will be presented as per Section 3.3.
4.1.6
Disease Characteristics
4.1.6.1
Definitions and Derivations
Time from original diagnosis to first dose of IP (in months) is calculated as: 
Time from original diagnosis (months)= (Date of first dose of IP-Date of original diagnosis+1)
( 365.25
12
)
Time since last cancer therapy to first dose of IP (in days) is calculated as:
Time since last therapy 
(days) = (Date of first dose of IP-Stop date of last cancer therapy+1) 
Time since diagnosis of metastatic disease to first dose of IP (in months) is calculated as:
Time since diagnosis of metastatic disease (months)= 
(Date of first dose of IP-date of first diagnosis of metastatic disease +1)
( 365.25
12
)


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Time since most recent date of progression to date of first dose of IP (in days) is calculated 
as:
Time since most recent date of progression 
(days)=  (Date of first dose of IP-date of most recent progression +1)
4.1.6.2
Presentation
Disease characteristics at baseline are summarised and listed based on the safety analysis 
set as defined by the current relevant TFL standards.
Summaries are to be produced that present the number and percentage of participants on 
their: 

Histology type at diagnosis

Tumour grade at diagnosis

American Joint Committee on Cancer (AJCC) stage at diagnosis 

Eastern Cooperative Oncology Group Performance Status (ECOG PS)  

Primary tumour location at diagnosis 

Local/metastatic sites at study entry

Tumour Node and Metastases (TNM) classification for primary tumour at time of 
diagnosis and study entry


Location of target lesions at baseline 
Summary statistics are presented for participants’ time from original diagnosis to first dose 
(months), time since last cancer therapy (days), time since diagnosis of metastatic disease 
(months), time since most recent progression (days), number of target Lesions (NTLs), sum 
of diameter of Target Lesions (TLs) and number of metastatic sites. 
Data for each Substudy will be presented as per Section 3.3.
4.1.7
Medical History and Concomitant Disease
4.1.7.1
Definitions and Derivations
Medical history and relevant surgical history, including both resolved and ongoing conditions 
at the time of study entry, are summarized by the primary system organ class (SOC) and 
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preferred term (PT) in accordance with the latest medical dictionary for regulatory activities 
(MedDRA) at the time of DBL/analysis.
Previous Immunotherapy 
The time from most recent immunotherapy to first dose of IP is calculated as:
Time since most recent immunotherapy treatment 
(Days)= (Date of first dose of IP-end date of last immunotherapy treatment +1)
The duration of the last immunotherapy prior to study entry is calculated as: 
Length of last immunotherapy treatment (days)=
(End date of last immunotherapy treatment - Start date of first immunotherapy treatment +1)
Where last immunotherapy is defined as the last immunotherapy administrated prior to study 
drug.  
The length of all prior immunotherapy prior to study entry is calculated as: 
Length of all immunotherapy treatments(days)= 1(𝐸𝑛𝑑𝐷𝑎𝑡𝑒𝑜𝑓𝑖𝑚𝑚𝑢𝑛𝑜𝑡ℎ𝑒𝑟𝑎𝑝𝑦𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡B -
C
BDE
𝑆𝑡𝑎𝑟𝑡𝑑𝑎𝑡𝑒𝑜𝑓𝑖𝑚𝑚𝑢𝑛𝑜𝑡ℎ𝑒𝑟𝑎𝑝𝑦𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡B + 1)
Where 𝑁total number of immunotherapies received by the patient before first dose of IP  
4.1.7.2
Presentation
Data for each Substudy will be presented as per Section 3.3.
Medical history, concomitant disease and surgical history are summarised for the safety 
analysis set by System Organ Class (SOC) and Preferred Term (PT).  
Summaries on participants’ medical history by system organ class and preferred term are 
produced.
Previous Cancer Therapy
Summaries of the number and percentage of participants who have had previous cancer 
treatments are provided by therapeutic class and Anatomical Therapeutic Chemical (ATC) 
classification and generic drug name for the safety analysis set. The number of regimens of 
previous anti-cancer therapies at baseline and best response in most recent regimen are 
summarised as a continuous and categorical variables. Previous treatments are summarised 
by number of regimens. Previous disease related chemotherapy treatments are summarised 
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characteristics are summarised for previous treatments: generic name, time since last dose, 
treatment status, treatment duration, best response, reason for therapy failure and platinum 
sensitivity status at study entry.
Previous Radiotherapy
Summaries of the number and percentage of participants who had at least 1 prior radiotherapy 
are presented for the safety analysis set. Details on previous radiotherapy are listed. 
Previous immunotherapy: 
Summary statistics are presented for time from the last immunotherapy treatment to first IP 
dose (days) and duration of last prior immunotherapy treatment (days). This information will 
also be presented for immediate immunotherapy, including only patients for whom the last 
therapy they had prior to study IP was immunotherapy.  Summary statistics are presented for 
the length all immunotherapy treatments. 
4.1.8
Prior and Concomitant Medications
4.1.8.1
Definitions and Derivations
For the purpose of inclusion in prior and/or concomitant mediation or therapy summaries, 
incomplete medication or radiotherapy start and stop dates are imputed as detailed in Section 
3.3.6.
Prior medications, concomitant medications and post medications are defined based on 
imputed start and stop dates as follows:
•
Prior medications are those taken prior to IP with a stop date prior to the first dose of IP. 
•
Concomitant medications are those with a stop date on or after the first dose date of IP 
and must have started prior to or during treatment so there is at least one day in common 
with the IP.
•
Post-treatment medication are those with a start date after the last dose of IP
4.1.8.2
Presentation
The number and percentage of participants who took prior, concomitant medications, or post 
treatment medications are summarised and listed for the safety analysis set by ATC code and 
the generic name/term coded by the World Health Organization Drug Dictionary 
(WHODrug). Concomitant medications include all concomitant medications taken on or after 
the date of first dose of study treatment or any concomitant medication started prior to the 
first dose of study treatment that continued beyond the date of first dose of study treatment.
The number and percentage of participants who have had post-treatment medications, 
therapy class and agents received are summarised, this includes the number of participants 


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who have had subsequent anti-cancer therapies, and the best response from subsequent 
therapy.
Metformin
The number and percentage of participants who took Metformin medication prior to IP 
treatment are summarised separately if data allows (i.e., more than 5 participants took 
Metformin treatment), else data are only listed. The time between last dose of Metformin and 
first dose of IP treatment are also summarised, and can be calculated by the below formula: 
Time since last Metformin dose (days)= 
(Date of first dose of IP-Date of last Metformin dose + 1)
Data for each Substudy will be presented as per Section 3.3.
4.2
Endpoint Analyses
This section covers details related to the endpoint analyses such as primary, secondary, and 
other endpoints including sensitivity and supportive analyses. Core endpoint analyses are 
described in Table 3.
Endpoints that are specific to ‘Substudy 1’ are provided in Table 4. Exploratory analyses for 
Substudy 1 will be reported separately from the CSR and therefore will be described outside 
of the SAP.
Table 3: Core Endpoint analysis
Statistical 
category
Endpoint
Population
Population level 
summary (analysis)
Details in 
section
Objective 1:  To assess safety and tolerability, characterize DLTs (in dose escalation parts only) and 
determine the MTD or RP2D of AZD8853 in participants with selected advanced/metastatic solid tumours
Primary
AEs, SAEs, 
clinically 
significant changes 
from baseline in 
clinical laboratory
parameters, vital 
signs, and ECG 
results, Incidence 
of AEs leading to 
discontinuation of 
AZD8853.
Safety analysis set 
Percentage of
participants with AEs, 
SAEs, clinically 
significant changes 
from baseline in 
clinical laboratory 
parameters, vital 
signs, and ECG 
results.
Percentages of 
participants with AE 
leading to
discontinuation
4.2.1
Objective 2: To determine the preliminary anti-tumour activity of AZD8853 in participants with selected 
advanced/metastatic solid tumours


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Statistical 
category
Endpoint
Population
Population level 
summary (analysis)
Details in 
section
Secondary
ORR according to 
RECIST v 1.1
Response evaluable 
set 
Rate and 90% CI (2-
sided CI) 
4.2.2
Secondary
DCR at Week 15 
according to 
RECIST v 1.1
Response evaluable 
set 
Rate and 90% CI (2-
sided CI) for each 
cohort at 15 weeks.
4.2.4
Secondary
DoR according to 
RECIST v 1.1
Subset of response 
evaluable set: 
participants with 
confirmed objective 
response
Kaplan-Meier plots 
and median DoR time 
estimated using 
Kaplan Meier 
method.
4.2.5
Secondary
PFS
Safety analysis set 
Kaplan-Meier plots 
and median PFS time 
estimated using 
Kaplan Meier 
method.
4.2.6
Secondary
Change in target 
lesion tumour size
Response evaluable 
set 
Percentage change in 
tumour size from 
baseline, at each 
timepoint is 
summarized by mean 
change and St Dev 
Percentage change 
from baseline for each 
participant is 
produced over time in 
a spider plot. 
Waterfall plots of 
percentage change 
from baseline and 
best percentage 
change from baseline 
is produced.
4.2.7
Secondary
OS
Safety analysis set 
Kaplan-Meier plots 
and median OS time 
estimated using 
Kaplan Meier 
method.
4.2.8
Objective 3: To assess the efficacy of AZD8853 using longitudinal blood samples in participants with 
selected advanced/metastatic solid tumours 
Secondary
Change in ctDNA 
from baseline
Safety analysis set 
Percentage change in 
ctDNA from baseline 
to each post baseline 
timepoint is 
summarized by mean 
change and St Dev. 
Maximum change is 
4.2.9


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Statistical 
category
Endpoint
Population
Population level 
summary (analysis)
Details in 
section
also summarised by 
mean and St. Dev. 
Objective 4: To determine the PK of AZD8853 in serum when administered in participants with selected 
advanced/metastatic solid tumours 
Secondary
PK
parameters
(include but not 
limited to Cmax 
and AUC)
PK analysis set
Summary of PK
profile of AZD8853
4.2.12
Objective 5: To assess the immunogenicity of AZD8853 in participants with selected advanced/metastatic 
solid tumours 
Secondary
ADAs against 
AZD8853 in
Serum
Immunogenicity 
analysis set
Incidence of 
detectable ADAs
against AZD8853 in
serum
4.2.13
ADA = antidrug antibodies; AUC = Area Under the Curve; AEs = Adverse Events; CI= Confidence Interval; 
ctDNA = circulating tumour deoxyribonucleic acid; DCR= disease control rate; DLT= dose limiting toxicity; 
DoR=duration of response; ECG= Electrocardiogram; MTD = Maximum Tolerated Dose; OS= overall 
survival; ORR=objective response rate; PFS=Progression Free Survival; PK =pharmacokinetics; RECIST = 
Response Evaluation Criteria in Solid Tumours v1.1; RP2D = Recommended Phase 2 Dose; SAEs = Serious 
Adverse Events; St. Dev = Standard Deviation.
Table 4: Substudy 1 Endpoints
Statistical 
category
Endpoint
Population
Population level 
summary (analysis)
Details in section
Objective 1:  To assess safety and tolerability, characterize DLTs (in dose escalation parts only) and 
determine the MTD or RP2D of AZD8853 in participants with selected advanced/metastatic solid tumours.
Primary (Part 
A only)
DLTs 
DLT evaluable 
set 
Number of 
participants 
with DLTs.
4.2.1.8
Objective 6: To evaluate the PD activity of AZD8853 by assessment of candidate biomarkers in 
participants with selected advanced/metastatic solid tumours (Part A and Part B only)
Secondary
Change in circulating 
GDF15 serum levels
PD analysis set 
Actual and percentage 
change in circulating 
GDF15 serum levels 
from pre-treatment 
(baseline) to each post 
baseline timepoints as 
well as the maximum 
change will be 
summarised using 
descriptive statistics 
such as mean change 
and St.Dev.
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Statistical 
category
Endpoint
Population
Population level 
summary (analysis)
Details in section
Objective 7: To evaluate the intra-tumoral PD activity of AZD8853 in participants with selected 
advanced/metastatic solid tumours (Part B only)
Secondary
Change in CD8 
tumour infiltration by 
IHC using baseline 
and on-treatment 
samples
Subset of PD 
analysis set 
(who have 
paired biopsies)
Change in CD8 
tumour infiltration by 
IHC between the pre-
treatment and on-
treatment biopsy will 
be summarised using 
descriptive statistics 
such as mean change 
and St.Dev.
4.2.11
BMI=Body Mass Index; CD8=cluster of differentiation 8; DoR=duration of response; DNA= Deoxyribonucleic 
acid; IHC=Immunohistochemistry;
; OS= overall survival; ORR= objective 
response rate; PD=pharmacodynamics; PFS= Progression Free Survival; PK=pharmacokinetics; PET= positron 
emission tomography; RNA = Ribonucleic acid; SAP = Statistical Analysis Plan; St. Dev = Standard Deviation; 
SMI= Skeletal muscle index; SUV = Standardized Update Value.
Efficacy analyses, except for OS and ctDNA, are based on programmatic application of 
Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 (Eisenhauer et al, 2009) to 
investigator assessed tumour measurements. Programmatic derivation guidance used for the 
application of RECIST v1.1 are provided in Appendix A in the Appendices, which is used to 
determine disease response. RECIST v1.1 data with overall visit response and best objective 
response are listed.
RECIST v1.1 data, overall visit response and best objective response are listed. Additional 
listing(s) are produced for tumour assessments per patient, BOR, DOR, DCR.  
Substudy 1
For Substudy 1, all efficacy analyses are presented separately for part A, B and C. For part 
A data is presented by dose level and overall. For part B, data is presented in separate tables 
for tumour type by dose level and overall. For part C, data is presented in separate tables for 
indication by dose level (as applicable at the time). Safety data will be presented as follows:
•
Part A only - during dose escalation.
•
Part B only (by tumour type) 
•
Part A+B+C if patients have the same dose and same disease 
•
Part C only (by indication)
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4.2.1
Safety
The Safety and tolerability primary endpoints are assessed in terms of AEs/ Serious Adverse 
Events (SAEs), AEs leading to discontinuation of AZD8853, DLTs, clinically significant 
changes from baseline in clinical laboratory parameters, vital signs, and electrocardiogram 
(ECG) results.
The domain safety also covers exposure and ECOGs. 
These variables are collected for all participants. All safety analyses are performed on the 
safety analysis set. Listings are provided for all participants or the safety analysis set 
depending on the availability of data.
DLT summaries or listings are provided on the DLT evaluable population set. 
4.2.1.1
Exposure
4.2.1.1.1
Definitions and Derivations
Infusion administered medications
Substudy 1:

Duration of exposure is defined by last date of actual dosing (i.e., a dose > 0 [mg] is 
given) in the last cycle plus 21 days minus the date of first treatment with IP plus 1 day. 
o
For participants who die whilst on study treatment or if a DCO occurs, duration of 
exposure is defined as date of death/DCO (whichever occurs first) minus the date of 
first treatment plus 1 day.
o
Therefore: Duration of exposure(days) = (min (last dose date where dose > 0 [mg] 
+ 21 days, date of death, date of DCO) – first dose date + 1). 

The duration of exposure in cycles is calculated as:
Duration of exposure (cycles)= The number of cycles in which at least one
portion of IP was administered (i.e., dose > 0 [mg])
If a cycle is prolonged due to toxicity, this should still be counted as one cycle.

The actual duration of exposure is calculated as:
Actual duration of exposure
(days)= Number of cycles participants received X 21 (days)
Duration of exposure is calculated as above, and dose interruptions are defined as any 
length of time where the participant has not taken any of the planned dose in accordance 


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with the protocol. The actual exposure calculation makes no adjustment for any dose 
reductions that may have occurred. 

Dose intensity of IP(s) is addressed by considering relative dose intensity (RDI), where 
RDI is the percentage of the actual dose delivered relative to the intended dose through 
to treatment discontinuation.  More specifically, RDI is defined as follows:  
RDI = 100 X d/D 
o
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. 

Percentage of first dose received, which is used to define the DLT population is 
calculated as  
𝑃𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒𝑜𝑓𝑑𝑜𝑠𝑖𝑛𝑔𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑= 𝐴𝑐𝑡𝑢𝑎𝑙𝑓𝑖𝑟𝑠𝑡𝑑𝑜𝑠𝑒𝑜𝑓𝐴𝑍𝐷8853 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑
𝑃𝑙𝑎𝑛𝑛𝑒𝑑𝑓𝑖𝑟𝑠𝑡𝑑𝑜𝑠𝑒𝑜𝑓𝐴𝑍𝐷8853 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑∗100
4.2.1.1.2
Presentation
Duration of exposure to IP in days is summarised by descriptive statistics and by frequency. 
Dose intensities are summarised by descriptive statistics and by the categories <75, 75-125, 
and >125. Exposure to IP, i.e., total amount of study drug received, are listed for all 
participants. 
Exposure swimmer plot(s) are produced, with a line presented for each participant to display 
relevant exposure and disposition details. 
Dosing deviations for IP are summarised with reasons for deviations for the following 
categories: delays and interruptions. The frequency counts and percentage of the number of 
participants with delays and/or interruptions and total count per participant are summarised. 
The frequency counts and percentage of the number of participants with dosing delays and 
total count dose delays per participant are summarised.
4.2.1.2
Adverse Events
MedDRA (using the latest or current version) are used to code the AEs. AEs are graded 
according to the National Cancer Institute Common Terminology Criteria for AEs (NCI 
CTCAE) (using the CTCAE version referenced in the CSP).
Treatment emergent AEs (TEAEs) are all AEs which onset or worsen in severity following 
the first administration of IP within the duration of the treatment period, up to and including 
97 days [90 days +/- 7 days] after the last dose of IP as per the study safety follow up period 


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but prior to subsequent cancer therapy. Worsening in severity is determined by comparison 
with the pre-treatment CTCAE grade of the AE recorded closest to the start of dosing.
For rules on missing or partial dates, see Section 3.3.6. AEs with a missing start time (or 
where time is not collected) which occur on the same day as first IP administration are 
reported as treatment emergent SAEs.
When assigning AEs to the relevant phase of the study the following rules apply and any 
deviations must be agreed by the study team:

Pre-treatment phase: All AEs with a start date after signing the informed consent form 
(ICF), prior to the first administration of IP that do not subsequently go on to worsen 
during the treatment emergent phase.

Treatment emergent phase: All AEs (starting or worsening) on or after the first dose of 
study intervention and within 97 days [90 days +/- 7 days] after the last dose of study 
IP or up to the day prior to start of subsequent therapy, whichever comes first.
SAEs
An SAE is an AE occurring during any study period that fulfils one or more of the 
following criteria:
• 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 participant
• Is an important medical event that may jeopardize the participant or may require medical
treatment to prevent one of the outcomes listed above.
AEs of special interest
An Adverse Event of Special Interest (AESI) is one of scientific and medical interest specific 
to understanding of the study intervention and may require close monitoring and rapid 
communication by the investigator to the sponsor. AESIs include but are not limited to:

 
 

 
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


 

Other AEs which are AESIs with AZD8853 include, but are not limited to:

)

 


More information regarding AESIs can be found in the CSP section 8.3.6. Other categories 
may be added, or existing terms may be modified as necessary. An AstraZeneca medically 
qualified expert after consultation with the Global Patient Safety Physician has reviewed the 
AEs of interest and identified which higher-level terms and which preferred terms contribute 
to each AESI. Further reviews may take place prior to DBL to ensure any further terms not 
already included are captured within the categories. Preferred terms used to identify AESI is 
listed before DBL.
Other Significant Adverse Events (OAE)
During the evaluation of the AE data, an AstraZeneca medically qualified expert reviews the 
list of AEs that were not reported as SAEs and AEs leading to discontinuation of IP.  Based 
on the expert’s judgement, AEs of 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 are performed for 
identification of OAEs. This review takes place prior to DBL, and any AEs identified are 
fully documented in meeting minutes.  Further review following DBL may result in ad-hoc 
OAEs being identified, in this case, the OAEs and resulting summaries are fully documented 
in the CSR.   
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.
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4.2.1.2.1
Presentation
All TEAEs are summarised and listed. AEs which are not treatment emergent are listed for 
the safety analysis set.
TEAEs are counted once for each participant for calculating percentages of participants 
experiencing TEAE. In addition, if the same TEAE occurs multiple times within a participant, 
the highest severity, and level of relationship observed are reported. For tables by MedDRA 
SOC and MedDRA PT, participants with multiple TEAEs are counted once for each SOC/PT.
An overall summary table of the number of participants experiencing each category of AEs 
is produced. The number of participants experiencing TEAEs by MedDRA SOC and PT are 
summarised and the severity, and relationship to study drug are summarised. Further splits 
by CTCAE grade, causal relationship to IP and AEs with Grade 3-5 are also summarised.
Separate tables present DLTs (applicable for Substudy 1 Part A only), AEs leading to 
discontinuation, SAEs, IP-related AEs, and other significant adverse events.
Details of any deaths are summarised and listed for all participants. SAEs leading to death 
are also summarised. 
SAEs
SAEs are summarised as described above for the TEAEs.
AEs of special interest
Grouped summary tables of certain MedDRA preferred terms are produced and may also 
show the individual preferred terms which constitute each AESI grouping. Groupings are 
based on preferred terms provided by the medical team prior to DBL, and a listing of the 
preferred terms in each grouping is provided.
Summaries of the above-mentioned grouped AE categories include number and percentage 
(%) of participants who have:

At least one AESI presented by event outcome

At least one AESI causally related to IP

At least one AESI leading to discontinuation of IP.
A summary of total duration (days) of AESI is provided for events which have an end date, 
and this may be supported by summaries of ongoing AESIs at death and, separately, at DCO.


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4.2.1.3
Clinical Laboratory, Blood Sample
4.2.1.3.1
Definitions and Derivations
Laboratory tests are grouped according to chemistry, haematology, and coagulation. 
Laboratory parameters are assessed at baseline as well as throughout the study.
For chemistry, haematology, and coagulant parameters, laboratory abnormalities with 
toxicity grades according to the NCI CTCAE version 5.0 are derived.
Change from baseline in haematology, clinical chemistry and coagulation endpoints are 
calculated for each post-dose visit. CTC grade is calculated at each visit. Maximum 
post-baseline CTC are also calculated. Absolute values are compared to the local laboratory 
reference range and classified as low (below range), normal (within range or on limits of 
range) and high (above range). All values classified as high or low are flagged on the listings.
Liver Function Parameters
Participants with elevated post-baseline Alanine Aminotransferase (ALT), Aspartate 
Aminotransferase (AST) or Total Bilirubin that fall into these categories are identified. 
Number and percentage of these participants are tabulated. The summaries are presented 
based on categories of the liver function parameters summarised below in Table 5.
Table 5: Liver function parameters
Liver Function Parameters
Category
ALT
•
≥3 × – ≤5 × ULN 
•
>5 × – ≤8 × ULN
•
>8 × ULN
AST
•
≥3 × – ≤5 × ULN 
•
>5 × – ≤8 × ULN
•
>8 × ULN
Total bilirubin
•
≥2 × – ≤3 × ULN
•
>3 × – ≤5 × ULN
•
>5 × – ≤10 × ULN 
•
>10 × ULN
ALT or AST
•
≥3 × – ≤5 × ULN
•
>5 × – ≤8 × ULN
•
>8 × ULN
Potential Hy’s law 
•
(AST ≥ 3 × ULN or ALT ≥ 3 × ULN) and (Total 
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Liver Function Parameters
Category
ALT = Alanine transaminase; AST = Aspartate transaminase; ULN: =upper limit of normal 
range.
a It includes all participants who have ALT or AST≥3xULN and total bilirubin (BILI) ≥2xULN, 
and in which the elevation in transaminases precede or coincide with (that is, on the same day as) 
the elevation in BILI. Hy’s law is potential Hy’s law, where no other reason, other than IMP, can 
be found to explain the combination of increases. 
4.2.1.3.2
Presentations
The changes in each laboratory parameter from baseline to each post-baseline visit are 
summarised graphically.
Laboratory abnormalities occurring from the start of IP administration to the last assessment 
on study as well as CTC grades are presented in listings together with further information 
about individual laboratory assessments. Worst toxicity grade, rates of grade 3-4 toxicity, 
and grade shifts of 2 or more from baseline to the maximum grade are presented. Summaries 
indicating hyper- and hypo- directionality of change are produced, where appropriate. 
Laboratory parameters that cannot be graded via NCI CTCAE are summarised with 
frequencies of post-baseline laboratory values categorized as low (L), normal (N), or high 
(H) using laboratory normal ranges compared to baseline.
Boxplots may be used to summarize changes in clinical laboratory results at each timepoint 
if the results are deemed of interest to present.
Chemistry and Haematology clinically significant on-treatment values worse than baseline 
will be presented. All clinically significant on-treatment values that were originally normal 
at baseline will be presented. On-treatment clinically significant values that were also 
clinically significant at baseline will be presented if CTCAE grade is higher than baseline, or 
if the clinically significant value is a change in direction (i.e. changed from clinically 
significant low value at baseline to clinically significant high value post baseline).  
Listings are provided for all laboratory results.
Liver Function Parameters
Number and percentage of participants with elevated post-baseline ALT, AST or Total 
Bilirubin are tabulated. Individual participant data where elevated ALT or AST plus total 
bilirubin fall into the “Potential Hy’s law” are summarised and/or listed.
A scatter plot of ALT versus total bilirubin, both expressed as multiples of the upper limit of 
normal (ULN), will be produced with reference lines at 3×ULN for ALT, and 2×ULN for 
total bilirubin. The scatter plot will be repeated for AST versus total bilirubin with reference 
lines at 3×ULN for AST, and 2×ULN for total bilirubin. In each plot, total bilirubin will be 
in the vertical axis. Liver biochemistry test results over time for patients who show elevated 


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ALT or AST (≥3xULN) and elevated total bilirubin (≥ 2xULN) (elevated results do not need 
to be present at the same visit), or a total bilirubin of ≥ 5xULN will be tabulated and plotted.
4.2.1.4
Clinical Laboratory, Urinalysis
4.2.1.4.1
Definitions and Derivations
Laboratory parameters are assessed at baseline as well as throughout the study. 
CTC grade is calculated for urinalysis at each visit.  Maximum on treatment CTC is also 
calculated.  Absolute values are compared to the local laboratory reference range and 
classified as low (below range), normal (within range or on limits of range) and high (above 
range). All values classified as high or low are flagged in the listings. 
4.2.1.4.2
Presentations
For urinalysis, shift from baseline to worst on treatment results are presented. Urinalysis 
abnormalities occurring from the start of IP administration to the last assessment on treatment 
are presented.
Urinalysis clinically significant on-treatment values worse than baseline will be presented. 
All clinically significant on-treatment values that were originally normal at baseline will be 
presented. On-treatment clinically significant values that were also clinically significant at 
baseline will be presented if CTCAE grade is higher than baseline.   
Listings are provided for urinalysis.
4.2.1.5
Other Laboratory Evaluations 
4.2.1.5.1
Definitions and Derivations
Pregnancy testing 
Pregnancy tests are obtained at baseline and at day 1 of each cycle. 
4.2.1.5.2
Presentations
Pregnancy testing 
Any pregnancy tests that result in a positive result are line listed by time-point at which the 
positive pregnancy result occurred.
4.2.1.6
Vital Signs
4.2.1.6.1
Definitions and Derivations
Vital sign parameters (body temperature, blood pressure, heart [pulse] rate, respiration rate, 
and body weight) are assessed at baseline and throughout the study. 


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4.2.1.6.2
Presentations
Vital signs are summarised by study visit which may include descriptive statistics for the 
value of the parameters and the changes from baseline. Absolute values and change from 
baseline for vital signs data at each timepoint are presented using box plots.
Listings are also provided for vital signs using the normal ranges in Table 6.
Table 6 Vital Signs Normal Ranges
AZ Test Name
Outside AZ defined 
reference range lower limit 
if
Outside AZ defined 
reference range upper limit 
if
AZ Unit
Diastolic blood 
pressure
<40
>110
mm Hg
Pulse 
<40
>160
beats/min
Systolic blood 
pressure
<70
>180
mm Hg
Temperature
<35
>38
° C
Weight
<40
>130
kg
4.2.1.7
Electrocardiogram
4.2.1.7.1
Definitions and Derivations
ECG parameters are assessed at baseline as well as throughout the study. ECG parameters 
include heart [pulse] rate, RR, PR, QRS, QT and QT interval corrected using Fridericia’s 
formula (QTcF). The QTcF is considered as the primary correction method to assess 
participant cardiac safety.
ECGs are performed at scheduled timepoints pre-dose and post-dose in single at on treatment 
visits and in triplicate at SCR and EOT. For triplicate measurements, the mean value of the 
triplicate measurement are recorded as the value of appropriate timepoint for pre-dose 
respective post-dose assessment. A triplicate measurement is only deemed missing where all 
triplicate values are missing, otherwise, if one value is missing the mean is taken from the 
two obtained measurements, and if two values are missing the value is taken as the one 
obtained measurement.  
From the resting 12-lead ECGs values of the QT and RR intervals, the QTcF is derived using 
the following formula:


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𝑄𝑇𝑐𝐹= 𝑄𝑇
𝑅𝑅
E
\
where RR is in seconds.
The values of QTcF (milliseconds) are re-derived from the values of RR and QT during the
creation of the reporting database.
The notable ECG interval values while on treatment are:

Maximum QTcF intervals > 450 milliseconds, > 480 milliseconds, and > 500 
milliseconds.

Maximum changes from baseline in QTcF > 30, >60, and > 90 milliseconds.
4.2.1.7.2
Presentations
ECG parameters are summarised using descriptive statistics by visit and change from 
baseline in ECG endpoints are calculated for each post-dose visit. Absolute values and 
change from baseline for ECG data at each timepoint are presented using box plots.
The number and percentage of participants having notable ECG interval values while on 
treatment are summarised.
Further, QT and QTcF intervals, at any observation on treatment, are summarised.
Listings are also provided for ECGs using the normal ranges in Table 7.
Table 7 ECG Normal Ranges
AZ Test 
Name
Outside AZ cardiac SKG 
reference range lower limit if
Outside AZ cardiac SKG 
reference range upper limit if
AZ Unit
PR 
<100
>240
msec
QRS 
<70
>120
msec
QT
<300
>450
msec
QTcF
<300
>450*
msec
HR
<45
>120
BPM
RR
<500
>1333
msec
*Cut-off values for categorical analyses recommended by ICH E14
BPM = Beats per minute, Msec = milliseconds


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4.2.1.8
Other Safety Assessments
4.2.1.8.1
Definitions and Derivations 
Maximum Tolerated Dose Evaluation (applicable to Substudy 1 Part A only)
See Section 6.6.5 of the CSP for the definition of a DLT. For reporting purposes, the DLTs 
are as approved and documented at the Safety Review Committee meetings.
After the escalation phase is completed, DLT rates at each dose level are estimated by 
isotonic regression (Ji et al, 2010). The weighted least squares regression model conditional 
on monotonic non-decreasing DLT rates with increasing dose and use the empirical 
(observed) DLT rates at each dose level as responses and sample sizes at each dose level as 
weights, along with the Pool Adjacent Violators Algorithm (PAVA) to estimate the DLT rate 
at each dose level using available software (eg, Cytel EAST or the function pava from the R 
package ‘ISO’). Given the DLT estimates for each dose level, the MTD is selected from all 
tried dose levels that have not been previously declared to be unsafe with a “de-escalate to 
the previous lower dose and the current dose is never used again due to unacceptable toxicity” 
(DU) decision according to the mTPI-2 decision table. With this constraint, the MTD is 
determined as the dose level with the DLT estimate closest to the target toxicity level of 
%. 
In the case of dose levels with estimated toxicity of equal distance (tied dose levels) from the 
target toxicity of 
%, the following approach is used (Ji et al, 2010): among all tied dose 
levels the highest dose level with target toxicity ≤ 
% is selected, unless all tied dose levels 
have estimated toxicity > 
%, in which case the lowest dose level is selected.
If no DLTs are observed meaning the MTD is unable to be concluded, the maximum per 
protocol dose will be used.
ECOGs
Performance status is assessed according to ECOG criteria at timepoints throughout the 
study. The ECOG criteria is summarised in section 8.2.2. of the CSP.
4.2.1.8.2
Presentations
Maximum Tolerated Dose Evaluation (applicable to Substudy 1 Part A only)
The MTD evaluation is based on the DLT evaluable population. The number and 
percentage of participants with DLT during dose escalation are presented by dose level.
ECOGs
The number and percentage of each participant in each ECOG category will be displayed by 
each timepoint. 
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4.2.2
Secondary Endpoint: Objective Response Rate
A secondary efficacy endpoint is objective response rate (ORR).
4.2.2.1
Definition
The ORR is programmatically derived based on the site investigator RECIST v1.1 data, and
using all scans regardless of whether they were scheduled or not.
Objective Response (OR) is defined as a programmatically derived, confirmed best overall 
response of Complete Response (CR) or Partial Response (PR) that occurs prior to the 
initiation of subsequent anticancer treatment and prior to progression. ORR is defined as 
the percentage of participants with OR.
A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and 
confirmed by repeat imaging not less than 4 weeks after the visit when the response was 
first observed with no evidence of progression between the initial and CR/PR confirmation 
visit.  Data obtained up until progression, or last evaluable assessment in the absence of 
progression, are included in the assessment of ORR. Also, only data obtained before the 
start of subsequent anticancer treatment (excluding radiotherapy) are included. Therefore, 
both visits contributing to a confirmed response must be prior to progression and prior to 
subsequent anticancer treatment.   
In the case where a participant has two non-consecutive visit responses of PR, then, if the 
time between the 2 visits of PR is greater than 4 weeks and there is no progressive disease 
between the PR visits, then a best response of PR is assigned.  Similarly, if a participant has 
visit responses of CR, Not Evaluable (NE), CR, then, as long as the time between the 2 
visits of CR is greater than 4 weeks, then a best response of CR is assigned.
In cases where CRC subjects may undergo potentially curative surgery at some point 
following treatment, an additional summary of responses will be provided to distinguish 
between surgically and drug-only induced responses as follow:
-
ORR where only responses prior to curative surgery are included in the numerator 
(secondary endpoint described in previous section).
-
ORR where subjects who have surgery that results in the absence of any tumour after 
surgery are treated as a CR and are included in the numerator.
Subjects receiving surgery should continue to be followed up for objective disease 
progression as defined by RECIST v1.1.
Overall visit response post curative surgical intervention derivation is described in section 7
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4.2.2.2
Derivations
See Section Definition 4.2.2.1.
4.2.2.3
Handling of dropouts and missing data
Handling of missing TL data is described in Appendix A (Section 7.1). 
4.2.2.4
Primary Analysis of Secondary Endpoint
ORR is based on a subset of all treated participants with measurable disease at baseline per 
the site investigator.
Summaries are produced that present the number and percentage of participants with a 
confirmed tumour response (CR/PR). The ORR is presented with a two-sided 90% CI using 
the Clopper-Pearson (exact probability) method. Participants that have missing OR 
assessments at all visits are considered as non-responders and are therefore counted in the 
denominator of ORR. The main analysis of ORR is based on the response evaluable set.
4.2.2.5
Sensitivity Analyses of the Secondary Endpoint
Sensitivity analysis is NA.
4.2.2.6
Subgroup Analyses
Subgroup analysis is NA.
4.2.3
Best Overall response
4.2.3.1
Definition
BOR is calculated based on the overall visit responses from each RECIST v1.1 assessment, 
described in Appendix A (Section 7.1). It is the best response a participant has had following 
start of IP, but prior to starting any subsequent cancer therapy and up to and including 
RECIST v1.1 progression or the last evaluable assessment in the absence of RECIST v1.1 
progression. Categorization of BOR is based on RECIST v1.1 using the following response 
categories: CR, PR, Stable Disease (SD); progressive disease; and NE.
BOR is determined programmatically based on RECIST v1.1. using all site investigator data 
up until the first progression event (i.e., progression or death). For participants whose 
progression event is death, BOR is calculated based upon all evaluable RECIST v1.1 
assessments prior to death. 
4.2.3.2
Derivations
For participants who die with no evaluable RECIST v1.1 assessments, if the death occurs ≤ 
15 weeks (i.e. 14 weeks [5 weeks + 9 weeks]  + 1 week to allow for a late assessment within 
the assessment window) after first dose of IP, then BOR is assigned to the progressive disease


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category. For participants who die with no evaluable RECIST v1.1 assessments, if the death 
occurs > 15 weeks after first dose then BOR is assigned to the NE category.
For CR/PR, the initial overall visit assessment that showed a response uses the latest of the 
dates contributing towards a particular overall visit assessment. A participant is classified as 
a responder if the RECIST v1.1 criteria for a CR or PR are satisfied at any time following 
first IP dose, prior to RECIST v1.1 progression and prior to starting any subsequent cancer 
therapy. CR or PR must be confirmed (see detail in Objective Response Section 4.2.2.1). 
For determination of a best response of SD, the earliest of the dates contributing towards a 
particular overall visit assessment is used. SD should be recorded at least 5 weeks (5 x 7 = 
35 days) from first dose.
4.2.3.3
Handling of dropouts and missing data
Handling of missing TL data is described in Appendix A (Section 7.1). Handling of missing 
subsequent treatment date is described in section 3.3.6. 
4.2.3.4
Primary Analysis of Secondary Endpoint
BOR is summarised by the number and percentage of participants for the following 
categories: CR, PR, SD, PD and NE. No formal statistical analyses are planned for BOR. The 
main analysis of BOR is based on the Response evaluable set.
4.2.3.5
Sensitivity Analyses
Sensitivity analysis is NA.
4.2.3.6
Subgroup Analyses
Subgroup analysis is NA.
4.2.4
Secondary Endpoint: Disease Control Rate at Study Week 15
DCR at study week 15 is a secondary endpoint.
4.2.4.1
Definition
Disease control is defined as a BOR of confirmed CR or PR or having SD (without 
subsequent cancer therapy) maintained for ≥ 14 weeks (study week 15) from first IP. Disease 
control rate at study week 15 weeks (DCR-15) is defined as the percentage of participants 
who have disease control at study week 15 weeks.
4.2.4.2
Derivations
A programmed derivation for DCR is: 

If participants have a BOR of confirmed CR or PR, they have disease control.


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
Or if a participant has SD to at least DCR time point (i.e., duration of SD DCR time 
point), they have disease control. (Note participants with unconfirmed responses 
should be included in this calculation.)
•
Duration of SD is defined as the time from first IP dose until the first 
documentation of disease progression or death due to any cause, whichever 
occurs first:

Duration of SD (days) = Disease progression or death or PFS 
censoring date – first IP dose date +1. SD after the start of subsequent 
cancer therapy should not be included in this duration.

Otherwise, they do not have disease control.
4.2.4.3
Primary Analysis of Secondary Endpoint
DCR at study week 15 is presented with a two-sided 90% CI using the Clopper-Pearson 
(exact probability) method. The main analysis of DCR is based on the Response Evaluable 
population.
4.2.5
Secondary Endpoint: Duration of Response
Duration of Response (DoR) is a secondary endpoint.
4.2.5.1
Definition
DoR is defined as the time from the date of first documented objective response (which is 
subsequently confirmed) until date of first documented disease progression or death (by any 
cause in the absence of disease progression). 
4.2.5.2
Derivations
DoR (Months)=
(Date of PFS event or censoring-date of first OR that is subsequently confirmed)+1
( 365.25
12
)
where PFS event is progression or death.
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 (which was subsequently 
confirmed). If a participant does not progress following a response, then their DoR is 
censored on the PFS censoring date. Only participants who have achieved OR (confirmed 
CR or confirmed PR) are evaluated and summarised for DoR. 
4.2.5.3
Handling of dropouts and missing data
Handling of missing TL data is described in Appendix A (Section 7.1).


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4.2.5.4
Primary Analysis of Secondary Endpoint
Only participants who have achieved objective response (CR or PR) are included in the 
summaries of DOR. If participant numbers allow (i.e., more than 5 participants are evaluated 
for DoR), Kaplan-Meier plots of DoR are presented. The median DoR and two-sided 90% 
CI are estimated using the Kaplan-Meier method. The percentage of participants remaining 
in response at 3, 6, 9 and 12 months, calculated using the Kaplan-Meier technique, are also 
presented. Swimmer plots that clearly show the profile of each participant who respond are 
also produced. 
4.2.5.5
Sensitivity Analyses of the Secondary Endpoint
Sensitivity analysis is NA.
4.2.5.6
Subgroup Analyses
Subgroup analyses is defined in section 4.2.2.6
4.2.6
Secondary Endpoint: Progression Free Survival
Progression Free Survival (PFS) is a secondary endpoint.
4.2.6.1
Definition
The PFS is defined as the time from first dose of IP until the date of first documented disease 
progression or death (by any cause in the absence of progression), regardless of whether the 
participant withdraws from study intervention or receives another anti-cancer therapy prior 
to progression.
4.2.6.2
Derivations
PFS (Months)=
(Date of PFS event or censoring-date of first dose of IP)+1
( 365.25
12
)
where PFS event is progression or death.
Participants who have not progressed or died at the time of analysis are censored at the time 
of the latest date of assessment from their last evaluable disease assessment.  However, if the 
participant progresses or dies immediately after two or more consecutive missed visits, the 
participant 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 (i.e., first visit at week six, then nine-weekly 
for till 52 weeks then twelve-weekly thereafter) the definition of 2 missed visits changes.  
If the previous RECIST v1.1 assessment is less than study day 288 (i.e. study week 42) and 
greater than study day 99 (study week 15), then two missed visits equates to 20 weeks since 


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the previous RECIST v1.1 assessment, allowing for early and late visits (i.e. 2 x 9 weeks + 
1 week for an early assessment + 1 week for a late assessment = 20 weeks). 
If the previous RECIST visit is after the visit assessment at study week 6 or study week 15, 
then two missed visits equate to: 
-
15 weeks (105 days), if study week 6 (5 weeks after 1st IP dose) and study week 15 
(14 weeks after 1st IP dose) are the two consecutive visits missed [ (1 x 5 weeks) + (1 
x 9 weeks) + 1 week for late assessment]. 
-
19 weeks (133 days), if study week 15 (14 weeks after 1st IP dose) and week 24 (23 
weeks after 1st IP dose) are the two consecutive visits missed [(1 x 9 weeks) + (1 x 9 
weeks) + 1 week for late assessment].
If the two missed visits occur over the period when the scheduled frequency of RECIST v1.1 
assessments changes from nine-weekly to twelve-weekly this equates to 23 weeks (i.e. take 
the average of 9 and 12 weeks which gives 10.5 weeks and then apply same rationale, hence 
2 x 10.5 weeks + 1 week for an early assessment + 1 week for a late assessment = 23 weeks).  
The time period for the previous RECIST v1.1 assessment is from study days 288 to 351 (i.e., 
study week 42 to study week 51).  
From study day 351 (study week 51 onwards [when the scheduling changes to twelve-weekly 
assessments]), two missed visits equate to 26 weeks (i.e. 2 x 12 weeks + 1 week for an early 
assessment + 1 week for a late assessment = 26 weeks). This is also summarised in the Table 
8 below.
Where study day, is the number of days on the study, in which Cycle 1 Day 1 is taken as 
study day 1.


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Table 8: Two missed visits rule for PFS for schedule changes
Scheduled Assessment
Previous RECIST assessment
Two missed RECIST visits 
window
5 weeks up to study 
week 6 then Q9 till study 
week 52
No evaluable RECIST visits or no 
baseline RECIST scan
(1 x 5 weeks) + (1 x 9 weeks) + 1 
week = 15 weeks (105 days)
5 weeks up to study 
week 6 then Q9 till study 
week 52
Baseline  
(1 x 5 weeks) + (1 x 9 weeks) + 1 
= 15 weeks (105 days)
5 weeks up to study 
week 6 then Q9 till study 
week 52
Study day 36
(Study week 6) 
2 x 9 weeks + 1 week = 19 weeks 
(133 days)
Q9W till study week 52
>Study day 99– Study day 288
(From study week 15 up to study week 
42)
2 x 9 weeks + 2 weeks = 20 weeks 
(140 days)
>Study day 288 – Study day 351 
(Study week 42 – Study week 51) 
(change period from Q9W to Q12W)
2 x [(9 weeks+12 weeks)/2] + 2 
weeks = 23 weeks (161 days)
Q12W thereafter
>Study Day 351 onwards
2 x 12 weeks + 2 weeks
RECIST = Response Evaluation Criteria in Solid Tumours v1.1;
If the participant 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 first IP dose (14 weeks plus 1 week allowing for a late assessment within the visit window) 
then the death date qualifies as a PFS event.
A summary of censoring rules and the date of progressive disease/death or censoring are 
given in  Table 9. Note that censoring overrides event in certain specified cases and the table 
below does not indicate the order for programming.


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Table 9: Summary of Censoring Rules for PFS
Situation
Date of progressive disease 
/Death or Censoring
PFS Outcome
Documented Progressive Disease or death in 
the absence of progression
Date of earliest documentation of 
progressive disease or date of 
death in the absence of 
progression
Event
Either no tumour assessment at baseline or no 
evaluable assessments post-baseline AND 
death prior to second scheduled post-baseline 
disease assessment  
Date of death
Event 
Either no tumour assessment at baseline or no 
evaluable assessments post-baseline AND no 
death prior to second scheduled post-baseline 
disease assessment
Date of first dose (Day 1)  
Censored
Progressive disease 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 (if available). 
Otherwise, the date of censoring is 
Date of first dose (Day 1)
Censored
On-going with neither progressive disease nor 
death at the time of analysis or lost to follow-
up or withdrawn consent
Date of last evaluable disease 
assessment
Censored
PFS = progression-free survival
The PFS time is always derived based on scan/assessment dates, and not on visit dates.
RECIST v1.1 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 participant for PFS the participant is censored at the latest of the dates 
contributing to a particular overall visit assessment. 
Note: for TLs only the latest scan date is recorded out of all scans performed at that 
assessment for the TLs and similarly for NTLs only the latest scan date is recorded out of all 
scans performed at that assessment for the NTLs.


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The number of participants alive and progression free at 3, 6, 9 and 12 months (PFS-3, PFS-
6, PFS-9, and PFS-12) is defined as the Kaplan-Meier estimate of PFS at 3, 6, 9 and 12 
months.  
‘Potential’ duration of follow-up for PFS is applicable only for PFS censored participants 
and is defined as follows:
Potential duration of follow up for PFS (Months)= 
(Date of PFS censoring-date of first dose of IP)+1
( 365.25
12
)
4.2.6.3
Handling of dropouts and Missing Data 
See section 4.2.6.2.
4.2.6.4
Analysis of the Secondary Endpoint
The main analysis of PFS is based on the safety analysis set. The number and percentage of 
participants experiencing a PFS event broken down by type of event/censoring and 
Kaplan-Meier plots of PFS are presented. The median PFS and its two-sided 90% CI are 
estimated using the Kaplan-Meier method if participant numbers allow. 
The treatment status at progression of participants at the time of analysis are summarised.  
This includes;

The number (%) of participants who were on treatment at the time of progression

The number (%) of participants who discontinued IP prior to progression

The number (%) of participants who have not progressed and were on treatment or 
discontinued treatment.
A summary of the duration of follow-up for PFS is included using median (range). This is 
presented for censored participants (including all types of PFS censoring).
The proportion of participants alive and progression free at 3, 6, 9 and 12 months and 
associated two-sided 90% CI are estimated using the Kaplan-Meier method.
4.2.7
Secondary Endpoint: Change in Target Lesion Tumour Size
Change in TL tumor size is a secondary endpoint.
4.2.7.1
Definition
This is based on RECIST v1.1 TL measurements taken at baseline and each post-baseline 
assessment.  Tumour size is the sum of the longest diameters (or short axis measurements for 


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lymph nodes) of the TLs. Baseline for RECIST v1.1 is defined to be the last evaluable 
assessment prior to first IP dose.  
An outcome endpoint for this study is percentage change from baseline in TL tumour size at 
each post-baseline assessment e.g., at Study week 15. 
The tumour size and percentage change from baseline in the sum of tumour size at each 
assessment are calculated. The best change in tumour size from baseline (i.e., 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 progressive 
disease,
•
prior to death in the absence of progression, 
•
prior to the start of subsequent anti-cancer therapy (including radiotherapy) 
•
or up to and including the last evaluable RECIST v1.1 assessment if the participant 
has not died, progressed, or started subsequent anti-cancer therapy.
Each post-baseline disease assessment for a participant that meets the following conditions 
are included: all TLs identified at baseline have measurements recorded at the current visit 
(i.e., they cannot be not done or not evaluable). If a lesion is recorded as <=5mm then this is 
used in the calculations. 
4.2.7.2
Derivations
For visit based summaries, whenever TL tumour size data for each post-baseline assessment 
(note: or visit at which progression was documented if before the post-line visit) is available 
then this is used in the analysis.  A windowing rule is applied and follows the protocol 
allowed visit window; therefore, any RECIST v1.1 scan performed within Study W6(D1-
D7), W15(D1-D7), W24±6D then Q9W±6D until W52, then Q12W±6D of the protocol 
scheduled visit is used for that visit.
The percentage change from baseline in TL tumour size at each post-baseline assessment is 
obtained for each participant taking the difference between the sum of the TLs at each post-
baseline assessment and the sum of the TLs at baseline divided by the sum of the TLs at 
baseline times 100. For example, the percentage change from baseline in TL tumour size for 
the post-baseline visit at study week 15 is calculated as follows: 
Percentage change from baseline in TL tumour size
=
(Study Week 15 - Baseline )
(Baseline)
× 100


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For best percentage change, if it cannot be calculated due to missing data (including if the 
participant has no TLs at baseline), a value of +20% is imputed as the best percentage change 
from baseline in the following situations (otherwise best percentage change is left as 
missing):
•
If a participant has no post-baseline assessment and has died;
•
If a participant has new lesions or progression of NTLs or TLs;
•
If a participant has withdrawn due to progressive disease and has no evaluable TL 
data before or at progressive disease.
For the outcome endpoint percentage change from baseline in TL tumour size at each post-
baseline assessment i.e., Study week 15, participants who progress before study week 15 
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 study week 15 assessment for these participants.
4.2.7.3
Primary Analysis of Secondary Endpoint
Only participants with measurable disease at baseline are included in summaries of change 
in tumour size (measurable disease is as denoted on the eCRF by the investigator).
The TL tumour size and percentage change in TL tumour size from baseline is summarised 
using descriptive statistics and presented at each timepoint. 
The median best percentage change from baseline and other summary statistics are presented, 
together with the number of participants. The median percentage change from baseline at 
each post baseline assessment timepoint and other summary statistics are presented, together 
with the number of participants.
The best percentage change from baseline in tumour size is presented graphically using 
waterfall plots, with the bars ordered from the largest increase to the largest decrease. 
Separate waterfall plots are used to present each participant’s best percentage change in TL 
tumour size as a separate bar. A reference line at the –30% change in TL tumour size level is 
added to the plots, which corresponds with the definition of ‘partial response’.  All 
progressions are marked with a ‘●’ or designated with patterns or colors for ORR categories.  
Flagged progressions on the percentage change in TL tumour size at a particular timepoint 
are based upon NTL or new lesion progression at that timepoint and flagged progressions on 
the best percentage change will be based upon NTL or new lesion progression at the same 
timepoint as the best percentage change.  The scale in these plots are fixed to be from -100 
to 100 to avoid presenting extreme values.  Values that are capped as a result of this restriction 
to the scale are marked with ‘#’.  Values are ordered in descending order with the imputations 
due to death appearing first followed by a gap followed by all other participants.  


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Additionally, ‘spider’ plots of percentage change from baseline in TL size by participant are 
presented.  This depicts each participant’s percentage change from baseline in TL tumour 
size as a line over time and progression due to non- target and/or new lesions are indicated.
4.2.8
Secondary Endpoint: Overall Survival
Overall Survival (OS) is a secondary efficacy endpoint.
4.2.8.1
Definition
Overall survival is defined as the time from the date of first IP dose until death due to any 
cause regardless of whether the participant withdraws from study therapy or receives another 
anti-cancer therapy.
4.2.8.2
Derivations
OS (Months)= 
(Date of death or censoring-date of first dose of IP)+1
( 365.25
12
)
Any participant not known to have died at the time of analysis is censored based on the last 
recorded date on which the participant was known to be alive.
Note: For any OS analysis performed (prior to the final OS analysis), in the absence of 
survival calls being made, it may be necessary to use all relevant eCRF fields to determine 
the last recorded date on which the participant was known to be alive for those participants 
still on treatment (since the SURVIVE module is only completed for participants off 
treatment if a survival sweep is not performed). The last date for each individual participant 
is defined as the latest among the following dates recorded on the eCRFs:
•
AE start, stop and change in severity dates
•
Admission and discharge dates of hospitalization
•
Physical examination, ECOG and ECG dates
•
IP Treatment administration dates 
•
End of treatment date
•
Concomitant medication start and stop dates
•
Laboratory test dates
•
Date of vital signs
•
Disease assessment dates on RECIST v1.1 eCRF


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•
Start and stop dates of alternative anticancer treatment
•
Date last known alive on survival status eCRF
•
End of study date 
The proportion of participants alive at 3, 6, 9 and 12 months (OS-3, OS-6, OS-9, OS12) is 
defined as the Kaplan-Meier estimate of OS at 3, 6, 9, and 12 months.
Duration of follow-up for OS is reported separately for censored participants and non-
censored participants and is defined as follows:
Duration of follow up for OS (Months) = 
(Date of death or censoring (date last known to be alive)-date of first dose of IP)+1
( 365.25
12
)
4.2.8.3
Handling of dropouts and missing data 
If a participant is known to have died where only a partial death date is available, then the 
date of death is imputed as the latest of the last date known to be alive +1 from the database 
and the death date using the available information provided:

For Missing day only – using the 1st of the month. 

For Missing day and Month – using the 1st of January.
If there is evidence of death but the date is entirely missing, it is treated as missing, i.e. 
censored at the last known alive date.
4.2.8.4
Primary Analysis of Secondary Endpoint
The analysis of OS is based on the safety population. The number and percentage of 
participants experiencing an OS event and Kaplan-Meier plots of OS are presented. The 
median OS and two-sided 90% CI are estimated using the Kaplan-Meier method if participant 
numbers allow. Summaries of the number and percentage of participants who have died, 
those still in survival follow-up, those lost to follow-up and those who have withdrawn 
consent are provided.
The proportion of participants alive at 3, 6, 9 and 12 months (OS-3, OS-6, OS-9, and OS-
12) and associated two-sided 90% CI are estimated using the Kaplan-Meier method.
A summary of the duration of follow-up for OS is included using median (range). This is 
presented separately for censored and non-censored participants.


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4.2.8.5
Sensitivity Analyses of the secondary endpoint 
Sensitivity analysis is NA.
4.2.8.6
Supplementary Analyses of the secondary endpoint 
Supplementary analysis is NA.
4.2.8.7
Subgroup analyses 
Subgroup analyses is defined in section 4.2.2.6
4.2.9
Secondary Endpoint: Changes in ctDNA from baseline
Changes in CtDNA from baseline is a secondary endpoint.
4.2.9.1
Definition and Derivations
Change in ctDNA is defined as the percentage change in ctDNA from baseline to each 
timepoint for the safety population. 
4.2.9.2
Derivations
Percentage change in ctDNA from baseline to each post baseline timepoint as well as the 
maximum change are analyzed descriptively on the Safety Population.
4.2.9.3
Primary Analysis of Secondary Endpoint
Percentage change from ctDNA from baseline to each timepoint is summarised by mean 
percentage change and St.Dev. Maximum change is also summaries by mean and St.Dev.
4.2.10
Secondary Endpoint: Change in circulating GDF15 serum levels 
(Applicable for Substudy 1: Part A and Part B only) 
4.2.10.1
Definition and Derivations
Changes in free GDF15 serum levels is defined as change in GDF15 serum levels from 
pre-treatment (baseline) to each post baseline timepoint on the PD population. 
4.2.10.2
Primary Analysis of Secondary Endpoint
The change in circulating free GDF15 serum levels from pre-treatment (baseline) to each 
post baseline timepoint, will be summarised using descriptive statistics. Standard summary 
statistics n, mean, St. Dev, median, minimum, and maximum will be presented. Summary of 
absolute values and percent change from baseline will be produced by cohort by visit. 
Listing of individual values is provided. 
Boxplot may be produced to represent the evolution of GDF15 over time. If a group has ≤ 10 
patients, line plot will be produced instead of boxplot.


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4.2.11
Secondary Endpoint: Change in CD8 tumour infiltration by IHC 
using baseline and on treatment samples (Applicable for Substudy 1: 
Part A and B only) 
4.2.11.1
Definition and Derivations
Changes in CD8 tumour infiltration by IHC are defined as change in CD8 tumour infiltration 
by IHC from pre-treatment (baseline) from on treatment fresh biopsies (C2D8 +/- 5 days) on 
the PD population.
Tissue obtained as part of mandatory paired biopsies obtained before and during treatment 
(Screening [Day -28 to -1], C2D1 and C2D8) will be assessed for CD8+ T cell tumour 
infiltration.
4.2.11.2
Primary Analysis of Secondary Endpoint
The change in CD8 tumour infiltration measured by IHC will be summarised using 
descriptive statistics, standard summary statistics n, mean, St. Dev, median, minimum, and 
maximum will be presented. 
Summary of absolute values and percent change from baseline will be produced.
Listing of individual values is provided. 
4.2.12
Pharmacokinetics 
This section covers details related to PK endpoints and analyses.
The (PK) parameters of the concentration data for AZD8853 and its metabolites (if 
metabolite[s] are defined and their concentrations are available) are derived using non-
compartmental methods in Phoenix® WinNonlin® Version 8.1 or higher (Certara) by 
Clinical Pharmacology and Marketed Products at AstraZeneca
Plasma PK Parameters
PK analysis is, where data allow, carried out using actual elapsed times determined from the 
PK sampling and dosing times recorded in the database. If actual elapsed times are missing, 
nominal times may be used at the discretion of the PK Scientist with approval from the AZ 
Clinical Pharmacology Scientist (CPS). Nominal sampling times may be used for any agreed 
interim PK parameter calculations. 
For each PK sampling period, plasma concentrations that are non-quantifiable (NQ) from the 
time of pre-dose sampling (t=0) up to the time of the first quantifiable concentration is set to 
a value of zero. After this time point, NQ plasma concentrations are set to missing for all 
concentration profiles. Where 2 or more consecutive concentrations are NQ at the end of a 


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profile, the profile is deemed to have terminated and therefore any further quantifiable 
concentrations are set to missing for the calculation of the PK parameters unless it is 
considered to be a true characteristic of the profile of the drug.
If an entire concentration-time profile is NQ, the profile is excluded from the PK analysis.
Cmax, Cmin, tmax, tlag and tlast are taken directly from the concentration-time profiles. 
Refer to Appendix B (Section 7.2) for the calculation of PK parameters including λz, Area 
under the curve (AUCs), Clearance (CL), Accumulation ratio (Rac), Temporal Change 
Parameter (TCP), and so on.
For each analyte, plasma concentrations for each scheduled time-point are summarised by 
Study Part, PK Day/Visit and Treatment dose level using appropriate descriptive statistics. 
Similar data (e.g., single dose or multiple doses for the same dosing regimen) from different 
Study Parts or PK Days/Visits may also be summarised together. Individual concentrations 
with time deviations of greater than ±10% from the protocol scheduled time, are used in the 
PK analysis but are flagged for exclusion from the summary tables and corresponding figures.
The following descriptive statistics are presented for plasma concentrations: 
•
n
•
n below Lower limit of quantification (LLOQ)
•
geometric mean (gmean)
•
geometric coefficient of variance (%) (gCV)
•
arithmetic mean (mean)
•
arithmetic standard deviation (Std Dev)
•
median
•
minimum (min) 
•
maximum (max)
•
The gmean is calculated as: 
exp(𝜇)
where μ is the mean of the data on the natural log scale.
The gCV is calculated as:
100 × d[exp(σ) −1]
where σ is the Std Dev of the data on the natural log scale.


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Where required for plots: The gSD is calculated as: 
exp(σ)
where σ is the Std Dev of the data on the natural log scale. 
The gmean ± gSD (gmean-gSD and gmean+gSD) are calculated as: 
exp[µ ± σ]
Protocol scheduled times are used to present the PK concentration summary tables and 
corresponding gmean concentration-time figures.
Handling of Non-Quantifiable Concentrations
Individual concentrations below the LLOQ of the bioanalytical assay are reported as NQ in 
the listings with the LLOQ defined in the footnotes of the relevant TFLs. Individual plasma 
concentrations that are Not Reportable are reported as NR and those that are missing are 
reported as NS (No Sample) in the listings. Plasma concentrations that are NQ, NR or NS are 
handled as follows for the provision of descriptive statistics:

Any values reported as NR or NS are excluded from the summary tables and 
corresponding figures.

At a time point where less than or equal to 50% of the concentration values are 
NQ, all NQ values are set to the LLOQ, and all descriptive statistics are calculated 
accordingly.

At a time point where more than 50% (but not all) of the values are NQ, the gmean 
and gCV% are set to Not calculable (NC). The maximum value is reported from 
the individual data, and the minimum and median are set to NQ.

If all concentrations are NQ at a time point, no descriptive statistics are calculated 
for that time point. The gmean, minimum, median and maximum are reported as 
NQ and the gCV% as NC.

The number of values below LLOQ (n < LLOQ) are reported for each time point 
together with the total number of collected values (n).
Three observations > LLOQ are required as a minimum for a plasma concentration or PK 
parameter (e.g. Cmax, Cmin, Clast) to be summarised. Two observations > LLOQ are 
presented as minimum and maximum with the other summary statistics as NC.
PK parameter Listings 


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All reportable PK parameters, including individual diagnostic and lambda z related 
parameters, are listed for each participant by Study Part, PK Day/Visit and Treatment, for
each analyte separately.
PK parameter descriptive statistics
All primary and secondary PK parameters are summarised for each analyte by Study Part, 
PK Day/Visit and Treatment dose using appropriate descriptive statistics. Similar parameter 
data (e.g., single dose or multiple doses for the same dosing regimen) from different Study 
Parts or PK Days/Visits may also be summarised together.
The descriptive statistics for PK parameters are presented as follows:

Cmax, Cmin, Clast, AUC(0-t), AUCinf, AUCτ, AUClast: present n, gmean, arithmetic 
mean of non log-transformed data (mean), arithmetic standard deviation (Std Dev), 
gCV(%), median, min and max.

t½λz, CL, Vss, MRT, : present n, arithmetic mean of non log-transformed data (mean), 
arithmetic standard deviation (Std Dev), median, min and max.

Cmax/D, AUCinf/D, AUC(0-t)/D, AUCτ/D , AUClast/D, λz, and all parameter ratios 
(e.g Rac, TCP, peak:trough ratio and fed to fasted ratios): present n, gmean, gCV(%), 
mean, Std Dev, median, min and max.

tmax, tlag, and tlast: present n, median, min and max.

Diagnostic parameters (e.g. t upper, t lower, n obs, Rsq adj and AUCextr): present n, 
arithmetic mean, Std Dev, gmean, gCV%, median, min and max.
Three values are required as a minimum for PK parameters to be summarised. Two values 
are presented as a min and max with the other summary statistics as NC.
If one or more values for a given parameter is zero, then no geometric statistics are calculated 
for that parameter and the results for geometric statistics are set to NA (Not Applicable).
Graphical presentation of PK data
All mean (arithmetic mean and/or gmean) plots or combined plots showing all participants 
by treatment are based on the PK analysis set. Individual plots by participant are based on 
the safety analysis set. Scatter plots for individual PK parameters versus Treatment dose 
present both summary parameter data and individual participant parameter data for each 
Treatment dose including only participants in the PK analysis set.
For consistency, the plasma concentration values used in the mean (arithmetic mean and/or 
gmean) data graphs are those given in the descriptive statistics summary table for each time 
point.


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For gmean concentration-time plots, NQ values are handled as described for the descriptive 
statistics; if the geometric mean is NQ, the value plotted is zero for linear plots and missing 
for semi-logarithmic plots. Any gmean±gSD error bar values that are negative are truncated 
at zero on linear concentration-time plots and omitted from semi-logarithmic plots.
For individual plots, plasma concentrations which are NQ prior to the first quantifiable 
concentration are set to a value of zero (linear plots only). After the first quantifiable 
concentration, any NQ plasma concentrations are regarded as missing.
Data permitting, the following figures are presented as appropriate:

Figures for the mean (arithmetic mean and/or gmean) plasma concentration-time 
data (with ±Std Dev and/or ±gSD error bars) presented on both linear and semi-
logarithmic scales using scheduled post-dose time as follows:
-
By PK Day for each analyte with all or selected single dose Treatments (e.g., 
dose level) overlaid on the same plot and/or all or selected multiple dose 
Treatments (e.g., dose levels and schedule) overlaid on the same plot 
-
By PK Treatment for each analyte with all or selected single dose PK days and 
all or selected multiple doses PK Days overlaid on the same plot 
-
By PK Treatment with all or selected single dose PK days for each analyte 
overlaid on the same plot and/or all or selected multiple doses PK Days for each 
analyte overlaid on the same plot

Individual participant plasma concentration-time data graphically presented on both 
linear and semi-logarithmic scales using actual time post-dose as:
-
By participant with all and/or selected PK Days for the same participant 
overlaid on the same plot
-
Combined individual plots with all participants overlaid on the same plot for 
each single dose Treatment (e.g., dose level) and/or each multiple dose 
Treatment (e.g., dose level and schedule)

Individual and summary single dose and/or multiple dose PK parameter data 
graphically presented on scatter plots of the PK parameter value 

Individual and summary single dose and/or multiple dose PK parameter data 
graphically presented as line plots of the PK parameter value against treatment with 
each individual and the mean value joined with a line between the treatment


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
Ratios of a single dose and/or multiple dose PK parameter value for one Treatment 
(e.g., in combination with another drug or under fed conditions) divided by the value 
for another Treatment (e.g., not in combination with the other drug or under fasted 
conditions respectively) plotted against each individual participant or against each 
Treatment

Scatter plot of pharmacokinetic parameters (Cmax, AUCinf and AUC(0-t)) versus 
dose presented on logarithmic scales
Precision and Rounding Rules for Pharmacokinetic Data
PK concentration data 
PK concentration data listings present to the same number of significant figures as the data 
received from the bioanalytical laboratory (usually but not always to 3 significant figures) 
and against the same units as received.
PK concentration descriptive statistics present 4 significant figures with the exception of 
the min and max which present 3 significant figures and n and n<LLOQ which present as 
integers.
PK parameter data
PK parameter listings are presented according to the following rules:

Cmax, Cmin and Clast: present to the same number of significant figures as received 
from the bioanalytical laboratory

tmax, tlast, tlag, t lower and t upper: present as received in the data, usually to 2 decimal 
places

AUCinf, AUC(0-t), AUCτ, AUClast, AUC/D, AUC(0-t)/D, AUCτ/D, AUClast/D, 
AUCextr, λz, t½λz, CL,MRT, Vss, Vz, all ratios of PK parameters (e.g. Rac, TCP, 
Peak:Trough ratio), Rsq adj, : present to 3 significant figures

F and Frel: present to 2 decimal places

n obs: present as an integer (no decimals)
The descriptive statistics for PK parameter data are presented to 4 significant figures with 
the exception of the min and max which are presented to 3 significant figures apart from the 
following:

λz: present to 5 significant figures with min and max to 3 significant figures


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
tmax, tlag, and tlast: present as received in the data, usually to 2 decimal places

number of values (n): present as an integer
4.2.13
Immunogenicity 
A summary of immunogenicity results is provided showing the number and percentage of 
participants who develop detectable Anti-Drug Antibodies (ADAs) against AZD8853, based 
on the participants in the immunogenicity analysis set. The number of ADA evaluable 
patients in the treatment group is used as the denominator for percentage calculation. 
Participants and/or data excluded from the immunogenicity analysis set are presented in 
separate outputs.
The following categories are included in the summary table:

ADA positive at baseline and/or post-baseline visits. The percentage of these participants 
in a population is known as ADA prevalence.

Treatment-induced ADA positive (positive post-baseline and not detected at baseline).

Treatment-boosted ADA positive (baseline ADA titer that was boosted greater than the 
variability of the assay (i.e., ≥ 4-fold increase)

Treatment-emergent ADA positive (either treatment-induced ADA positive or 
treatment-boosted ADA positive). The percentage of these participants in a population 
is known as ADA incidence.

ADA positive post-baseline and positive at baseline.

ADA positive at baseline and not detected post-baseline.

Persistent positive, defined as ADA negative at baseline and having at least 2 post-
baseline ADA positive measurements with ≥ 16 weeks between first and last positive, or 
an ADA positive result at the last available post baseline assessment.

Transient positive, defined as ADA negative at baseline and at least one post- baseline 
ADA positive measurement and not fulfilling the conditions for persistently positive.
Blood samples collected outside of the scheduled time window are summarized at the next 
nominal time point if that does not already have a value, otherwise it is presented in listings 
with data excluded from summary outputs.
ADA results will also be listed for participants included in the immunogenicity analysis set.


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5
INTERIM ANALYSIS
Substudy 1 
In the efficacy expansions (Part C1 and Part C2) an interim analysis is performed after the 
20th participant in each expansion has had the opportunity for 2 on-treatment RECIST v1.1 
assessments or has discontinued or withdrawn from treatment. Enrolment will continue while 
this analysis is ongoing. The analysis will provide tolerability and safety data and will also 
provide a reasonable chance to determine if there is a lack of efficacy. 
 
 
 
 
6
REFERENCES
Clopper et al, 1934
Clopper C, Pearson E. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika. 1934;26(4):404-413.
Eisenhauer et al, 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST v1.1 guideline (version 1.1). 
Eur J Cancer. 2009 Jan;45(2):228-47.
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;5823-33.
Ji et al, 2010
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-
finding trials. Clin Trials. 2010 Dec;7(6):653-63.
7
APPENDICES
7.1
Appendix A RECIST 
Derivation of RECIST v1.1 Visit Responses
For all participants, the RECIST v1.1 tumour response data is used to determine each 
participant’s visit response according to RECIST version 1.1. It is also used to determine if 
and when a participant has progressed in accordance with RECIST version 1.1 and their best 
objective response to IP.  
CCI


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Baseline radiological tumour assessments are performed no more than 28 days before the 
start of IP and ideally as close as possible to the start of IP Tumour assessments are performed 
6 weeks after 1st IP then every 9 weeks, until week 52 then every 12 weeks until disease 
progression. 
If an unscheduled assessment is performed, and the participant has not progressed, every 
attempt is made to perform the subsequent assessments at their scheduled visits. This 
schedule is followed in order to minimize any unintentional bias caused by some participants 
being assessed at a different frequency than other participants.
From the investigator’s review of the imaging scans, the RECIST v1.1 tumour response data 
is used to determine each participant’s visit response according to RECIST version 1.1. At 
each visit, participants are programmatically assigned a RECIST version 1.1 visit response 
of CR, PR, SD, or Progressive Disease, using the information from TLs, NTLs and new 
lesions and depending on the status of their disease compared with baseline and previous 
assessments. If a participant has had a tumour assessment that cannot be evaluated, then the 
participant is assigned a visit response of NE (unless there is evidence of progression in which 
case the response is assigned as Progressive Disease).
Please refer to Table 10 for the definitions of CR, PR, SD and Progressive Disease. 
RECIST v1.1 outcomes (i.e. PFS, ORR etc.) are calculated programmatically for the site 
investigator data (see last section of this Appendix) from the overall visit responses. 
Target Lesions (TLs) – site investigator data
Measurable disease is defined as having at least one measurable lesion, not previously 
irradiated, which is ≥ 10 mm in the longest diameter (LD), (except lymph nodes which must 
have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging 
(MRI) and which is suitable for accurate repeated measurements. A participant can have a 
maximum of five measurable lesions recorded at baseline with a maximum of two lesions 
per organ (representative of all lesions involved and suitable for accurate repeated 
measurement) and these are referred to as TLs.  If more than one baseline scan is recorded, 
then measurements from the one that is closest and prior to first IP dose is used to define the 
baseline sum of TLs. It is the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement. In which circumstance the next largest lesion, which can be 
measured reproducibly, is selected.
All other lesions (or sites of disease) not recorded as TL are identified as NTLs at baseline.  
Measurements are not required for these lesions, but their status are followed at subsequent 
visits.


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Note: For participants who do not have measurable disease at entry (i.e. no TLs) but have 
non-measurable disease, evaluation of overall visit responses are based on the overall NTL 
assessment and the absence/presence of new lesions (see section below for further details). 
If a participant does not have measurable disease at baseline, then the TL visit response is 
Not Applicable (NA).
Table 10: TL Visit Responses (RECIST v1.1)
Visit Responses
Description
Complete response (CR)
Disappearance of all TLs.  Any pathological lymph nodes selected 
as TLs must have a reduction in short axis to <10mm.
Partial response (PR)
At least a 30% decrease in the sum of diameters of TLs, taking as 
reference the baseline sum of diameters as long as criteria for 
progressive disease are not met.
Progressive disease 
A ≥ 20% increase in the sum of diameters of TLs and an absolute 
increase of ≥ 5mm, taking as reference the smallest sum of 
diameters since treatment started including the baseline sum of 
diameters.
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease.
Not evaluable (NE)
Only relevant in certain situations (i.e. if any of the TLs were not 
assessed or not evaluable or had a lesion intervention at this visit).  
Note: If the sum of diameters meets the progressive disease 
criteria, progressive disease overrides not evaluable as a TL 
response.
Not Applicable (NA)
No TLs are recorded at baseline.
CR = Complete Response; NA = Not Applicable; NE = Not Evaluable; PR = Partial Response; SD = Stable 
Disease; TL = target lesion.
Rounding of TL data
For calculation of progressive disease and PR for TLs percentage changes from baseline and 
previous minimum are rounded to one decimal place before assigning a TL response.  For 
example, 19.95% is rounded to 20.0% but 19.94% is rounded to 19.9%  
Missing TL data 
For a visit to be evaluable then all TL measurements are recorded.  However, a visit response 
of progressive disease is still assigned if any of the following occurred

A new lesion is recorded,

An NTL visit response of progressive disease is recorded,


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
The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥5mm, from nadir even assuming the non-recorded TLs have disappeared. 
Note: the nadir can only be taken from assessments where all the TLs had a LD 
recorded. 
If the TL visit response is not recorded as progressive disease, then the TL visit response is 
NE. 
If there is at least one TL measurement missing and a visit response of progressive disease
cannot be assigned, the visit response is NE.
If all TL measurements are missing, then the TL visit response is NE.  Overall visit response 
is also NE, unless there is a progression of non-TLs or new lesions, in which case the response 
is progressive disease.
Lymph nodes
For lymph nodes, if the size reduces to < 10mm then these are considered non-pathological. 
However, a size is still given, and this size is still used to determine the TL visit response as 
normal.  In the special case where all lymph nodes are < 10mm and all other TLs are 0mm 
then although the sum may be > 0mm the calculation of TL response should be over-written 
as a CR. 
TL visit responses subsequent to CR
Only CR, progressive disease or NE can follow a CR.  If a CR has occurred, then the 
following rules at the subsequent visits must be applied:

If all lesions meet the CR criteria (i.e. 0mm or < 10mm for lymph nodes) then response 
is set to CR irrespective of whether the criteria for progressive disease of TL is also met 
i.e. if a lymph node short axis increases by 20% but remains < 10mm. 

If some lesion measurements are missing but all other lesions meet the CR criteria (i.e., 
0mm or < 10mm for lymph nodes) then response is set to NE irrespective of whether the 
criteria for progressive disease of TL is also met i.e. if a lymph node short axis increases 
by 20% but remains < 10mm. 

If not all lesions are missing, and those that are non-missing do not meet the CR criteria 
(i.e. a pathological lymph node selected as TL has short axis ≥ 10mm or the reappearance 
of previously disappeared lesion), then response is set to progressive disease.

If all lesions are missing the response is set to NE.
TL too big to measure
If a TL becomes too big to measure this is indicated in the database and a size (‘x’) above 
which it cannot be accurately measured is recorded.  If using a value of x in the calculation 


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of TL response does not give an overall visit response of progressive disease, then this is 
flagged and reviewed by the study team.  It is expected that a visit response of progressive 
disease remains in the vast majority of cases.  
TL too small to measure
If a TL becomes too small to measure, then this is indicated as such on the case report form 
and a value of 5mm is entered into the database and used in TL calculations. However, a 
smaller value is used if the radiologist has not indicated ‘too small to measure’ on the case 
report form and has entered a smaller value that can be reliably measured.  If a TL response 
of progressive disease results (at a subsequent visit) then this is reviewed by the study team 
blinded to treatment assignment.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e., lesion irradiated prior to entry into the study) are recorded 
as NTLs and should not form part of the TL assessment.
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation / palliative surgery / embolization but note this does not include protocol specified 
biopsies), are handled in the following way. Once a lesion has had intervention then it is 
treated as having intervention for the remainder of the study noting that an intervention most 
likely shrinks the size of tumours: 

Step 1: the diameters of the TLs (including the lesions that have had intervention) are 
summed and the calculation is performed in the usual manner. If the visit response is 
progressive disease, this remains as a valid response category. 

Step 2: If there is no evidence of progression after step 1, treat the lesion diameter (for 
those lesions with intervention) as missing. If progressive disease has not been assigned, 
then the visit response is set as NE.
At subsequent visits, the above steps are repeated to determine the TL and overall visit 
response.  When calculating the previous minimum, lesions with intervention are treated as 
missing.
Lesions that split in two
If a TL splits in two, then the LDs of the split lesions are summed and reported as the LD for 
the lesion that split.
Lesions that merge
If two TLs merge, then the LD of the merged lesion are recorded for one of the TL sizes and 
the other TL size is recorded as 0mm.


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Change in method of assessment of TLs
Computerised tomography (CT), magnetic resonance imaging (MRI) and clinical 
examination are the only methods of assessment that can be used within a trial, with CT and 
MRI being the preferred methods and clinical examination only used in special cases. If a 
change in method of assessment occurs, between CT and MRI this is considered acceptable 
and no adjustment within the programming is needed.  
If a change in method involves clinical examination (e.g., CT changes to clinical examination 
or vice versa), any affected lesions are treated as missing.   
Non-target lesions (NTLs) and new lesions – site investigator data.
At each visit, the investigator is to record an overall assessment of the NTL response. This 
section provides the definitions of the criteria used to determine and record overall response 
for NTL at the investigational site at each visit.
NTL response is derived based on the investigator’s overall assessment of NTLs as follows 
in Table 11.
Table 11: NTL Visit Responses
Visit Responses
Description
Complete response (CR)
Disappearance of all NTLs present at baseline with all lymph 
nodes non-pathological in size (<10 mm short axis).
Progressive disease 
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions. In all cases, the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy.
Non-CR/Non progressive disease 
Persistence of one or more NTLs with no evidence of 
progression.
Not evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and, in the investigator's opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: For participants without TLs at baseline, this is relevant if 
any of the NTLs were not assessed at this visit and the 
progression criteria have not been met.
Not Applicable (NA)
Only relevant if there are no NTLs at baseline.
CR = Complete Response; NA = Not Applicable; NE = Not Evaluable; NTL = non-target lesion; TL= target 
lesion.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in 
TLs, the overall tumour burden has increased sufficiently to merit a determination of disease 
progression.  A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to 
qualify for unequivocal progression status.


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Details of any new lesions are also recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow up assessment in an anatomical location that was not scanned 
at baseline is considered a new lesion and indicates disease progression.
The finding of a new lesion should be unequivocal: i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
New lesions are identified via a Yes/No tick box. The absence and presence of new lesions 
at each visit are listed alongside the TL and NTL visit responses.
A new lesion indicates progression, so the overall visit response is progressive disease
irrespective of the TL and NTL response.
If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and 
the new lesion details are blank, this is not evidence that no new lesions are present but should 
not overtly affect the derivation. 
Symptomatic progression is not a descriptor for progression of NTLs: it is a reason for 
stopping study therapy and is not included in any assessment of NTLs.
Participants with ‘symptomatic progression’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed.
Overall visit response – site investigator data
Table 12 defines how the previously defined TL and NTL visit responses are combined with 
new lesion information to give an overall visit response.


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Table 12: Overall visit responses
TARGET
NON-TARGET
NEW LESIONS
OVERALL VISIT 
RESPONSE
CR
CR or NA
No (or NE)
CR
CR
Non-CR/Non-
progressive disease or NE
No (or NE)
PR
PR
Non- progressive disease 
or NE or NA
No (or NE)
PR
SD
Non- progressive disease 
or NE or NA
No (or NE)
SD
Progressive Disease
Any
Any
Progressive Disease 
Any
Progressive Disease
Any
Progressive Disease 
Any
Any
Yes
Progressive Disease 
NE
Non- progressive disease 
or NE or NA
No (or NE)
NE
NA
CR
No (or NE)
CR
NA
Non-CR/Non-
progressive disease 
No (or NE)
SD
NA
NE
No (or NE)
NE
NA
NA
No (or NE)
NED
CR = Complete Response; NA = Not Applicable; NE = Not Evaluable; NED = No evidence of disease; PR = 
Partial Response; SD = Stable Disease.
Following curative surgical intervention, each subject’s TL visit response will be captured 
and assigned as previously outlined in section 7.1.
NTL visit response will be derived based on the Investigator’s overall assessment of 
NTLs and the overall visit response will be derived as follows in Table 13.
Table 13: Overall visit responses post curative surgical intervention*
TARGET
NON-TARGET
NEW LESIONS
OVERALL VISIT 
RESPONSE
CR
CR, NE (or NA)
No (or NE)
CR
CR or NA
CR, NE (or NA)
Yes
Progressive Disease
NA
CR or NE
No (or NE)
CR
CR = Complete Response; NA = Not Applicable; NE = Not Evaluable; PR = Partial Response; SD = Stable 
Disease.
* It is assumed that if the subject’s disease burden has reduced enough in response to therapy to enable surgery, 
then those subjects should be regarded as having a CR (assuming all evidence of disease is removed).
Curative surgical interventions will be identified from the Subsequent Cancer therapy (CAPRX2) form and 
the data will be reviewed case-by-case by the study team for confirmation.


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7.2
Appendix B PK Parameter Derivation 
Pharmacokinetic parameter definitions and derivations are described in Table 14 below.
Table 14: Pharmacokinetic parameter definitions and derivations
Parameter Symbol
(used in CSP/SAP/
CSR)
Definition
Derivation
AUC(t1-t2)
Partial area under the plasma 
concentration-time
curve from time t1 to time t2
Using the linear up/log down trapezoidal 
rule
AUCτ
Area under plasma 
concentration-time curve in 
the
dose interval
Using the linear up/log down trapezoidal 
rule
AUCinf
Area under plasma 
concentration-time curve 
from zero to infinity
Calculated by AUC(0-t) and then 
extrapolated by Clast/λz to infinity
AUClast
Area under plasma 
concentration-time curve 
from zero to the last 
quantifiable concentration
Using the linear up/log down trapezoidal 
rule
AUCextr
Extrapolated area under the 
curve from tlast to infinity, 
expressed as percentage of 
AUCinf
AUMCinf
Area Under the first Moment 
Curve from time 0 to infinity
Using the linear up/log down trapezoidal 
rule
AUMClast
Area Under the first Moment 
Curve from time 0 to the 
time of the last quantifiable 
concentration (at tlast)
Using the linear up/log down trapezoidal 
rule
AUMCextr
Extrapolated Area Under the 
first Moment Curve from 
time tlast to infinity, 
expressed as percentage of 
AUMCinf
Cavg
Average drug concentration 
over a dosing interval
AUCτ/ τ


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Parameter Symbol
(used in CSP/SAP/
CSR)
Definition
Derivation
C0
Drug concentration in 
plasma at time zero 
following bolus intravenous 
injection
Clast
Last observed (quantifiable) 
concentration
Cmax
Maximum observed plasma 
(peak) drug concentration
Cmin
Minimum observed plasma 
drug concentration
Ctrough
Observed lowest drug 
concentration reached before 
the next dose is administered
CL
Total body clearance of drug 
from plasma after 
intravascular administration
DoseIV/AUCinf
CL/F
Apparent total body 
clearance of drug from 
plasma after extravascular 
administration
Dose/AUCinf
λz
Terminal elimination rate 
constant
Estimated from linear regression of the 
terminal part of the log concentration versus 
time curve
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
λz span ratio
Time period over which λz 
was determined as ratio of 
t½λz
λz period (i.e., λz upper- λz lower) /t½λz
F
Fraction of administered 
dose systemically available / 
absolute bioavailability
(AUCinf/AUCinfIV) x (DoseIV/Dose)
Frel
Fraction of administered 
dose systemically available 
relative to standard reference 
such as alternative 
formulation (note: not iv) / 
relative bioavailability
(AUCinf/AUCinfREF) x (DoseREF/Dose)


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Parameter Symbol
(used in CSP/SAP/
CSR)
Definition
Derivation
MRTinf
Mean residence time of the 
unchanged drug in the 
systemic circulation
AUMC/AUCinf
Rac AUC, Cmax
Accumulation ratio for 
AUC, Cmax
Steady state AUCτ/first dose AUCτ,
Steady state Cmax/first dose Cmax
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)
tmax
Time to reach peak or 
maximum observed 
concentration or response 
following drug 
administration
tmin
Time of occurrence of Cmin
tlag
Time delay between drug 
administration and the first 
observed concentration in 
plasma
tlast
Time of last observed 
(quantifiable) concentration
TCP
Temporal change parameter 
in systemic exposure (also 
known as: time dependency, 
temporal parameter change, 
linearity index)
Steady state AUCτ /first dose AUCinf
Steady state Cmax/first dose Cmax
t½λz
Half-life associated with 
terminal slope (λz) of a 
semi-logarithmic
concentration-time curve
ln 2/λz
Vss
Volume of distribution at 
steady state from an iv dose
MRT x CL
Vss/F
Volume of distribution 
(apparent) at steady state 
following extravascular 
administration
MRT x CL/F
Vz
Volume of distribution 
following iv administration 
(based on terminal phase)
CL/λz


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Parameter Symbol
(used in CSP/SAP/
CSR)
Definition
Derivation
Vz/F
Volume of distribution 
(apparent) at steady state 
following extravascular 
administration (based on 
terminal phase)
(CL/F)/λz
Points to consider for selection of data points for estimating the elimination rate 
constant
The terminal elimination rate constant (lambda z [λz]) is calculated by log-linear regression 
of the terminal portion of the concentration time profile. The following points should be 
considered and, and in general, should ensure a good estimate of λz:

If there is more than one phase apparent, use only data points from the terminal 
phase.

Use 3-6 measured concentrations spanning three half-lives.

Include the last measurable concentration if possible.

Include only observations after Cmax.

The Rsq value shows the goodness-of-fit (the precision) in the choice of points. 
The Rsq adjusted value also shows the goodness-of-fit but takes into 
consideration the number of points used in the estimation. To achieve a good 
precision in the estimation, the Rsq adjusted value should be high, e.g., a value of 
>0.8 is indicative of a good correlation.
Alternative approaches may adequately meet study objectives. In such cases, reported 
diagnostic parameters should be referred to and precision discussed in the CSR as necessary.
Points to consider for Area Under the Curve zero to infinity
The extrapolated area under the plasma concentration vs. time curve is calculated using the 
trapezoidal rule. In general, the ‘Linear up/Log down’ calculation method is appropriate.
To ensure a robust estimate of AUCinf, the extrapolation (AUCextr) should be relatively 
small as a percentage of the whole AUCinf (e.g., ≤20%).
Alternative approaches may adequately meet study objectives. In such cases, reported 
diagnostic parameter AUCextr should be referred to and accuracy and precision discussed in 
the CSR as necessary.


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