A Phase I/II Open-label, Multi-center Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD7789, an Anti-PD-1 and Anti-TIM-3 Bispecific Antibody, in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma.
Phase: PHASE1
Conditions: Relapsed or Refractory Classical Hodgkin Lymphoma
Sponsor: AstraZeneca

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Clinical Study Protocol 
Study Intervention 
Sabestomig (AZD7789) 
Study Code 
D9571C00001 
Version 
5 
Date 
07 May 2024 
A Phase I/II Open-label, Multi-center Study to Assess Safety, 
Tolerability, Pharmacokinetics and Preliminary Efficacy of 
AZD7789, an anti-PD-1 and anti-TIM-3 Bispecific Antibody, in 
Patients with Relapsed or Refractory Classical Hodgkin 
Lymphoma  
Sponsor Name: AstraZeneca 
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden 
Regulatory Agency Identifier Number(s) 
IND: 157025 
EudraCT: 2021-003569-36 
EU CT: 2022-502773-41-00 
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: D9571C00001 
Version Number: 5 
Study Intervention: Sabestomig (AZD7789) 
Study Phase: Phase I/II 
Redacted for Public Disclosure

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Short Title: Open-label, Multi-center Study to Assess the Safety and Preliminary Efficacy of 
AZD7789 in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (cHL) 
SUMMARY OF CHANGES  
DOCUMENT HISTORY 
Document 
Date 
Protocol Version 5 
07 May 2024 
Protocol Version 4 
11 July 2023 
Protocol Version 3 
1 November 2022 
Protocol Version 2 
24 September 2021 
Original Protocol 
23 July 2021 
 
Version 5 (07 May 2024) 
This modification is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
and in the EU Clinical Trials Regulation Article 2, 2 (13).  
Overall Rationale for the Modification: 
The primary rationale for the changes implemented in this protocol modification is to provide 
continued access to sabestomig (AZD7789) through a post-trial access program for 
participants who are deriving clinical benefit at the time of data cut-off for the final analysis of 
the study. Assessment of these participants will revert to standard of care at the investigational 
site, with the exception of safety reporting. Further changes were made for clarification and to 
address inconsistencies.  

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Summary of Changes: 
List of Substantial Modifications 
Section # and name 
Description of change 
Brief rationale 
Section 1.3 Schedule of 
Activities Tables 2 and 4 
6.9 Continued Access to 
Study Intervention After the 
End of the Study 
8 Study Assessments and 
Procedures  
8.9 Assessments for 
Participants Who Transition 
to PTAP 
Added PTAP guidance including test 
assessments and samples at last study 
visit prior to the final study DCO 
Added requirement for safety reporting to 
continue during PTAP 
Clarified that the EoT visit would not be 
required for participants entering the 
PTAP 
To provide continued access to 
sabestomig (AZD7789) to 
participants who continue to 
derive clinical benefit from 
treatment beyond the end of 
study. Final assessments at last 
study visit prior to PTAP 
initiation (at the time of DCO) 
was added to further inform on 
exploratory endpoints. EoT visit 
is not required for participants 
continuing on PTAP because 
patients are continuing on 
treatment; this will avoid 
confusion with sample labeling. 
5.1 Inclusion Criteria (15b, 
15c, 16, 17a, 17c)  
8.3.10.2 Paternal Exposure 
Revised time period for use of 
contraception and donation of sperm and 
ova to 90 days after last dose of 
sabestomig 
To align with updated 
pharmacokinetic data that shows a 
mean half-life for sabestomig of 
approximately 10 to 11 days 
DCO = data cut-off; EoT = end of treatment; PTAP = Post-trial Access Program. 
 
List of Non-substantial Modifications 
Section # and name 
Description of change 
Brief rationale 
Throughout the document 
Administrative change: 
The version numbering was updated. 
Typographical errors were corrected, and 
minor clarifications were made. 
Editorial updates 
Throughout the document 
Added investigational product name 
sabestomig 
To provide the nonproprietary 
name of the investigational 
product 
Section 1.3 Schedule of 
Activities - Tables 1, 2, 3, and 
48.6.1 Collection of 
Mandatory Samples for 
Biomarker Analysis 
Corrected matrix from plasma to whole 
blood for collection of circulating tumor 
DNA and circulating biomarkers 
To clarify the correct matrix 
for the sample collection, 
reflecting the sample collected 
at the study site and the 
subsequent samples that are 
analyzed 
 

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Section # and name 
Description of change 
Brief rationale 
Section 1.3 Schedule of 
Activities - Tables 2 and 3 
Deleted footnote regarding additional 
glycated hemoglobin assessments for 
participants with evidence or suspicion of 
diabetes mellitus development 
To reduce burden of additional 
test for participants 
Section 1.3 Schedule of 
Activities - Table 4  
Clarified text for sample 
collection/assessments at combined EoT 
visit and Day 30 post-last dose follow-up 
visit when timelines/windows overlap.  
 
 
Clarified that if a participant begins a new 
treatment shortly after discontinuation and 
within the EoT biopsy window, a biopsy 
should not be collected 
To clarify which tests and data 
should be obtained when EoT 
and Day 30 post-last dose visit 
are combined to limit 
sample/assessment duplication 
and ensure samples from both 
visits are collected at one 
timepoint 
To ensure accurate 
interpretation of biopsy results 
4.4 End of Study Definition 
Revised cross-reference to Section 6.7 to 
correct section heading Section 6.6.7 
Linking error 
6.9 Continued Access to Study 
Intervention After the End of 
the Study 
8.3.1 Time Period and 
Frequency for Collecting AE 
and SAE Information 
Added text regarding AE and SAE 
collection time period following 
discontinuation of sabestomig 
To provide timing for 
collection of AEs and SAEs 
during the PTAP and to clarify 
that AEs and SAEs will be 
collected regardless of 
participants’ initiation of new 
anticancer treatment up to 
required timelines in protocol 
Section 1.3 Schedule of 
Activities – Table 4 
7.1 Discontinuation of Study 
Intervention 
Added text regarding last study contact for 
participants in safety or survival follow-up 
To clarify last study-related 
contact and documentation 
during safety or survival 
follow-up 
8.3.6 Adverse Events of 
Special Interest 
Updated AESI terminology 
To align AESI terminology 
with updates from current 
MedDRA coding and to align 
the PT terms coded to the 
medical concepts across the 
Sponsor bispecifics 
platform/program 
development 
Appendix A1 Regulatory and 
Ethical Considerations 
Added text regarding reporting of 
SUSARs in the EudraVigilance database 
To comply with EU CTR 
language standards on 
reporting of SUSARs 
Appendix B2 Contraception 
Methods 
Added statement regarding acceptable use 
of oral contraceptives (only highly 
effective when associated with inhibition 
of ovulation). 
To comply with CTFG 
guidance on the 
recommendations related to 
contraception and pregnancy 
testing 

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Section # and name 
Description of change 
Brief rationale 
Appendix C3 International 
WG Consensus Response 
evaluation Criteria in 
Lymphoma (Younes et al 
2017 [RECIL 2017]) 
Added definitions of response per RECIL 
criteria 
To provide further definitions 
of RECIL response to align 
with AstraZeneca clinical 
study protocol template 
language 
AE = adverse event; AESI = adverse event of special interest; CTFG = Clinical Trials Facilitation Group; 
EoT = end of treatment; EU CTR = European Union Clinical Trials Regulation; MedDRA = Medical Dictionary 
for Regulatory Activities; PT = preferred term; PTAP = Post-trial Access Program; RECIL = Response-
evaluation Criteria in Lymphoma; SAE = serious adverse event; SUSAR = suspected unexpected serious adverse 
reaction; WG = Working Group. 
 

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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
SUMMARY OF CHANGES .................................................................................................... 2 
TABLE OF CONTENTS .......................................................................................................... 6 
LIST OF TABLES .................................................................................................................. 10 
LIST OF APPENDICES ......................................................................................................... 11 
1. 
PROTOCOL SUMMARY.................................................................................... 13 
1.1 
Synopsis ................................................................................................................ 13 
1.2 
Schema .................................................................................................................. 19 
1.3 
Schedule of Activities ........................................................................................... 20 
2. 
INTRODUCTION ................................................................................................ 39 
2.1 
Study Rationale ..................................................................................................... 39 
2.2 
Background ........................................................................................................... 39 
2.2.1 
Programmed Cell Death Protein-1 and T Cell Immunoglobulin and Mucin 
Domain-containing Protein-3 ............................................................................... 39 
2.2.2 
Disease Background and Current Landscape ....................................................... 40 
2.2.3 
Clinical Development Rationale for Dual PD-1 and TIM-3 Blockade ................ 41 
2.2.4 
Sabestomig Background ....................................................................................... 41 
2.2.4.1 
Sabestomig Nonclinical Pharmacology ................................................................ 42 
2.2.4.2 
Sabestomig Nonclinical Pharmacokinetics........................................................... 42 
2.2.4.3 
Sabestomig Nonclinical Toxicology..................................................................... 42 
2.3 
Benefit/Risk Assessment ...................................................................................... 44 
2.3.1 
Risk Assessment ................................................................................................... 44 
2.3.2 
Benefit Assessment ............................................................................................... 45 
2.3.3 
Overall Benefit: Risk Conclusion ......................................................................... 45 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................... 47 
4. 
STUDY DESIGN ................................................................................................. 51 
4.1 
Overall Design ...................................................................................................... 51 
4.1.1 
Part A: Dose Escalation ........................................................................................ 51 
4.1.2 
Part B: Dose Expansion ........................................................................................ 52 
4.1.3 
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................. 52 
4.2 
Scientific Rationale for Study Design .................................................................. 53 
4.2.1 
Rationale for Endpoints ........................................................................................ 54 
4.3 
Justification for Dose ............................................................................................ 54 
4.3.1 
Rationale for Calculation of the Starting Dose in the Ongoing First-In-Human 
Study (D9570C00001) .......................................................................................... 55 
4.3.2 
Calculation of the First-In-Human Dose Based on Pharmacokinetic and 
Pharmacodynamic Modelling and Simulation ..................................................... 56 

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4.3.3 
Clinical References for PD-1 and TIM-3 Targeting Agents to Support Starting 
Dose Selection for Sabestomig ............................................................................. 56 
4.3.4 
Calculation of Safety Margins for the First-In-Human Dose of Sabestomig ....... 59 
4.4 
End of Study Definition ........................................................................................ 60 
4.5 
Study Stopping Criteria ........................................................................................ 60 
5. 
STUDY POPULATION ....................................................................................... 62 
5.1 
Inclusion Criteria .................................................................................................. 62 
5.2 
Exclusion Criteria ................................................................................................. 66 
5.3 
Lifestyle Considerations ....................................................................................... 70 
5.4 
Screen Failures...................................................................................................... 70 
6. 
STUDY INTERVENTION .................................................................................. 70 
6.1 
Study Intervention(s) Administered ..................................................................... 71 
6.1.1 
Investigational Products........................................................................................ 71 
6.1.2 
Identity of Investigational Product(s) ................................................................... 71 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 72 
6.2.1 
Sabestomig Infusion Preparation and Administration .......................................... 73 
6.2.1.1 
Preparation ............................................................................................................ 73 
6.2.1.2 
Administration ...................................................................................................... 75 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................. 76 
6.4 
Study Intervention Compliance ............................................................................ 76 
6.5 
Concomitant Therapy ........................................................................................... 76 
6.5.1 
Premedication ....................................................................................................... 77 
6.5.2 
Rescue Medicine ................................................................................................... 77 
6.6 
Dose Modification ................................................................................................ 80 
6.6.1 
Starting Dose, Dose Escalation Scheme, and Stopping Criteria .......................... 80 
6.6.1.1 
Accelerated Titration Design ................................................................................ 81 
6.6.1.2 
Modified Toxicity Probability Interval ................................................................. 82 
6.6.2 
Dose Expansion .................................................................................................... 84 
6.6.3 
Definition of Dose-limiting Toxicity .................................................................... 84 
6.6.4 
Definition of Maximum Tolerated Dose .............................................................. 86 
6.6.5 
Definition of Optimal Biological Dose ................................................................ 87 
6.6.6 
Definition of DLT-evaluable Participants ............................................................ 87 
6.6.7 
Safety Review Committee .................................................................................... 87 
6.6.8 
Dose Modification and Toxicity Management ..................................................... 88 
6.7 
Dose Delay............................................................................................................ 89 
6.8 
Treatment Beyond Progression............................................................................. 89 
6.9 
Continued Access to Study Intervention After the End of the Study ................... 89 
6.10 
Treatment of Overdose ......................................................................................... 90 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................ 91 
7.1 
Discontinuation of Study Intervention ................................................................. 91 

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8.3.13 
Medication Error, Drug Abuse and Drug Misuse ............................................... 115 
8.3.13.1 
Timelines ............................................................................................................ 115 
8.3.13.2 
Medication Error ................................................................................................. 116 
8.3.13.3 
Drug Abuse ......................................................................................................... 116 
8.3.13.4 
Drug Misuse........................................................................................................ 116 
8.4 
Reporting of Overdose ........................................................................................ 116 
8.5 
Human Biological Samples ................................................................................ 117 
8.5.1 
Pharmacokinetics ................................................................................................ 117 
8.5.1.1 
Determination of Drug Concentration ................................................................ 118 
8.5.2 
Immunogenicity Assessments ............................................................................ 118 
8.5.3 
Pharmacodynamics ............................................................................................. 118 
8.6 
Human Biological Sample Biomarkers .............................................................. 118 
8.6.1 
Collection of Mandatory Samples for Biomarker Analysis ............................... 118 
8.6.2 
Tissue Samples ................................................................................................... 119 
8.6.2.1 
Tumor Tissue Samples ....................................................................................... 119 
8.6.2.2 
Non-tumor Tissue Biopsy at Toxicity ................................................................ 121 
8.6.3 
Collection of Optional Biomarker Samples ........................................................ 122 
8.7 
Optional Genomics Initiative Sample ................................................................. 122 
8.8 
Health Economics/Medical Resource Utilization and Health Economics ......... 122 
8.9 
Assessments for Participants Who Transition to PTAP ..................................... 122 
9. 
STATISTICAL CONSIDERATIONS ............................................................... 123 
9.1 
Statistical Hypotheses ......................................................................................... 123 
9.2 
Sample Size Determination ................................................................................ 123 
9.3 
Populations for Analyses .................................................................................... 124 
9.4 
Statistical Analyses ............................................................................................. 126 
9.4.1 
General Considerations ....................................................................................... 126 
9.4.2 
Efficacy Analyses ............................................................................................... 127 
9.4.2.1 
Primary Endpoint(s)............................................................................................ 127 
9.4.2.2 
Secondary Endpoint(s)........................................................................................ 128 
9.4.3 
Safety Analyses .................................................................................................. 130 
9.4.3.1 
Maximum Tolerated Dose Evaluation ................................................................ 130 
9.4.3.2 
Analysis of Adverse Events ................................................................................ 131 
9.4.3.3 
Analysis of Other Safety Data ............................................................................ 131 
9.4.4 
Other Analyses.................................................................................................... 132 
9.4.4.1 
Pharmacokinetics and Pharmacodynamics ......................................................... 132 
9.4.4.2 
Immunogenicity .................................................................................................. 132 
9.4.4.3 
Biomarkers .......................................................................................................... 132 
9.4.4.4 
Patient-Reported Outcomes ................................................................................ 133 
9.5 
Interim Analyses ................................................................................................. 133 
9.5.1 
Relapsed or Refractory cHL, Anti-PD-1/PD-L1 Exposed ................................. 134 
9.5.2 
Relapsed or Refractory cHL, Anti-PD-1/PD-L1-naïve ...................................... 135 
9.6 
Data Monitoring Committee ............................................................................... 136 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .......................................................................................... 137 
11. 
REFERENCES ................................................................................................... 263 
 
LIST OF FIGURES 
Figure 1 
Study Flow Diagram ................................................................................... 19 
Figure 2 
Hepatitis B Screening Tests and Eligibility Algorithm ............................... 67 
Figure 3 
Continuous Objective Response Rate Monitoring for Anti-PD-1/PD-L1 
Exposed Participants ................................................................................. 135 
Figure 4 
Continuous Objective Response Rate Monitoring for Anti-PD-1/PD-L1 
Naïve Participants ..................................................................................... 136 
Figure 5 
NCI PRO-CTCAE Questionnaire Example .............................................. 213 
Figure 6 
NCI Peds-PRO-CTCAE Questionnaire Example ..................................... 217 
Figure 7 
 .................................................................... 232 
Figure 8 
 ............ 233 
Figure 9 
........... 234 
Figure 10 
PGI-TT questionnaire ................................................................................ 235 
Figure 11 
 ................................................................................... 236 
Figure 12 
 .................................................................................. 237 
Figure 13 
 .......................................................................... 238 
 
LIST OF TABLES  
Table 1 
Schedule of Activities for Screening Period (Parts A and B) ..................... 20 
Table 2 
Schedule of Activities for the Intervention Period (Part A Dose 
Escalation) ................................................................................................... 23 
Table 3 
Schedule of Activities for the Intervention Period (Part B Dose 
Expansion) ................................................................................................... 29 
Table 4 
Schedule of Activities for Disease Progression, End of Treatment, and 
Follow-up Period (Parts A and B) ............................................................... 35 
Table 5 
Primary Objectives and Endpoints .............................................................. 47 
Table 6 
Secondary Objectives and Endpoints .......................................................... 48 
Table 7 
Exploratory Objectives and Endpoints ........................................................ 49 
Table 8 
Safety Margins of Doses of Sabestomig Used in the Proposed Dose 
Escalation Scheme ...................................................................................... 59 
Table 9 
Criteria for Adequate Organ and Marrow Function .................................... 64 
Table 10 
Investigational Product ................................................................................ 71 
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Table 11 
Preparation of Diluted Sabestomig for IV Administration Using a 
Syringe Pump .............................................................................................. 74 
Table 12 
Prohibited Concomitant Medications .......................................................... 78 
Table 13 
Permitted Concomitant Medications ........................................................... 79 
Table 14 
Sabestomig Planned and Intermediate Dose Levels ................................... 81 
Table 15 
Modified Toxicity Probability Interval-2 Algorithm .................................. 84 
Table 16 
Radiology Scans for Tumor Assessments ................................................... 96 
Table 17 
Clinical Safety Laboratory Variables ........................................................ 107 
Table 18 
Tumor Sample Requirement at Each Time Point ..................................... 120 
Table 19 
Estimated Response Rate and 80% Two-sided Confidence Interval Out 
of 
Participants (Cohort B1) .................................................................. 124 
Table 20 
Estimated Response Rate and 80% Two-sided Confidence Interval Out 
of 
Participants (Cohort B2) .................................................................. 124 
Table 21 
Study Populations ...................................................................................... 125 
Table 22 
Operating Characteristics of Bayesian Continuous Monitoring of Cohort 
B1 .............................................................................................................. 135 
Table 23 
Operating Characteristics of Bayesian Continuous Monitoring of Cohort 
B2 .............................................................................................................. 136 
Highly Effective Methods of Contraception ......................................................................... 144 
Deauville 5-point scale .......................................................................................................... 150 
Evaluation of Overall Response Using the Modified Lugano Criteria ................................. 151 
Integrated Radiological Overall Response ............................................................................ 152 
Overall Response Assessment ............................................................................................... 152 
Table 1: RECIL 2017 Response categories based on assessment of target lesions .............. 155 
Key Differences Between RECIL 2017 and Lugano 2014 ................................................... 156 
 
LIST OF APPENDICES  
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations ........................ 138 
Appendix B 
Contraception Guidance ............................................................................ 144 
Appendix C 
Response Evaluation Using the Modified Lugano (Cheson et al, JCO 
2014) and RECIL (Younes et al, Ann Oncol 2017) Criteria ..................... 145 
Appendix D 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ......................................................................... 157 
Appendix E 
Handling of Human Biological Samples ................................................... 163 
Appendix F 
Optional Genomics Initiative Sample ....................................................... 165 
Appendix G 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ............................................................................ 168 
Appendix H 
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis .............................. 176 
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Appendix I 
Dosing Modification and Toxicity Management Guidelines for 
Sabestomig Monotherapy .......................................................................... 178 
Appendix J 
Clinical Outcome Assessment Questionnaires .......................................... 212 
Appendix K 
Abbreviations ............................................................................................ 241 
Appendix L 
Protocol Version History ........................................................................... 247 
 

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1. 
PROTOCOL SUMMARY  
1.1 
Synopsis  
Protocol Title: 
A Phase I/II Open-label, Multi-center Study to Assess Safety, Tolerability, Pharmacokinetics 
and Preliminary Efficacy of AZD7789, an Anti-PD-1 and Anti-TIM-3 Bispecific Antibody, in 
Patients with Relapsed or Refractory Classical Hodgkin Lymphoma 
Short Title: 
Open-label, Multi-center Study to Assess the Safety and Preliminary Efficacy of AZD7789 in 
Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (cHL) 
Rationale: 
The cellular microenvironment of classical Hodgkin Lymphoma (cHL) is characterized by a 
paucity of B cell-derived malignant Hodgkin Reed-Sternberg (HRS) cells within a tumor 
microenvironment (TME) comprised of non-malignant stromal and immune cells. Despite 
extensive immune cell infiltration, the antitumor immune response is ineffective. It is 
hypothesized that this is due to the ability 
 
. 
Hodgkin Reed-Sternberg cells co-opt the programmed cell death protein-1 (PD-1) pathway 
and upregulate PD-1 ligands by several mechanisms including copy gain alterations of 9p24.1. 
Topographical analysis of cHL TME demonstrated that HRS cells with programmed cell 
death-ligand 1 (PD-L1) overexpression were in close proximity to PD-1+ CD4+ T cells within 
the TME. Furthermore, reports demonstrated that PD-1 expression on CD4+ T cells, within the 
cHL TME, is more frequently observed on the T helper 1 (Th1) effector cells compared to 
CD4+ Tregs, which are in turn largely PD-1 negative. Consequently, a double immune evasion 
strategy exists within cHL, whereby Th1-mediated immune responses are likely dysfunctional 
while the immunosuppressive Treg cells retain functionality. 
Due to the strong scientific rationale, anti-PD-1/PD-L1 therapy entered clinical trials and 
yielded a breakthrough in relapsed or refractory (r/r) cHL. However, as monotherapy, less 
than 20% of patients achieved a complete response (CR) and results were not durable. 
, the relative 
 
 suggests 
 contribute to promote 
. 
 
 and 
 is an immune checkpoint 
(IC) that has been associated with 
 and has recently been implicated as a 
resistance mechanism following PD-1 therapy. While data in cHL is limited, 
 
expression has been observed in cHL. Therefore, co-targeting both PD-1 and 
 
may reinvigorate 
 and lead to more durable 
. 
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never received an anti-PD-1/PD-L1 therapy previously. Approximately 180 participants will 
receive treatment with sabestomig in the study at up to approximately 
 sites globally. 
Part A Dose Escalation will evaluate up to 8 dose levels of sabestomig and consist of up to 
participants with r/r cHL. Cohorts A1 to A4 will be single participant cohorts with 4 dose 
levels of sabestomig (2, 7, 22.5, and 75 mg) based on an accelerated titration design (ATD). 
However, the operating model will switch to a modified toxicity probability interval-2 
(mTPI-2) algorithm should a DLT or Grade 2 or greater treatment-emergent adverse event 
(TEAE) occur. 
Cohorts A5, A6, and A7 for subsequent dose levels of sabestomig (225, 750, and 1500 mg) 
will enroll 3 participants based on the mTPI-2 algorithm to establish the safety of sabestomig. 
Based on emerging data, the optional Cohort A8 (at 2000 mg) may open and may also enroll 
up to 
participants. After a cohort is declared safe (eg, Cohort A5, A6, A7 or A8) and based 
on emerging safety, efficacy, PK and biomarker data, the cohort may be expanded (up to 
 
participants); the cohorts may be opened in parallel to fill their rosters of up to 
 participants 
each (mini dose expansion). Intermediate dose levels (50, 150, 450, 1000, 1250, and 1750 mg) 
may be explored if warranted by emerging safety, PK, pharmacodynamics, biomarker, and 
response data. 
The planned starting dose will be 2 mg (dose level 1). Participants will be evaluated for DLTs 
during a 28-day DLT evaluation period. 
Part B Dose Expansion may be considered once a recommended Phase 2 dose (RP2D) is 
determined in Part A Dose Escalation and will evaluate the safety, tolerability, PK, 
pharmacodynamic, and antitumor activity of sabestomig at the determined RP2D in 2 cohorts 
(Cohorts B1 and B2) described below. 
Cohort B1: Approximately 
participants with cHL who have received at least 2 prior lines 
of systemic treatment and have subsequently relapsed or become refractory to treatment and 
have been previously treated with at least 2 cycles of anti-PD-1/PD-L1 based therapy. 
Participants in Cohort B1 will be identical to those of the dose escalation stage. For this 
reason, enrolment of a larger sample size will provide a clearer confirmatory efficacy signal. 
 
 
. 
Cohort B2: Approximately 
 participants with cHL who have received at least 2 prior lines 
of systemic treatment and have subsequently relapsed or become refractory to treatment, but 
have not received an anti-PD-1/PD-L1 based therapy. 
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Disclosure Statement: 
This is a dose escalation and expansion study in which treatment is not blinded. 
Number of Participants: 
Approximately 180 participants will be treated with sabestomig, with up to 
 participants in 
Part A (Dose Escalation) and 
 participants in Part B (Dose Expansion). Additional 
participants may be enrolled if additional dose levels, expansion cohorts, treatment schedules 
are explored, or participants require replacement for any reason. 
Note: “Enrolled” means a participant’s, or their legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study 
but are not assigned in the study, are considered “screen failures” unless otherwise specified 
by the protocol. 
Intervention Groups and Duration: 
Following an initial screening period of up to 4 weeks, eligible participants will receive 
sabestomig every 3 weeks (Q3W) administered via intravenous infusion at the selected dose 
starting on Cycle 1 Day 1. Participants will be treated with study intervention for a maximum 
of 35 cycles, or until disease progression, unacceptable toxicity, withdrawal of consent, or if 
other reasons to discontinue treatment occur. All participants will be followed for survival 
until the end of study, regardless of whether treatment was discontinued. 
No dose reductions of sabestomig will be allowed. Dose modification (hold or delay) and 
toxicity management for sabestomig-related toxicity, including management of 
immune-mediated reactions, infusion-related reactions, and non-immune-mediated reactions 
are provided in the Toxicity Management Guidelines (Appendix I). 
Safety Review Committee: 
A study-specific Safety Review Committee will provide ongoing safety surveillance of the 
study, with regularly scheduled reviews of safety, PK, and other relevant data. This committee 
will be responsible for making recommendations for dose escalation or dose de-escalation 
decisions and making recommendations regarding further conduct of the study during all 
phases of the study. 
Statistical Methods: 
The efficacy endpoints of Complete Response Rate (CRR), Objective Response Rate (ORR), 
Duration of Response (DoR), and Duration of Complete Response (DoCR) will be 
summarized on the response-evaluable analysis set (defined as all dosed participants who had 
measurable disease at baseline). The efficacy endpoints of Progression-free survival (PFS), 
and overall survival (OS) will be summarized on the full analysis set (defined as all 
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participants who received any amount of study intervention). The CRR/ORR and its 
confidence intervals will be summarized by dose level. The DoR/DoCR will be summarized 
using descriptive statistics and Kaplan-Meier plots, where there are sufficient numbers of 
responders. The PFS and OS will be summarized by dose level, and Kaplan-Meier plots will 
be provided. 
Safety and tolerability will be assessed in terms of DLTs, adverse events (AEs)/serious AEs 
(SAEs), immune-mediated adverse events (imAEs), vital signs, clinical chemistry/hematology 
parameters, and clinically significant abnormalities in electrocardiograms (ECGs). All safety 
analyses will be performed on the safety analysis set (defined as all participants who received 
any amount of study intervention). The number and percentage of participants with AEs in 
different categories (eg, causally related, Common Terminology Criteria for Adverse Events 
Grade ≥ 3, etc.) will be summarized by dose level; events in each category will be further 
summarized by Medical Dictionary for Regulatory Activities system organ class and preferred 
term. The SAEs will be summarized separately. All safety data including clinical chemistry, 
hematology, coagulation, urinalysis, vital signs, and clinically significant abnormalities in 
ECGs will be listed individually by participant and appropriately summarized. 
Individual sabestomig concentrations will be tabulated by dose level along with descriptive 
statistics. Relevant descriptive statistics of non-compartmental PK parameters will be 
provided if data allow and may include AUC, Cmax, clearance, and t½ if data allow. 
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of participants who develop detectable ADAs to sabestomig. 
Interim safety analysis will be conducted in Part B after approximately 
participants have 
received the first dose at least  
 to data cut-off, using the interim safety 
population (defined as all participants who received the first dose at least 
 to data 
cut-off). For both Cohorts (B1 and B2) in Part B, interim efficacy analyses to assess futility 
will be performed in a continuous manner using 
 and will 
begin after approximately 
participants in each respective cohort are included in the interim 
response-evaluable population (defined as all dosed participants who had measurable disease 
at baseline and received first dose at least 
 prior to data cut-off). Following this initial 
interim efficacy analysis, subsequent interim efficacy analyses may be performed after every 
 additional participants for Cohort B1 and every  additional participants for Cohort B2 that 
gets included in the interim response-evaluable population, until all participants are enrolled 
and evaluated. For any interim futility analyses, an objective response is defined as either a 
CR or PR as per Modified Lugano criteria, and a complete response is defined as a CR as per 
Modified Lugano Criteria. For any interim analysis of Cohort B1, participants dosed at RP2D 
in Part A will be included. 
 
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1.3 
Schedule of Activities  
The SoA to be performed during the screening period is presented in Table 1. The SoA to be 
performed during the intervention period is presented in Table 2 for Part A Dose Escalation 
and Table 3 for Part B Dose Expansion. The SoA to be performed at disease progression, at 
EoT, and during the follow-up period is presented in Table 4. 
Table 1 
Schedule of Activities for Screening Period (Parts A and B)       
Study Period 
Screening 
Visit 
V1 
Procedure/Study Day 
Day -28 
to -1 
Informed consent and assignment of participant identification number (Section 5.1 and 
Appendix A) 
X 
Demography (including race and ethnicity, per local regulations) 
X 
Medical/surgical history and comorbid conditions (includes substance usage; Section 8.2.1) 
X 
Full physical examination including height and weight (Section 8.2.2) 
X 
12-lead ECG (triplicate; Section 8.2.4) a 
X 
Left ventricular ejection fraction by echocardiogram/ multiple-gated acquisition scan 
(Section 8.2.5) 
X 
Vital signs including pulse oximetry (Section 8.2.3) 
X 
Pulmonary function test (FEV1), restricted to eligible participants with pre-existing obstructive or 
fibrotic lung conditions (Section 8.2.8) b 
X 
Eastern Cooperative Oncology Group performance status (Section 8.2.6) 
X 
Assessment of B-symptoms (Section 8.1.1) 
X 
Assessment of AEs/SAEs (Section 8.3) 
X 
Concomitant medications (Section 6.5) 
X 
Verify eligibility criteria (Sections 5.1 and 5.2) 
X 
COVID-19 testing c 
X 
Blood and Urine Tests for Safety 
Clinical Chemistry (Section 8.2.7) 
X 
Hematology (Section 8.2.7) 
X 
Cardiac troponin (Section 8.2.7) 
X 
Glycated hemoglobin (Section 8.2.7) 
X 
Thyroid function (thyroid-stimulating hormone, and free thyroxine and free triiodothyronine as 
indicated; Section 8.2.7) d 
X 
Anti-thyroid antibodies (anti-thyroid peroxidase antibodies, thyroglobulin antibodies, thyrotropin 
receptor antibodies; Section 8.2.7) 
X 
Coagulation parameters (Section 8.2.7) 
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Table 1 
Schedule of Activities for Screening Period (Parts A and B)       
Study Period 
Screening 
Visit 
V1 
Procedure/Study Day 
Day -28 
to -1 
Cortisol stimulation test, if adrenal insufficiency is suspected (Section 8.2.7) 
X 
Hepatitis A, B, and C; HIV-1 and HIV-2 virology (Sections 5.1 and 8.2.7) e 
X 
Pregnancy test (serum or urine; women of childbearing potential only; Section 8.2.7) f 
X 
Urinalysis (Section 8.2.7) 
X 
Biomarker Evaluations g 
Whole blood for 
 (Section 8.6.1) 
X 
Whole blood for i
(flow; Section 8.6.1) 
X 
Serum for
 (Section 8.6.1) 
X 
Whole blood for 
 and 
 (Section 8.6.1) 
X 
Whole blood for 
(Section 8.6.1) 
X 
Tumor Tissue Sample g 
Archival tumor tissue sample from first diagnosis, if available (all participants; Section 8.6.2.1) 
X 
Mandatory archival or fresh tumor tissue biopsy collected within 4 months prior to enrolling in 
this study (for participants in Part A mini-expansion and Part B; Section 8.6.2.1) h 
X 
Disease Assessments 
Disease assessment scans; positron emission tomography computed tomography scan i 
X 
Collection of relevant tumor marker data, if available 
X 
a 
All ECGs will be obtained in triplicate (all within a 5-minute time period). Whenever ECGs and blood 
draws are scheduled for the same nominal time, the blood draws should occur last. 
b 
The FEV1 should be greater than 50% of predicted value or for FEV/FVC ratio, the fifth percentile of the 
lower limit of normal (American Thoracic Society definition of moderately severe). 
c 
For all participants in the study, all local institutional standards for COVID-19 must be followed for testing. 
For participants with a known previous COVID-19 infection in the last 3 months, a negative PCR test must 
be documented within 72 hours prior to the first dose. 
d 
Free thyroxine and triiodothyronine only to be measured if thyroid-stimulating hormone is abnormal or if 
suspicion of an adverse event related to the endocrine system. 
e 
Participants with active hepatitis A, B, or C are excluded. Participants who have chronic hepatitis B and 
receiving suppressive antiviral therapy are allowed on study if ALT is normal and viral load is controlled; 
controlled hepatitis B viral load is defined as serum hepatitis B virus DNA < 100 IU/mL by PCR. 
Participants who have chronic hepatitis C are allowed to be enrolled if ALT is normal and hepatitis C virus 
RNA is undetectable by PCR, either spontaneously or in response to a successful prior course of anti-
hepatitis C therapy. 
f 
A urine or serum pregnancy test is acceptable; if urine test is positive or equivocal, then serum β-hCG 
testing should be performed for confirmation. 
g 
For participants in mainland China only, samples will not be collected. 
h 
Recent biopsy within the last 4 months is required for participants in Part A mini-expansion and Part B 
unless medically contraindicated. Within that time period, participant must not have received any anti-cHL 
treatment since the last line of therapy, otherwise fresh tissue is required. For participants in Part A Dose 
Escalation, tumor tissues biopsy within prior 4 months is optional.  
i 
AstraZeneca may request prior images/scans performed up to 6 months prior to start of study intervention.  
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Abbreviations: AE: adverse event; ALT: alanine transaminase; COVID-19: coronavirus disease 2019; ECG: 
electrocardiogram; FEV1: forced expiratory volume over 1 second; FVC: forced vital capacity; HIV: Human 
immunodeficiency virus; PCR: polymerase chain reaction; SAE: serious adverse event. 

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Table 2 
Schedule of Activities for the Intervention Period (Part A Dose Escalation)  
Study Period 
Intervention Period 
Visit 
V2 
V3 
V4 
V5 
V6 
V7 
V8-Vn 
Cycle Number and Day 
C1D1 
C1D3 
C1D8 
C1D15 
C2D1 
C2D8 
C3D1-CnD1 a 
Procedure/Window 
 
 
± 1 D 
± 3 D 
± 1 D 
± 3 D 
± 3 D 
Abbreviated (symptom-directed) physical 
examination including weight 
(Section 8.2.2) b 
X 
 
X 
X 
X b 
X 
X b 
12-lead ECG (triplicate) (Section 8.2.4) c 
X c 
 
X 
 
X c 
X 
C3D1 c, C4D1 c, and as clinically 
indicated thereafter 
Left ventricular ejection fraction by 
echocardiogram/ multiple-gated 
acquisition scan (Section 8.2.5) d 
As clinically indicated 
Vital signs including pulse oximetry 
(Section 8.2.3) e 
X e 
 
X 
X 
X e 
X 
X e 
Eastern Cooperative Oncology Group 
performance status (Section 8.2.6) 
X 
 
 
 
X 
 
X 
Assessment of B-symptoms 
(Section 8.1.1) 
X 
 
 
 
X 
 
X 
Assessment of adverse events and serious 
adverse events (Section 8.3) 
----------------------------------------------------------------------X--------------------------------------------------------------------------------→ 
Concomitant medications (Section 6.5) 
----------------------------------------------------------------------X--------------------------------------------------------------------------------→ 
Blood and Urine Tests for Safety 
Chemistry (Section 8.2.7) f 
X g 
X 
X 
X 
X 
 
X 
Hematology (Section 8.2.7) f 
X g 
X 
X 
X 
X 
 
X 
Cardiac troponin (Section 8.2.7) f 
If clinically indicated 
Glycated hemoglobin (Section 8.2.7) 
 
 
 
 
 
 
C3D1, C5D1, C7D1, C9D1, 
C11D1, C13D1, C15D1, C17D1, 
C19D1, C21D1, C23D1, C25D1, 
C27D1, C29D1, C31D1, C33D1, 
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Table 2 
Schedule of Activities for the Intervention Period (Part A Dose Escalation)  
Study Period 
Intervention Period 
Visit 
V2 
V3 
V4 
V5 
V6 
V7 
V8-Vn 
Cycle Number and Day 
C1D1 
C1D3 
C1D8 
C1D15 
C2D1 
C2D8 
C3D1-CnD1 a 
Procedure/Window 
 
 
± 1 D 
± 3 D 
± 1 D 
± 3 D 
± 3 D 
Thyroid function (thyroid-stimulating 
hormone, and free thyroxine and free 
triiodothyronine as indicated h; 
Section 8.2.7) f 
X g 
 
 
X 
X 
 
X 
Anti-thyroid antibodies (anti-thyroid 
peroxidase antibodies, thyrotropin 
receptor antibodies, thyroglobulin 
antibodies; Section 8.2.7) 
As clinically indicated 
Coagulation parameters (Section 8.2.7) f 
X g 
 
X 
X 
X 
 
X 
Hepatitis B and C virology 
(Section 8.2.7) i 
 
 
 
 
 
 
C5D1, C9D1, C13D1, C17D1, 
C21D1, C25D1, C29D1, and 
C33D1 
Pregnancy test (urine or serum; women 
of child-bearing potential only; 
Section 8.2.7) f 
X g 
 
 
 
X 
 
X 
Urinalysis (Section 8.2.7) 
As clinically indicated 
Blood Tests for PK and Immunogenicity 
Serum for sabestomig PK (Section 8.5) j 
X j 
X 
X 
X 
X  
X 
C3D1, C4D1, C5D1, C6D1, then 
C8D1, C10D1, C14D1, C18D1, 
C26D1, C34D1, and CnD1a 
Serum for sabestomig ADA 
(Section 8.5) k 
X 
 
 
 
X 
X 
C3D1, C4D1, C5D1, C6D1, then 
C8D1, C10D1, C14D1, C18D1, 
C26D1, C34D1, and CnD1a 
Biomarker Evaluations 
Whole blood for 
 
 (Section 8.6.1) l 
X 
 
X m 
 
X 
X  
C3D1, C4D1, C5D1, C6D1, then 
C10D1, C14D1, C18D1, C22D1, 
C26D1, C30D1, and C34D1  
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Table 2 
Schedule of Activities for the Intervention Period (Part A Dose Escalation)  
Study Period 
Intervention Period 
Visit 
V2 
V3 
V4 
V5 
V6 
V7 
V8-Vn 
Cycle Number and Day 
C1D1 
C1D3 
C1D8 
C1D15 
C2D1 
C2D8 
C3D1-CnD1 a 
Procedure/Window 
 
 
± 1 D 
± 3 D 
± 1 D 
± 3 D 
± 3 D 
Whole blood for 
 
(flow) (Section 8.6.1) l 
X 
 
X m 
X 
X 
X  
C3D1, C4D1, C5D1, C6D1, 
C10D1, C14D1, C18D1, and 
CnD1a 
Serum for 
 
(Section 8.6.1) l 
X 
 
X m 
X 
X 
X  
X 
Serum for 
 analysis 
(Section 8.6.1) l 
X 
 
X m 
X 
X 
X 
X and CnD1a 
Whole blood for 
 
and circulating biomarkers 
(Section 8.6.1) l 
X 
 
X m 
X 
X 
X  
C3D1, C4D1, C5D1, C6D1, then 
C10D1, C14D1, C18D1, C22D1, 
C26D1, C30D1, C34D1, and 
CnD1a 
Whole blood for 
 (Section 8.6.1) l 
X 
 
X m 
X 
X 
X  
C3D1, C4D1, C5D1, and C6D1 
Genomics Initiative (optional, 
exploratory genetic saliva sample; 
Section 8.7 and Appendix F) n 
X 
 
 
 
 
 
 
Biopsies 
Optional Tumor tissue biopsy 
(Section 8.6.2.1) 
 
 
X (± 2 D) m 
 
 
 
 
Optional non-tumor tissue biopsy 
(Section 8.6.2.2) 
At toxicity; if clinically indicated 
Study Intervention Administration 
Premedication (Section 6.5.1) 
X 
 
 
 
X 
 
X 
Sabestomig administration o (Section 6) 
X 
 
 
 
X 
 
X 
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Table 2 
Schedule of Activities for the Intervention Period (Part A Dose Escalation)  
Study Period 
Intervention Period 
Visit 
V2 
V3 
V4 
V5 
V6 
V7 
V8-Vn 
Cycle Number and Day 
C1D1 
C1D3 
C1D8 
C1D15 
C2D1 
C2D8 
C3D1-CnD1 a 
Procedure/Window 
 
 
± 1 D 
± 3 D 
± 1 D 
± 3 D 
± 3 D 
Disease Assessments 
Imaging disease assessment (Section 8.1, 
Table 16) p 
At least 10 days after sabestomig administration in Cycle 
 and 
then thereafter at Year 1 from the date of the first infusion, 
then Q6M until PD, start of new anti-cHL therapy or EoS (whichever occurs first).  
Of note: if a participant in CR receives radiotherapy alone as consolidation, imaging for disease assessment should continue until 
the participant meets the criteria mentioned above.   
 
a 
If the participant is deriving clinical benefit per investigator assessment at the time of final study DCO and is planned to continue treatment if the study 
transitions to PTAP, the participant will complete their last planned dosing visit before the final study DCO. The following samples will need to be 
collected if they are not planned as scheduled assessments during this visit: serum for PK, ADA, and 
 analysis; whole blood for 
 and 
 and circulating biomarkers. During the treatment visits after the final DCO, participants will continue to 
receive sabestomig per the dosing schedule (Q3W) and should be followed according to the institution's standard-of-care assessments. No further data 
collection is required except for safety reporting (see Section 6.9). 
b 
On dosing days, the physical examination will be conducted prior to sabestomig administration. 
c 
All ECGs will be obtained in triplicate (all within a 5-minute time period). Collection times for ECGs on days of sabestomig administration are shown 
below. Whenever ECGs and blood draws (eg, PK/ADA) are scheduled for the same nominal time, the blood draws should occur last. The timing of the 
ECG should be such that it allows the blood draw to occur at the proper nominal time. 
 
Collection Times for ECGs on Sabestomig Dosing Days 
Cycle Number and 
Day 
Prior to SOI 
(within 30 min prior to SOI) 
Post EOI 
30 min (± 5 min) 
1 h (± 5 min) 
4 h (± 15 min) 
C1D1 
X 
X 
 
X 
C2D1, C3D1, and 
C4D1 
X 
 
X 
 
C5D1, C6D1, etc. 
As clinically indicated 
 
d 
If clinically indicated, and at the Investigator’s discretion, a consultation with a cardiologist is recommended for follow-up.   
e 
Collection times for vital signs and pulse oximetry on days of sabestomig administration are shown below. Whenever vital signs and blood draws (eg, 
PK/ADA) are scheduled for the same nominal time, the blood draws should occur last. The timing of the vital signs assessment should be such that it allows 
the blood draw to occur at the proper nominal time. 
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Collection Times for Vital Signs and Pulse Oximetry on Sabestomig Dosing Days 
Cycle Number and 
Day 
Prior to SOI 
(within 30 min 
prior to SOI) 
Every 15 min 
(± 5 min) During 
Infusion 
EOI 
(± 5 min) 
Post EOI 
30 min 
(± 5 min) 
1 h 
(± 10 min) 
2 h 
(± 10 min) 
3 h 
(± 10 min) 
4 h 
(± 15 min) 
C1D1 
X 
X 
X 
X 
X 
X 
X 
X 
C2D1, C3D1, and 
C4D1 
X 
X 
X 
X 
X 
 
 
 
C5D1, C6D1, etc. 
X 
 
 
X 
 
 
 
 
 
f 
All safety laboratory results must be reviewed by the Investigator or designee prior to sabestomig administration. 
g 
If screening assessment was performed within the 5 days prior to C1D1 (Days -5 to -1), then the assessment does not need to be performed prior to SOI on 
C1D1. 
h 
Free thyroxine and triiodothyronine only to be measured if thyroid-stimulating hormone is abnormal or if suspicion of an adverse event related to the 
endocrine system. 
i 
Hepatitis B virology testing during treatment and follow-up is required for participants with positive HbsAg or isolated positive anti-hepatitis B core 
antibody (negative HbsAg and negative antibody to hepatitis B surface antigen) at screening and for any participant where clinically indicated. Participants 
with positive HbsAg must remain on antiviral therapy, per institutional practice, to ensure adequate viral suppression during the study intervention and 
follow-up periods. Controlled hepatitis B viral load is defined as serum hepatitis B virus DNA < 100 IU/mL by PCR. 
Hepatitis C virology testing during treatment and follow-up is only required for participants with positive hepatitis C antibody at screening and for any 
participant where clinically indicated. Controlled hepatitis C viral load is defined as undetectable hepatitis C virus RNA by PCR either spontaneously or in 
response to a successful prior course of anti-hepatitis C therapy. 
j 
Collection times for serum samples for PK on days of sabestomig administration are shown below. On days when sabestomig is not administered (C1D8, 
C1D15, and C2D8), only one serum sample for PK is required during the visit. 
 
Collection Times for Serum Samples for PK on Sabestomig Dosing Days 
Cycle Number and Day 
Prior to SOI (within 
30 min prior to SOI) 
EOI (+15 min) 
Post EOI 
4 h (± 15 min) 
48 h (± 2 h) 
C1D1 
X 
X 
X 
X (collected at C1D3 visit) 
C2D1, C3D1, C4D1, C5D1, C6D1, C8D1, 
C10D1, C14D1, C18D1, C26D1, C34D1, 
and CnD1a 
X 
X 
 
 
 
k 
On sabestomig dosing days, serum samples for ADA will be collected within 30 minutes prior to SOI and may be collected at the same time as the prior to 
SOI serum sample for PK. 
l 
On sabestomig dosing days, the sample should be collected prior to start of sabestomig administration. 
m 
If tumor biopsy will be collected on C1D8 (± 2 D) then C1D8 Biomarker Evaluation samples should be collected prior to surgery on the same day as the 
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n 
If, for any reason, the sample is not drawn at screening, it may be collected at any visit until the last study visit. Only one sample should be collected per 
participant for genetics during the study. The genetic informed consent addendum must be signed prior to sample collection. Refer to Appendix F for 
inclusion/exclusion criteria specific to the Genomics Initiative and further details on the optional Genomics Initiative sample. 
o 
Each dose of sabestomig will be infused over approximately 60 minutes (-5 min to +15 min). Participants should be closely monitored during and after 
infusions, as described in Section 6.2.1.2. Following completion of the first treatment cycle, participants may receive additional treatment with sabestomig 
if dosing criteria defined in Section 6.1.2 are met. For participants with a known previous COVID-19 infection in the last 3 months, a negative PCR test 
must be documented within 72 hours prior to the first dose of sabestomig. In the event of a COVID-19 infection while on active treatment with sabestomig, 
the investigatory should use their judgement to delay treatment depending on the clinical situation of the participant (see also Section 6.7). 
p 
At least 10 days post infusion, but prior to the next infusion. Disease response should be assessed by PET-CT as per Modified Lugano criteria (2014) until 
participant achieves CR. Once CR is achieved, contrast CT may replace PET-CT to monitor disease response until PD is suspected. If PD is suspected, PD 
must be confirmed by PET scan. Disease response assessments will be according to the Investigator evaluation using Modified Lugano (Cheson et al, 2014) 
and RECIL (Younes et al, 2017) criteria. In the event pseudo progression is suspected by imaging, a PET-CT scan should be repeated at least 4 weeks after 
the previous assessment to confirm progression or response.  
Abbreviations: ADA: anti-drug antibody; C: cycle; cHL: classical Hodgkin Lymphoma; CR: complete response; CT: computed tomography; D: day(s); 
DCO: data cut-off; ECG: electrocardiogram; EOI: end of infusion; EoS: End of Study; HbsAg: hepatitis B surface antigen; h: hour; min: minute; PCR: 
polymerase chain reaction; PD: progressive disease; PET-CT: positron emission tomography-CT; PK: pharmacokinetic(s); PTAP: post-trial Access Program; 
Q3W: every 3 weeks; Q6M: every 6 months; SOI: start of infusion; TIM-3: T cell immunoglobulin and mucin domain-containing protein-3; V: visit.  

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Table 3 
Schedule of Activities for the Intervention Period (Part B Dose Expansion)    
Study Period 
Intervention Period 
Visit 
V2 
V3 
V4 
V5 
V6 
V7-Vn 
Cycle Number and Day 
C1D1 
C1D8 
C1D15 
C2D1 
C2D8 
C3D1-CnD1 
Procedure/Window 
 
± 1 D 
± 3 D 
± 1 D 
± 3 D 
± 3 D 
Abbreviated (symptom-directed) physical 
examination including weight (Section 8.2.2) a 
X 
X 
X 
X a 
X 
X a 
12-lead ECG (triplicate) (Section 8.2.4) b 
X b 
X b 
 
X b 
X b 
C3D1 b, C4D1 b, and as clinically 
indicated thereafter 
Left ventricular ejection fraction by 
echocardiogram/ multiple-gated acquisition 
scan (Section 8.2.5) c 
As clinically indicated 
Vital signs including pulse oximetry 
(Section 8.2.3) d 
X d 
X 
X 
X d 
X 
X d 
Eastern Cooperative Oncology Group 
performance status (Section 8.2.6) 
X 
 
 
X 
 
X 
Assessment of B-symptoms (Section 8.1.1) 
X 
 
 
X 
 
X 
Assessment of AEs/SAEs (Section 8.3) 
------------------------------------------------------------------X-----------------------------------------------------------------------------→ 
Concomitant medications (Section 6.5) 
------------------------------------------------------------------X-----------------------------------------------------------------------------→ 
Blood and Urine Tests for Safety 
Clinical Chemistry (Section 8.2.7) e 
X f 
X 
X 
X 
 
X 
Hematology (Section 8.2.7) e 
X f 
X 
X 
X 
 
X 
Cardiac troponin (Section 8.2.7) e 
If clinically indicated 
Glycated hemoglobin (Section 8.2.7) 
 
 
 
 
 
C3D1, C5D1, C7D1, C9D1, C11D1, 
C13D1, C15D1, C17D1, C19D1, 
C21D1, C23D1, C25D1, C27D1, 
C29D1, C31D1, C33D1 and C35D1 
Thyroid function (thyroid-stimulating 
hormone, free thyroxine, and free 
triiodothyronine as indicated g; Section 8.2.7) e 
X f 
 
X 
X 
 
X 

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Table 3 
Schedule of Activities for the Intervention Period (Part B Dose Expansion)    
Study Period 
Intervention Period 
Visit 
V2 
V3 
V4 
V5 
V6 
V7-Vn 
Cycle Number and Day 
C1D1 
C1D8 
C1D15 
C2D1 
C2D8 
C3D1-CnD1 
Procedure/Window 
 
± 1 D 
± 3 D 
± 1 D 
± 3 D 
± 3 D 
Anti-thyroid antibodies (anti-thyroid 
peroxidase antibodies, thyroglobulin 
antibodies, thyrotropin receptor antibodies; 
Section 8.2.7) 
As clinically indicated 
Coagulation parameters (Section 8.2.7) e 
X f 
X 
X 
X 
 
X 
Hepatitis B and C virology (Section 8.2.7) h 
 
 
 
 
 
C5D1, C9D1, C13D1, C17D1, 
C21D1, C25D1, C29D1 and C33D1 
Pregnancy test (urine or serum; women of 
childbearing potential only; Section 8.2.7) e 
X f 
 
 
X 
 
X 
Urinalysis (Section 8.2.7) 
As clinically indicated 
Blood Tests for PK and Immunogenicity 
Serum for sabestomig PK (Section 8.5) i, j 
X  
X 
X 
X 
X k 
C4D1 and C6D1 only j  
Serum for sabestomig ADA (Section 8.5) l 
X 
 
 
X 
 
C4D1, C6D1, C8D1, C10D1, 
C14D1, C18D1, C26D1 and C34D1 
Biomarker Evaluations m 
Whole blood for 
 
l (Section 8.6.1) m,n 
X 
X o 
 
X 
X  
C3D1, C4D1, C5D1, C6D1, then 
C10D1, C14D1, C18D1, C22D1, 
C26D1, C30D1 and C34D1 
Whole blood for 
(flow) 
(Section 8.6.1) m,n 
X 
X o 
X 
X 
X  
C3D1, C4D1, C5D1, C6D1, then 
C10D1, C14D1 and C18D1 
Serum for 
 
(Section 8.6.1) m,n 
X 
X o 
X 
X 
X  
X 
Serum for 
 analysis 
(Section 8.6.1) m,n 
X 
X o 
X 
X 
X 
X 
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Table 3 
Schedule of Activities for the Intervention Period (Part B Dose Expansion)    
Study Period 
Intervention Period 
Visit 
V2 
V3 
V4 
V5 
V6 
V7-Vn 
Cycle Number and Day 
C1D1 
C1D8 
C1D15 
C2D1 
C2D8 
C3D1-CnD1 
Procedure/Window 
 
± 1 D 
± 3 D 
± 1 D 
± 3 D 
± 3 D 
Whole blood for 
 and 
circulating biomarkers (Section 8.6.1) m,n 
X 
X o 
X 
X 
X  
C3D1, C4D1, C5D1, C6D1, then 
C10D1, C14D1, C18D1, C22D1, 
C26D1, C30D1 and C34D1 
Whole blood for 
 (Section 8.6.1) m,n 
X 
X o 
X 
X 
X  
C3D1, C4D1 C5D1 and C6D1 
Genomics Initiative (optional, exploratory 
genetic saliva sample; Section 8.7 and 
Appendix F) p 
X 
 
 
 
 
 
Biopsies q,m 
Tumor tissue biopsy (Section 8.6.2.1) q 
 
X (± 2D) o 
 
 
 
 
Optional non-tumor tissue biopsy 
(Section 8.6.2.2) 
At toxicity, if clinically indicated 
PRO Collection r 
Tolerability [Adults: PRO-CTCAE + PGI-TT  
Adolescents: Peds-PRO-CTCAE] 
C1D1 as baseline then Q1W from Week 1 until Week 6, then Q3W from Week 7 until Week 18, then Q6W from Week 19 
until EoT or disease progression. Refer to Vendor’s Study Information Guide and training for window of completion.  
Physical function [Adults
 
Adolescents: 
 
 
C1D1 as baseline then Q3W from Week 1 until Week 18, then Q6W from Week 19 until EoT or disease progression. Refer to 
Vendor’s Study Information Guide and training for window of completion. 
Disease symptoms and health status [Adults: 
  
] 
C1D1 as baseline then Q6W from Week 1 until EoT or disease progression. Refer to Vendor’s Study Information Guide and 
training for window of completion. 
Change [Adults: PGIC] 
At Week 10, 19, 37, 67, and 103. Refer to Vendor’s Study Information Guide and training for window of completion. 
Study Intervention Administration 
Premedication (Section 6.5.1) 
X 
 
 
X 
 
X 
Sabestomig administration (Section 6) s 
X 
 
 
X 
 
X 
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Table 3 
Schedule of Activities for the Intervention Period (Part B Dose Expansion)    
Study Period 
Intervention Period 
Visit 
V2 
V3 
V4 
V5 
V6 
V7-Vn 
Cycle Number and Day 
C1D1 
C1D8 
C1D15 
C2D1 
C2D8 
C3D1-CnD1 
Procedure/Window 
 
± 1 D 
± 3 D 
± 1 D 
± 3 D 
± 3 D 
Disease Assessments 
Imaging disease assessment (Section 8.1, 
Table 16) t 
At least 10 days after sabestomig administration in Cycle 
 and 
then thereafter at Year 1 from the date of the first 
infusion, then Q6M until PD, start of new treatment for HL or EoS (whichever occurs first).  
Of Note: if a participant in CR receives RT as consolidation, imaging disease assessment should continue until the participant 
meet the criteria mentioned in the paragraph above.   
 
a 
On dosing days, the physical examination will be conducted prior to sabestomig administration. 
b 
All ECGs will be obtained in triplicate (all within a 5-minute time period). Collection times for ECGs on days of sabestomig administration are shown 
below. Whenever ECGs and blood draws (eg, PK/ADA) are scheduled for the same nominal time, the blood draws should occur last. The timing of the 
ECG should be such that it allows the blood draw to occur at the proper nominal time. Day 8 assessment only to be performed if cardiac signal is detected in 
Part A. 
 
Collection Times for ECGs on Sabestomig Dosing Days 
Cycle Number and Day 
Prior to SOI (within 30 mins prior to SOI) 
1 h (± 5 mins) Post EOI 
C1D1, C2D1, C3D1, and C4D1 
X 
X 
C5D1, C6D1, etc. 
As clinically indicated 
 
c 
If clinically indicated, and at the Investigator’s discretion, a consultation with a cardiologist is recommended for follow-up.   
d 
Collection times for vital signs and pulse oximetry on days of sabestomig administration are shown below. Whenever vital signs and blood draws (eg, 
PK/ADA) are scheduled for the same nominal time, the blood draws should occur last. The timing of the vital signs assessment should be such that it allows 
the blood draw to occur at the proper nominal time. 
 
Collection Times for Vital Signs and Pulse Oximetry on Sabestomig Dosing Days 
Cycle Number and Day 
Prior to SOI (within 30 mins prior to 
SOI) 
EOI (± 5 min) 
30 mins (± 10 min) Post EOI 
C1D1 
X 
X 
X 
C2D1, C3D1, C4D1, etc. 
X 
 
X 
 
e 
All safety laboratory results must be reviewed by the Investigator or designee prior to sabestomig administration. 
f 
If screening assessment was performed within the 5 days prior to C1D1 (Days -5 to -1), then the assessment does not need to be performed prior to SOI on 
C1D1. 
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g 
Free thyroxine and triiodothyronine only to be measured if thyroid-stimulating hormone is abnormal or if suspicion of an adverse event related to the 
endocrine system. 
h 
Hepatitis B virology testing during treatment and follow-up is required for participants with positive HbsAg or isolated positive anti-HBc (negative HbsAg 
and negative antiHBs) at screening and for any participant where clinically indicated. Participants with positive HbsAg must remain on antiviral therapy, 
per institutional practice, to ensure adequate viral suppression during the study intervention and follow-up periods. Controlled hepatitis B viral load is 
defined as serum hepatitis B virus DNA < 100 IU/mL by PCR. 
Hepatitis C virology testing during treatment and follow-up is only required for participants with positive hepatitis C antibody at screening and for any 
participant where clinically indicated. Controlled hepatitis C viral load is defined as undetectable hepatitis C virus RNA by PCR either spontaneously or in 
response to a successful prior course of anti-hepatitis C therapy. 
i 
Collection times for serum samples for PK on days of sabestomig administration are shown below. On days when sabestomig is not administered (C1D8 
and C1D15), only one serum sample for PK is required during the visit. 
 
Collection Times for Serum Samples for PK on Sabestomig Dosing Days 
Cycle Number and Day 
Prior to SOI (within 30 mins prior to SOI) 
EOI (+15 mins) 
C1D1, C2D1, C4D1, C6D1 
X 
X 
 
 
j 
For participants in mainland China, collection times for serum samples for PK on days of sabestomig administration are shown below. One serum sample 
for PK is required on days when sabestomig is not administered (C1D8, C1D15, C2D8) and is to be collected during the visit.  
 
Collection Times for Serum Samples for PK on Sabestomig Dosing Days 
Cycle Number and Day 
Prior to SOI (within 30 min prior to 
SOI) 
EOI (+15 min) 
Post EOI 
4 h (± 15 min) 
48 h (± 2 h) 
C1D1 
X 
X 
X 
X (collected at visit) 
C2D1, C4D1, C6D1, C8D1, C10D1, C14D1, 
C18D1, C26D1, C34D1 
X 
X 
 
 
 
k 
Sample to be collected only in mainland China. 
l 
On sabestomig dosing days, serum samples for ADA will be collected within 30 minutes prior to SOI and may be collected at the same time as the prior to 
SOI serum sample for PK. 
m 
These samples will not be collected in mainland China. 
n 
On sabestomig dosing days, the sample should be collected prior to start of sabestomig administration. 
o 
If tumor biopsy will be collected on C1D8 (± 2 D) then C1D8 Biomarker Evaluation samples should be collected prior to surgery on the same day as the 
biopsy (to coincide with the biopsy) 
p 
If, for any reason, the sample is not drawn at screening, it may be collected at any visit until the last study visit. Only one sample should be collected per 
participant for genetics during the study. The genetic informed consent addendum must be signed prior to sample collection. Refer to Appendix F for 
inclusion/exclusion criteria specific to the Genomics Initiative and further details on the optional Genomics Initiative sample. 

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Table 4 
Schedule of Activities for Disease Progression, End of Treatment, and Follow-up Period (Parts A and B)     
Procedure/Visit (Window) 
At Disease 
Progression a 
EoT b 
Post-treatment Safety Follow-up c 
Survival Follow-up c 
+ 14 D 
Day 30 Post Last 
Dose (± 7 D) 
Day 90 Post Last 
Dose (± 7 D) 
 Q6M Post Last Disease 
Assessment (± 14 D) 
Abbreviated (symptom-directed) physical 
examination including weight (Section 8.2.2) 
 
X 
X 
X 
 
12-lead ECG (triplicate) (Section 8.2.4)  
 
X 
 
 
 
Left ventricular ejection fraction by echocardiogram/ 
multiple-gated acquisition scan (Section 8.2.5) d 
 
X 
If clinically indicated. 
 
Vital signs including pulse oximetry (Section 8.2.3) 
 
X 
X 
X 
 
Eastern Cooperative Oncology Group performance 
status (Section 8.2.6) 
 
X 
X 
X 
 
Assessment of B-Symptoms (Section 8.1.1) 
 
X 
X 
X 
 
Assessment of AEs/SAEs (Section 8.3) 
 
-------------------------------------X-------------------------------------→ 
 
Concomitant medications (Section 6.5) 
 
-------------------------------------X-------------------------------------→ 
 
Subsequent anticancer therapy 
X 
X 
X 
X 
X 
Survival status (by telephone, email, or clinic visit) 
X 
X 
X 
X 
X 
Disease status post HSCT if applicable (by 
telephone, email, or clinic visit) e 
 
 
 
 
X 
Blood and Urine Tests 
Clinical Chemistry (Section 8.2.7) 
 
X 
X 
X 
 
Hematology (Section 8.2.7) 
 
X 
X 
X 
 
Glycated hemoglobin (Section 8.2.7) 
 
X 
 
X 
 
Thyroid function (thyroid-stimulating hormone, free 
thyroxine, and free triiodothyronine as indicated f; 
Section 8.2.7) 
 
X 
X 
X 
 
Anti-thyroid antibodies (anti-thyroid peroxidase 
antibodies, thyroglobulin antibodies, thyrotropin 
receptor antibodies; Section 8.2.7) 
 
X 
X 
X 
 
Hepatitis B and C virology (Section 8.2.7) g 
 
 
X 
 
 

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Table 4 
Schedule of Activities for Disease Progression, End of Treatment, and Follow-up Period (Parts A and B)     
Procedure/Visit (Window) 
At Disease 
Progression a 
EoT b 
Post-treatment Safety Follow-up c 
Survival Follow-up c 
+ 14 D 
Day 30 Post Last 
Dose (± 7 D) 
Day 90 Post Last 
Dose (± 7 D) 
 Q6M Post Last Disease 
Assessment (± 14 D) 
Pregnancy test (urine or serum; women of 
child-bearing potential only; Section 8.2.7) 
 
X 
X 
X 
 
Urinalysis (Section 8.2.7) 
 
X 
X 
 
 
Blood Tests for PK and Immunogenicity 
Part A Dose Escalation and Part B for patients from 
mainland China: Serum for sabestomig PK 
(Section 8.5) 
  
X 
X 
 
 
Part A Dose Escalation and Part B for patients from 
mainland China: Serum for sabestomig ADA 
(Section 8.5) 
  
X 
X 
X 
 
Blood Tests for Biomarker Evaluations h 
Whole blood for 
 
(Section 8.6.1) i 
X 
X 
X 
 
 
Whole blood for 
 (flow) 
(Section 8.6.1) i 
X 
X 
 
 
 
Serum for 
 (Section 8.6.1) i 
X 
X 
X 
 
 
Serum for 
 analysis (Section 8.6.1) i 
X 
X 
X 
X 
 
Whole blood for 
 and 
circulating biomarkers (Section 8.6.1) i 
X 
X 
X 
X 
 
Whole blood for 
 (Section 8.6.1) i 
X 
X 
X 
 
 
PRO Collection (Part B only) 
Tolerability [Adults: PRO-CTCAE + PGI-TT  
Adolescents: Peds-PRO-CTCAE] 
 
Xj 
 
 
 
Physical function [Adults
 
Adolescents: 
 
 
 
Xj 
 
 
 
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Table 4 
Schedule of Activities for Disease Progression, End of Treatment, and Follow-up Period (Parts A and B)     
Procedure/Visit (Window) 
At Disease 
Progression a 
EoT b 
Post-treatment Safety Follow-up c 
Survival Follow-up c 
+ 14 D 
Day 30 Post Last 
Dose (± 7 D) 
Day 90 Post Last 
Dose (± 7 D) 
 Q6M Post Last Disease 
Assessment (± 14 D) 
Disease symptoms and health status [Adults: 
  
Adolescents: 
] 
 
Xj 
 
 
 
Biopsies j, h 
Optional tumor tissue biopsy (Section 8.6.2.1) k 
X 
Xk 
 
 
 
Non-tumor tissue biopsy (Section 8.6.2.2) 
 
At toxicity, if clinically indicated 
 
Disease Assessments 
Imaging disease assessment (Section 8.1, Table 16) l 
At least 10 days after sabestomig administration in Cycle 
 and 
then thereafter at Year 1 then Q6M to be 
continued beyond the Day 90 post last dose visit if participant still in response, until PD, start of new treatment for 
cHL or EoS (whichever occurs first)  
a 
This visit is only required for participants who discontinued for disease progression. 
b 
The EoT visit can be combined with the Day 30 post-last dose follow-up visit if timelines/windows overlap. At this combined visit, required tests and assessments between 
both the EoT and Day 30 post last dose visit must be performed, ensuring there are no duplicates. If the participant is planned to continue on sabestomig treatment at the time 
of the final study DCO and as the study transitions to PTAP, the EoT visit will not be performed. The participant will complete the last dosing visit per SoA Table 2 before 
the final DCO. 
c 
All participants in Safety or Survival follow-up at the time of final study DCO will be contacted by the study site prior to the final study DCO to confirm their survival status 
and to inform participants that this was the last study-related contact, and no further survival data will be collected in respect to the study. Sites are requested to document 
this last contact in the source records. 
d 
If clinically indicated, and at the Investigator’s discretion, a consultation with a cardiologist is recommended for follow-up.   
e 
To be collected only for participant who received any dose of the study drug and underwent HSCT while in response (CR or PR) without any other treatment between last 
dose of sabestomig and start of pre-conditioning for HSCT. 
f 
Free thyroxine and triiodothyronine only to be measured if thyroid-stimulating hormone is abnormal or if suspicion of an adverse event related to the endocrine system. 
g 
Hepatitis B virology testing during treatment and follow-up is required for participants with positive HbsAg or isolated positive anti-HBc (negative HbsAg and negative anti 
HBs) at screening and for any participant where clinically indicated. Participants with positive HbsAg must remain on antiviral therapy, per institutional practice, to ensure 
adequate viral suppression during the study intervention and follow-up periods. Controlled hepatitis B viral load is defined as serum hepatitis B virus DNA < 100 IU/mL by 
PCR. 
Hepatitis C virology testing during treatment and follow-up is only required for participants with positive hepatitis C antibody at screening and for any participant where 
clinically indicated. Controlled hepatitis C viral load is defined as undetectable hepatitis C virus RNA by PCR either spontaneously or in response to a successful prior course 
of anti-hepatitis C therapy. 
h 
These samples will not be collected in mainland China.   
i 
All ECGs will be obtained in triplicate (all within a 5-minute time period). Whenever ECGs and blood draws (eg, PK/ADA) are scheduled for the same nominal time, the 
blood draws should occur last. The timing of the ECG should be such that it allows the blood draw to occur at the proper nominal time. 
j 
Refer to Vendor’s Study Information Guide and training for window of completion. 
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2. 
INTRODUCTION  
Sabestomig (AZD7789) is a 
 
). 
 
. Programmed cell death protein-1 and TIM-3 are part of a complex 
system of cell surface receptors that, when bound to their cognate ligands, provide co-
inhibitory signals to T cells to modulate their activity. 
 and 
 is 
. AstraZeneca is developing 
sabestomig for the treatment of r/r cHL in patients having either refractory or have developed 
a resistance to PD-1 selective treatment or are anti-PD-1/PD-L1-naïve. 
2.1 
Study Rationale  
Multiple reports have identified a high correlation in PD-1 and TIM-3 expression on tumor 
infiltrating lymphocytes across multiple indications with dual receptor expression associated 
with diminished functionality (Biton et al, 2018, Fourcade et al, 2010, Thommen et al, 2015). 
 
 
 
 
 
 
. 
2.2 
Background  
2.2.1 
Programmed Cell Death Protein-1 and T Cell Immunoglobulin and 
Mucin Domain-containing Protein-3  
Programmed cell death protein-1 and TIM-3 are immunoregulatory proteins associated with 
diminished T cell functionality (Jones et al, 2008, Monney et al, 2002). The PD-1 receptor 
was one of the first co-inhibitory cell surface molecules identified to regulate T cell activation 
and function (Ishida et al, 1992). Programmed cell death protein-1 is transiently upregulated 
upon TCR stimulation, with the highest cell surface expression observed on T cells 
experiencing chronic antigen exposure (Wherry et al, 2015), and mediates inhibitory effects 
on T cell activation upon engagement with its ligands, PD-L1 or PD-L2 (Freeman et al, 2000, 
Hui et al, 2017, Latchman et al, 2001). Agents that inhibit the PD-1/PD-L1 pathway 
demonstrate clinical activity in a wide range of cancers relative to the previous SoC and have 
led to several regulatory approvals by the US FDA and/or the EMA for the treatment of 
various malignancies (Chai et al, 2020). 
The TIM-3 receptor is an immunoregulatory protein associated with diminished T cell 
functionality (Monney et al, 2002, Wolf et al, 2020). Although generally undetectable on 
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peripheral blood T cells, cell surface levels of TIM-3 are upregulated upon TCR stimulation of 
CD4+ and CD8+ T cells, with highest expression observed upon chronic antigen exposure or 
within the TME (Fourcade et al, 2010, Jones et al, 2008). Unlike other known IC receptors, 
TIM-3 does not contain an immunoreceptor tyrosine-based inhibitory motif within its 
cytoplasmic tail (Rangachari et al, 2012). However, TIM-3 has been shown to regulate T cell 
responses through mediating effects on the TCR signaling cascade (Lee et al, 2011, 
van de Weyer et al, 2006). Multiple reports have highlighted a role for TIM-3 in diminishing 
T cell responses within nonclinical cancer models, with blockade of TIM-3 to its putative 
ligands reversing immune-inhibitory effects (Fourcade et al, 2010, Ngiow et al, 2011, 
Sakuishi et al, 2010). In addition to conventional T cells, TIM-3 can be expressed by 
regulatory T cells, natural killer cells and myeloid cell subsets, and has been shown to 
modulate activity within these cellular subsets (Chiba et al, 2012, Gao et al, 2012, 
Ndhlovu et al, 2012, Sakuishi et al, 2010). 
2.2.2 
Disease Background and Current Landscape  
Classical Hodgkin lymphoma is an uncommon malignancy, accounting for less than 1% of all 
cancers but is amongst the most common in young adults. The disease has a bimodal 
distribution with an increased incidence in young adults as well as in patients 65 years and 
older. There are no clearly defined risk factors for the development of this disease and the 
cause of Hodgkin lymphoma remains unknown. Factors shown to be associated with cHL 
include familial factors, viral exposures, and immune suppression. 
Despite the high cure rate with initial therapy, approximately 5% to 10% of patients with 
Hodgkin lymphoma are refractory to initial treatment and 10% to 30% of patients will relapse 
after achieving an initial complete remission. High dose chemotherapy followed by an ASCT 
is the SoC for many patients who relapse following a response to initial chemotherapy. 
Patients with r/r cHL who progress after ASCT have poor prognosis, with a median OS of 
2 to 4 years in the pre-PD-1 blockade era. Overall survival is similarly poor in patients with 
primary refractory disease and those ineligible for ASCT. 
Inhibitors of PD-1, nivolumab and pembrolizumab, have demonstrated effective antitumor 
activity and tolerable safety in patients with cHL that progressed after ASCT and/or 
brentuximab vedotin, an antibody–drug conjugate targeting CD30. Programmed cell death 
protein-1 inhibitors can also be considered for the treatment of patients with refractory cHL 
who are ineligible for ASCT because of comorbidities. Although there is a high initial 
response with an ORR above 70%, CR is only achieved in 25% to 40% of patients with many 
ultimately relapsing (Armand et al, 2018, Younes et al, 2016, Zinzani et al, 2020). 
An unmet medical need exists for both r/r cHL patients with IO acquired resistance, 
specifically to anti-PD-1/PD-L1 based therapy and also for patients with r/r cHL post 
ASCT/ASCT ineligible given the high risk of relapse with single agent PD-1 blockade. 

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2.2.3 
Clinical Development Rationale for Dual PD-1 and TIM-3 Blockade  
The cellular microenvironment of cHL is characterized by a paucity of B cell-derived 
malignant HRS cells within a TME comprised of non-malignant stromal and immune cells 
(Connors et al, 2020). Despite extensive immune cell infiltration, the antitumor immune 
response is ineffective. It is hypothesized that this is due to the ability of HRS cells modulate 
the TME to avoid immune cell recognition and killing (Weniger and Küppers, 2021). 
Hodgkin Reed-Sternberg cells co-opt the PD-1 pathway and upregulate PD-1 ligands by 
several mechanisms including copy gain alterations of 9p24.1. Topographical analysis of cHL 
TME demonstrated that HRS cells with PD-L1 overexpression were in close proximity to 
PD-1+ CD4+ T cells, within the TME, (Carey et al, 2017). Furthermore, reports demonstrated 
that PD-1 expression on CD4+ T cells, within the cHL TME, is more frequently observed on 
Th1 effector cells compared to CD4+ Tregs, which are in turn largely PD-1 negative. 
Consequently, a double immune evasion strategy exists in cHL, whereby Th1-mediated 
immune responses are likely dysfunctional while the immunosuppressive Treg cells retain 
functionality (Cader et al, 2018). 
Although the targeting of the PD-1 axis shows clinical potential, the relative lack of complete 
responders suggests additional mechanisms contribute to promote HRS survival 
(Ansell et al, 2015). T cell immunoglobulin and mucin domain-containing protein-3, is an IC 
that has been associated with dysfunctional T cells (Jones et al, 2008, Sakuishi et al, 2010) and 
has recently been implicated as a resistance mechanism following PD-1 therapy. While data in 
cHL is limited, TIM-3 expression has been observed in cHL (El Halabi et at, 2020). 
Therefore, co-targeting both PD-1 and TIM-3 in cHL 
 
. This study will investigate the safety, tolerability, PK, 
and antitumor activity of sabestomig, a PD-1/TIM-3 bispecific mAb, in the r/r cHL 
population. The study design comprises of two parts: Part A consists of a dose escalation that 
will enroll r/r cHL participants and Part B a dose expansion, which will enroll in Cohort B1 r/r 
cHL participants who were previously exposed to anti-PD-1/PD-L1 based therapy and in 
Cohort B2 r/r cHL participants who are naïve to anti-PD-1/PD-L1 therapy. 
2.2.4 
Sabestomig Background  
Sabestomig is briefly summarized below. A detailed description of the chemistry, 
pharmacology, and nonclinical data for sabestomig is provided in the Investigator’s Brochure. 
Sabestomig is a 
 with an engineered Fc domain 
to reduce Fc effector function that specifically binds PD-1 and TIM-3. Programmed cell death 
protein-1 and TIM-3 are part of a complex system of cell surface receptors that when bound to 
their cognate ligands, provide co-inhibitory signals to T cells to modulate their activity. Dual 
blockade of PD-1 and TIM-3 is expected to restore the 
 of 
 
 within the 
. 
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2.2.4.1 
Sabestomig Nonclinical Pharmacology  
The ability of sabestomig to engage TIM-3 and PD-1 receptors and thereby promote 
immune-mediated antitumor responses was evaluated in in vitro and in vivo studies. 
Sabestomig demonstrated binding to human PD-1 and human TIM-3 receptors, in addition to 
 PD-1 and TIM-3 receptors. In in vitro functional assays utilizing 
 
from healthy human donors, sabestomig promoted increased antigen-driven 
 
 
 and 
 of a human tumor cell line over an isotype 
control and the parental 
, the variable domains of which 
were used for generation of the 
 binding fragment of sabestomig. 
Sabestomig was also evaluated in 2 distinct xenograft 
 and an 
 
model of human cancer. Across multiple donors and model systems, 
sabestomig demonstrated an 
 burden compared to
 
alone. 
2.2.4.2 
Sabestomig Nonclinical Pharmacokinetics  
In the non-GLP 
PK/pharmacodynamic and toxicity study, 
 
 received a 
 of 
mg/kg of sabestomig. The dose was well tolerated but 
in
 of 
 was detected after a 
 of sabestomig. 
The presence of 
 correlated with accelerated sabestomig clearance after Day 11. 
In the GLP 
 toxicity study of sabestomig administered IV in 
 
with a 
, the increases in sabestomig mean 
Cmax and the AUCτ values were approximately proportional to the increase in dose level 
from 
 mg/kg/dose. The clearance was 
 across all dose groups. 
 PK 
exposure was observed for a total of 
, including 
 and 
 at 
mg/kg,  males and  females at 
 mg/kg, and  males at 
 mg/kg. In the 
other 
monkeys administered sabestomig whose PK exposures were not impacted by 
, 
any 
 results did not produce reduced PK exposure. These events did not impact 
the overall inferences and conclusions drawn from the PK analysis for this study. 
2.2.4.3 
Sabestomig Nonclinical Toxicology  
A nonclinical safety assessment package was conducted in support of the FTIH clinical study 
with sabestomig and included: 
1 
A non-GLP 
 PK/pharmacodynamic study evaluating a 
IV dose of 
mg/kg, 
2 
A 4-week repeated dose GLP toxicology study in 
 evaluating 
repeated weekly IV doses of 
, and 
 mg/kg with a 12-week recovery period, 
and 
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The full details of the chemistry, pharmacology, efficacy, and safety of sabestomig is provided 
in the Investigator’s Brochure. 
2.3 
Benefit/Risk Assessment  
More detailed information about the known and anticipated benefits and potential risks of 
sabestomig may be found in the Investigator’s Brochure. 
2.3.1 
Risk Assessment  
This is the second trial in humans for sabestomig (the first study will be ongoing at the start of 
the current study). There are no identified risks based on human clinical data of sabestomig at 
this time. 
Cell surface levels of PD-1 and TIM-3 are transiently upregulated upon TCR stimulation on 
CD4+ and CD8+ T cells in the TME (Fourcade et al, 2010, Jones et al, 2008). In addition to 
conventional T cells, TIM-3 can be expressed on the cell surface of regulatory T cells, natural 
killer cells, and myeloid cell subsets and has been shown to modulate activity within these 
cellular subsets (Chiba et al, 2012, Gao et al, 2012, Ndhlovu et al, 2012, Sakuishi et al, 2010). 
Checkpoint blockade of PD-1 and TIM-3 predominantly inhibits their negative regulatory 
mechanisms and subsequently invigorates T cells to unleash antitumor responses (ie, 
cytotoxicity, proliferation, and cytokine secretion). Neither for the individual blockade of each 
receptor nor for dual blockage are super agonistic or cascade effects anticipated. 
The observed effects in the 4-week GLP study were considered to be related to the 
immunogenicity and associated ADA formation and its downstream effects. Such reactions 
are considered specific to monkeys as a reaction to a foreign human protein and not 
considered predictive of potential immunogenicity reactions in humans (Brennan et al, 2010). 
The potential for sabestomig to induce cytokine production was assessed using human whole 
blood and human PBMCs (Section 2.2.4.3). Sabestomig induced mild 
 
compared to its isotype control. The 
 was more than 
 lower than in 
positive controls using strong T cell activating antibodies. In this assay, sabestomig did not 
cause release of any other measured cytokines. Based on these data, sabestomig is considered 
low risk for inducing cytokine release syndrome. 
Programmed cell death protein-1 targeting the checkpoint inhibitor axis, PD-1/PD-L1, has a 
well characterized safety profile with adverse reactions consisting predominantly of imAEs. 
Such imAEs are well characterized and various internationally recognized management 
guidelines are available to treat patients experiencing imAEs (Brahmer et al, 2018, 
Puzanov et al, 2017). The majority of imAEs are low-grade, monitorable, manageable, and 
reversible with immunosuppressive treatment. Publicly available safety information on 
anti-TIM-3 antibodies currently in clinical trials indicate- that monotherapy as well as 
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combination therapy with anti-PD-1 antibodies lead to imAEs which were mainly mild 
(Grade ≤ 2). Grade 3 to 4 AEs were reported in approximately 4% to 11% of participants 
(Borate et al, 2019, Curigliano et al, 2019). 
Therefore, imAEs are an important potential risk of sabestomig and include, but are not 
limited to, pneumonitis, gastrointestinal disorders (especially diarrhea and colitis), hepatitis, 
endocrinopathies, nephritis and renal dysfunction, skin disorders, encephalitis, myocarditis, 
and neurological and musculoskeletal inflammatory disorders. Other potential risks include 
abnormal investigations (changes in laboratory parameters [eg, elevation of amylase, lipase], 
increased triglycerides and cholesterol, hyperkalemia, hyponatremia), and worsening of 
existing autoimmune inflammatory conditions. 
Further potential risks of sabestomig are immune reactivity (ADA formation potentially 
leading to development of immune complex disease and vasculitis) and cytokine release 
syndrome. Like with any other biologic, there are potential risks of IRRs and hypersensitivity 
reactions. 
For more information on the risks of sabestomig administration please refer to the 
Investigator’s Brochure and current version of the TMGs in Appendix I. 
2.3.2 
Benefit Assessment  
Agents that competitively inhibit the PD-1/PD-L1 pathway demonstrated improved clinical 
activity including clinical meaningful improvements of survival in a wide range of cancers, 
including cHL, relative to the previous SoC and have led to several regulatory approvals by 
the US FDA and the EMA for the treatment of various malignancies (Chai et al, 2020).  
However, patients who initially respond to anti-PD-1/PD-L1 based therapy may experience 
disease progression due to acquired resistance mediated by exhausted T cells overexpressing 
inhibitory receptors including PD-1 and TIM-3 (Bai et al, 2017, Thommen et al, 2015). In 
vitro and in vivo studies have demonstrated the ability of sabestomig to engage both TIM-3 
and PD-1 and thereby promote enhanced immune-mediated antitumor responses compared to 
targeting PD-1 alone (Section 2.2.4). 
 
 
 
2.3.3 
Overall Benefit: Risk Conclusion  
To minimize potential risks to participants, the study design integrates guidelines for inclusion 
and exclusion criteria (Sections 5.1 and 5.2), safety monitoring (Sections 8.1.4 and 8.3), 
TMGs (Section 6.6.8), starting dose, dose escalation scheme, stopping criteria (Section 6.6.1), 
and review of safety, PK, and pharmacodynamic data by the SRC (Section 6.6.7). 
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Taking into account the measures to minimize risk to participants in the study, the potential 
risks identified in association with sabestomig are justified by the anticipated benefits that 
may be afforded to participants with r/r cHL. 
For details on study conduct during civil crisis, natural disaster, or public health crisis, eg, 
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4. 
STUDY DESIGN  
4.1 
Overall Design  
This Phase I/II, open-label, multi-center, dose escalation and dose expansion study will 
evaluate the safety, tolerability, PK, pharmacodynamics, and antitumor activity of sabestomig 
in adult/young adult participants with r/r cHL. The study includes two parts: Part A Dose 
Escalation and Part B Dose Expansion. 
Part A Dose Escalation will enroll participants with r/r cHL previously treated with 
anti-PD-1/PD-L1 based therapy.  
Part B Dose Expansion will be subdivided into Cohort B1, enrolling a patient population 
identical to Part A, and Cohort B2 enrolling participants who never received an 
anti-PD-1/PD-L1 therapy previously. 
Approximately 180 participants (
participants in Part A Dose Escalation and 
 participants in Part B Dose Expansion) will receive treatment with sabestomig at 
approximately 
 sites globally. 
All participants will be followed for survival until the end of study as defined in Section 4.4, 
regardless of whether treatment was discontinued. 
The overall study flow is presented in Figure 1 and further details can be found in 
Section 4.1.1 for Part A (Dose Escalation) and Section 4.1.2 for Part B (Dose Expansion). 
4.1.1 
Part A: Dose Escalation  
Part A Dose Escalation will evaluate up to 8 dose levels of sabestomig and consist of up to 
 participants with r/r cHL in order to determine a RP2D. Cohorts A1 to A4 will be single 
participant cohorts with 4 dose levels of sabestomig (2, 7, 22.5, and 75 mg) based on an ATD 
(Section 6.6.1.1). However, the operating model will switch to a mTPI-2 algorithm should a 
Grade 2 or greater TEAE occur during the DLT period (Section 6.6.1.2). 
Cohorts A5, A6, and A7 for subsequent dose levels of sabestomig (225, 750, and 1500 mg) 
will enroll participants based on the mTPI-2 algorithm to establish the safety of sabestomig 
(Section 6.6.1.1). Based on emerging data, the optional Cohort A8 (at 2000 mg) may open and 
may also enroll up to 
 participants. After a cohort is declared safe (eg, Cohort A5, A6, A7 
or A8) and based on emerging safety, efficacy, PK and biomarker data, the cohort may be 
expanded (up to 
 participants); the cohorts may be opened in parallel to fill their rosters of 
up to 
 participants each (mini dose expansion).Intermediate dose levels (50, 150, 450, 1000, 
1250, and 1750 mg) may be explored if warranted by emerging safety, PK, pharmacodynamic, 
biomarker, and response data (Section 6.6.1 and Table 14). 
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The planned starting dose will be 2 mg (dose level 1). Participants will be evaluated for DLTs 
during a 28-day DLT evaluation period. Refer to Section 6.6 for further details regarding the 
ATD, mTPI-2 algorithm, and DLT definitions. 
Participants will receive sabestomig Q3W administered via IV infusion at the selected dose 
starting on Cycle 1 Day 1. All participants will be treated for a maximum of 35 cycles, until 
disease progression, unacceptable toxicity, withdrawal of consent, or other reason for 
discontinuation (Section 7). 
4.1.2 
Part B: Dose Expansion  
Part B Dose Expansion may be considered once the RP2D is determined in Part A Dose 
Escalation and will evaluate the safety, tolerability, PK, pharmacodynamic, and antitumor 
activity of sabestomig at the determined RP2D in 2 cohorts (Cohorts B1 and B2) described 
below. 
Cohort B1: Approximately up to 
 participants with cHL who have received at least 2 prior 
lines of systemic treatment and have subsequently relapsed or become refractory to treatment 
and have been previously treated with at least 2 cycles of anti-PD-1/PD-L1 based therapy. 
Participants in Cohort B1 will be identical to those of the dose escalation stage. For this 
reason, enrolment of a larger sample size will provide a clearer confirmatory efficacy signal. 
For the analysis in Cohort B1, participants treated at the RP2D in Part A (N=
) will be 
combined with participants enrolled in Part B, which gives a total sample size of 
approximately up to 
. 
Cohort B2: Approximately up to 
participants with cHL who have received at least 2 prior 
lines of systemic treatment and have subsequently relapsed or become refractory to treatment 
but have not received an anti-PD-1/PD-L1 based therapy. 
Participants will receive sabestomig Q3W administered via IV infusion at the RP2D 
(determined during Part A Dose Escalation) starting on Cycle 1 Day 1. All participants will be 
treated for a maximum of 35 cycles until disease progression, unacceptable toxicity, 
withdrawal of consent, or other reason for discontinuation (Section 7). 
The opening of Part B is dependent on emerging data from Part A. Cohorts B1 and B2 may 
open for enrollment either in parallel or sequentially at the discretion of AstraZeneca. 
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 
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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 AstraZeneca 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 minimize 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: 
• 
Rescreening: Rescreening for screen failure and to confirm eligibility to participate in the 
clinical study can be performed in previously screened participants; refer to Section 5.4. 
The Investigator should confirm this with AstraZeneca. 
• 
Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 
• 
Exploratory sample collection: AstraZeneca may provide sample collection strategy 
guidance for exploratory samples. 
 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix H. 
4.2 
Scientific Rationale for Study Design  
Sabestomig will be evaluated in adult/young adult participants with r/r cHL. Classical 
Hodgkin Lymphoma is considered to be sensitive to IC blockade achieving an ORR of over 
70%. However, patients who initially respond to an anti-PD-1/PD-L1 based therapy may 
experience disease progression due to acquired resistance mediated by exhausted T cells 
overexpressing inhibitory receptors including PD-1 and TIM-3. Therefore, targeting both PD-
1 and TIM-3 with sabestomig represents a promising therapeutic approach 
 
. 
The CSP includes two parts: Part A Dose Escalation and Part B Dose Expansion. The 
proposed population for dose escalation is comprised of adult/young adult participants with r/r 
cHL with at least 2 prior lines of systemic therapy. Sabestomig also targets PD-1 and therefore 
is anticipated to provide clinical benefit from the PD-1 blockade mediated anticancer 
response. Inclusion of, anti-PD-1/PD-L1-naïve in the expansion Cohort B2 provides an 
 
 
 
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4.2.1 
Rationale for Endpoints  
The primary objective of the study is to assess safety and tolerability and to identify the MTD 
or OBD, and a RP2D of sabestomig. The MTD will be determined by DLTs during the 
dose escalation phase (Sections 6.6.4 and 9.4.3.1). The rate of any observed DLTs will be 
used to establish the MTD in Part A Dose Escalation, and standard safety endpoints, such as 
AEs, SAEs, abnormal laboratory parameters, vital signs, and ECGs, will be used to assess the 
safety profile of sabestomig throughout the study. The RP2D will be selected by the Steering 
Committee and AstraZeneca based on the OBD determined by pooling and evaluating all 
available PK, pharmacodynamic, target engagement, efficacy, safety, and tolerability data.   
To understand the efficacy of sabestomig in r/r cHL, this study will incorporate response 
assessment parameters during dose escalation (Part A) and dose expansion (Part B). To 
evaluate the antitumor activity of sabestomig the ORR, DoR, and PFS will be assessed. 
Participants will be evaluated by the Investigator, for disease response using the Modified 
Lugano and RECIL criteria as secondary endpoints. Additionally, in Part B only, disease 
response will be evaluated by a blind independent review committee using Modified Lugano 
Criteria. All participants will be followed up to evaluate OS. Of note, in the Part A, imaging 
must be archived and transferred to the BICR to allow retrospective disease response 
assessment in participants treated at a potential RP2D.  
The study will also characterize the PK of sabestomig to determine drug exposure. 
Immunogenicity will be examined to assess its impact on PK, safety, and preliminary efficacy 
of sabestomig. Potential biological activity will also be explored by assessing 
pharmacodynamic and exploratory biomarkers and antitumor activity. 
4.3 
Justification for Dose  
The rationale for selecting the starting dose of 2 mg Q3W for the proposed study 
(D9571C00001) is based on modeling and simulation of the PK/pharmacodynamic data and 
the prior clinical experience reported on PD-1 and TIM-3 targeting checkpoint inhibitors, the 
PD-1 inhibitors nivolumab and pembrolizumab (USPI OPDIVO® and USPI KEYTRUDA®) 
and the TIM-3 targeting mAbs MBG543 and TSR-022 (Curigliano et al, 2019, 
Davar et al, 2018), in conjunction with the safety margin calculated from the NOAEL of 
 mg/kg sabestomig in 
 from the GLP toxicology study. 
In addition, an unnecessary low starting dose would expose an excess of participants with high 
unmet medical need to exposure levels of sabestomig unable to drive pharmacodynamic 
effects in the tumor, thereby preventing the possibility to derive benefit from sabestomig 
treatment and to generate data useful for clinical development of sabestomig. 
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4.3.2 
Calculation of the First-In-Human Dose Based on Pharmacokinetic and 
Pharmacodynamic Modelling and Simulation  
For the PK/pharmacodynamic modeling and simulation approach, a population PK model was 
developed to describe the PK of sabestomig in 
. By extrapolating to 
humans from monkey PK data in sabestomig, the predicted PK parameters in humans were 
comparable with observed human PK of MEDI5752, which is an AstraZeneca developed 
anti-PD-1/CTLA-4 bispecific 
 
 as sabestomig. MEDI5752 is currently in Phase I/Ib development; dose 
escalation has been completed and expansion cohorts in solid tumors including NSCLC are 
ongoing (D7980C00001 [NCT03530397] and D7980C00003 [NCT04522323]). The half-life 
of sabestomig in human is projected to be about 
; hence, a dosing interval of Q3W is 
proposed for this study. 
A PK/pharmacodynamic model was developed to describe the dual TMDD of sabestomig in 
humans. Taking into consideration the similarities between MEDI5752 and sabestomig 
described above, the linear PK parameters were set at typical human values for MEDI5752. 
The saturable component of the TMDD model was assumed to be due to the binding of 
sabestomig to the cell-surface PD-1 and TIM-3 as well as soluble TIM-3 in the periphery. For 
human simulations, the in vitro binding data including antibody affinity and antigen density as 
well as the antigen internalization data were incorporated in the model to predict the receptor 
occupancy of PD-1 and TIM-3 in the periphery following IV administration of sabestomig at 
various dose levels. The starting dose of 2 mg sabestomig corresponded to predicted levels of 
occupancy of PD-1 of approximately 
% and 
% of baseline at steady state Cmin and 
Cmax of sabestomig, and TIM-3 occupancy of 
% and 
% of baseline at steady state Cmin 
and Cmax of sabestomig. 
The predicted receptor occupancy levels were in line with data in the public domain with the 
observed full PD-1 saturation levels for the PD-1 targeting antibodies, nivolumab and 
pembrolizumab, in the periphery at the starting doses of 0.3 mg/kg nivolumab 
(Agrawal et al, 2016, Brahmer et al, 2010) and 1.0 mg/kg pembrolizumab (Patnaik et al, 2015) 
in the Phase I studies, as well as the predicted full TIM-3 occupancy at the RP2D of TIM-3 
targeting antibodies, 400 mg Q2W/800 mg Q4W MBG453 (Wei et al, 2020) in the bone 
marrow and the observed 80% peripheral TIM-3 occupancy at Cmin at 900 mg Q3W 
TSR-022 (Davar et al, 2018). 
4.3.3 
Clinical References for PD-1 and TIM-3 Targeting Agents to Support 
Starting Dose Selection for Sabestomig  
Several PD-1 targeting agents have been approved for a broad range of both solid tumor and 
hematological indications and are established as SoC treatments. Pembrolizumab 
(KEYTRUDA®) and nivolumab (OPDIVO®) have been the first PD-1 targeting agents to be 
approved for the treatment of adult patients with cHL that has relapsed or progressed after 
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SoC treatment including autologous hematopoietic stem cell transplantation and brentuximab 
vedotin. Both PD-1 targeting agents have a well characterized benefit-risk profile (USPI 
OPDIVO® and USPI KEYTRUDA®) across solid and hematologic indications. 
Publicly available data regarding AEs of TIM-3 in combination with PD-1 targeting agents 
(Curigliano et al, 2019, Weiss et al, 2017, Lakhani et al, 2020) indicate a safety profile 
consistent with what has been shown for other PD-1 checkpoint targeting inhibitors 
(Wang et al, 2019). Immune-mediated AEs associated with these agents are monitorable and 
manageable based on well-established TMGs (Brahmer et al, 2018, Puzanov et al, 2017). 
Sym021 is a humanized IgG1 mAB targeting PD-1 and Sym023 is a recombinant, fully 
human antibody that binds TIM-3 (Lakhani et al, 2020). A FIH Phase 1 dose escalation study 
combining Sym021 with Sym022 (anti-LAG) or Sym021 with Sym023 (anti-TIM-3) in 
advanced or metastatic solid tumor malignancies or lymphomas is ongoing (NCT03311412). 
The dose escalation studies of Sym021, Sym022, and Sym023 as singe agents has been 
completed. The MTD was not reached for any single agent. The Sym021 dose was fixed at 
3 mg/kg based on PK/pharmacodynamic analysis for subsequent combination with Sym022 or 
Sym023. The MTD was not reached for any combination. Part 2 Arm B combining Sym021 
RP2D with Sym023 enrolled 17 patients and was well tolerated with AE profiles typical of IC 
inhibitors. The most commonly observed Grade 3 or Grade 4 treatment-related adverse events 
included 5 events: ALT increase (5.9%), lymphopenia/lymphocytes decreased (5.9%), fatigue 
(5.9%), cough (5.9%) and rash (5.9%). Objective responses in the Part 2 Arm B combination 
of Sym021+Sym023 included 2 PRs. Evaluation of antitumor activity of Sym021+023 
doublets in select tumor types post-PD-1/PD-L1 treatment are planned.  
In a phase Ib study of MBG543, a humanized IgG4 TIM-3 mAb, clinical trial conducted in 
patients (n=155) with HR-MDS/AML, TIM-3 receptor occupancy in bone marrow > 95% in 
≥ 95% of patients was predicted at steady state for doses of 400 mg Q2W and 800 mg Q4W 
(Wei et al, 2020). Given the free blood flow of bone marrow with peripheral circulation, 
similarly high receptor occupancy in the periphery can be assumed. Overall, MBG453 + 
hypomethylating agent (decitabine or azacitidine) was safe and well tolerated with a low rate 
of study discontinuation due to AEs (3.4% [4/116]). Rates of most common grade ≥ 3 TEAEs 
and rates of Grade ≥ 3 possible imAEs related to study intervention did not appear to be dose 
dependent. Among 35 evaluable patients with HR-MDS, CR/metabolic CR/PR rates were 
50.0%, 33.3% and 54.5% at MBG453 doses of 240 mg Q2W, 400 mg Q2W and 800 mg 
Q4W. Among 60 evaluable patients with AML, CR/CR without hematologic recovery/PR 
rates were 35.3%, 37.5% and 31.6%, respectively. There were no notable differences in 
responses across the 3 doses. 
TSR-022 is a humanized IgG4 mAb targeting TIM-3. Phase I AMBER is a dose escalation 
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with the anti-PD-1 mAb TSR-042 (NCT02817633) in advanced solid tumors. Part 1a of this 
study investigated single -agent dose escalation in patients with solid tumors at dose ranges 
from 0.03 up to 10 mg/kg (Weiss et al, 2017). The MTD was not reached and only one DLT 
was observed at the highest dose level, Grade 3 immune-related lipase elevation without 
symptoms. The drug was well tolerated with mainly Grade ≤ 2 treatment-related toxicities. In 
addition to the reported DLT there was only one treatment-related AE Grade 3 at dose level 
1 mg/kg, dyspnea in conjunction with Grade 2 pneumonitis in a patient with extensive 
mediastinal disease and vena cava syndrome. Preliminary signs of a clinical antitumor effect 
were observed at the dose of 10 mg/kg. In an additional dose escalation, Part 1c investigated 
the combination of TSR-022 in 54 patients with solid tumors at dose levels of 100 mg, 300 mg 
and 900 mg with the anti-PD-1 mAb TSR-042, which was administered at 500 mg 
(Davar et al, 2018). 
There was approximately 50%, 70%, and 80% peripheral TIM-3 saturation at Cmin at 
100 mg, 300 mg and 900 mg Q3W, respectively. No DLTs were observed for the 
combination. The highest treatment-related toxicities reported were one Grade 3 event of rash 
at the 100 mg dose level and one Grade 4 event of hypothyroidism at 900 mg dose level. The 
reported data indicate a trend for dose-dependent antitumor activity with one PR observed for 
the combination at a TSR-022 dose of 100 mg and 3 PRs at a dose of 300 mg. No efficacy 
data has been provided for the highest dose level. Part 2 expansion cohorts included patients 
treated at the same 3 dose levels of TSR-022 in combination with TSR-042 administered at 
500 mg (100 mg, n=41; 300 mg, n=110; 900 mg, n=22), both agents administered on a Q3W 
schedule. For the overall cohort, the rate of patients with treatment-related Grade 3 AEs at 
each dose level was below 10% (9.2%, 8.2%, 0%), observed AEs consisted predominantly of 
rash, including 1 participant with Grade 4 lipase increase and 2 participants with immune-
related AEs of hypothyroidism and pancreatitis. 
Most recently, clinical safety data have been disclosed regarding the PD-L1/TIM-3 bispecific 
antibody LY3415244. The Phase I study evaluating safety and efficacy of this molecule in 
participants with advanced cancer was terminated early during the escalation phase due to 
significant immunogenicity to both arms of the molecule leading to loss of target engagement. 
In addition, 2 out of 12 participants with high ADA levels developed hypersensitivity 
reactions (Hellmann et al, 2021). 
No clinical safety data have been disclosed regarding the bispecific antibody RG7769. 
However, based on information in the public domain the compound has completed dose 
escalation and the RP2D has been set to 2100 mg Q2W. 
Overall, the reported AEs of anti-TIM-3 in combination with PD-1 targeting agents indicate 
that the safety profile is consistent with what has been shown for other PD-1 checkpoint 
targeting inhibitors and similar across tumor types. 

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4.3.4 
Calculation of Safety Margins for the First-In-Human Dose of 
Sabestomig  
In the completed 4-week GLP toxicology study with weekly IV dosing of 
 mg, 
 mg, 
and 
 mg/kg, the NOAEL was determined to be 
 mg/kg based on the absence of 
 and 
. Mean plasma AUC data obtained after 4-week repeat 
dosing at the NOAEL (
 mg/kg/week) provide a 
safety margin to the predicted 
AUC at the proposed FIH starting dose of 2 mg Q3W while the mean Cmax gives a 7000-fold 
safety margin to the predicted Cmax at the starting dose of 2 mg Q3W (Table 8). 
Sabestomig will be administered at escalating dose intervals with a starting dose of 2 mg (dose 
level 1). The proposed dose escalation scheme is 2, 7, 22.5, 75, 225, 750, 1500 to 2000 mg 
Q3W. Dose escalation for the first 4 dose levels of sabestomig (ie, 2, 7, 22.5, and 75 mg 
Q3W) is planned to follow an ATD with Cohorts 1 to 4 as single participant cohorts. Dose 
escalation for the subsequent 4 dose levels of sabestomig (225, 750, 1500, and 2000 mg) will 
follow the mTPI-2 algorithm with Cohorts 5, 6, and 7 with up to 
 participants each, with the 
optional last cohort, Cohort 8 that will also consist of up to 
participants. If predefined 
safety criteria are met in an ATD cohort, dose escalation will switch to the mTPI-2 algorithm 
for all subsequent dose levels (Section 6.6.1). 
Table 8 
Safety Margins of Doses of Sabestomig Used in the Proposed Dose 
Escalation Scheme       
Dose of 
Sabestomig 
(mg/75 kg) 
AUCcyno 
(μg·day/mL) 
Predicted 
Human AUCh 
(μg∙day/mL) 
Safety Margin 
(AUCcyno/ 
AUCh) 
Cmax,cyno 
(μg/mL) 
Predicted 
Human 
Cmax,h 
(μg/mL) 
Safety Margin 
(Cmax,cyno/ 
Cmax,h) 
2 
 
 
 
 
 
 
7 
 
 
 
 
22.5 
 
 
 
 
75 
 
 
 
 
225 
 
 
 
 
750 
 
 
 
 
1500 
 
 
 
 
2000 
 
 
 
 
 
Safety margins were calculated based on predicted AUCh and Cmax,h relative to the 
AUCcyno (43626 μg∙day/mL) and Cmax,cyno (3500 μg/mL) following administration of a 100 mg/kg dose in 
 (Study 8419789). 
Abbreviations: AUCcyno: area under the concentration-time curve from time zero to Day 21 at steady state in 
 AUCh: area under the concentration-time curve from time zero to Day 21 at steady state 
in humans; Cmax,h: maximal concentration in humans at steady state; Cmax,cyno: maximal concentration in 
 at steady state. 
 
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4.4 
End of Study Definition  
For the purpose of Clinical Trial Transparency (CTT) the definition of the end of the study 
differs under FDA and EU regulatory requirements: 
European Union requirements define study completion as the last visit of the last subject for 
any protocol related activity. 
Food and Drug Administration requirements defines two completion dates: 
Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure with 
different completion dates, this term refers to the date on which data collection is completed 
for all of the primary outcomes. 
Study Completion Date – the date the final participant is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures and 
AEs (for example, last participant’s last visit), whether the clinical study concludes according 
to the pre-specified protocol or is terminated. 
A participant is considered to have completed the study if the participant has completed all 
phases of the study including the last visit or the last scheduled procedure shown in the SoA 
(Table 4), including survival follow-ups. 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA (Table 4) for the last participant in the study 
globally. 
Participants may be withdrawn from the study if the study itself is stopped (see Section 4.5, 
Section 6.6.7 and Appendix A 9). 
See Section 6.9 for details on participant management following the final DCO as well as 
following the end of study. 
4.5 
Study Stopping Criteria  
Part A and Part B Study Stopping Criteria: 
AstraZeneca reserves the right to pause recruitment, 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, at least one of the following: 

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• A fatal event (Grade 5) deemed related to study therapy by AstraZeneca and in discussion 
with the SRC (probable or certain causality based on WHO-UMC after full etiological 
work-up). This will also result in a comprehensive review of safety. 
• Any unexpected and Grade 4 life-threatening events deemed related to study therapy that 
exposed participants to unacceptable risk as assessed by the SRC in discussion with 
AstraZeneca. 
• One or more Grade 4 immune related AEs unmanageable with implementation of the 
current toxicity management guidelines instituted in the protocol and/or as per institution 
of local practice as assessed by the SRC in discussion with AstraZeneca. 
Note: As immune-mediated AEs such as pneumonitis and myocarditis are important 
potential risks, these events will be further addressed at time of the safety interim analysis 
described below and will not be considered as stopping criteria. 
• AstraZeneca decision that study participants are placed at undue safety risk. 
 
Part A Mini Expansion Study Stopping Criteria: 
Of note, during the mini expansion in the Part A portion of the study, if one or more mini 
expansions occur in parallel with different dose levels being evaluated (as per protocol design, 
see Section 4.1.1); the stopping criteria described above will apply independently to each 
individual cohort. The enrollment would be paused in the impacted dose level cohort but 
would not affect the other ongoing dose level cohorts if no stopping criterion was met. 
Part B Study Stopping Criteria: 
During the conduct of Part B, in addition to the stopping criteria applicable for Part A and 
Part B, the following criteria apply to participants treated at RP2D regardless of the cohort 
they are enrolled in (Cohort B1, B2 as well as participants treated in Part A mini expansion): 
• At the time of interim safety analysis during Part B (after approximately 
participants 
have received the first dose at least 3 months prior to data cut-off), the study recruitment 
may be paused, pending investigation by AstraZeneca in discussion with SRC, if at least 
one of the following events occur: 
- 
Incidence of Grade ≥ 3 immune-mediated AEs deemed to be related to study drug, 
above the following limits: 
o ≥ 10 % participants experiencing Grade ≥ 3 pneumonitis 
o ≥ 10 % participants experiencing Grade ≥ 3 myocarditis 
o ≥ 10 % participants experiencing Grade ≥ 3 immune complex disease and 
vasculitis 
o ≥ 10 % participants experiencing Grade ≥ 3 rash 
o ≥ 10 % participants experiencing Grade ≥ 3 colitis 
o ≥ 10% participants experiencing systemic drug hypersensitivity reactions 
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- 
25% participants discontinuing study treatment due to any grade, treatment-related AE 
Additional reasons to stop the study at any time may also include: 
• 
Participant enrollment is unsatisfactory. 
• 
Noncompliance that might significantly jeopardize the validity or integrity of the study. 
• 
AstraZeneca decision to terminate development of the study intervention. 
• 
AstraZeneca decision to terminate the study based on a planned futility analysis. 
• 
AstraZeneca decision to discontinue the development of the study treatment in the 
proposed indications (see Section 7.1).  
 
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. 
If the study or components of the study is 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. 
5. 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria are met: 
Informed Consent 
1 
Capable of giving signed informed consent or assent, if required per local regulations, as 
described in Appendix A, which includes compliance with the requirements and 
restrictions listed in the ICF and in this protocol. 
2 
Written informed consent and any locally required authorization obtained from the 
participant prior to performing any protocol-related procedures. For participants from 
16 to < 18 years of age, their legally authorized representative must give their signed 

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written informed consent, as appropriate, and participants will sign an assent form, if 
required per local regulations. 
3 
Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of samples for optional genetic research that supports Genomic 
Initiative (Section 8.7 and Appendix F). Participants who decline participation in genomic 
initiative are still eligible for the main study. 
 
Age 
4 
Must be ≥ 16 years of age at the time of signing the ICF. 
 
Type of Participant and Disease Characteristics 
5 
Eastern Cooperative Oncology Group performance status of 0 or 1 at screening. 
6 
Predicted life expectancy of ≥ 12 weeks. 
7 
Must have at least one PET-avid measurable lesion according to Modified Lugano 
Criteria after the last line of therapy. A measurable lesion is a lesion that can be clearly 
measured in at least 2 perpendicular dimensions (LDi and SDi). The LDi must be: 
(a) For nodal lesions: LDi > 1.5 cm, 
(b) For extranodal lesions (eg, Hepatic, lung nodules): LDi > 1 cm, 
(c) The LDi and the SDi should be measured on the same slice. 
8 
Adequate organ and bone marrow function as defined in Table 9. 

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Table 9 
Criteria for Adequate Organ and Marrow Function        
Type 
Parameter 
Value 
Hematological a 
Hemoglobin 
≥ 8.0 g/dL (4.96 mmol/L) 
Blood transfusions (packed red blood cells) permitted 
10 days prior to first dose 
Absolute neutrophil count 
≥ 1.0 x 109/L (1,000 per mm3) 
Granulocyte colony-stimulating factor permitted 
7 days prior to first dose 
Platelet count 
≥ 75 x 109/L (75,000 per mm3) 
Platelet transfusions permitted 5 days prior to first dose 
Hepatic a 
Total bilirubin 
≤ 1.5 x ULN in the absence of Gilbert’s syndrome 
≤ 3 x ULN and direct bilirubin < 30% of TBL in the 
absence of hemolysis if the participant has Gilbert’s 
syndrome 
Alanine transaminase and 
aspartate transaminase 
≤ 2.5 x ULN 
≤ 5 x ULN in the case of liver involvement  
Renal a 
Calculated creatinine 
clearance by modified 
Cockcroft Gault b 
≥ 45 mL/minute 
Cardiac c 
LVEF 
LVEF ≥ 45% (or ≥ institutes’ lower limit of normal) 
confirmed by ECHO or MUGA. 
Pulmonary d 
FEV1 
FEV1 >50% of predicted value 
Abbreviations: ECHO: echocardiogram; FEV1: forced expiratory volume over 1 second; LVEF: Left ventricular 
ejection fraction; MUGA: multigated acquisition scan; ULN: upper limit normal. 
a 
To receive subsequent cycles of sabestomig (from cycle 2 onwards) thresholds for adequate marrow, renal, 
and liver function must be met. Laboratory evaluations must be performed up to 3 days prior to initiation of 
each cycle of treatment; transfusion and granulocyte colony stimulating factor support is permissible. 
b 
Rostoker et al, 2007. 
c 
If clinically indicated, and at the Investigator’s discretion, a consultation with a cardiologist is 
recommended for follow-up.   
d 
If assessed – pulmonary function testing is only required for those eligible participants with pre-existing 
obstructive or fibrotic lung conditions. 
 
9 
Part A Dose Escalation: 
Must have a diagnosis of cHL histologically proven based on criteria established by the 
World Health Organization as documented in medical records. 
(a) Documented active disease requiring treatment that is r/r defined as: 
• Recurrence/relapse of disease after response to prior line(s) of therapy. 
• Progressive Disease (refractory) during the treatment regimen preceding entry 
into the study. 
(b) Failed at least 2 prior lines of systemic therapy. 
(c) Have had at least 3 cycles of an anti-PD-1/PD-L1 based therapy. 

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(d) No previous treatment with anti-TIM-3. 
(e) Previous anti-CTLA-4 treatment is allowed, however, only up to 2 months prior to 
study entry.  
10 Part B Dose Expansion: 
(a) Cohort B1: Meets all Part A criteria; 9(a), 9(b), 9(d), 9(e), and have had at least 
2 cycles of an anti-PD-1/PD-L1 based therapy. 
(b) Cohort B2: Meets Part A criteria; 9(a), 9(b), 9(d), 9(e), and have never previously 
received an anti-PD-1/PD-L1 based therapy. 
 
Tissue Requirements (see Section 8.6.2.1 for additional details) 
11 Participants enrolled in Part A dose escalation: If available, provision of sufficient tumor 
material from an archival tissue at time of first diagnosis and/or within 4 months prior to 
initiating study intervention. 
12 Participants in Part A mini expansion: Provision of sufficient tumor material at screening 
from an archival tissue sample collected at first diagnosis and an archival tissue sample 
collected within the prior 4 months. If archival tissue sample is not available within prior 
4 months, or when participant received any anti-cHL treatment since biopsy was taken, 
provision of sufficient tumor material at screening from a fresh tissue sample (core or 
excisional biopsy), unless medically contraindicated. 
13 Participants enrolled in Part B Dose expansion cohorts (Cohorts B1 and B2): Provision of 
sufficient tumor material at screening from an archival tissue sample collected at first 
diagnosis and an archival tissue sample collected within the prior ≤ 4 months. If archival 
tissue sample is not available within prior 4 months, or when participant received any 
anti-cHL treatment since biopsy was taken, provision of sufficient tumor material at 
screening from a fresh tissue sample (core or excisional biopsy) unless medically 
contraindicated. 
Note: On-treatment biopsy is mandatory in Part B, unless medically contraindicated. 
Tumor biopsy will not be collected in mainland China. 
 
Reproduction and Contraception 
14 Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. Refer to 
Appendix B for definitions of women of childbearing potential and highly effective 
methods of contraception. 
15 Female participants of childbearing potential: 
(a) Must have negative pregnancy test at screening and prior to any administration of 
sabestomig. 

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(b) If sexually active with a non-sterilized male partner, must use at least one highly 
effective method of birth control from screening to 90 days after the last dose of 
sabestomig. 
(c) It is strongly recommended that non-sterilized male partners of female participants of 
childbearing potential use a male condom plus spermicide, from screening to 90 days 
after the last dose of sabestomig. 
NOTE: Male condoms are not reliable as a sole contraception method. 
16 Female participants must not breastfeed and must not donate, or retrieve for their own 
use, ova, or plan to get pregnant from screening to 90 days after the last dose of 
sabestomig. 
17 Non-sterilized male participants who are sexually active with a female partner of 
childbearing potential: 
(a) Must use a condom with spermicide from screening to 90 days after the last dose of 
sabestomig. 
NOTE: Male condoms are not reliable as a sole contraception method). 
(b) It is strongly recommended that female partners of a male participant also use at least 
one highly effective method of contraception throughout this period. 
(c) Male participants must refrain from fathering a child or donating sperm during the 
study and for 90 days after the last dose of sabestomig. 
 
Other 
18 Minimum body weight ≥ 40 kg for all participants. 
 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1 
Participants with either of the following are excluded: 
(a) Previous history of allogeneic stem cell transplant. 
(b) Previous history of organ transplant 
(c) Autologous stem cell transplant ≤ 3 months prior to study entry 
(d) CAR-T based therapies ≤ 3 months prior to study entry 
2 
Unresolved toxicities of ≥ Grade 2 (NCI CTCAE v5.0) from prior therapy (excluding 
peripheral neuropathy, vitiligo, alopecia, and endocrine disorders that are controlled with 
replacement hormone therapy, and asymptomatic laboratory abnormalities), unless 
immune-mediated then refer to Exclusion criteria 3. 
3 
Any prior ≥ Grade 3 imAE while receiving prior checkpoint inhibitor immunotherapy or 
any unresolved imAE ≥ Grade 2 (excluding Grade 2 vitiligo, alopecia, and endocrine 
disorders that are controlled with replacement hormone therapy).    

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4 
Must not have experienced a toxicity that led to permanent discontinuation of prior 
immunotherapy. 
5 
Participants with CNS involvement or leptomeningeal disease. 
6 
Any venous or arterial thromboembolic event within ≤ 6 months prior to the first dose of 
study intervention. 
7 
Infectious disease exclusions: 
(a) Active infection including TB (clinical evaluation that includes clinical history, 
physical examination, and radiographic findings and TB testing in line with local 
practice). 
(b) HIV (positive for HIV-1 or HIV-2 antibodies). 
(c) Active hepatitis A. 
(d) Chronic or active hepatitis B, however, participants who have chronic hepatitis B and 
are 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 HBV 
DNA < 100 IU/mL by PCR (Regev et al, 2020); see Figure 2. 
NOTE: Participants with controlled hepatitis B viral load must remain on antiviral 
therapy, per institutional practice, during the study intervention and follow-up periods 
to ensure adequate viral suppression.  
Figure 2 
Hepatitis B Screening Tests and Eligibility Algorithm  
 
Abbreviations: -: negative; +: positive; ALT: alanine transaminase; anti-HBs: antibody to hepatitis B 
surface antigen; anti-HBc: hepatitis B core antibody; HbsAg: hepatitis B surface antigen; 
HBV: hepatitis B virus. 
 
(e) Chronic or active hepatitis C; however, participants who have chronic hepatitis C are 
allowed to be enrolled if ALT is normal and HCV RNA undetectable by PCR, either 
spontaneously or in response to a successful prior course of anti-hepatitis C therapy 
(Regev et al, 2020). 

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(f) For all participants in the study, all local institutional standards for COVID-19 must 
be followed for testing. For participants with a known previous COVID-19 infection 
in the last 3 months, a negative PCR test must be documented within 72 hours prior to 
the first dose. For timing of COVID-19 vaccination, see Section 6.5. 
8 
History of arrhythmia (such as multifocal premature ventricular contractions, bigeminy, 
trigeminy, ventricular tachycardia), which requires treatment (NCI CTCAE v5.0 
Grade 3); symptomatic or uncontrolled atrial fibrillation despite treatment, or 
asymptomatic sustained ventricular tachycardia. 
9 
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection 
requiring IV antibiotics, cardiomyopathy of any etiology, symptomatic congestive heart 
failure (as defined by New York Heart Association class ≥ 3), uncontrolled hypertension, 
uncontrolled diabetes mellitus, unstable angina pectoris, history of myocardial infarction 
within the past ≤ 6 months, history of myocarditis, serious chronic gastrointestinal 
conditions associated with diarrhea, active noninfectious skin disease (including 
≥ Grade 2 (CTCAE v5), rash urticarial, dermatitis, ulceration, or psoriasis, but excluding 
stable plaque psoriasis from the definition of active disease). 
10 Psychiatric illness/social situations/substance abuse disorders that would limit compliance 
with study requirements, substantially increase risk of incurring AEs, or compromise the 
ability of the participant to give written informed consent. 
11 Active or prior documented pathologically confirmed 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) Vitiligo or alopecia. 
(b) 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) Celiac disease controlled by diet alone. 
12 Past medical history of confirmed ILD, drug-induced ILD, radiation pneumonitis 
requiring steroid treatment, or any evidence of clinically active ILD or active 
pneumonitis. 
13 Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of study intervention or still recovering from prior surgery. 
NOTE: Local surgery of isolated lesions for palliative intent is acceptable. 

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14 Radiotherapy within ≤ 3weeks of the first dose of sabestomig exceptions are: 
(a) Local treatment of isolated lesions, excluding target lesions (for palliative intent is 
acceptable). 
(b) Mediastinal irradiation not permissible < 3 months of the first dose of sabestomig. 
15 Other invasive malignancy within 2 years prior to screening with the exception of: 
(a) Malignancy treated with curative intent and with no evidence of active disease present 
for more than 2 years before screening and considered to be at low risk of recurrence 
by the treating physician. 
(b) Adequately treated lentigo malignant melanoma without current evidence of disease 
or adequately controlled non-melanomatous skin cancer. 
16 Congenital long QT syndrome or history of QT prolongation associated with other 
medications that cannot be changed or discontinued based on a cardiologist assessment. 
Current or Prior Therapy 
17 Current or prior use of immunosuppressive medication within 14 days prior to the first 
dose of study intervention. The following are exceptions to this criterion: 
(a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection). 
(b) Systemic corticosteroids at physiological doses not to exceed 10 mg/day of 
prednisone or its equivalent. 
(c) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication). 
18 Any concurrent chemotherapy, radiotherapy, investigational, biologic, or hormonal 
therapy for cancer treatment. 
(a) Concurrent use of hormonal therapy for noncancer-related conditions (eg, insulin for 
diabetes and hormone replacement therapy) is acceptable. 
(b) A washout period of at least 28 days after the last chemotherapy, radiotherapy, 
investigational, biologic, or hormonal therapy for cancer treatment must be followed 
before the administration of sabestomig. 
19 Receipt of live attenuated vaccine within 30 days prior to the first dose of study 
intervention. 
NOTE: Participants should not receive live vaccine while receiving study intervention 
and up to 30 days after the last dose of study intervention. 
 
Concurrent or Prior Clinical Study Experience 
20 Concurrent enrollment into another interventional clinical trial, unless it is an 
observational (noninterventional) clinical study or during the follow-up period of an 
interventional study. 
21 Known allergy or hypersensitivity to sabestomig or any of the excipients of sabestomig. 

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Other Exclusions 
22 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
23 Judgment by the Investigator that the individual should not participate in the study if they 
are unlikely to comply with study procedures, restrictions, and requirements. 
24 Previous dosing with sabestomig initiated in this study. 
 
5.3 
Lifestyle Considerations  
Due to the nature of sabestomig (Section 2), no interactions are foreseen with the consumption 
of meals, caffeine, alcohol, the use of tobacco or nicotine containing products, or strenuous 
(more than usual) activity. Normal lifestyle activities may continue while participating in this 
study. 
The requirements and restrictions pertaining to reproduction and contraception use for both 
female and male participants and their partners are further detailed in the inclusion criteria 
(Section 5.1) and Appendix B. 
Restrictions for concomitant medications are described in Section 6.5. 
For further details about considerations for the COVID-19 pandemic and mitigation strategies 
for study disruption due to civil unrest, natural disaster, and Public Health Crisis, please refer 
to Appendix H. 
5.4 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once if confirmed by AstraZeneca. Rescreened participants should be assigned the 
same participant number as for the initial screening. 
6. 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention intended to be administered 
to a study participant according to the study protocol. 

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6.1 
Study Intervention(s) Administered  
6.1.1 
Investigational Products  
Sabestomig (AZD7789) will be supplied by AstraZeneca as either a 
 or
 
product as described in Table 10. Commercially available 
 
 for injection will be supplied by each 
site. 
Table 10 
Investigational Product       
Study intervention 
Sabestomig (AZD7789) 
Type 
Biologic 
Dosage Form 
Sabestomig is supplied as either a 
 or 
. 
Sabestomig 
 mg:  
 for 
 for infusion 
Sabestomig 
 mg: 
 for 
 for infusion 
Unit dose strength(s) 
 mg 
) or 
 mg (
  
 mg/mL 
Dosage level(s) 
Part A (Dose Escalation): 
• 
Planned dose levels: 2, 7, 22.5, 75, 225, 750, 1500, and 
2000 mg Q3W. 
• 
Intermediate dose levels: 50, 150, 450, 1000, 1250, and 
1750 mg Q3W. 
Part B (Dose Expansion): 
• 
Recommended Phase 2 dose determined in Part A Dose 
Escalation administered Q3W. 
Route of administration 
Intravenous infusion 
Use 
Experimental 
IMP or non-investigational medicinal 
product 
IMP (study intervention) 
Sourcing 
Provided centrally by AstraZeneca. 
Packaging and labeling 
Study intervention will be provided in vials in a carton. Each vial 
and carton will be labeled in accordance with country regulatory 
requirements. 
Abbreviations: IMP: investigational medicinal product; Q3W: every 3 weeks; w/v: weight/volume. 
6.1.2 
Identity of Investigational Product(s)  
Sabestomig will be supplied as either a 
 or a 
.   
Sabestomig 
Product 
Sabestomig will be supplied in a vial as a 
 mg 
 product for 
 
 for infusion. The reconstituted solution contains 
mg/mL sabestomig in 
 
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 it has a 
pH 6.0 and a density of 1.045 g/mL. The post-reconstitution label-claim volume is 
 mL. 
Sabestomig 
 Product 
Sabestomig will be supplied as a concentrate for solution for infusion. Sabestomig 
 mg 
will be supplied in vials containing 
mg/mL sabestomig in 
 
 it has a pH 
and a density of 
 g/mL. The label-claim volume is 
 mL.  
The investigational product 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 labeled with the same unique sequence number range. 
Dosing Criteria for Cycles ≥ 2 
Following completion of the first treatment cycle, participants may receive additional 
treatment with sabestomig when the following conditions are met: 
• 
The participant does not meet any criteria for discontinuation of IMP as listed in 
Section 7.1 
• 
The participant has adequate marrow, renal, and liver function, outlined in Table 9. Note: 
Laboratory evaluations must be performed up to 3 days prior to initiation of each cycle of 
treatment; transfusion and granulocyte colony stimulating factor support is permissible. 
• 
If the participant experiences an AE following administration of study intervention in the 
previous dosing cycle, the participant must not meet criteria for dose omission or 
permanent discontinuation and must meet retreatment guidelines as outlined in the 
toxicity management guidelines as defined in Appendix I. 
 
6.2 
Preparation/Handling/Storage/Accountability  
• 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
• 
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled 
 
) with access limited to the Investigator and authorized site staff. 
• 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
• 
Further guidance and information for the final disposition of unused study interventions 
are provided in the Investigational Product Manual. 
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6.2.1 
Sabestomig Infusion Preparation and Administration  
6.2.1.1 
Preparation  
Sabestomig is a
 product, 
. The reconstituted Drug 
Product is a 
 
.  
Sabestomig 
 Drug Product is a 
 
.  
Each vial selected for dose preparation should be inspected. If any defects are noted with the 
investigational product(s), the Investigator and site monitor should be notified immediately. 
The dose of sabestomig for administration must be prepared by the pharmacy staff members 
(or an appropriate designee trained in study drug preparation), using aseptic technique in 
compliance with local regulations and site requirements.  
The total time from needle puncture of the sabestomig vial to the start of administration must 
not exceed 24 hours. Of this time, not more than hours may be at room temperature, with the 
remaining time at 
, otherwise a new dose must be prepared from 
new vials. 
The volume of sabestomig (in mL) to add to the IV bag is calculated as follows: 
 
where 
. 
Sabestomig does not contain preservatives; any unused portion of the vial must be discarded 
immediately after use. 
Sabestomig 
 Product 
No incompatibilities between sabestomig 
 product and the following component 
materials of construction have been observed when diluted in 0.9% sodium chloride for 
injection: 
• 
 
• 
 
• 
 
• 
 
 
To reconstitute, slowly add 
mL of sWFI by tilting the vial to one side such that the liquid 
stream is directed along the wall of the vial and not directly upon the 
 product. 
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Gently swirl the solution until all solids are dissolved. Gently invert the vial to dissolve any 
solids that may be present at the neck of the vial or on the stopper. DO NOT SHAKE OR 
VIGOROUSLY AGITATE THE VIAL. Visually inspect the solution to ensure that the entire 
content of the 
 product is completely reconstituted. A thin layer of bubbles on the 
surface of the 
is normal. 
If a closed system transfer device (CSTD) must be used to withdraw the sWFI for 
reconstitution, then a new syringe and syringe adapter must be used to withdraw the 
reconstituted product, ie, do not re-use the same syringe and syringe adapter that was used for 
withdrawal of sWFI to withdraw the product. This will prevent additional dilution resulting 
from addition of residual sWFI contained in the syringe and syringe adapter. 
Doses of sabestomig less than or equal to 
 mg will be prepared using a polypropylene 
syringe containing 
 for injection. Dose preparation will be achieved 
using the following method: 
1. Dilute sabestomig drug product with 
 for injection in a 
polypropylene syringe according to the appropriate dose level, as shown in Table 11. 
2. Gently invert the syringe several times until the solution is completely mixed. 
Table 11 
Preparation of Diluted Sabestomig for IV Administration Using a 
Syringe Pump       
Dose (mg) 
Volume of 
sabestomig 
(mL) 
Volume of 0.9% 
(w/v) saline 
(mL) 
Concentration of 
diluted 
sabestomig 
(mg/mL) 
Dose volume of 
diluted sabestomig 
to be administered 
(mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: IV: intravenous; w/v: weight/volume. 
 
Doses of sabestomig between 
mg and 
mg will be prepared using an IV bag 
containing 
 for injection. Add the calculated volume of sabestomig for 
each dose level to the IV bag. The IV bag size should be selected such that the final 
concentration is within 
 mg/mL, however the selected IV bag size must not be 
 
 for patients 
. Mix the bag by gently inverting to 
ensure homogeneity of the dose in the bag. Additional details regarding dose preparation are 
provided in the IP Handling Instructions. 
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The tubing will be flushed with a volume equal to the tubing volume, according to local 
practices, to ensure the full dose is administered. Infusion time does not include the final flush 
time. 
Administration from IV Bag 
Sabestomig infusions are to be administered through an IV administration set with a 
or 
μm filter; acceptable configurations include an IV set containing an in-line filter or the 
attachment of a separate filter to the distal end of the IV tubing.  
The sabestomig infusion time is 1 hour (-5 minutes to + 15 minutes); however, if there are 
interruptions, the total allowed time must not exceed 4 hours with the infusion bag kept at 
room temperature, otherwise a new dose must be prepared from new vials.  
Do not co-administer other drugs through the same infusion line.  
The IV line will be flushed with a volume equal to the IV line volume, according to local 
practices, to ensure the full dose is administered. Infusion time does not include the final flush 
time. 
6.3 
Measures to Minimize Bias: Randomization and Blinding  
This study does not include blinding or randomization in order to minimize bias. However, 
participants will be assigned to dosing cohorts (or dose levels) on a “first come, first served” 
basis. When cohorts are opened in parallel for mini expansion Cohorts A5 to A8, participants 
will be assigned in such a way as to fill the cohorts equally, starting with the highest dose that 
has been declared safe by the SRC. However, prioritization may be given to cohorts where 
potential clinical activity has been observed. 
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 if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study-site staff other than the person administering the 
study intervention. 
6.5 
Concomitant Therapy  
Any medication or vaccine or supplement (including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
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• 
Reason for use. 
• 
Dates of administration including start and end dates. 
• 
Dosage information including dose, frequency, and route of administration. 
 
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Use of concomitant medications including over-the-counter medications, herbal supplements, 
vitamins, etc., from time of screening until the final study visit is not permitted without first 
consulting with the Investigator or delegate. 
Prohibited concomitant medications are detailed in Table 12 and permitted concomitant 
medications are detailed in Table 13. 
6.5.1 
Premedication  
Thirty minutes prior to each dose of sabestomig, participants will receive diphenhydramine 
25 to 50 mg PO and acetaminophen/paracetamol 500 mg PO. 
Post-infusion, acetaminophen/paracetamol may be given at 4, 8, and 12 hours. All participants 
should be well hydrated prior to all doses of sabestomig.  
The addition of steroid premedication (prednisone equivalent dose is ≤ 10 mg/day) may be 
warranted if CRS or significant IRRs are observed with diphenhydramine and an antipyretic 
alone. Refer to Appendix I for CRS/IRR toxicity management guidelines. 
Following completion of Part A, if there are no or minimal occurrences of CRS or IRRs, the 
need for premedication will be made optional through a future protocol version. 
6.5.2 
Rescue Medicine  
The study site will supply rescue medication that will be obtained locally. For example, the 
following rescue medications may be used (list not exhaustive): 
1 
Tumor Necrosis Factor inhibitors (infliximab). 
2 
Anti-IL-6 (tocilizumab). 
3 
Nonselective adrenergic agonist (epinephrine). 
 
The date and time of rescue medication administration as well as the name and dosage 
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Table 12 
Prohibited Concomitant Medications       
Prohibited Medication/Class of Drug 
Usage 
Any investigational therapy including 
anticancer therapy other than those under 
investigation in this study. 
Should not be given concomitantly while the participant is 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 participant is on 
study intervention (Concurrent use of hormones for 
non-cancer-related conditions [eg, insulin for diabetes and 
hormone replacement therapy] is acceptable. Local treatment of 
isolated lesions, excluding target lesions, for palliative intent is 
acceptable [eg, by local surgery or radiotherapy]). 
Live attenuated vaccines. 
Should not be given within 30 days prior to the first dose 
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 tumor necrosis factor-α blockers. 
Should not be given concomitantly or used for premedication 
prior to the immunotherapy infusions. The following are 
allowed exceptions: 
Premedication prior to infusion of sabestomig as outlined in 
Section 6.5.1. 
 Use of immunosuppressive medications for the management of 
study intervention-related AEs. 
For ≥ Grade 2 IRRs after Cycle 1 Day 1 per institutional 
standards and at the Investigator’s discretion; however, steroids 
should not be used as routine premedication for Grade 1 or 2 
IRRs (refer to Section 6.6.8 and Toxicity Management 
Guidelines [Appendix I]). 
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.). 
Herbal and natural remedies which may 
have immune-modulating effects. 
Should not be given concomitantly. 
Abbreviation: IRR: infusion-related reaction. 
 

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Table 13 
Permitted Concomitant Medications       
Supportive Medication/Class of Drug 
Usage 
Premedication for management of diarrhea, 
nausea, and vomiting. 
Permitted after but not before the first dose of study 
intervention. 
Blood transfusions 
Permitted at any time after Cycle 1 Day 1. 
Erythropoietin 
Prophylactic erythropoietin should not be started during 
Cycle 1 of the study but may be started during Cycle 2 and 
after. 
G-CSF 
G-CSF should not be used prophylactically during Cycle 1, 
but may be considered after Cycle 1 following discussion 
with the Study Physician. 
Megestrol acetate 
Permitted for appetite stimulation. 
Bisphosphonates 
Permitted for treatment of bone metastases. 
Concomitant medications or treatments 
(eg, paracetamol/acetaminophen or 
diphenhydramine) deemed necessary to 
provide adequate prophylactic or supportive 
care, except for those medications identified 
as “prohibited,” as listed in Table 12. 
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. 
Permitted 
COVID-19 vaccine. 
COVID-19 vaccine is permitted as per local 
standards/guidance, while following the recommended 
guidance below: 
Part A (Dose Escalation): 
Cycle 1: It is strongly advised to avoid vaccination for at least 
72 hours prior to administration of the first dose of 
sabestomig and during the dose-limiting toxicity evaluation 
period. 
Cycle 3 and beyond: It is strongly advised to avoid 
vaccination for at least 72 hours prior to or after 
administration of sabestomig. 
Part B (Dose Expansion): 
Cycle 1 and beyond: It is strongly advised to avoid 
vaccination for at least 72 hours prior to or after 
administration of sabestomig. 
Abbreviations: COVID-19: coronavirus disease 2019; G-CSF: granulocyte colony stimulating factor. 
 

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6.6 
Dose Modification  
6.6.1 
Starting Dose, Dose Escalation Scheme, and Stopping Criteria  
Dosing will begin at 2 mg sabestomig. The justification for the starting dose and the 
dose escalation scheme is discussed in Section 4.3. 
The dose for subsequent cohorts or a decision to stop recruitment to Part A (Dose Escalation) 
will be agreed by the SRC after review of the data from each cohort (Section 6.6.7). 
Rules for dose escalation will be initiated using an ATD (Simon et al, 1997) for the first 
4 dose levels (Section 6.6.1.1). If predefined safety criteria are met, dose escalation will 
switch to the mTPI-2 algorithm (Guo et al, 2017, Ji et al, 2010). After the first 4 dose levels, 
rules for dose escalation will be conducted using the mTPI-2 algorithm (Section 6.6.1.2). 
Once the mTPI-2 algorithm is triggered, all future dose escalations will follow the mTPI-2 
algorithm. The maximum dose increments will be modified from shown in the study schema 
(Figure 1) as follows: 
• 
Limit the maximum dose increment to 100% if participants of a given cohort experience 
1 Grade ≥ 2 imAE during the DLT period that does not decrease to Grade 1 within 
72 hours. 
• 
Limit the maximum dose increment to 50% if participants of a given cohort experience 
2 or more Grade ≥ 2 imAEs during the DLT period that do not decrease to Grade 1 within 
72 hours. 
• 
Limit the maximum dose increment to 50% if participants of a given cohort experience 
1 imAE DLT during the DLT period. 
• 
Limit the maximum dose increment to 30% if participants of a given cohort experience 
2 DLTs during the DLT period. 
 
In each cohort, participant dosing will be staggered such that administration of the first dose is 
separated by at least 24 hours before the second participant is dosed. Provided there are no 
serious or unexplained safety issues, as determined by the SRC, dosing of the remainder of the 
cohort will continue as suitable participants are identified. However, should ambiguous 
findings occur, the SRC may choose to stagger the start of dosing for the remainder of the 
cohort of participants. 
The sabestomig planned and intermediate dose levels that may be studied during dose 
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Table 14 
Sabestomig Planned and Intermediate Dose Levels       
Planned Cohort 
Planned Dose Levels 
Cohort A1 
2 mg 
Cohort A2 
7 mg 
Cohort A3 
22.5 mg 
Cohort A4 
75 mg 
Cohort A5 
225 mg 
Cohort A6 
750 mg 
Cohort A7 
1500 mg 
Cohort A8 
2000 mg 
Intermediate Cohort 
Intermediate Dose Levels a 
Cohort A3.5 
50 mg 
Cohort A4.5 
150 mg 
Cohort A5.5 
450 mg 
Cohort A6.25 
1000 mg 
Cohort A6.5 
1250 mg 
Cohort A7.5 
1750 mg 
a 
Only to be considered by decision of the Safety Review Committee in consideration of the totality of the 
data available. Other intermediate dose levels may be evaluated prior to declaring the recommended 
Phase 2 dose. 
Abbreviation: mTPI-2: modified toxicity probability interval-2. 
 
6.6.1.1 
Accelerated Titration Design  
For dose levels < 225 mg (Cohorts 1 to 4), dose escalation will follow an ATD and will be 
 participant cohorts. Cohorts 5, 6, 7, and the optional last cohort, Cohort 8, will follow 
an mTPI-2 and will consist of 
 participants. The enrolled participants must complete 
the DLT evaluation period before a dose escalation decision is made by the SRC. 
At any ATD dose level, dose escalation will switch from ATD dose escalation to the mTPI-2 
dose escalation algorithm if the initially enrolled participant has any of the following during 
the DLT evaluation period: 
• 
Any DLT. 
• 
Any ≥ Grade 2 TEAE. 
 
Once the mTPI-2 algorithm is triggered, all further dose escalation will follow mTPI-2 
algorithm. 
Intra-participant Dose Escalation 
Participants in the ATD cohorts (Part A, Cohorts A1-A4) are allowed to escalate at any higher 
dose level considered to be safe after they have completed a minimum of 2 cycles of the 
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protocol, and provided they did not present any DLT or unacceptable toxicity since the 
treatment onset and have not met any of the criteria for treatment discontinuation in 
Section 7.1 (Ribas et al, 2005). The objective is to provide the above-defined participants the 
opportunity to be treated at higher and presumably more effective doses. 
6.6.1.2 
Modified Toxicity Probability Interval  
A minimum of  and a maximum of 
 participants will be enrolled at a given dose level for 
Part A. Dose escalation to the next dose level will be conducted using the mTPI-2 algorithm 
with a target DLT rate of 30% and an equivalence interval (25%, 33%). A minimum of 
 participants must complete the DLT evaluation period before making an escalation decision. 
Dose escalation will consist of 4 planned dose levels of sabestomig. Intermediate dose levels 
may be explored if warranted by emerging safety, PK, pharmacodynamic, biomarker, and 
efficacy data. Dose escalation and de-escalation recommendations will follow the mTPI-2 
algorithm schema below: 
1 
A minimum of  evaluable participants are required in each dose level unless 
unacceptable toxicity is encountered in the first  participants prior to enrollment of the 
third participant, which would require dose de-escalation per the mTPI-2 algorithm. For a 
dose level that has fewer than  participants who are DLT-evaluable, participants will be 
replaced. 
2 
If a de-escalation decision is made, choice of de-escalation to the previous dose level 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, and into which mini 
expansion cohort participants have since been enrolled at that dose level, these 
mini-expansion cohort participants may be included in further dose escalation decisions. 
3 
If a stay (“S”) decision is made, additional participants will be enrolled up to a maximum 
of 
 participants for a given dose level. 
4 
Administration of the first dose of sabestomig will be staggered by a minimum of 
24 hours between the first and second participants in each dose escalation cohort. Intra-
participant dose escalation will not be allowed during the mTPI-2 part of dose escalation. 
5 
At the discretion of AstraZeneca, dose escalation may be stopped before an MTD is 
reached. 
6 
The MTD will be determined by isotonic regression analysis applied to DLT rates 
observed during dose escalation using the mTPI-2 method (Ji et al, 2010). 
 
Participants enrolled into ATD dose escalation cohorts may be considered evaluable for 
dose escalation decision-making purposes using mTPI-2 algorithm if the dose under 
investigation is identical to one previously assessed by ATD dose escalation. 
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Description of the Modified Toxicity Probability Interval-2 Algorithm 
The mTPI-2 algorithm employs a simple beta-binomial Bayesian model. The prior distribution 
for all dose levels is Beta(1,1). The posterior distribution for all dose levels is Beta(1+a, 1+b), 
where a and b are the number of participants with and without a DLT at the current dose level, 
respectively. The posterior density of the toxicity probability is divided into multiple intervals 
with equal length. These intervals are categorized as underdosing, proper dosing, and 
overdosing in terms of 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. Given an interval and a probability distribution, the unit probability mass of 
that interval is defined as the probability of the interval divided by the length of the interval. 
The design for the dose escalation phase of the study uses a target DLT rate of 30% and an 
equivalence interval (25%, 33%) 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 80% or more probability of exceeding the target DLT 
rate of 30% (ie, Probability [DLT > 30% data] ≥ 80%) with at least participants treated and 
evaluated at that dose level. In Table 15, dose escalation/de-escalation decision rules are 
computed based on the above information. 
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Table 15 
Modified Toxicity Probability Interval-2 Algorithm       
Number 
of DLTs 
Number of Evaluable Participants Treated at Current Dose Level 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 c 
0 
S a 
S a 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
S b 
S b 
S e 
S 
E 
E 
E 
E 
E 
E 
E 
E 
2 
 
DU d 
DU 
DU 
D 
D 
S 
S 
E 
E 
E 
E 
3 
 
 
DU 
DU 
DU 
DU 
DU 
D 
D 
S 
S 
E 
4 
 
 
 
DU 
DU 
DU 
DU 
DU 
DU 
D 
D 
D 
5 
 
 
 
 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
DU 
a 
Changed from “E” to “S” as a minimum of  evaluable participants are needed to make a dose escalation 
decision. 
b 
Changed from “D” to “S” as a minimum of evaluable participants are needed to make a dose escalation 
decision. 
c 
The “S” cells in original modified toxicity probability interval-2 algorithm are modified to either E or D 
according to whether the observed DLT rate is < or ≥ the target toxicity of 30%, respectively. 
d 
If at the first dose level, participants can choose to early terminate the trial or not based on their own 
discretion. 
e 
Changed from “D” to “S” to ensure the mTPI-2 algorithm performs as conservatively as the standard 3+3 
design if a single DLT is observed among the first 3 participants at a new dose level. 
Note: Target toxicity (%) is 30% and equivalence interval (25%, 33%). The sample size cap for each dose level 
will be 
 participants. 
Abbreviations: D: de-escalate to the next lower-dose level; DLT: dose-limiting toxicity; DU: current dose is 
unacceptably toxic; E: escalate to the next higher dose level; S: stay at the current dose level. 
Sources: Modified from Guo et al, 2017 and Ji et al, 2010. 
 
6.6.2 
Dose Expansion  
Participants enrolled in Part B Dose Expansion will receive sabestomig Q3W administered via 
IV infusion at the RP2D determined during Part A Dose Escalation. 
The opening of Part B is dependent on emerging data from Part A. Cohorts B1 and B2 may 
open for enrollment either in parallel or sequentially at the discretion of AstraZeneca. The 
opening of Cohort B2 will be gated on emerging antitumor activity data from participants 
enrolled in Part A and/or Cohort B1. 
6.6.3 
Definition of Dose-limiting Toxicity  
The DLTs will be evaluated during Part A Dose Escalation. The DLT evaluation period will 
be 28 days from the first dose of sabestomig on Cycle 1 Day 1. Participants who do not 
remain in the study for the entire duration of the DLT evaluation period, for reasons other than 
DLT, will be considered non-evaluable for DLT evaluation and will be replaced with another 
participant at the same dose level if needed to ensure a minimum of 
 evaluable 
participants in the ATD and mTPI-2 cohorts, respectively. 
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A DLT will be defined during Part A Dose Escalation as any ≥ Grade 3 AE as per NCI 
CTCAE version 5 unless unequivocally due to underlying malignancy or an extraneous cause. 
The modifications and exceptions to this are detailed below. 
The following conditions will be considered as DLTs: 
• 
Any death not clearly due to the underlying disease or extraneous causes. 
• 
Grade 4 imAE. 
• 
Any ≥ Grade 3 non-infectious pneumonitis irrespective of duration. 
• 
Any ≥ Grade 3 non-infectious colitis irrespective of duration. 
• 
Liver transaminase elevation: 
− 
Isolated liver transaminase elevation > 5 x but ≤ 10 x ULN that does not downgrade 
to AST/ALT ≤ 3 x ULN or less within 7 days after onset with optimal medical 
management including systemic corticosteroids. 
− 
Transaminase elevation > 10 x ULN regardless of duration or reversibility. 
− 
Isolated TBL elevation > 3 x ULN that does not downgrade to ≤ 1.5 x ULN within 
7 days after onset with optimal medical management (for participants with Gilbert’s 
syndrome: TBL > 3 x ULN and doubling of direct bilirubin that does not downgrade 
to baseline value within 7 days). 
− 
Any increase in AST/ALT > 3 x ULN and concurrent increase in TBL ≥ 2 x ULN, 
regardless or duration or reversibility, where no other reason, other than the 
investigational product(s), can be found to explain the combination of increases (for 
participants with Gilbert’s syndrome: TBL > 3 x ULN and doubling of direct 
bilirubin that does not downgrade to baseline value within 7 days). 
• 
Any Grade 3 imAE, including rash, pruritus, or diarrhea (NOTE: this excludes colitis or 
pneumonitis, as these AEs are already defined above), that does not downgrade to 
Grade 2 or less within 7 days after onset of the event despite maximal supportive care 
including systemic corticosteroids. 
• 
Grade 3 nausea, vomiting, or diarrhea that does not resolve to Grade 2 or less within 
3 days of initiation of maximal supportive care. 
• 
Neutropenia. 
− 
≥ Grade 3 neutropenia, without associated fever or systemic infection, which does 
not improve by at least one grade within 7 days of onset. 
• 
Thrombocytopenia: 
− 
Grade 4 thrombocytopenia lasting more than 7 days. 
− 
≥ Grade 3 thrombocytopenia associated with a Grade ≥ 2 bleeding, which in the 
opinion of the Investigator, is related to study intervention. 
• 
Grade 4 anemia not related to the underlying disease or any extraneous cause. 

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• 
Cytokine Release Syndrome (CRS): 
− 
Grade 4 CRS of any duration. 
− 
Grade 3 CRS that does not improve to Grade ≤ 2 within 72 hours. 
 
The following conditions will not be considered as DLTs: 
• 
Grade 3 fatigue lasting ≤ 7 days. 
• 
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy with resolution of the symptoms within 14 days after treatment onset. 
• 
Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes) that resolves to ≤ Grade 1 within 
7 days after onset. 
• 
Vitiligo or alopecia of any AE Grade. 
• 
Grade 3 or Grade 4 lymphopenia (unless associated with clinical sequelae). 
• 
Grade 3 laboratory abnormalities that are not associated with clinical signs or symptoms 
(eg, hyperlipasemia or hyperamylasemia not associated with clinical signs or symptoms 
or radiographic features suggestive of pancreatitis) and are reversed with appropriate 
maximal medical intervention within 7 days. 
 
Immune-mediated AEs are defined as AEs of an immune nature (ie, inflammatory) in the 
absence of a clear alternative etiology. In the absence of clinical abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to 
designation as a DLT. 
An AE not listed above or an AE meeting the DLT criteria above but occurring outside of the 
DLT-evaluation period, may be defined as a DLT after consultation with AstraZeneca and 
Investigators based on the emerging safety profile. 
6.6.4 
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 algorithm. With this constraint, the 
MTD will be determined as the dose level with the DLT estimate closest to the target toxicity 
level of 30%. 
In the case of dose levels with estimated toxicity of equal distance (tied dose levels) from the 
target toxicity of 30%, the following approach will be used (Ji et al, 2010): among all tied 
dose levels the highest dose level with target toxicity ≤ 30% will be selected, unless all tied 
dose levels have estimated toxicity > 30%, in which case the lowest dose level will be 
selected. 

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6.6.5 
Definition of Optimal Biological Dose  
The OBD will be determined from the safety, efficacy, PK, pharmacodynamic, and biomarker 
data during the dose escalation phase. The RP2D will be selected by AstraZeneca in 
discussion with the members of the Study Steering Committee, based on the totality of the 
data from the dose escalation phase of the study. 
Pharmacokinetic and pharmacodynamic data collected in Parts A and B will provide 
demonstration of adequate drug exposure and high target binding level. Data demonstrate that 
clinical efficacy of the approved anti-PD-1 agents, pembrolizumab and nivolumab, is 
associated with PD-1 receptor occupancy (RO) > 90%, thereby suggesting that a similar level 
of PD-1 inhibition by sabestomig will confer clinical benefit at least equivalent to that of 
pembrolizumab and nivolumab. 
6.6.6 
Definition of DLT-evaluable Participants  
For decisions on dose escalation, an evaluable participant is defined as a participant who has 
received sabestomig and has completed the DLT period (28 days after receiving 1st dose of 
sabestomig) or has experienced a DLT during the DLT period. 
6.6.7 
Safety Review Committee  
To ensure safety surveillance of developmental compounds in line with regulatory 
expectations for safety assessment committees, AstraZeneca has systematic and robust 
internal processes in place. This includes processes with clearly described roles and 
responsibilities that are owned by AstraZeneca’s Patient Safety organization. These processes 
are designed to monitor the evolving safety profile (ie, review of cumulative SAEs, or other 
important safety information) by designated cross-functional teams in a timely manner at 
predefined intervals or on an ad-hoc basis. 
In addition to AstraZeneca’s internal processes, a study-specific SRC, in accordance with its 
charter, will provide ongoing safety surveillance of the study, with regularly scheduled 
reviews of safety, PK, and other relevant data. The SRC comprises of members of 
AstraZeneca and investigators. This committee may also meet to review data at other time 
points (eg, in response to AEs assessed as medically relevant by the Study Physician). This 
committee will be responsible for making recommendations for dose escalation or dose de-
escalation decisions and making recommendations regarding further conduct of the study 
during all phases of the study including suspension or stopping of the trial. The SRC will 
review the totality of all available clinical, laboratory safety and all other relevant data prior to 
adjudicating on dose escalation/de-escalation decisions based on the dose escalation rules. All 
decisions by this committee will be documented and shared in writing with all participating 
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During Part A, in addition to continuous monitoring as per AstraZeneca pharmacovigilance 
process, the SRC will evaluate toxicities occurring study wide. In addition, to assess potential 
late toxicity occurring beyond the DLT window, an analysis of cumulative safety data will be 
performed and shared with the SRC when 1) once at least 6 participants have completed at 
least 2 cycles of study drug, and 2) after completion of Part A (Dose Escalation) and prior to 
moving to Part B (Dose Expansion).  
The membership, roles, responsibilities, and decision-making process will be detailed in the 
SRC charter. 
6.6.8 
Dose Modification and Toxicity Management  
If a participant experiences a clinically significant and/or unacceptable toxicity including a 
DLT not attributable to the disease or disease-related processes under investigation, dosing 
will be interrupted, and supportive therapy will be administered. 
All toxicities will be graded according to NCI CTCAE v5.0. 
The following general guidance should be followed for management of toxicities: 
• 
Treat each of the toxicities with maximum supportive care (including withholding the 
agent suspected of causing the toxicity if required). 
• 
If the symptoms promptly resolve with supportive care, consideration should be given to 
resuming the assigned study intervention along with appropriate continuing supportive 
care. If medically appropriate, dose modifications (eg, dose interruption) are permitted. 
• 
All dose modifications (eg, dose interruption, discontinuation) should be documented 
with clear reasoning and documentation of the approach taken. 
• 
Dose reductions are not permitted. 
 
Toxicity Management Guidelines have been developed to assist Investigators with the 
recognition and management of toxicities associated with use of the IC inhibitor sabestomig. 
The TMGs are provided in Appendix I. 
These TMGs are applicable to the management of participants receiving sabestomig as 
specified in the CSP. The TMGs provide information for the management of 
immune-mediated reactions, IRRs, and non-immune-mediated reactions that may be observed 
with monotherapy or combination checkpoint inhibitor regimens, with specific instructions for 
checkpoint inhibitor-specific dose modifications (including permanent discontinuation) and 
treatment interventions. Investigators are advised however to use local practice guidelines and 
consult local references for the management of toxicities observed with other anticancer 
treatment. 

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6.7 
Dose Delay  
In the event of treatment-related toxicities, study intervention should be permanently 
discontinued if sabestomig is not given for more than 12 weeks.  
If treatment interruption is caused by intercurrent illness that is not a direct consequence of 
sabestomig-related toxicity (ie, COVID-19 infection), the option to restart treatment can be 
offered beyond 12 weeks following discussion with the AstraZeneca representative. In the 
event of a COVID-19 infection, the investigator should use their judgment to delay treatment 
with sabestomig depending on the clinical situation of the participant. 
6.8 
Treatment Beyond Progression  
Participants may continue to be treated with the scheduled regimen and dose assigned at the 
discretion of the Investigator until one of the following criteria is met: 
• 
Disease progression based on the Modified Lugano criteria assessed by the Investigator or 
pathological progression confirmed by biopsy. The assessment of PD must be confirmed 
by a repeat evaluation made by PET.  
• 
Any of the study intervention discontinuation criteria is met. 
• 
Clinical symptoms or signs indicating clinically significant PD such that the benefit-risk 
ratio of continuing therapy is no longer justified based on Investigator judgment. 
• 
Decline in ECOG performance status compared to baseline. 
• 
Rapid PD or threat to vital organs/critical anatomical sites (eg, spinal cord compression) 
requiring urgent alternative medical intervention, and/or continuation of study therapy 
would prevent institution of such intervention. 
 
Pseudo progression: 
During immunomodulatory agent therapy (eg, checkpoint inhibitors, BTK inhibitors, CAR 
T-cell therapy, bi-specific antibody, lenalidomide, brentuximab-vedotin), imaging findings 
suggestive of PD without clinical deterioration may instead represent a tumor flare (also called 
pseudo-progression). To avoid early termination of the study treatment, if a 
pseudo-progression is suspected (eg, in presence of tumor flare with no clinical deterioration), 
it is recommended that a lymph node biopsy (if applicable) and a subsequent imaging at least 
4 weeks apart from the initial assessment (and within a maximum of 12 weeks) is done, to 
confirm true PD versus a tumor flare/pseudo-progression.   
6.9 
Continued Access to Study Intervention After the End of the 
Study  
AstraZeneca will continue to supply sabestomig in the continued access phase of the study (ie, 
PTAP), if the participant consents to this, and while in the opinion of the investigator and in 
agreement with the medical monitor, the participant is benefiting from the treatment. 

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Treatment will continue until PD occurs as judged by the investigator, completion of a 
participant’s current 35‑cycle treatment period, or until meeting any other discontinuation 
criteria defined in Section 7.1. Participants should be followed according to the institution's 
SoC assessments and as deemed appropriate by the investigators. It is recommended that 
investigators continue to observe ongoing participants at the frequency employed prior to the 
final DCO. No further data collection is required, except for safety reporting. The investigator 
and any designees are responsible for detecting, documenting, and recording events that meet 
the definition of AE and SAE and special situations (see Sections 8.3, 8.4, and Appendix D). 
Adverse events will be collected from time of signature of ICF throughout the PTAP until 90 
days after the last dose of sabestomig, regardless of whether the participant has initiated a new 
anticancer treatment. 
Protocol dose modification and stopping criteria are to be followed while a participant is 
receiving sabestomig. A change in the dose/schedule of sabestomig should only occur for 
safety reasons, based on the investigator’s judgment, and should follow the approach for dose 
reduction and discontinuation as described in this protocol. 
In the event that product development reaches a point where alternative product supply 
options become available, then these alternative product supply options will be discussed by 
AstraZeneca with the investigator. AstraZeneca will work with the investigator to transition 
the participant(s) to alternative supply, where possible. In the event that AstraZeneca 
terminates further development of the study intervention, AstraZeneca will continue to supply 
study intervention where possible, however the supply may become unavailable. AstraZeneca 
will notify investigators in advance if supply of study intervention must be discontinued. 
In the event that a rollover or safety extension study is available at the time of the final DCO 
and database closure, participant(s) currently receiving treatment with sabestomig may be 
transitioned to such a study, and the current study would reach its end. The rollover or safety 
extension study would ensure treatment continuation with visits and assessments per its 
protocol, as applicable. Any participant who would be proposed to move to such a study 
would be asked to sign a new ICF, as applicable. 
6.10 
Treatment of Overdose  
For this study, any dose of study intervention in excess of that specified in this CSP will be 
considered an overdose. 
In the event of an overdose, the Investigator should: 
• 
Evaluate the participant to determine, in consultation with the Study Clinical Lead, if 
possible, whether study intervention should be interrupted or whether the dose should be 
reduced. 

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• 
Closely monitor the participant for any AE/SAE and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. Refer to Section 8.4 
for details of AE/SAE reporting related to overdose. 
• 
Obtain a plasma sample for PK analysis if requested by the Study Clinical Lead 
(determined on a case-by-case basis) on day of visit (after end of infusion) if no other PK 
samples are scheduled; alternatively, up to 3 days from the date of the last dose of study 
intervention. 
• 
Document the quantity of the excess dose as well as the duration of the overdose. 
 
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 drug. Note that discontinuation from study drug is NOT the same thing as 
discontinuation from the study. 
Participants may be discontinued from study drug in the following situations: 
• 
Confirmed disease progression by PET-CT. 
• 
An AE that meets criteria for discontinuation of study drug (as defined in Sections 6.6.3 
and 6.6.8 and the Toxicity Management Guidelines, Appendix I) or in the opinion of the 
Investigator or AstraZeneca warrants discontinuation of further dosing. 
• 
Investigator determination that the participant is no longer benefiting from study 
intervention. 
• 
Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. 
• 
Pregnancy or intent to become pregnant (Section 8.3.10). 
• 
Non-compliance with the CSP (Investigator or participant). 
• 
Participant incorrectly initiated on study intervention. 
− 
When the reason does not impact safety consider the risk/benefit to the participant of 
stopping treatment. 
• 
Unexpected, significant, or unacceptable risk to the participants enrolled in the study. 
• 
AstraZeneca termination of study for reasons including but not limited to unfavorable 
risk/benefit or change in drug development plan. 
 
If study drug is permanently discontinued, the participant will remain on study to be evaluated 
for protocol-specified assessments including follow-up of any AEs and survival follow-up. At 
the time of study drug discontinuation, the participant will be followed-up for safety and a 
visit will be performed 30 and 90 days after receiving the last dose of sabestomig.  

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Participants discontinuing study treatment due to PD:  
Imaging for disease assessment will stop and participants will enter the safety and survival 
follow-up. 
Participants discontinuing study treatment while in response (PR/CR) or with SD: 
Participants will enter the safety follow-up and will carry on with efficacy assessments by 
imaging until PD, start of a new anti-cHL therapy or EoS, whichever comes first (Table 4 and 
Table 16).  
Note:  
• 
Radiotherapy administered alone after the last dose of sabestomig while a participant is in 
CR, with a consolidation intent will not be considered as a new anti-cHL line of therapy. 
Therefore, the participant should carry on the efficacy follow-up and perform disease 
assessment by imaging as per SoA (Table 16). 
• 
Participant in CR/PR who proceeds to HSCT without any treatment between the last dose 
of sabestomig and the start of the conditioning regimen will be followed-up for disease 
assessment post-transplant as per SoC and data on their disease status will be collected in 
the EDC as part of the survival follow-up. 
 
See the SoA (Table 1, Table 2, Table 3, and Table 4) 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.  
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, 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. 
All participants in Safety or Survival follow-up at the time of final study DCO will be 
contacted by the study site prior to the final study DCO to confirm their survival status and to 
inform participants that this was the last study-related contact, and no further survival data 
will be collected in respect to the study. Sites are requested to document this last contact in the 
source records. 
7.2 
Participant Withdrawal from the Study  
• 
A participant may withdraw from the study at any time at their own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 

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• 
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 a participant agrees 
to modified follow-up options, the participant will not be considered to have withdrawn 
from the study (see Section 7.1). 
• 
At the time of withdrawal from the study, if possible, an EoT visit should be conducted, 
as shown in the SoA. See the SoA (Table 4) for data to be collected at the time of the EoT 
Visit. 
• 
If the participant withdraws consent for disclosure of future information, AstraZeneca 
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 they still agree for 
existing samples to be used in line with the original consent. If they request 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. 
 
7.3 
Lost to Follow-up  
A participant will be considered lost to follow-up if the participant 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, the participant will be considered to 
have withdrawn from the study. 
 
Site personnel, or an independent third-party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants who received any dose of 
study intervention. Public sources may be searched for vital status information. If vital status 
is determined as deceased, this will be documented, and the participant will not be considered 
lost to follow-up. AstraZeneca personnel will not be involved in any attempts to collect vital 
status information. 

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Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A. 
8. 
STUDY ASSESSMENTS AND PROCEDURES  
• 
Study procedures and their timing are summarized in the SoA (Table 1, Table 2, Table 3, 
and Table 4). Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with AstraZeneca immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
AstraZeneca will continue to supply sabestomig in the continued access phase of the 
study (ie, PTAP) if the participant provides consent and while the participant is benefiting 
from the treatment, in the opinion of the investigator and in agreement with the medical 
monitor (see Section 6.9 and Section 8.9 for further details).  
• 
Adherence to the study design requirements, including those specified in the SoA 
(Table 1, Table 2, Table 3, and Table 4), 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. 
− 
Retesting of laboratory values during the screening period is allowed. 
• 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count and imaging assessments) and obtained before signing of the ICF, may be utilized 
for screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA (Table 1, Table 2, 
Table 3, and Table 4). 
 
A total of approximately 110 mL of blood will be required for all screening tests, which will 
be conducted during the 28-day screening period. No more than approximately 300 mL of 
blood will be collected between Days 1 and 21 after the first dose of study intervention within 
any cohort. No more than approximately 100 mL of blood will be drawn on any visit day after 
Cycle 1. The total volume to be collected will depend on the number of doses administered 
and the length of follow-up. 
8.1 
Disease Response Assessment  
Sites will be required to store electronic copies of all scans, and AstraZeneca 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 AstraZeneca 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 AstraZeneca, an 
independent central review of all scans used in disease assessment guidelines for imaging 
collection and storage will be provided in a separate document. 

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Participants will be evaluated by the Investigator for disease response using the Modified 
Lugano and RECIL criteria as secondary endpoints. Additionally, in Part B only, disease 
response will be evaluated by a BICR using Modified Lugano criteria. All participants will be 
followed up to evaluate OS. In the Part A of the study, imaging must be archived and 
transferred to the BICR to allow retrospective disease response assessment in participants 
treated at RP2D.  
Efficacy assessments will be performed until PD/relapse, death, lost to follow-up, start of new 
treatment for cHL or withdrawal of the consent (whichever comes first). For participants 
discontinuing the study intervention due to other causes (eg, due to toxicities), disease 
follow-up will continue as per SoA until PD/relapse or start of new treatment for cHL is 
documented. 
In the event pseudo progression is suspected by imaging, a PET-CT scan should be repeated at 
least 4 weeks after the previous assessment to confirm progression or response (Section 6.7) 
provided that the participants’ clinical condition is stable. However, repeat imaging must be 
performed earlier than the next 12-week assessment where there is clinical suspicion of 
progression. The assessment of “clinically stable” must meet the following criteria: 
• 
Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression. 
• 
No decline in ECOG performance status. 
• 
Absence of rapid progression of disease. 
• 
Absence of progressive tumor at critical anatomical sites (eg, cord compression) requiring 
urgent alternative medical attention. 
 
Radiological response should be integrated with clinical data and pathological findings, where 
available. Regardless of the radiological response, new or worsening of clinical findings 
indicative of lymphoma progression will result in an overall response of PD. 
Unless unequivocally attributed to the disease, whenever possible the presence of a new lesion 
should be confirmed by biopsy. Biopsies at PD/relapse are not mandatory but recommended. 
If clinically indicated, unscheduled assessments can be performed at any time during the 
study. 
8.1.1 
B-symptoms  
B-symptoms are constitutional symptoms defined as any one or more of the following 
disease‑related symptoms or signs: 

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• 
Unintentional weight loss of 10% or more within the previous 6 months, 
• 
Fevers > 100.5°F or 38.0°C for ≥ 2 weeks without other evidence of infection, or 
• 
Night sweats for > 1 month without evidence of infection. 
 
B-symptoms should not be reported as AEs and will be collected when a disease response 
assessment is performed during treatment and as clinically indicated.  
The presence of B-symptoms should not be used in the overall response assessment as per 
Lugano 2014 criteria. In fact, the presence of residual symptoms in the absence of detectable 
disease by imaging does not preclude the designation of complete response.  
8.1.2 
Efficacy Assessment Types  
All efficacy assessments captured at baseline and during the study will include the following 
evaluations: Physical examination and imaging by PET-CT scan (preferred modality). 
Physical Examination 
Lesions detected by physical examination will only be considered measurable if superficial, 
eg, skin nodules, and palpable lymph nodes and spleen. Documentation by color photography 
including ruler is recommended for estimating the size of skin lesions and photographic 
documentation should be submitted to BICR and kept in medical records. Unless 
unequivocally related to lymphoma, new or worsened abnormalities should be reported as AE. 
Radiological Assessments 
Imaging is required for all participants, PET, and contrast CT scans to be performed as 
indicated in the SoA and in Table 16. If the study treatment is discontinued prior to PD, 
participant in response PR or CR (including participant in CR who received radiotherapy with 
consolidation intent) or stable disease will continue to be monitored for efficacy until PD, 
death, start of a new anti-cHL treatment, whichever comes first as per Table 16. If the 
treatment is discontinued prior to Year 1, the timepoints for disease assessment should follow 
approximately those of regular treatment administration.  
Note: participant in CR/PR who proceeds to HSCT without any treatment between the last 
dose of sabestomig and the start of the conditioning regimen will be followed-up for disease 
assessment post-transplant as per SoC and data on their disease status will be collected in the 
EDC as part of the survival follow-up. 
Table 16 
Radiology Scans for Tumor Assessments  
Timepoints 
Radiologic Scans a 
Screening 
Contrast CT 
PET 
During the study b 
 
Contrast CT 
PET 
 
 
Contrast CT 
PET 
CCI
CCI

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Timepoints 
Radiologic Scans a 
 
 
Contrast CT 
PET 
 
Year c 1 
Contrast CT 
PET 
 
Q6M until EoS c 
Contrast CT 
PET 
a 
Disease response should be assessed by PET-CT as per Modified Lugano criteria (2014) until participant achieves CR. 
Once CR is achieved, contrast CT may replace PET-CT until PD is suspected. If PD is suspected, PD must be 
confirmed by PET scan. 
b 
At least 10 days post infusion, but prior to the next infusion. 
c 
Calculated from the time of first dose (± 2 weeks). 
Abbreviations: CT computed tomography; EoS: end of study; PD: progressive disease; PET-CT: positron emission 
tomography-CT. 
 
Imaging modalities selected at baseline should remain consistent during the study; participants 
should have imaging assessments done at the participating study center or an acceptable 
alternate imaging facility using an identical imaging protocol and similar equipment. 
The following options can be used:  
• 
If PET-CT is of diagnostic quality with contrast, a separate CT/MRI with contrast is not 
required.  
• 
If PET-CT is of diagnostic quality BUT without contrast, a separate CT/MRI with 
contrast is preferred but not mandatory.  
• 
If PET-CT is not of diagnostic quality, a separate diagnostic-quality CT should be 
performed per SoC practices. In the event of contrast shortage, if a change in modality 
from CT to MRI is necessary, consider following the participant with MRI at least until 
the shortage is over.  
 
Note: Diagnostic quality CT means that acquisition parameters, such as tube current, voltage, 
and exposure, of CT portion of PET are similar/comparable to a routine abdominal/pelvic CT 
scan done for diagnostic purposes, as per site’s SoC.  
Brain MRI or brain CT with contrast (if possible) will be performed at baseline only if there is 
a prior history of CNS involvement or if there are neurologic signs or symptoms present and 
as clinically indicated during the study.  
• 
CT scans: 
− CT scans should be performed with contiguous cuts in slice thickness of 5 mm or 
less. Spiral CT should be performed using a 5-mm contiguous reconstruction 
algorithm. 
− The CT scans should cover the neck, chest, abdomen, and pelvis and any other 
disease sites as clinically indicated. 
− If the use of CT IV contrast is clinically contraindicated or frequent contrast CT 
scans are not allowed by the local IRB/Ethics Committee, an MRI may be used for 
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imaging assessments. In cases where MRI is desirable, the MRI must be obtained at 
screening and at all subsequent response-evaluations. 
− Disease response should be assessed by PET-CT as per Modified Lugano criteria 
(2014) until participant achieves CR. 
− For all participants who achieve CR, a CT with contrast may replace PET-CT to 
monitor disease response until PD is suspected. If PD suspected, PD must be 
confirmed by PET. 
− If PET and CT scans are performed on the same day, PET must be performed prior to 
contrast-enhanced CT.  
− For participants who require both a CT with contrast and a PET together, a CT 
without contrast is permissible during the Investigator assessed response period (Part 
A only) provided that the institution can provide accurate measurement without 
contrast for the CT portion per the Investigator. 
• 
MRI scans: 
− 
MRI scan is acceptable for measurement of lesions provided that the same 
anatomical plane is used for serial assessments. If possible, the same imaging device 
should be used for serial evaluations. 
• 
PET: 
− 
The PET scans should cover the whole body from base of skull to mid-thigh. The 
visual interpretation of PET scans will be performed using the 5-point scale 
Deauville criteria (Appendix C 2). Target lesions selected at baseline (max 6) must 
meet the measurability criteria and show FDG-avid uptake. Lesions visible on PET 
but not measurable on CT/MRI should be assigned as non-target lesions. Refer to 
Appendix C Lugano for additional details.   
 
8.1.3 
Blinded Independent Central Review Assessment  
For Part B of the study, radiological imaging, including unscheduled disease assessments, will 
be transmitted by the sites to the vendor designated by AstraZeneca for central review by 
BICR. Of note, in Part A, imaging must be archived and transferred to the BICR vendor to 
allow retrospective disease response assessment in participants treated at a potential RP2D. 
All imaging assessments submitted for BICR should have a corresponding local efficacy 
assessment completed in eCRFs. De-identified copies of all radiology results may be 
requested by AstraZeneca. If PET scans are submitted to the BICR vendor, information 
including participant height, weight, administered dose, time between dose administration and 
imaging, and glucose level are required for each time point. Further details will be provided in 
the Imaging BICR charter and imaging acquisition guideline.  
8.1.4 
Patient-reported Outcomes  
For Part B, assessment of patient-reported outcomes (PROs) will be undertaken to examine 
the impact of treatment on symptoms and function, as well as assessment of lymphoma ‘B’ 

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8.1.4.1 
Patient-Reported Outcomes version of the Common Terminology Criteria for 
Adverse Events (PRO-CTCAE)  
PRO-CTCAE is a PRO measurement system developed to evaluate symptomatic toxicity in 
participants on cancer clinical trials. The PRO-CTCAE Item Library includes 124 items 
representing 78 symptomatic toxicities drawn from the CTCAE. PRO-CTCAE items evaluate 
the symptom attributes of frequency, severity, interference, amount, presence/absence. Each 
symptomatic AE is assessed by 1 to 3 attributes. Conditional branching logic is used with 
electronic data capture, thereby reducing respondent burden. The recall period is the past 
7 days and PRO-CTCAE responses are scored from 0 to 4 (or 0/1 for absent/present).  
In this study, 19 symptomatic toxicities are selected based upon anticipated AEs from 
previous preclinical data and regimen-specific information about the anticipated profile of 
symptomatic AEs. Thus, the total number of questions that participants will answer will range 
from 19 (assuming that no branching questions are triggered ie, the participant answers ‘0’ to 
the initial question for each symptom) to 37 items (assuming that all possible branching 
questions are triggered for every symptom posed to the participant).  
8.1.4.2 
Pediatric Patient-Reported Outcomes version of the Common Terminology 
Criteria for Adverse Events (Peds-PRO-CTCAE)  
The pediatric module includes 130 items representing 62 symptomatic toxicities and permits 
self-reporting by children and adolescents ages 7 to 17 years. In this study, 17 symptomatic 
toxicities are selected. Two symptoms included in the adult version are missing from the 
pediatric module and therefore cannot be included in the pediatric tool; these are ‘rash’ and 
‘sweating.’ Thus, the total number of questions that participants will answer will range from 
17 (assuming that no branching questions are triggered, ie, the participant answers ‘0’ to the 
initial question for each symptom) to 42 items (assuming that all possible branching questions 
are triggered for every symptom posed to the participant). 
8.1.4.3 
European Organization for Research and Treatment of Cancer (EORTC) 
Item List (IL)XX  
The EORTC Item Library is an online platform comprising more than 1000 individual items 
from over 70 EORTC questionnaires. As static questionnaires might not always be sufficient 
to meet the demands of quickly evolving treatment modalities, selecting items from EORTC 
Item Library offers new opportunities to leverage existing EORTC items and capture 
additional constructs (eg, symptoms, functioning, and global health status/quality of life) that 
are relevant to a given study.  
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group to assess 
cancer-specific HRQoL, functioning, and symptoms for use in cancer clinical studies. It has 
undergone extensive testing and validation as well as detailed cross-cultural testing and 
validation (Aaronson et al, 1993). The EORTC QLQ-C30 is a 30-item self-administered 
questionnaire designed for all cancer types. Questions are grouped into 5 multi-item functional 

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scales (physical, role, emotional, cognitive, and social), 3 multi-item symptom scales (fatigue, 
pain, and nausea/vomiting), a 2-item global HRQoL (QL2) scale, 5 single items assessing 
additional symptoms commonly reported by patients with cancer (dyspnea, loss of appetite, 
insomnia, constipation, and diarrhea), and 1 item on the financial impact of the disease. All 
but 2 questions have 4-point scales: “Not at All,” “A Little,” “Quite a Bit,” and “Very Much.” 
The QL2 items have 7-point scales with ratings ranging from “Very poor” to “Excellent.” 
Participants answer the QLQ-C30 questions in reference to how they have been over the past 
week. For each of the 15 domains, final scores are transformed such that they range from 0 to 
100, where higher scores indicate better functioning, better HRQoL, or greater level of 
symptoms (Aaronson et al, 1993). 
For adult participants only in this study, EORTC ILXX combines three single items from the 
Item Library to assess night sweats, fevers, and weight loss, plus the two QL2 items assessing 
overall HRQL and overall health.  
8.1.4.4 
  
The PROMIS Physical Function (PF) item bank (
) is an assessment tool that was 
designed using well-specified instrument development protocols with an item bank that allows 
for assessment across a wide range of activities and levels of ability (Cella et al, 2010). 
The 
 – 
 is currently under qualification as an 
indicator of treatment benefit in PF among adults with advanced or metastatic cancer and will 
provide the primary support for the assessment of PF in the current trial. Data from 
 
 will capture participants’ perceived ability to perform specific activities over the 
past days. 
8.1.4.5 
  
The
 was designed to assess physical functioning and 
mobility in a pediatric population (DeWitt et al, 2011). It was developed based on the 
. The measure includes  items asking about functional 
tasks such as standing independently, standing on tiptoes, using stairs etc. All questions use a 
 recall period, are written in the past tense, and have a standard 
 response scale 
from “
” to “
 
8.1.4.6 
Patient Global Impression of Treatment Tolerability  
For adult participants only, the PGI-TT item is included to assess how a participant perceives 
the overall burden of treatment-related side effects of cancer treatment over the past 7 days. 
Participants will be asked to choose the response that best describes the level of burden by the 
side effect of their cancer treatment over the past week. The response options are: “not at all”, 
“a little bit”, “somewhat”, “quite a bit”, and “very much”. This item is included to aid in the 
interpretation of other PRO measures and to evaluate the overall impact of treatment-related 
side effects. 
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8.1.4.7 
  
For adult participants only, the 
 is a 
 questionnaire assessing how a 
participant perceives the overall severity of cancer symptoms over the past 
. The 
response options are: 
”. This item is included to aid 
in the interpretation of other PRO measures and to evaluate the overall impact of treatment on 
the global severity of cancer symptoms. 
8.1.4.8 
  
For adult participants only, the 
 is a single-item questionnaire assessing how a 
participant perceives overall change in health status since the start of study intervention. The 
response options are “
 
”.   
8.1.4.9 
  
The 
 will be used to explore the impact of treatment and disease state on health 
state utility. The 
, developed by the 
, is a generic questionnaire that 
provides a simple descriptive profile of health and a single index value for health status used 
for economic appraisal (EuroQol, 2019). The 
 questionnaire is comprised of  
 that cover  dimensions of health (eg, mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression). Participants assess their health today using the 
, which ranges from 0 (
). The 
 is validated for use by respondents aged 
  
8.1.4.10 
Administration of Patient-Reported Outcome Questionnaires  
PRO will be implemented in Part B once approved and available at the site. Baseline PRO 
questions should be completed after informed consent and before the first dose of the study 
drug. PRO questionnaires that are completed at study sites must be completed prior to 
treatment administration performed at the site and ideally before any discussions of health 
status to avoid biasing the participant’s responses to the questions. As feasible, site staff 
should also ensure PRO questionnaires are completed prior to other study procedures, such as 
collection of laboratory samples, to further minimize bias. Each site must allocate the 
responsibility for the administration of the electronic device and PRO instruments 
(subsequently referred to as “ePRO”) to a specific individual (eg, a research nurse or study 
coordinator) and, if possible, assign a backup person to cover if that individual is absent. A 
web back-up may be available to answer the questionnaires if there are technical problems 
with the device or if preferred by the participant. 
PRO questionnaires that will be self-administered electronically at home by the participants 
will be completed by using an application installed on handheld devices (participant’s own 
device or provisioned device) at the time points indicated in the SoA. The device may either 
belong to the participant (“bring your own device”) or be provisioned for the study by the 
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Sponsor. Participants should complete the ePROs prior to or at the site if the assessment time 
point coincides with a scheduled site visit. Alerts will remind participants when ePRO 
assessments should be completed. Participants should be instructed to bring the device to all 
visits. The amount of time needed to complete questionnaires at each time point will vary 
based on the specific questionnaires being administered. At Cycle 1 Day 1, adult participants 
will need approximately 12 to 17 minutes for questionnaire completion; adolescent 
participants will need approximately 9 to 14 minutes. For subsequent completions, including 
EoT, approximately 8 to 17 minutes will be required for adults to complete questionnaires at 
each timepoint; adolescent participants will require 7 to 15 minutes for subsequent 
completions.  
The below instructions should be followed when collecting PRO data: 
• 
The research nurse or appointed site staff should explain to participants the value and 
relevance of these data, so participants are motivated to comply with questionnaire 
completion.  
• 
Participants should be informed that these questions are being asked to find out, directly 
from them, how they feel. 
• 
The research nurse or appointed site staff must train the participant on how to use the 
ePRO device using the materials and training provided by the ePRO vendor. 
• 
The research nurse or appointed site staff must provide guidance on who to call if there 
are problems with the device when the participant is completing the ePRO at home. 
• 
Participants should be instructed to bring visual aids for reading (eg, glasses or contact 
lenses) to the baseline visit and all subsequent visits. If visual aids are not available at the 
visit, PRO questionnaires may be completed after the visit during the available window.  
• 
It is vital that the ePRO reporting is initiated at Cycle 1 Day 1, as specified in the 
module-specific SoA to capture the effect of study intervention. The ePRO device must 
be charged and fully functional at the beginning of the baseline visit to ensure that the 
PROs can be completed at the start of the visit. 
• 
PRO questionnaires should be completed by the participant in a quiet and private location 
whether completing the questionnaires at home or at a site visit. If completing at a site 
visit, the participant should be given sufficient time to complete the PRO questionnaires 
at their own speed. 
• 
The order in which PRO questionnaires are to be completed will be pre-programmed into 
the ePRO device. Not all PRO questionnaires will be administered at every time point. 
Please refer to the SoA. PRO questionnaires will be completed in the following order: 
PRO-CTCAE/Peds-PRO-CTCAE, PGI-TT, 
 
 
, 
. 
• 
The research nurse or appointed site staff should stress that the information is not 
routinely shared with study staff. Therefore, if the participant has any medical problems, 
they should discuss them with the doctor or research nurse separately from the ePRO 
assessment. 
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• 
The research nurse or appointed site staff must remind participants that there are no right 
or wrong answers and avoid introducing bias by not clarifying items.  
• 
The participant should be instructed not to receive help from relatives, friends, or clinic 
staff when responding to the PRO questionnaires. 
• 
Site staff should not read or complete the PRO questionnaires on behalf of the participant.  
• 
The participant should bring the ePRO device to each site visit so the research nurse or 
appointed site staff can check if there are available PRO questionnaires to be completed 
and that the device is functioning properly. 
• 
All questionnaires must be completed electronically via application on a handheld device 
or via web; paper questionnaires are not allowed in this study. 
• 
If the participant is unable to complete the questionnaire (eg, being blind, illiterate, not 
fluent in the available language), that participant is exempted from completing PRO 
questionnaires but may still participate in the study. If the ePRO system is not ready, the 
participant is exempt from completing the PRO questionnaires during that time only but 
may still participate in the study. When the ePRO system is available, the participant is 
required to complete the PRO questionnaires. If the participant cannot complete the PRO 
questionnaires due to reasons other than being blind, illiterate, not fluent in the available 
language, or the ePRO system is not ready, the Sponsor’s study team must be contacted to 
determine if the participant can be exempted. Participants exempted in this regard should 
be flagged appropriately by the site staff in the source documents and in the designated 
eCRF. 
• 
Site staff must administer questionnaires available in the language that the participant 
speaks and understands. Questions must not be read in an available language and 
translated into another language for the participant. 
• 
Reminders should be provided to participants, as needed to ensure compliance with the 
assessment schedules. 
• 
The research nurse or appointed site staff should monitor compliance since minimizing 
missing data is a key aspect of study success. 
• 
The research nurse or appointed site staff will review the completion status of 
questionnaires throughout the study and during site visits and document the reason(s) why 
a participant could not complete assessments, in the source documents and in the 
designated eCRF. If the site receives an email notification regarding the participant’s 
compliance, appropriate action will be taken (eg, discussion with participant to improve 
compliance, a check-in call from the site to ask the participant if they have any difficulties 
in completing questionnaires on schedule). A solution to enhance/resolve compliance 
should be discussed with the participant. Discussions and compliance review should be 
reflected in source documents. 
 
8.2 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Table 1, Table 2, 
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8.2.1 
Medical History  
A medical and surgical history, including but not limited to, substance usage (eg, smoking and 
alcohol consumption history), comorbid conditions, tumor diagnosis and histology, PD-L1 
status, EBV status, and prior cancer therapies, will be obtained at screening. Based on findings 
from medical history, ongoing current conditions will be given a baseline grade 
(NCI CTCAE v5.0). Increases in severity of pre-existing conditions during the study will be 
considered AEs, with resolution occurring when the grade returns to the baseline grade or 
below. 
8.2.2 
Physical Examinations  
A complete physical examination will be performed at screening and will include assessments 
of the head, eyes, ears, nose, and throat, respiratory, cardiovascular, gastrointestinal, 
urogenital, musculoskeletal, neurological, psychiatric, dermatological, hematologic/lymphatic 
systems, and weight and height. 
An abbreviated symptom-directed physical examination (including weight) will be conducted 
during the intervention and follow up periods. 
Physical examinations will be performed at time points specified in the SoA (Table 1, Table 2, 
Table 3, and Table 4). On dosing days, the physical examination will be conducted prior to 
sabestomig administration.  
8.2.3 
Vital Signs  
Vital signs (body temperature, blood pressure, pulse rate, and respiratory rate) and pulse 
oximetry will be measured at time points specified in the SoA (Table 1, Table 2, Table 3, and 
Table 4). 
In addition, oxygen saturation by pulse oximetry should be obtained at any time if a 
participant has any new or worsening respiratory symptoms. A reading at rest and on exertion 
should be obtained at each time point. The extent of the exertion should be based on the 
judgment of the Investigator but should remain consistent for each participant throughout the 
study. If a participant’s status changes, the Investigator can alter the extent of the exertion 
based on their medical judgment. If a participant shows changes on the pulse oximetry or 
other pulmonary-related signs (eg, hypoxia, fever) or symptoms (eg, dyspnea, cough) 
consistent with the possible pulmonary AE, the participant should be immediately evaluated to 
rule out pulmonary toxicity. 
8.2.4 
Electrocardiograms  
The ECGs will be performed at time points specified in the SoA (Table 1, Table 2, Table 3, 
and Table 4).Whenever ECGs and blood draws (eg, PK/ADA) are scheduled for the same 

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nominal time, the blood draws should occur last. The timing of the ECG should be such that it 
allows the blood draw to occur at the proper nominal time. 
The ECGs will be performed in triplicate (all 3 ECGs to be performed within a 5-minute time 
period, at least 1 minute apart) and the mean value of the triplicate measurement will be 
recorded at the local site as the baseline value. 
All ECG recordings will be made with the participant in a supine position having rested in this 
position for at least 5 minutes before the start of the ECG. 
Digital copies of ECGs may be held centrally by a central ECG provider and stored for 
potential independent analysis during, or at the end of, the study at AstraZeneca’s discretion. 
The central independent review will not replace the local review by the Investigator or other 
medically qualified designee. 
Electronic software will be used to assess the following parameters: pulse rate, QRS, QT, and 
QTcF time intervals. All ECGs must be reviewed by the Principal Investigator or a medically 
qualified designee before the SOI (for time points prior to the SOI) and before the participant 
is permitted to leave the clinic (for post infusion time points). In case of a clinically significant 
ECG abnormality (eg, occurrence of de- or re-polarization disorders, arrhythmic disorders), 
including QTcF of > 500 milliseconds, a minimum of 2 additional 12-lead ECGs should be 
obtained over a brief interval (eg, 30 minutes) to confirm the abnormality based on manual 
over-read by a medically qualified person. Such abnormalities and any obvious changes in 
ECG parameters from baseline will be assessed by the Principal Investigator for clinical 
significance. If clinically significant, the ECG abnormality should be recorded as an AE in the 
eCRF. 
Clinical interpretation and any associated management of participants related to ECG 
abnormalities will be done locally and will be based on interpretation by a medically qualified 
person at the site. 
8.2.5 
Echocardiogram/Multiple-gated Acquisition Scan  
Left ventricular ejection fraction will be measured by ECHO or MUGA scan at screening, 
EoT, and as clinically indicated during the study, eg, if the participant exhibits any symptoms 
indicative of myocarditis (eg, chest pain, dyspnea, palpitations, etc.) or other cardiac AEs 
(Section 1.3). 
8.2.6 
Eastern Cooperative Oncology Group Performance Status  
The ECOG performance status will be assessed at time points specified in the SoA (Table 1, 
Table 2, Table 3, and Table 4) based on the following (Oken et al, 1982): 
0 – Fully active, able to carry on all pre-disease performance without restriction. 

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1 – Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light housework, office work. 
2 – Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 – Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 – Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 – Dead. 
 
8.2.7 
Clinical Safety Laboratory Assessments  
Blood and urine samples for determination of clinical chemistry, hematology, coagulation, 
and urinalysis will be collected at time points specified in the SoA (Table 1, Table 2, Table 3, 
and Table 4). 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF. 
The clinical chemistry, hematology, and urinalysis 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. 
The clinical safety laboratory variables will be measured as described in Table 17 below. 
Table 17 
Clinical Safety Laboratory Variables       
Hematology 
White blood cell count (total and differential); Absolute and differential % 
lymphocyte count; Absolute and differential % monocyte count; Absolute and 
differential % neutrophil count; Absolute and differential % eosinophil count; 
Absolute and differential % basophil count; Red blood cell count; Platelet 
count; Hemoglobin; Hematocrit; Erythrocyte sedimentation rate; Mean 
corpuscular volume; Ferritin. 
Clinical Chemistry 
Sodium; Potassium; Phosphorous; Blood urea nitrogen or urea; Creatinine; 
Creatinine clearance, Glucose; Chloride; Bicarbonate; Magnesium; ALT, 
AST, ALP a; GGT; TBL (direct and indirect); Total protein; Albumin; Lipase; 
Amylase; Uric acid; C-reactive protein; Lactate Dehydrogenase, Creatinine 
phosphokinase; Lipids (triglycerides, cholesterol). 
Glycated hemoglobin 
Glycated hemoglobin. 
Cardiac troponin 
Cardiac Troponin. 
Urinalysis b 
Color; Appearance; specific gravity; pH; Protein; Glucose; Ketones; Blood; 
Bilirubin. 
Pregnancy test c 
Urine hCG or serum β-hCG. 

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Table 17 
Clinical Safety Laboratory Variables       
Hematology 
White blood cell count (total and differential); Absolute and differential % 
lymphocyte count; Absolute and differential % monocyte count; Absolute and 
differential % neutrophil count; Absolute and differential % eosinophil count; 
Absolute and differential % basophil count; Red blood cell count; Platelet 
count; Hemoglobin; Hematocrit; Erythrocyte sedimentation rate; Mean 
corpuscular volume; Ferritin. 
Coagulation parameters 
Prothrombin time; PTT (or activated PTT); international normalized ratio; 
Fibrinogen. Additional testing, including but not limited to, D-dimer, fibrin 
split products, and further evaluation for hypercoagulable condition may be 
considered as needed per clinical assessment. 
Thyroid function tests 
Thyroid function tests: TSH, and free T4 and free T3 if indicated (free T3 and 
T4 only be measured if TSH is abnormal or suspicion of an adverse event 
related to the endocrine system); Anti-thyroid antibodies (anti-thyroid 
peroxidase antibodies, thyrotropin receptor antibodies, and thyroglobulin 
antibodies) measured at screening and as clinically indicated. 
Hepatitis and HIV virology 
Hepatitis A virus immunoglobulin M; HbsAg, hepatitis B core antibody total, 
antibody to HbsAg, quantitative PCR for hepatitis B virus DNA; HCV 
antibody, PCR for HCV RNA; HIV-1 or HIV-2 antibodies. 
Cortisol stimulation test 
(ACTH) 
Cortisol stimulation test, if adrenal insufficiency is suspected. 
a 
Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed concurrently. If TBL is ≥ 2 x ULN, 
indirect bilirubin should be assessed unless previously documented Gilbert’s disease. 
b 
Urinalysis (dipstick acceptable). Urine microscopy (including white blood cells/high power field, red blood cells/high 
power field) is to be assessed if other urinalysis measurements are abnormal or if clinically indicated. 
c 
A urine or serum pregnancy test is acceptable; if urine test is positive or equivocal, then serum β-hCG testing should be 
performed for confirmation. 
Note: In case a participant shows an AST or ALT ≥ 3 x ULN together with TBL ≥ 2 x ULN, refer to Appendix G “Actions 
required in cases of increases in liver biochemistry and evaluation of Hy’s Law,” for further instructions. 
Abbreviations: ACTH: adrenocorticotropic hormone; ALP: alkaline phosphatase; ALT: alanine transaminase; AST: aspartate 
transaminase; GGT: Gamma-glutamyl transpeptidase; HbsAg: hepatitis B surface antigen; hCG: human chorionic 
gonadotropin; HCV: hepatitis C virus; HIV: human immunodeficiency virus; PCR: polymerase chain reaction; PTT: Partial 
Thromboplastin Time; T3: triiodothyronine; T4: thyroxine; TBL: total bilirubin; TSH: thyroid-stimulating hormone; 
ULN: upper limit of normal. 
8.2.8 
Pulmonary Lung Function Tests  
Evaluation of pulmonary lung function will only be required during screening for eligible 
participants with pre-existing obstructive or fibrotic lung conditions. Testing will be done 
locally according to the recommendation of the Official Statement of the European 
Respiratory Society and American Thoracic Society [Miller et al, 2005]. 
Forced Expiratory Volume in the 1st second will be assessed at screening under medical 
supervision from a FVC maneuver. The highest value from 3 technically satisfactory attempts 
will be recorded (irrespective of the curve they come from). The chosen value should not 
exceed the next one by more than 150 mL. If the difference is larger, up to 8 measurements 
will be made and the largest value be reported. The ratio FEV/FVC will be derived from these 
highest values of each parameter. The FEV1 should be greater than 50% of predicted value or 
for FEV/FVC ratio, the fifth percentile LLN. Lung function measurements will be done with 
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All sites will use local equipment and local spirometry lab will be used. 
8.3 
Adverse Events and Serious Adverse Events  
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
The definitions of an AE or SAE can be found in Appendix D. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized 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  
Adverse events will be collected from time of signature of ICF throughout the treatment 
period and including the follow-up period until 90 days after the last dose of study 
intervention. 
Serious AEs will be collected from the time of signing of ICF until the end of the study. 
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 AstraZeneca.  
Adverse event and SAE collection will be performed per specified timelines regardless of 
whether the participant has initiated a new anticancer treatment. See Section 6.9 for reporting 
of AEs and SAEs during PTAP. 
8.3.2 
Follow-up of AEs and SAEs  
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the Investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Adverse Event Variables 
The following variables will be collected for each AE: 
• 
Adverse Event (verbatim), 
• 
The date and time when the AE started and stopped, 
• 
NCI CTCAE v.5.0 grade and grade changes, with the date of change, 

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• 
Whether the AE is serious or not, 
• 
Investigator causality rating against the Investigational product(s) (yes or no), 
• 
Action taken with regard to investigational product(s), 
• 
Adverse Event caused participant’s withdrawal from study (yes or no), and 
• 
Outcome. 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE, 
• 
Date Investigator became aware of SAE, 
• 
Seriousness criteria, 
• 
Date of hospitalization, 
• 
Date of discharge, 
• 
Probable cause of death, 
• 
Date of death, 
• 
Autopsy performed, 
• 
Causality assessment in relation to study procedure(s), and 
• 
Causality assessment to other medication. 
 
8.3.3 
Causality Collection  
The Investigator should assess causal relationship between investigational product 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 investigational product?’ 
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes.’ 
A guide to the interpretation of the causality question is found in Appendix D. 
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 or since 
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. When/if a diagnosis is confirmed, the eCRF should be updated to 
record the diagnosis and remove the associated signs and symptoms. 

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8.3.5 
Adverse Events Based on Examinations and Tests  
The results from the CSP mandated laboratory tests, vital signs, and clinically significant 
abnormalities in ECGs will be summarized in the CSR. 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs, and 
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 investigational product, or are considered to 
be clinically relevant as judged by the Investigator (which may include but is not limited to 
consideration as to whether treatment or non-planned visits were required or other action was 
taken with the study intervention, eg, dose adjustment or 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, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.3.6 
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 characterize and understand them in association with 
the use of a study intervention. 
The AESIs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. The AEs will be assessed by the Investigator for severity, 
relationship to the study intervention, possible etiologies, 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. 
The AESIs for sabestomig include events with a potential inflammatory or immune-mediated 
mechanism and which may require more frequent monitoring and/or interventions such as 
steroids, immunosuppressants and/or hormone replacement therapy. Additionally, IRRs and 

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events of similar presentation are considered AESIs for sabestomig. These AESIs are being 
closely monitored in clinical studies with sabestomig. 
An imAE is an event that is associated with drug exposure, is consistent with an immune-
mediated mechanism of action and has no clear alternate etiology. Serologic, immunologic, 
and histologic (biopsy) data, as appropriate, should be used to support an imAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes of the imAE. 
The imAEs that may be observed with sabestomig (based on the available nonclinical and 
clinical data, review of the cumulative literature, reported toxicities for the same class of 
agents, and biological plausibility) and are considered AESIs for this study include, but are 
not limited to: 
• 
Respiratory disorders: Pneumonitis, ILD 
• 
Gastrointestinal disorders: Diarrhea, colitis, intestinal perforation 
• 
Endocrinopathies: Hyperthyroidism and hypothyroidism (including thyrotoxicosis), 
adrenal insufficiency, diabetes mellitus, pituitary inflammation (hypophysitis), and 
hyperpituitarism and hypopituitarism 
• 
Hepatic disorders: Elevated transaminases and hepatitis 
• 
Renal disorders: Nephritis, nephropathy, elevated serum creatinine, and 
glomerulonephritis/sclerosis 
• 
Cardiac disorders: Myocarditis and pericarditis 
• 
Skin disorders: Rash, pruritus, dermatitis, vitiligo, psoriasis, SJS/TEN, pemphigus, and 
lichen planus 
• 
Other rare imAEs including encephalitis, hemophagocytic lymphohistiocytosis, 
myositis/polymyositis, uveitis, iridiocyclitis, arthritis, Guillain-Barre syndrome, 
myasthenia gravis, vasculitis, hemolytic anemia, aplastic anemia, anemia, and sarcoidosis 
 
Other aEs which are considered to be AESIs with sabestomig include but are not limited to: 
• 
Infusion-related reactions; hypersensitivity including anaphylactic/anaphylactoid and 
other allergic reactions 
• 
Immune complex disease and vasculitis 
• 
Cytokine release syndrome 
 
8.3.7 
Hy’s Law  
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 x ULN together with TBL ≥ 2 x ULN may 
need to be reported as SAEs. Refer to Appendix G for further instruction on cases of increases 
in liver biochemistry, evaluation of HL, and participants with pre-existing liver metastases. 

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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 investigational product is being studied. It may be an increase in 
the severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE. Events, which are unequivocally 
due to disease progression, should not be reported as an AE during the study, unless the 
disease progression worsens in terms of time-course or severity compared to what would 
normally be expected for that participant, or if the Investigator considers that there was a 
causal relationship between treatment with the study medication(s) or protocol 
design/procedures and the disease progression in which case must be reported as an 
SAE/SUSAR, due to the medical significance of the event. 
8.3.9 
Reporting of Serious Adverse Events  
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within one 
calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening aEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within one 
calendar day ie, immediately but no later than 24 hours of when he or she becomes aware of 
it. 
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative. If the EDC system 
is not available, then the Investigator or other study-site staff reports an SAE to the 
appropriate AstraZeneca representative by telephone. The AstraZeneca representative will 
advise the Investigator/study-site staff how to proceed. 
For further guidance on the definition of an SAE, see Appendix D. 
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for the AstraZeneca drug. 

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8.3.10 
Pregnancy  
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
• 
If the pregnancy is discovered before the study participant has received any study 
intervention. 
 
8.3.10.1 
Maternal Exposure  
If a participant becomes pregnant during the course of the study, investigational product 
should be discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product 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) should be followed up and documented even if the 
participant was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within one day, ie, immediately but no 
later than 24 hours of when they become aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
(initial fatal/life-threatening or follow-up fatal/life-threatening) or 5 (other serious initial and 
follow-up) 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. 
The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy. 
8.3.10.2 
Paternal Exposure  
Male participants should refrain from fathering a child or donating sperm during the study and 
for 90 days following the last dose of study intervention. 
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 90 days after the 
last dose of study intervention should, if possible, be followed up and documented in the 

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Pregnancy Report Form. Consent from the partner must be obtained before the Pregnancy 
Report Form is completed. 
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 
coinvolvement of PD, 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 postmortem may be helpful in the assessment of the cause of 
death, and if performed, a copy of the postmortem 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, Drug Abuse and Drug Misuse  
8.3.13.1 
Timelines  
If an event of medication error, drug abuse, or drug misuse occurs in the course of the study, 
then the Investigator or other site personnel informs the appropriate AstraZeneca 
representatives within one calendar day, ie, immediately but no later than 24 hours of when 
they become aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within one (initial fatal/life-threatening or follow-up 

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fatal/life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error, drug abuse, or misuse (see Section 8.3.9) and 
within 30 days for all other events. 
8.3.13.2 
Medication Error  
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant. 
The full definition and examples of medication error can be found in Appendix D 4. 
8.3.13.3 
Drug Abuse  
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix D 4. 
8.3.13.4 
Drug Misuse  
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
The full definition and examples of drug misuse can be found in Appendix D 4. 
8.4 
Reporting of Overdose  
For this study, any dose of study intervention in excess of that specified in this CSP will be 
considered an overdose. 
• 
An overdose with associated aEs is recorded as the AE diagnoses/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 IMP or AstraZeneca NIMP 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 become aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for overdoses associated with an SAE (see Section 8.3.9) and within 
30 days for all other overdoses. 

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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 E. 
Note: In mainland China, all human biological samples will only be collected or analyzed 
after approval by relevant local authorities. For additional details regarding sample and data 
collection/test/disposal in China, please refer to the China specific Human Genetic Resource 
management plan. 
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.  
Samples collected from participants in China will be destroyed or repatriated within one year 
of the CSR. 
• 
The PK 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. 
− 
The PK samples may be disposed of or anonymized by pooling. Additional analyses 
may be conducted on the anonymized, pooled 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 characterization 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. ADA samples collected from participants in China will 
be disposed of within one year of the CSR. 
 
8.5.1 
Pharmacokinetics  
Blood samples will be collected for measurement of serum concentrations of sabestomig at 
time points specified in the SoA (Table 1, Table 2, Table 3, and Table 4). 
Samples may be collected at additional time points during the study if warranted and agreed 
upon between the Investigator and AstraZeneca, 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. 

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Serum samples will be used to analyze the PK of sabestomig. Samples collected for analyses 
of sabestomig 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, labeled, stored, and shipped as detailed in the Laboratory Manual. 
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  
Blood samples for determination of ADA responses in serum to sabestomig will be collected 
at time points specified in the SoA (Table 1, Table 2, Table 3, and Table 4) and will be 
assayed by bioanalytical test sites operated by or on behalf of AstraZeneca, using an 
appropriately validated bioanalytical method. 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 (eg, neutralizing antibodies). Samples will be collected, labeled, stored, and 
shipped as detailed in the Laboratory Manual. 
8.5.3 
Pharmacodynamics  
Blood (including serum and plasma) and tumor samples will be collected at time points 
specified in the SoA (Table 1, Table 2, Table 3, and Table 4) and will be evaluated to 
determine changes in immune and tumor–associated profile following sabestomig treatment 
and characterize pharmacodynamic biomarkers associated with sabestomig clinical outcomes. 
Pharmacodynamic evaluation includes but is not limited to 
 changes and 
 
 between baseline and following treatment. 
8.6 
Human Biological Sample Biomarkers  
8.6.1 
Collection of Mandatory Samples for Biomarker Analysis  
By consenting to participate in the study the participant consents to participate in the 
mandatory research components of the study. 
Samples for biomarker research are required and will be collected from all participants in this 
study at time points specified in the SoA (Table 1, Table 2, Table 3, and Table 4). 
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 and 
 will be evaluated for exploratory protein, RNA and 
DNA biomarkers associated with 
 to assess 
correlations with disease activity, effects of study intervention, clinical outcomes, and toxicity. 
These biomarker measurements will support understanding of the mechanism of action of 
sabestomig and may guide the identification of participants who are most likely to respond to 
sabestomig. 
The following samples are mandatory and will be collected from all participants (unless 
otherwise noted) at time points specified in the SoA (Table 1, Table 2, Table 3, and Table 4): 
• 
Tumor tissue samples, see Table 18 (Section 8.6.2). 
• 
Whole blood for 
). 
• 
Whole blood for 
 
• 
Whole blood for 
 and circulating biomarkers. 
• 
Serum for 
 and 
 
• 
Whole blood for 
. 
 
Note: The above collection of biomarker samples is not applicable in mainland China. 
8.6.2 
Tissue Samples  
8.6.2.1 
Tumor Tissue Samples  
Tumor sample requirements for all participants in this study are described in Table 18. Tumor 
samples are defined as either archival or fresh tumor samples. 
Note: The above collection of tumor tissue samples is not applicable in mainland China. 
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• 
If archival tumor tissue FFPE blocks are not available for sectioning at screening, then 
archival tumor FFPE unstained slides are acceptable if sectioned less than 4 months prior 
to the first dose of study intervention. 
− 
A minimum of 10 unstained slides is required for biomarker determination and an 
additional 5 to 10 unstained slides for exploratory biomarker analysis. 
• 
If archival tumor tissues are greater than 4 months prior to first dose of study intervention, 
then an additional fresh tumor tissues biopsy is required. 
 
Fresh Tumor Tissue Samples 
Fresh tumor tissue biopsies must meet the following criteria to be acceptable samples: 
• 
Only core biopsies or excisional biopsies are acceptable. Samples from fine-needle 
aspiration are not acceptable. 
• 
Part A Dose Escalation cohorts: For participants who undergo tumor biopsies at screening 
and/or on treatment, it is preferred, though not required, that the biopsied lesion be 
distinct from any target lesion used in the Modified Lugano criteria. 
• 
Part B Dose Expansion cohorts: For participants who undergo biopsies at screening 
and/or on treatment, the biopsied lesion must be distinct from any target lesion used in the 
Modified Lugano criteria. 
 
Time points for sample collection are presented in Table 18. For all participants in the study, 
additional fresh tumor biopsies may also be considered if clinically indicated and feasible, eg, 
at disease progression or for mixed responses or pseudo-progression. 
If clinically feasible, at each fresh tumor sample time point, participants will undergo core 
image-guided needle biopsies. Per institutional practice, image-guided fresh core needle tumor 
biopsies (preferably 18 gauge or larger needle) should be preferentially obtained from tumor 
tissues that are safely accessible, as determined by the Investigator. If possible, sample same 
site for pre-treatment and C1D8 biopsies. Sites should confirm adequacy of tumor biopsy 
material at the time of the procedure. 
8.6.2.2 
Non-tumor Tissue Biopsy at Toxicity  
For all participants in the study who undergo non-tumor tissue biopsies (eg, skin, liver, or 
kidney) to evaluate toxicity, involved tissue should be biopsied if clinically indicated and 
feasible and following the participant’s consent. Adjacent uninvolved tissue should also be 
biopsied if the participant consents. 

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Samples will be assessed for predictive and/or pharmacodynamic immune-related biomarkers 
associated with toxicity profile using assays, including but not limited to, IHC, multiplex 
immunofluorescence, RNA expression, and proteomic analyses. Details for fresh non-tumor 
tissue biopsy sample collection, processing, storage, and shipment are provided in the 
Laboratory Manual. 
Note: The above collection of tissue biopsy samples is not applicable in mainland China. 
8.6.3 
Collection of Optional Biomarker Samples  
Collection of optional samples for biomarker research is also part of this study as specified in 
the SoA (Table 1, Table 2, Table 3, and Table 4) and is subject to agreement to optional 
consent. Refer to Section 8.6.2 for additional details for optional tissue samples collected 
during the study. 
Note: The above collection of biomarker samples is not applicable in mainland China. 
8.7 
Optional Genomics Initiative Sample  
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in the SoA (Table 1) and is subject to agreement in the ICF addendum. 
A saliva sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study. 
See Appendix F for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found either in 
the appendices or in the Laboratory Manual. For storage and destruction of genetic samples 
see Appendix F. 
 
Note: Optional Genomics Initiative Samples will not be collected in mainland China. 
8.8 
Health Economics/Medical Resource Utilization and Health 
Economics  
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
8.9 
Assessments for Participants Who Transition to PTAP  
Participants who continue to derive clinical benefit from treatment with sabestomig per 
investigator assessment and are still enrolled at the time of the final DCO, will proceed with 
the continued planned 21-day dosing schedule of sabestomig in the PTAP for this study. 

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AstraZeneca will inform investigators of planned and activated PTAP initiation timelines 
within each country, if available. The participant’s last scheduled dosing visit prior to the final 
study DCO will include collection of samples indicated in the SoA Table 2 in addition to 
planned assessments for the scheduled dosing visit, ensuring no duplicates. See Section 6.9 for 
further details about PTAP. 
9. 
STATISTICAL CONSIDERATIONS  
The statistical analyses will be performed by AstraZeneca or its representatives. A 
comprehensive SAP will be prepared. 
9.1 
Statistical Hypotheses  
There are no planned formal statistical hypotheses to be tested in this study. 
9.2 
Sample Size Determination  
Approximately 180 participants will be treated with sabestomig, with up to 
 participants in 
Part A (Dose Escalation) and 
 participants in Part B (Dose Expansion). Additional 
participants may be enrolled if additional dose levels, expansion cohorts, treatment schedules 
are explored, or participants require replacement for any reason. 
Note: “Enrolled” means a participant’s, or their legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
but are not assigned in the study, are considered “screen failures” unless otherwise specified 
by the protocol. 
Part A Dose Escalation 
The primary objective of this study is to investigate the safety and tolerability and estimate a 
RP2D of sabestomig for further evaluation. Hence the number of participants has been based 
on the desire to obtain adequate tolerability, safety, PK, efficacy, and biological data while 
exposing as few participants as possible to the study intervention and study procedures. 
The number of participants treated during Part A Dose Escalation will depend upon the 
toxicities observed as the study progresses. With participants treated at each ATD dose level 
(single participants each for Cohorts 1 to 4) and a maximum of 
 participants treated at each 
mTPI-2 dose level (with 
 participants each for Cohorts 5, 6, 7, and 8 [optional cohort]), up 
to 
participants may be treated for the 8 planned sabestomig dose levels (4 dose levels for 
ATD and 4 dose levels for mTPI-2). Additional participants may be required if additional dose 
levels or dosing schedules are explored. Given that the mTPI-2 algorithm leads to a dose 
escalation decision if there is no DLT in the first  participants treated in a dose level cohort, 
the actual sample size evaluated may be smaller than 
 participants. 
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Table 21 
Study Populations       
Population/Analysis set 
Description 
Endpoint/Output 
Enrolled 
All participants who sign the Informed Consent Form, 
or whose legally authorized representative a sign the 
Informed Consent Form.  
Disposition 
Full / Safety 
All participants who received any amount of study 
intervention 
Exposure 
Safety  
Baseline and 
demography 
PFS 
OS 
Interim safety 
All participants who received the first dose at least 6 
weeks prior to data cut-off 
Safety at interim 
DLT-evaluable 
Participants enrolled in the dose escalation phase who 
have received sabestomig and completed the DLT 
evaluation period (defined as 28 days after the start of 
study intervention) or who experience any DLT 
DLT 
Response-evaluable 
All dosed participants who had measurable disease at 
baseline 
ORR 
CRR 
BOR 
Duration of response 
Duration of complete 
response 
Interim response-evaluable 
 
All dosed participants who had measurable disease at 
baseline and received first dose at least 10 weeks prior 
to data cut-off 
Efficacy at interim 
PK 
All participants who received at least 1 dose of study 
intervention with at least 1 reportable concentration 
PK concentrations 
PK parameters 
Pharmacodynamics 
All participants who received at least 1 dose of study 
intervention with at least 1 reportable 
pharmacodynamic measurement 
Pharmacodynamic 
endpoints 
Immunogenicity 
All participants who received at least 1 dose of study 
intervention with at least 1 reportable immunogenicity 
measurement 
Immunogenicity 
endpoints 
Exploratory biomarkers 
All participants that participate in the exploratory 
biomarker research 
Biomarker endpoints 
a 
Legally authorized representative will be required to sign a statement of informed consent and informed 
assent from the participant (as appropriate) 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 center. 
Individual PK concentration and parameter data for any participants not included in the PK analysis set or 
excluded from the descriptive summary tables, figures, and/or inferential statistical analyses will be included in 
the listings and flagged with an appropriate footnote. 
DoR is reported for the subset of participants with objective response. 
DoCR is reported for the subset of participants with complete response. 
Abbreviations: BOR: best overall response; CRR: Complete Response Rate; DLT: dose-limiting toxicity; 
DoR: Duration of Response; DoCR: Duration of Complete Response; ORR: Objective Response Rate; 
OS: Overall Survival; PFS: Progression-free Survival; PK: pharmacokinetic(s). 

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9.4 
Statistical Analyses  
The SAP will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the 
most important endpoints including primary and key secondary endpoints. Any deviations 
from this plan will be reported in the CSR. 
9.4.1 
General Considerations  
Analysis will be performed by AstraZeneca or its representatives, including CROs. A 
comprehensive SAP will be developed and will describe the patient populations to be included 
in the analyses, the analyses including any subgroup analyses or sensitivity analyses, and the 
procedures to account for missing, unused, and spurious data. 
Data will be presented by dose level in Part A and cohorts in Part B; no direct statistical 
comparisons will be made between any 2 dose levels or cohorts. For Cohort B1, participants 
treated at the RP2D in Part A will be included. 
Continuous variables will be summarized by the number of observations, mean, standard 
deviation, median, minimum, and maximum. Geometric mean and coefficient of variation 
may be presented as applicable. Categorical variables will be summarized by frequency counts 
and percentages for each category. Unless otherwise stated, percentages will be calculated 
based on the population total, by dose level or cohort and by time point as appropriate. Time 
to event variables will be presented using the Kaplan-Meier methodology including median 
time calculated from the Kaplan-Meier curves.  
An interim analysis will be performed as detailed in Section 9.5. 
The primary analysis for Part B will be conducted at least 3 months after the final enrolled 
participant has received their first dose of sabestomig. 
A final analysis may be performed 6 months after the last participant begins treatment or when 
AstraZeneca stops the study, whichever occurs first. 
SAS® version 9.4 (as a minimum) will be used for analyses presented in CSR. 
Baseline will be considered the last non-missing value obtained prior to the first dose of study 
intervention. Any information taken after first dose of study intervention will be regarded as 
post-baseline information. Detailed rules for deriving baseline values are described in the 
SAP. 
Unless stated otherwise, two-sided cIs will be produced at 95%. 

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As appropriate, time windows will be defined for data summaries presented by visit. Time 
windows are described in the SAP. 
Depending on the extent of any impact, summaries of data relating to participants diagnosed 
with COVID-19, and impact of COVID-19 on study conduct (in particular, missed visits, 
delayed or discontinued study intervention, and other protocol deviations) may be generated. 
Further details will be provided in the SAP. 
9.4.2 
Efficacy Analyses  
The efficacy endpoints of ORR, CRR, DoR and DoCR will be summarized on the 
response-evaluable analysis set. The efficacy endpoints of, PFS, and OS will be summarized 
on the full analysis set. Additional subgroup analysis of efficacy may be performed as 
specified in the SAP. 
9.4.2.1 
Primary Endpoint(s)  
Objective Response Rate 
The ORR is defined as the percentage of participants with a CR or PR, with the denominator 
defined as the number of participants in the response-evaluable analysis set.  
Data obtained until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR, regardless of whether the participant withdraws 
from therapy. Participants who discontinue treatment without a response, receive subsequent 
anti-lymphoma therapy and then respond will not be included as responders in the ORR. 
The ORR will include data of all scans, regardless of whether it was scheduled or not. 
The ORR will be presented by the number and percentage of participants with a response 
(CR/PR) including 95% cIs based on exact binomial proportions. 
Best overall response will also be summarized by n (%) for each category, with no formal 
statistical analysis presented. 
The ORR as assessed by BICR based on Modified Lugano criteria for lymphoma is the 
primary efficacy endpoint in Cohort B1 in Dose Expansion. The ORR is a secondary endpoint 
for Part A Dose Escalation assessed by Investigator based on Modified Lugano criteria and 
RECIL criteria. 
Complete Response Rate 
The CRR is defined as the percentage of participants with a CR, with the denominator defined 
as the number of participants in the response-evaluable analysis set.  

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Data obtained until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of CRR, regardless of whether the participant withdraws 
from therapy. Participants who discontinue treatment without a response, receive subsequent 
anti-lymphoma therapy and then respond will not be included as responders in the CRR. 
The CRR will include data of all scans, regardless of whether it was scheduled or not. 
The CRR will be presented by the number and percentage of participants with CR including 
95% cIs based on exact binomial proportions. 
The CRR as assessed by BICR based on Modified Lugano criteria for lymphoma is the 
primary efficacy endpoint in Cohort B2 in Dose Expansion. The CRR is a secondary endpoint 
for Part A Dose Escalation assessed by Investigator based on Modified Lugano criteria and 
RECIL criteria. 
9.4.2.2 
Secondary Endpoint(s)  
Duration of Response 
The DoR is defined as the time from the date of first documented response, assessed by 
Investigator for Part A and by BICR for Cohorts B1 and B2, using the Modified Lugano 
criteria, until the date of documented progression or death due to any cause (in the absence of 
disease progression). The end of response should coincide with date of progression or death 
from any cause used for the PFS endpoint. The time of the initial response will be defined as 
the latest of the dates contributing towards the first visit that was CR or PR. 
The analysis will include all participants in the response-evaluable analysis set who had a 
response, regardless of whether the participant withdraws from therapy. 
If a participant does not progress following a response, then the DoR will use the PFS 
censoring time. 
Kaplan-Meier plots of DoR will be presented if data permitted. Median DoR, including 95% 
CIs, will also be presented, calculated from the Kaplan-Meier curve. In addition, the number 
of participants still responding at 3, 6, and 12 months after initial response will also be 
presented. Swimmer plots that clearly show the profile of each participant who responds will 
also be produced. 
Duration of Complete Response 
The DoCR is defined as the time from first documented CR, assessed by the Investigator for 
Part A and by BICR for Cohorts B1 and B2, using Modified Lugano criteria, until the date of 
documented relapse/progression or death due to any cause (in the absence of disease 
progression). 

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The analysis will include all participants in the response-evaluable analysis set who had a 
response, regardless of whether the participant withdraws from therapy. 
If a participant does not progress following a response of CR, then the DoCR will use the PFS 
censoring time. 
Kaplan-Meier plots of DoCR will be presented if data permitted. Median DoCR, including 
95% CIs, will also be presented, calculated from the Kaplan-Meier curve. In addition, the 
number of participants still responding at 3, 6, and 12 months after initial response will also be 
presented. Swimmer plots that clearly show the profile of each participant who responds will 
also be produced. 
Progression-free Survival 
PFS is defined as the time from first dose until the earlier of the date of first documented 
disease progression, per Lugano classification as assessed by the Investigator for Part A (by 
BICR for Cohorts B1 and B2), or death (by any cause in the absence of disease progression or 
subsequent anticancer treatment). Participants who have not progressed or died at the time of 
analysis, or have unknown status, will be censored at the time of the latest date of assessment 
from their last evaluable assessment. Additional information and supportive/sensitivity 
analyses will be provided in the SAP. 
The PFS time will always be derived, based on scan/assessment dates, not visit dates. 
Disease assessments/scans contributing toward a particular visit may be performed on 
different dates. The following rules will be applied: 
• 
Date of progression will be determined, based on the earliest of the dates of the 
component that triggered the progression.  
• 
When censoring a participant for PFS, the participant will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
 
Kaplan-Meier plots of PFS will be presented. Summaries of the number and percentage of 
participants experiencing a PFS event, and type of event (progression or death) will be 
provided along with the median PFS, its 95% CI and the proportion of participants who were 
progression free at 3, 6, 12, 18, and 24 months. 
The treatment status at progression of participants at the time of the analysis will be 
summarized. This will include the number and percentage of participants who were on 
treatment at the time progression, the number and percentage of participants who discontinued 
study intervention prior to progression, the number and percentage of participants who have 
not progressed and were on treatment or discontinued treatment. This will also provide a 

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distribution of number days prior to progression for participants who have discontinued 
treatment. 
Overall Survival 
The OS is defined as the time from the start of treatment until death due to any cause 
regardless of whether participant withdraws from treatment or receives another anti-
lymphoma therapy. 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. 
Note: Survival follow-up phone calls will be made in the week following the date of DCO for 
the analysis, if participants are confirmed to be alive or if the death date is after the DCO date 
the participants will be censored at the date of DCO. 
The OS data will be presented similarly to the presentation described for PFS. 
9.4.3 
Safety Analyses  
Safety and tolerability will be assessed in terms of DLTs, AEs/SAEs, imAEs, vital signs, 
clinical chemistry/hematology parameters, and clinically significant abnormalities in ECGs. 
These variables will be collected for all participants where applicable. All safety analyses will 
be performed on the safety analysis set. Additional subgroup analysis of safety may be 
performed, as specified in the SAP. 
9.4.3.1 
Maximum Tolerated Dose Evaluation  
The MTD evaluation will be based on the DLT-evaluable population. After each escalation 
stage is completed, final DLT rates at each dose level will be estimated by isotonic regression 
(Ji et al, 2010). The weighted least squares regression model will assume monotonic 
non-decreasing DLT rates with increasing dose, and use the empirical (observed) DLT rates at 
each dose level as responses and dose level sample sizes as weights, along with the pool 
adjacent violators algorithm to estimate the DLT rate at each dose level using available 
software such as EAST® and R. Given the DLT estimates for each dose level, the MTD will 
be selected from all tried dose levels that have not been previously declared to be unsafe 
(Probability [DLT > 30% data] ≥ 80%) 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 30%. 
In the case of dose levels with estimated toxicity of equal distance (tied dose levels) from the 
target toxicity of 30%, the following approach will be used (Ji et al, 2010): among all tied 
dose levels, the highest dose level with target toxicity ≤ 30% will be selected, unless all tied 
dose levels have estimated toxicity > 30%, in which case the lowest dose level will be 
selected. 
The number and percentage of participants with a DLT will also be presented by dose level. 

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9.4.3.2 
Analysis of Adverse Events  
The MedDRA will be used to code AEs. All AEs will be graded according to the NCI 
CTCAE v5.0. The number of participants in each dose level experiencing each AE will be 
summarized by MedDRA system organ class and preferred term. The number and percentage 
of participants with AEs in different categories (eg, causally related, NCI CTCAE Grade ≥ 3, 
etc.) will be summarized by dose level; events in each category will be further summarized by 
MedDRA system organ class and preferred term. The SAEs and imAEs will be summarized 
separately. 
Any AE occurring before the first dose of study intervention will be included in the data 
listings but not in the summary tables of AEs. The AE 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/severity) during the study 
intervention or safety follow-up periods, ie, from the date of first dose of study intervention up 
to 90 days after the last dose of study intervention. Any AEs in the safety follow-up period 
that occur after a participant has received further therapy for cancer (following discontinuation 
of study intervention) will be flagged in the data listings and will not be defined as 
treatment-emergent. 
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 judgment, 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 blood 
pressure)/clinically significant abnormalities in ECGs will be performed for identification of 
OAEs. Examples of these could be marked hematological and other laboratory abnormalities, 
and certain events that lead to intervention (other than those already classified as serious), 
dose reduction, or significant additional treatment. 
9.4.3.3 
Analysis of Other Safety Data  
All safety data including clinical chemistry, hematology, coagulation, urinalysis, vital signs, 
and clinically significant abnormalities in ECGs will be listed individually by participant and 
appropriately summarized. For all laboratory variables that are included in NCI CTCAE v5.0, 
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. The DLTs will be 
displayed in a listing. 
Duration of exposure will be summarized. 

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Clinical Laboratory Parameters 
Laboratory parameters will be assessed at baseline as well as throughout the study. 
Frequencies of worst observed Grade 0 to 4 toxicity, as defined by NCI CTCAE v5.0, will be 
presented for each laboratory parameter. The analysis will present worst grade observed and 
the rates of participants with Grade 3 or 4 toxicity. Also, laboratory parameters will be 
assessed by presenting tables containing information related to 2-grade (or greater) laboratory 
shifts from baseline as well as descriptively over time. 
Vital Signs 
Descriptive statistics will be provided for the vital signs measurements and changes from 
baseline by scheduled time of evaluation and by treatment part, including the EoT visit as well 
as for the maximum and minimum post-baseline values. 
Electrocardiograms 
The ECG parameters will be assessed at baseline by the Investigator as well as throughout the 
study and an overall ECG evaluation will be recorded. Overall ECG evaluation at baseline and 
throughout the study may be summarized. 
9.4.4 
Other Analyses  
9.4.4.1 
Pharmacokinetics and Pharmacodynamics  
Individual sabestomig concentrations will be tabulated by dose level along with descriptive 
statistics. Relevant descriptive statistics of non-compartmental PK parameters will be 
provided if data allow and may include AUC, Cmax, clearance, and t½ if data allow. If the 
data merit, population PK, PK/pharmacodynamic relationships, and/or exposure 
response/safety analyses will be performed, and details of the analyses will be described in a 
separate document.  
9.4.4.2 
Immunogenicity  
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of participants who develop detectable ADAs to sabestomig. The potential impact 
of ADAs on PK, pharmacodynamics, and safety will be assessed if data allow. Samples 
confirmed positive for ADAs may also be evaluated for neutralizing antibody activity. 
9.4.4.3 
Biomarkers  
Biomarker analysis at baseline and/or on treatment (pharmacodynamics) will be assessed for 
participants in each cohort that may be detailed in the SAP. The relationship of exploratory 
biomarkers to clinical outcomes may be presented. Biomarker exploratory analyses may be 
described in a separate analysis plan and may be reported outside the CSR in a separate report 
as an addendum, or separately in a scientific report or publication. The results of this 

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biomarker assessment may be pooled with biomarker data from other studies with the study 
intervention to generate hypotheses to be tested in future research. 
Antitumor activity will be also evaluated by measuring changes in 
 level and profile 
following administration of sabestomig. 
9.4.4.4 
Patient-Reported Outcomes  
All PRO tolerability-related analyses will use the safety analysis set. PROs will be scored 
according to the relevant scoring manuals. Full detail of PRO endpoint derivation will be 
documented in the SAP along with the analysis methodology.  
The secondary PRO endpoints include the following: 
• Proportion of participants reporting different levels of presence/magnitude/interference 
(as applicable) of diarrhea, rash, and fatigue, over time based on PRO-CTCAE or 
Peds-PRO-CTCAE 
• Proportion of participants reporting different levels of overall side-effect bother over 
time based on the PGI-TT 
• Proportion of participants reporting different levels of quality of life/health over time 
based on the EORTC ILXX QL2 items 
Single items and subscales from the PRO questionnaires and health status measures to be used 
are described in Section 8.1.4. Details of all statistical analyses, including analyses for other 
exploratory PRO endpoints, will be described in full in the SAP. 
9.5 
Interim Analyses  
Efficacy Interim Analyses 
Interim analyses will be performed in a continuous manner for Part B using 
 
 (Lee and Liu, 2008). The prior distribution of the ORR is Beta(1,1). For 
each cohort, interim analyses will begin after approximately 
 participants in each respective 
cohort are included in the interim response-evaluable population (Section 9.3). For Cohort B1, 
participants treated at the RP2D in Part A will be included. 
Following this initial interim analysis, subsequent interim analyses may be performed after 
every 
 additional participants in Cohort B1 and every additional participants in Cohort B2 
get included in the interim response-evaluable population, until all participants are enrolled 
and evaluated. The interim analyses will be conducted to determine futility, where the 
stopping criteria for futility will be based on the interim response-evaluable set. For any 
interim futility analyses, an objective response is defined as either a CR or PR as per the 
CCI
CCI
CCI
CCI
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Modified Lugano criteria (Appendix C), and a complete response is defined as a CR as per the 
Modified Lugano criteria (Appendix C). 
The ORR as assessed by Investigator based on Modified Lugano criteria for lymphoma is the 
interim efficacy endpoint. As appropriate, the ORR as assessed by BICR based on Modified 
Lugano criteria may also be considered. Recruitment will not be paused while the participants 
required for the interim analysis are evaluated. Any decision to stop recruitment in a specific 
cohort will be at the discretion of AstraZeneca and will be based on emerging efficacy, safety, 
and tolerability. 
Further details will be included in the SAP. 
Interim Safety Analyses 
Interim safety analysis will be conducted in Part B after approximately 
 participants have 
received the first dose at least 3 months prior to data-cut off, using the interim safety 
population. The study recruitment may be paused, pending investigation by AstraZeneca in 
discussion with SRC, if at least one of the safety events described in Section 4.5 (Part B Study 
Stopping Criteria) occur.  
For safety stopping purposes, data from both B1 and B2 will be combined. Safety data from 
subjects in Part A who are treated at the RP2D will also be included analysis of data from 
Part B. 
Further details will be included in the SAP. 
9.5.1 
Relapsed or Refractory cHL, Anti-PD-1/PD-L1 Exposed  
The prior distribution of the ORR is Beta (1,1). The Target Value (TV) is set to demonstrate a 
 over the benchmark 
  
At final analysis: 
• 
No-Go criterion is met if the probability that the true ORR exceeds the pre‑specified TV 
of 
 
 
Given the observed data during the continuous monitoring stage, the Bayesian predictive 
probability is calculated as the probability of reaching a No-Go decision should the treatment 
group be enrolled and evaluated to the planned final sample size of 
 Further enrolment 
may be terminated if futility is met at any interim looks, which is defined as a > 95% 
predicted probability of meeting the No-Go criterion upon full enrolment of 
 participants 
given the currently observed data. 
CCI
CCI
CCI
CCI
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
 

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Appendix A Regulatory, Ethical, and Study Oversight Considerations 
A 1 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants. 
• 
AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca. 
• 
The Investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations. 
 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the Investigator to AstraZeneca 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. 
• 
AstraZeneca 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. AstraZeneca will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (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 
requirements and AstraZeneca policy and forwarded to Investigators as necessary. 
− 
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 
• 
An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from AstraZeneca will 
review and then file it along with the [Investigator’s Brochure or state other documents] 
and will notify the IRB/IEC, if appropriate according to local requirements. 

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• 
In the EU, the Sponsor will comply with safety reporting requirements and procedures as 
described in the European Clinical Trials Regulation (EU CTR) No. 536/2014. All 
SUSARs to investigational medicinal product will be reported to the EudraVigilance 
database within the required regulatory timelines. 
 
Regulatory Reporting Requirements for Serious Breaches 
• 
Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met. 
− A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study. 
• 
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it. 
• 
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches. 
− AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If EU 
Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter details 
of serious breaches into the European Medicines Agency (EMA) Clinical Trial 
Information System (CTIS). It is important to note that redacted versions of serious 
breach reports will be available to the public via CTIS. 
• 
The investigator should have a process in place to ensure that: 
− The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach 
− A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca. 
A 2 
Financial Disclosure 
Investigators and sub-Investigators will provide AstraZeneca with sufficient, accurate 
financial information as requested to allow AstraZeneca to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course 
of the study and for one year after completion of the study. 
A 3 
Informed Consent Process 
• 
The Investigator or their representative will explain the nature of the study to the 
participant or their legally authorized representative and answer all questions regarding 
the study. 

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• 
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 below the age of 18 years will be required to provide their 
assent, if required by local regulations, and participants or their legally authorized 
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 center. 
• 
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 authorized 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 
authorized representative. 
 
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The Investigator or authorized 
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 AstraZeneca. Any participant records 
or datasets that are transferred to AstraZeneca 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 their personal study-related data will be used by 
AstraZeneca 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 their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by AstraZeneca, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 
A 5 
Committees Structure 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 

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addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to Investigators. 
A 6 
Dissemination of Clinical Study Data 
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons, as otherwise statistical analysis is not relevant. 
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available. The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted. 
A 7 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on an electronic case report form 
(eCRF) unless transmitted to AstraZeneca 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, including definition of study-critical data items 
and processes (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. 
• 
AstraZeneca or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Monitoring Plan. 
• 
AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
AstraZeneca assumes accountability for actions delegated to other individuals (eg, 
CROs). 
• 
Study monitors will perform ongoing source data verification as per the 
Monitoring Plan(s) to confirm that data entered into the eCRF by authorized 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 

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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 a minimum of 25 years after study completion or 
as required by local regulations or institutional policies, according to the AstraZeneca 
Global Retention and Disposal (GRAD) Schedule. No records may be destroyed during 
the retention period without the written approval of AstraZeneca. No records may be 
transferred to another location or party without written notification to AstraZeneca. 
 
A 8 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• 
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• 
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. 
AstraZeneca designee reserves the right to close the study site, temporarily suspend, or 
permanently terminate the study or any component of the study at any time for any reason at 
the sole discretion of AstraZeneca (see Section 4.5). 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 AstraZeneca or Investigator may include but 
are not limited to: 

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• 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, AstraZeneca’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, AstraZeneca shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. 
The Investigator shall promptly inform the 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. 
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 AstraZeneca 
before submission. This allows AstraZeneca to protect proprietary information and to 
provide comments. 
• 
AstraZeneca will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, AstraZeneca will generally 
support publication of multi-center 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 Contraception Guidance 
B 1 
Definitions 
• 
Women not of childbearing potential are defined as women who are either permanently 
sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are 
post-menopausal. 
• 
Women will be considered post-menopausal if they have been amenorrhoeic for 
12 months prior to the planned date of first dose of study intervention without an 
alternative medical cause. The following age-specific requirements apply: 
− 
Women < 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range. 
− 
Women ≥ 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments. 
• 
A highly effective method of contraception is defined as one that can achieve a failure 
rate of < 1% per year when used consistently and correctly. 
 
B 2 
Contraception Methods 
The highly effective methods of contraception are described in the table below. 
Highly Effective Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system (IUS) a 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner b 
• 
Sexual abstinence c 
Combined (estrogen and progestogen containing 
hormonal contraception) 
• 
Oral (combined pill) 
• 
Injectable 
• 
Transdermal (patch) 
Progestogen-only hormonal contraception associated 
with inhibition of ovulation d 
• 
Injectable 
• 
Implantable 
a 
This is also considered a hormonal method. 
b 
With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate). 
c 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the 
participant. However, periodic or occasional abstinence, the rhythm method, and the withdrawal method are 
not acceptable methods of contraception. 
d 
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action 
(eg, minipill), is not accepted as a highly effective method. In line with the Clinical Trials Facilitation 
Group guidance on the recommendations related to contraception and pregnancy testing in clinical trials, 
oral contraceptives are only highly effective when associated with inhibition of ovulation. 

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Appendix C Response Evaluation Using the Modified Lugano (Cheson et 
al, JCO 2014) and RECIL (Younes et al, Ann Oncol 2017) 
Criteria 
C 1 
Modified Lugano (Cheson et al, 2014) 
The purpose of this document is to provide guidance to the Investigators on the assessment of 
efficacy in Hodgkin and Non-Hodgkin lymphoma studies conducted by AstraZeneca. 
 General definitions  
Tumor lesions will be categorized as follows: 
• 
Baseline: Baseline assessments are those assessments performed as close as possible to 
the start of study treatment. Baseline scans will be used to confirm eligibility based on the 
presence of measurable disease and as reference to assess disease response to study 
treatment. No anti-lymphoma treatment (including palliative RT) should be implemented 
between the baseline scans and the first planned dose.  
• 
Nodal vs Extranodal: a lesion can be categorized as: 
• 
Nodal (a lymph node or a nodal mass), or 
• 
Extranodal (a lesion located in other organs, including liver and bone marrow; 
Tonsils, Waldever’s ring, and spleen are considered nodal tissue). 
 
• 
Measurable Lesions – a measurable lesion is a lesion that can be clearly measured in at 
least two perpendicular dimensions by CT/MRI (longest diameter [LDi] and shortest 
diameter [sDi]). The LDi and SDi will be measured in the transverse plane.  A lesion is 
considered measurable if: 
• 
For nodal lesions: LDi > 1.5 cm, 
• 
For extranodal lesion (eg hepatic, lung nodules): LDi > 1 cm, 
• 
The Ldi and the SDi should be measured on the same slice. 
 
• 
Bulky disease – the presence of a bulky disease is captured by the LDi on CT scan. For 
HL, bulky is defined as a single nodal mass, of 10cm or greater than a third of the 
transthoracic diameter at any level of thoracic vertebrae.  
 
• 
Target Lesions – At baseline, all lesions up to a maximum of 6 measurable nodal or 
extranodal lesions should be identified as target lesions at baseline and followed 
throughout the study. 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 which 
can be measured reproducibly should be selected. Target lesions should be identified from 
different body regions representative of the patient’s overall disease burden and include 
mediastinal and retroperitoneal disease, if involved. A bulky lesion can also be selected as 
target lesion. Target lesions must meet the measurability criteria and show FDG-avid 

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uptake. Lesions visible on PET but not measurable on CT/MRI should be assigned as 
non-target lesions. When selecting the target lesions, consider the following:  
− 
Target lesions should be identified from different body regions representative of the 
participant’s overall disease burden and include mediastinal and retroperitoneal 
disease, if involved.   
− 
A bulky lesion can also be selected as target lesion.   
− 
Target lesions should be selected from those of the largest size that can be measured 
reproducibly.  
− 
In certain anatomical sites (inguinal, axillary, and portocaval), normal lymph nodes 
may exist in a very narrow, elongated form. Clinical judgment should be used when 
selecting these lesions are target lesions.   
− 
Because of the variable anatomical coverage of scans at different timepoints, it is 
preferrable not to select as target lesions nodal lesions located in the higher cervical 
and/or lower inguinal districts.  
For the selected target lesions, the sum of the product of the perpendicular diameters 
(SPD) will be calculated with the percentage change from baseline for assessment of 
response and nadir for assessment of progression.  
 
• 
Non-target Lesions – All other lesions (including nodal, extranodal, and assessable 
disease) not selected as target lesions, as well as truly non-measurable sites of disease 
should be followed as non-measurable disease (eg, Cutaneous, gastrointestinal, bone, 
spleen, liver, kidney, pleural or pericardial effusions, ascites) and should be factored into 
the overall response assessment. Non-target lesions will be documented at baseline and 
throughout the study qualitatively (for example: present, absent/normalized /clear 
progression). Measurement of these lesions is not required to be documented in the eCRF. 
 
• 
Organ Involvement 
− 
Spleen involvement: Spleen will be considered to be normal if size of its vertical 
length (cranial-caudal measurement) is ≤ 13 cm. Spleen vertical length will be 
assessed at screening and all subsequent response-evaluations. Splenic nodules 
should be considered as extra-nodal lesions and treated as target, non-target or new 
lesions are appropriate. 
− 
Liver involvement: Given variability in body habitus and the impact of numerous 
medical conditions, liver size by physical examination or CT scan is not a reliable 
measure of hepatic involvement by lymphoma. For these reasons, liver size will not 
be collected in eCRFs. The presence of a diffuse or focal uptake with or without focal 
or disseminated nodules support liver involvement. Intrahepatic lesions should be 
considered as target, non-target, or new lesion as applicable. 
 
• 
Bone Marrow involvement: Bone marrow involvement by lymphoma documented by 
biopsy and/or aspirate or by PET will be reported on the eCRF as positive, negative or 
unknown.  
 

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• 
Other, skin and soft tissue lesions: Skin lesions histologically proven for lymphoma 
should be preferably selected as Non-target lesions due to variability in measurement on 
skin photography. If skin is the only site of measurable disease, colour photographs 
including a ruler should be submitted to BICR (as applicable) and stored in medical 
records. Measurements should be reported in eCRFs at each disease response assessment 
if these lesions are selected as target lesions. 
 
• 
New Lesions – Lesions which were not present at the baseline, but are visible at a 
subsequent timepoint: 
− 
Nodal lesion of > 1.5 cm in any axis, 
− 
Extranodal lesion of > 1 cm in any axis.  
− 
In case of appearance of a new extranodal lesion ≤ 1 cm, a biopsy confirmation of 
lymphoma is always preferable to rule out a benign origin, unless not feasible 
(lesions too small) or if the procedure is medically contraindicated.  
The appearance of a new lesion, even if all other lesions are decreasing should be 
considered progression.  
 
• 
Staging and Classification  
− 
Stage: Extent of disease should be described at baseline using the Revised Ann Arbor 
classification (Table 2). 
− 
Symptoms: according to the absence (A) or presence (B) of disease related 
symptoms. Only patients with HL need to be assigned the designations A or B 
because symptoms only direct treatment in that disease. 
 

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C 2 
Modified Lugano Response-evaluation Criteria 
(Cheson et al, 2014) 
 

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Deauville 5-point scale: The use of PET/CT is standard for FDG-avid lymphomas and 
whenever aggressive transformation is suspected. Variation in FDG uptake in a nodal or 
extranodal sites indicative for lymphoma will be visually assessed using the Deauville 5-point 
scale. The scale ranges from 1 to 5, where 1 is best and 5 is the worst. Each FDG-avid (or 
previously FDG-avid) lesion is rated independently. 
Deauville 5-point scale 
Score 
Description 
Score 1 
No uptake above background 
Score 2 
Uptake ≤ mediastinum 
Score 3 
Uptake > mediastinum, but ≤ liver 
Score 4 
Uptake moderately > liver a 
Score 5 
Uptake markedly higher than liver and/or new lesion a 
X (New) 
Areas of uptake unlikely to be related to lymphoma b 
a 
Barrington et al (2014) suggest the following: “The terms moderately and markedly were not defined 
initially, because there were insufficient data to define scores quantitatively. Meanwhile, it is suggested 
according to published data that score 4 be applied to uptake greater than the maximum SUV in a large 
region of normal liver and score 5 to uptake 2 × to 3 × greater than the maximum SUV in the liver.” 
b 
Barrington SF, Mikhaeel NG, Kostakoglu L, et al: Role of imaging in the staging and response 
assessment of lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging 
Working Group. J Clin Oncol 32:3048-3058, 2014 
Abbreviation: SUV: standardized uptake value. 
 
It is recognized that in Waldeyer’s ring or extranodal sites with high physiologic uptake or 
with activation within spleen or bone marrow (eg, following chemotherapy or G-CSF 
treatment), the uptake may be greater than normal mediastinum and/or liver. In this 

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circumstance, complete CR may be inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the tissue has high physiologic uptake.  
In presence of new areas of FDG uptake that are unlikely to be related to lymphoma but are 
thought to be of inflammatory or infectious origin by the Investigator, the reporter should 
assign ‘X’ in addition to the Deauville score. For example, if there is a complete resolution of 
all uptake with no abnormal nodes but new lesions likely to be related to another etiology 
occur, the total score should be of DS 1X rather than DS 5. Additionally, these lesions should 
be tracked and should not be used to determine the PET response at subsequent assessments. 
Evaluation of Overall Response 
The possible outcomes for Overall Response Assessment are: CR, PR, SD, PD or Unknown.   
Any clinical, laboratory, histopathologic or cytologic findings accounting for a discrepancy 
between the radiological response and the oncologic overall disease response, should be 
appropriately documented in eCRFs.  
The following tables are intended as general guidance only for Investigators and do not 
cover all possible scenarios. Clinical judgment should be applied.  
The Investigator-assessed Overall Response Assessment and respective date will be captured 
on the eCRF. In presence of an overall response of PD, the overall disease response date is the 
earliest date when PD was documented by any method (eg, bone marrow, CT/MRI or PET 
scan). In presence of an overall response of CR/PR/SD/Unknown, the overall disease response 
date is the latest date when the response was documented/confirmed.  
The table below provides overall responses for all possible combinations of tumor responses 
in target and non-target lesions with or without the appearance of new lesions. 
Evaluation of Overall Response Using the Modified Lugano Criteria 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
No target lesion a  
CR 
No 
CR 
CR 
Not evaluable b 
No 
PR 
CR 
Non-CR/ 
non-PD 
No 
PR 
PR 
Non-PD and not evaluable b 
No 
PR 
Stable disease 
Non-PD and 
not evaluable b 
No 
Stable disease 
Not all evaluated 
Non-PD 
No 
Not evaluable 
No target lesion a 
Not all evaluated 
No 
Not evaluable 
No target lesion a 
Non-CR/ 
non-PD 
No 
Non-CR/ 
non-PD 

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Evaluation of Overall Response Using the Modified Lugano Criteria 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
PD 
Any 
Yes/No 
PD 
Any 
Unequivocal PD 
Yes/No 
PD 
Any 
Any 
Yes 
PD 
No target lesion a 
Unequivocal PD 
Yes/No 
PD 
No target lesion a 
Any 
Yes 
PD 
a 
Defined as no target lesion at baseline. 
b 
Not evaluable is defined as either when no or only a subset of lesion measurements are made at an 
assessment. 
Abbreviation: CR: complete response; PD: progressive disease; PR: partial response. 
Modified Lugano: Response-evaluated Criteria 
 
Integrated Radiological Overall Response   
PET-based 
Overall Response 
CT/MRI-based 
Overall Response 
Radiological 
Overall Response 
CMR  
Any b 
CR  
PMR  
Any b 
PR  
NMR  
Any b 
SD  
UNK a  
CR/PR/SD + prior PET response of CMR (as long as the CT 
response remains stable/improves as compared to the previous 
timepoint when PET was available)  
CR  
UNK a  
CR/PR + prior PET PMR or no PET (as long as the CT response 
remains stable/improves as compared to the previous timepoint 
when PET was available)  
PR  
UNK a  
CR/PR + prior PET NMR   
SD  
UNK a  
Any response except for PD (but has worsened from the previous 
timepoint when PET was available)  
UNK  
UNK a  
UNK  
UNK  
UNK a  
PD  
PD  
PMD  
Any  
PD  
a 
PET not done/not available.  
b 
Depending on the histology of the lymphoma. For lymphomas with variable avidity, CT PD could lead to 
an overall assessment of PD.  
CMR: complete metabolic response; CR: complete response; NMR: no metabolic response; PD: progressive 
disease; PMD: progressive metabolic disease; PR: partial response; SD: stable disease; UNK: unknown.  
 
Overall Response Assessment   
Radiological 
Overall Response  
Bone Marrow  
Aspirate/Biopsy  
Clinical findings (Physical 
Examination/ Lesion Biopsy)  
Overall Response 
Assessment  
CR  
Negative (+ 28 days from 
radiological assessment) or negative 
at baseline   
No evidence of PD  
CR  

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CR  
Positive at baseline and positive (no 
new involvement) + 28 days from 
radiological assessment; or positive 
at the previous timepoint and not 
repeated  
No evidence of PD  
PR  
PR/SD  
Any but new or recurrent 
involvement  
No evidence of PD  
PR/SD  
PD  
Any  
Any  
PD  
Any  
New or recurrent BM involvement   
Any  
PD  
Any  
Any  
New or recurrent lymphoma 
manifestation  
PD  
BM: bone marrow; CR: complete response; PD: progressive disease; PR: partial response; SD: stable disease; 
UNK: unknown.  
 
Additional response assessment guidelines: 
• 
Nodes or Extranodal lesions that split when disease is responding: If a confluent nodal 
mass splits into several discrete nodes, the individual product of the perpendicular 
diameters (PPDs) of the nodes should be summed together to represent the PPD of the 
split lesion; this PPD is added to the sum of the PPDs of the remaining lesions to measure 
response. If subsequent growth of any or all of these discrete nodes occurs, the nadir of 
each individual node is used to determine progression (as if each individual node was 
selected as a target lesion at baseline).  
• 
Nodes or extranodal lesions that become confluent: If a group of target lymph nodes 
becomes confluent, the PPD of the current confluent mass should be compared with the 
sum of the PPDs of the individual nodes, with more than 50% increase in the PPD of the 
confluent mass compared with the sum of individual nodes necessary to indicate 
progressive disease. The LDi and shortest diameter are no longer needed to determine 
progression.  
• 
The presence of residual symptoms in the absence of detectable disease by imaging does 
not preclude the designation CR.   
 
C 3 
International WG Consensus Response evaluation Criteria in 
Lymphoma (Younes et al 2017 [RECIL 2017]) 
The purpose of this document is to provide guidance to the Investigators on the assessment of 
efficacy in Hodgkin and Non-Hodgkin lymphoma studies conducted by AstraZeneca.   
Complete response:  
• 
Complete response is defined as a complete resolution of all target lesions by CT scans 
with complete normalization of FDG-PET uptake in all areas (Deauville score of 1–3), 
and bone marrow biopsy negativity (if it was positive or unknown at baseline). If 
pre-treatment PET scan was negative, lymph nodes that measured ≥ 15mm in the long 
axis should regress to < 10 mm. CR is also defined as achievement of a partial remission 

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by CT scan criteria (reduction in sum of longest diameters by CT imaging by > 30%) with 
normalization (Deauville score 1–3) of FDG-PET activity in FDG-avid lymphoma. 
However, because targeted agents may alter glucose uptake and/or metabolism, 
normalizing of FDG-PET imaging alone is not sufficient by itself to determine CR status 
unless accompanied with a significant (> 30%) decrease in the sum of diameters. 
Accordingly, a reduction in the sum of diameters by ≤ 30% with normalization of 
FDG-PET uptake should not be considered a CR unless documented by a negative tissue 
biopsy. 
 
Partial response:  
• 
Partial response is defined as a reduction of the sum of longest diameters of target lesions 
by ≥ 30%. 
 
Minor response:  
• 
This is a provisional category. Minor response is defined as a reduction in the SLD of 
target lesions by ≥ 10% but < 30%, without the appearance of any new lesions, and 
irrespective of PET scan results. 
 
Stable disease:  
• 
Stable disease is defined as changes in the SLD of targeted lesions ranging between 
reduction of < 10% to an increase by ≤ 20% without the appearance of a new lesion, and 
irrespective of PET results. 
 
Progressive disease:  
• 
Progressive disease is defined as an increase in the SLD of target lesions by > 20%, 
and/or appearance of a new lesion (≥ 10mmof the longest diameter) irrespective of 
FDG-PET results. In case of small FDG-PET avid lesions, a biopsy is recommended 
whenever possible. PD per RECIL is based on imaging findings only. 

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Table 1: RECIL 2017 Response categories based on assessment of target lesions 
 
 
 
 

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Key Differences Between RECIL 2017 and Lugano 2014  
Parameter 
Lugano 2014 
RECIL 2017 
Number of target lesions  
Max. 6  
Max. 3  
Measurement method  
Bi-dimensional: perpendicular  
Diameters (LDi, SDi)  
Uni-dimensional:   
LDi  
Extranodal lesion 
measurability criteria   
LDi ≥ 10 mm  
LDi ≥ 15 mm  
Spleen assessment 
integration in the Overall 
Response  
Present  
Absent  
Complete Response  
Regression of all nodal masses to LDi 
≤ 15 mm.  
No extralymphatic sites of disease  
Regression of all target lesions and all 
nodes with LDi < 10 mm.  
Minor Response  
No  
Yes, reduction in sum of long diameters  
between ≥ 10% and < 30%  
Stable Disease  
- 50% to + 50%  
decrease < 10% to increase ≤ 20%  
Progressive Disease  
Increase in the sum of products of 
perpendicular diameters by > 50%, or any 
single lesion by > 50%  
Increase in sum of the longest diameters 
by 20%. For relapse from CR, at least 
one lesion should measure 2 cm in the 
long axis with or without PET activity  
Abbreviations: CR: complete response; LDi: long diameter of any target lesion; Max: maximum; PET: positron 
emission tomography; SDi: short diameter of any target lesion.  
 
 

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Appendix D Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
D 1 
Definition of Adverse Events 
An adverse event (AE) is the development of any untoward medical occurrence in a patient or 
clinical study participant administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable 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. Note: B-Symptoms (Section 8.1.1) will not be 
reported as AEs.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered. 
D 2 
Definitions of Serious Adverse Event 
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-participant hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity.  
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above. 
 
Adverse Events for malignant tumors 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 judgment on an individual event basis 
should be applied to clarify that the malignant tumor event should be assessed and reported as 
a non-serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, 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 tumor event in question is a new 
malignant tumor (ie, it is not the tumor for which entry into the study is a criterion and that is 
being treated by the investigational product under study and is not the development of new or 
progression of existing metastasis to the tumor under study). Malignant tumors that – as part 
of normal, if rare, progression – undergo transformation (eg, Richter’s transformation of 
B cell chronic lymphocytic leukemia into diffuse large B cell lymphoma) should not be 
considered a new malignant tumor. 
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). 
Hospitalization 
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 judgment 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, hospitalization, disability or incapacity but may jeopardize 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 
judgment must be used. 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment. 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine. 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm. 
• 
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization. 
• 
Development of drug dependency or drug abuse. 
 

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Intensity Rating Scale: 
• 
Mild (awareness of sign or symptom, but easily tolerated), 
• 
Moderate (discomfort sufficient to cause interference with normal activities), 
• 
Severe (incapacitating, with inability to perform normal activities). 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix D 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix D 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix D 2. 
The grading scales found in the revised National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized 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). 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL)#. 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL##. 
• 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 Death related to AE. 
 
A semicolon indicates ‘or’ within the description of the grade. 
# 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
## 
Self-care ADL refer to bathing, dressing, and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 

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D 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 recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed 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. 

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D 4 
Medication Error, Drug Abuse, and Drug Misuse 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP 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 participant received the drug 
• 
Did not occur, but circumstances were recognized 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, eg, wrong route or wrong site of administration 
• 
Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet 
• 
Drug not stored as instructed, eg, kept in the fridge when it should be at room temperature 
• 
Wrong participant received the medication (excluding Interactive Response 
Technology/Randomization and Trial Supply Management [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 
• 
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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Drug Abuse 
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect. 
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded 
to the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used 
both if the drug abuse happened in a study participant or if the drug abuse involves a person 
not enrolled in the study (such as a relative of the study participant). 
Examples of drug abuse include but are not limited to: 
• 
The drug is used with the intent of getting a perceived reward (by the study participant or 
a person not enrolled in the study) 
• 
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high  
 
Drug Misuse 
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant). 
Examples of drug misuse include but are not limited to: 
• 
The drug is used with the intention to cause an effect in another person 
• 
The drug is sold to other people for recreational purposes  
• 
The drug is used to facilitate assault in another person 
• 
The drug is deliberately administered by the wrong route 
• 
The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole 
• 
Only half the dose is taken because the study participant feels that he/she is feeling better 
when not taking the whole dose 
• 
Someone who is not enrolled in the study intentionally takes the drug 
 

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Appendix E Handling of Human Biological Samples 
E 1 
Chain of Custody 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples while at site. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal. 
AstraZeneca or delegated representatives will keep oversight of the entire lifecycle 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 lifecycle. 
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. 
E 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 
analyzed, 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. 
E 3 
International Airline Transportation Association 6.2 Guidance 
Document 
LABELING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  
Category A pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900: 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name 
• 
UN 3373 – Biological Substance, Category B are to be packed in accordance with 
UN 3373 and IATA 650. 
 
Exempt – Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these regulations unless they 
meet the criteria for inclusion in another class. 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations. 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf). 
• 
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry ice content. 
 

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Appendix F Optional Genomics Initiative Sample 
F 1 
Use/Analysis of DNA 
• 
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments, or medications. Therefore, where local regulations and 
Institutional Review Board/Independent Ethics committee allow, a saliva sample will be 
collected for DNA analysis from consenting participants. 
• 
This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome. 
• 
The results of genetic analyses may be reported in a separate study summary. 
• 
AstraZeneca will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
 
F 2 
Genetic Research Plan and Procedures 
Selection of Genetic Research Population 
• 
All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study. 
 
Inclusion Criteria 
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol (CSP) and: Provide informed 
consent for the Genomics Initiative sampling and analyses. 
Exclusion Criteria 
• 
Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following: 
− 
Previous allogeneic bone marrow transplant.  
− 
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection. 
 
Withdrawal of Consent for Genetic Research 
• 
Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 
withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
Section 7.2 of the main CSP. 
 

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Collection of Samples for Genetic Research 
• 
The saliva sample for this genetic research will be obtained from the participants at 
screening. Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding participants who may withdraw due to an adverse 
event (AE). If for any reason the sample is not drawn at screening, it may be taken at any 
visit until the last study visit. Only one sample should be collected per participant for 
genetics during the study. 
 
Coding and Storage of DNA Samples 
• 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years, from the date of last participant last visit, after which they will be destroyed. 
DNA is a finite resource that is used up during analyses. Samples will be stored and used 
until no further analyses are possible or the maximum storage time has been reached. 
• 
An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organization. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organizations working with the DNA). 
• 
The link between the participant enrolment organization code and the second number will 
be maintained and stored in a secure environment, with restricted access at AstraZeneca 
or designated organizations. The link will be used to identify the relevant DNA samples 
for analysis, facilitate correlation of genotypic results with clinical data, allow regulatory 
audit, and permit tracing of samples for destruction in the case of withdrawal of consent. 
 
Ethical and Regulatory Requirements 
• The principles for ethical and regulatory requirements for the study, including this 
genetics research component, are outlined in Appendix A. 
 
Informed Consent 
• 
The genetic component of this study is optional and the participant may participate in 
other components of the main study without participating in this genetic component. To 
participate in the genetic component of the study the participant must sign and date both 
the consent form for the main study and the addendum for the Genomics Initiative 
component of the study. Copies of both signed and dated consent forms must be given to 
the participant and the original filed at the study center. The Principal Investigator(s) is 
responsible for ensuring that consent is given freely and that the participant understands 
that they may freely withdrawal from the genetic aspect of the study at any time. 
 

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

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Appendix G Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law 
G 1 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.  
Specific guidance on managing liver abnormalities can be found in Section 6.6.8 and 
Appendix I. 
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 central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated alanine aminotransferase (ALT) from a central laboratory 
and/or elevated total bilirubin (TBL) from a local laboratory. 
The Investigator will also review adverse event (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. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than Drug-Induced Liver Injury (DILI) caused by the Investigational Medicinal Product 
(IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting serious adverse events (SAEs) and AEs according to the outcome of the review and 
assessment in line with standard safety reporting processes. 
G 2 
Definitions 
Potential Hy’s Law 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3 x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2 x ULN at any point during the study 
following the start of study intervention irrespective of an increase in Alkaline Phosphatase 
(ALP).  

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Hy’s Law 
AST or ALT ≥ 3 x ULN together with TBL ≥ 2 x ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
G 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 x ULN 
• 
AST ≥ 3 x ULN 
• 
TBL ≥ 2 x ULN 
 
Central Laboratories Being Used: 
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the Investigator (also sent to 
AstraZeneca representative). 
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the Investigator will: 
• 
Notify the AstraZeneca. 
• 
Request a repeat of the test (new blood draw) by the central laboratory without delay. 
• 
Complete the appropriate unscheduled laboratory eCRF module(s) with the original local 
laboratory test result. 
 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay: 
• 
Determine whether the participant meets PHL criteria (see Section G 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results). 
 

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Local Laboratories Being Used: 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Notify the AstraZeneca representative. 
• 
Determine whether the participant meets PHL criteria (see Section G 2 for definition) by 
reviewing laboratory reports from all previous visits. 
• 
Promptly enter the laboratory data into the laboratory eCRF. 
 
G 4 
Follow-up 
G 4.1 
Potential Hy’s Law Criteria Not Met 
If the participant does not meet PHL criteria the Investigator will: 
• 
Inform the AstraZeneca representative that the participant has not met PHL criteria. 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
 
G 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 
intervention (see Section G 6). 
• 
Notify the AstraZeneca representative who will then inform the central Study Team. 
• 
Within one day of PHL criteria being met, the Investigator will report the case as an 
SAE of Potential Hy’s Law; serious criteria ‘Important medical event’ and causality 
assessment ‘yes/related’ according to CSP process for SAE reporting. 
• 
For participants who 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 etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. If central laboratories are used, this includes 
deciding which tests available in the HL laboratory kit should be used. 

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− 
Complete the 3 Liver eCRF Modules as information becomes available. 
 
#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. 
G 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. 
• 
If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AstraZeneca standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
• 
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  
− 
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply.  
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
 

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If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made: 
• 
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting. 
• 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 
 
G 6 
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Intervention 
This section is applicable to participants with liver infiltration/involvement who meet PHL 
criteria on study intervention, having previously met PHL criteria at a study visit prior to 
starting study intervention. 
At the first on study intervention occurrence of PHL criteria being met the Investigator will 
determine if there has been a significant change in the participants’ condition# compared with 
the last visit where PHL criteria were met#  
• 
If there is no significant change no action is required. 
• 
If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Section G 4.2. 
 
#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. 
G 7 
Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a participant meets PHL criteria on study intervention and has 
already met PHL criteria at a previous on study intervention visit (see Section G 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.  

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The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
• 
Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study, eg, chronic or progressing malignant disease, severe infection, 
or liver disease or did the participant meet PHL criteria prior to starting study intervention 
and at their first on study intervention visit as described in Section G 6 of this Appendix. 
 
If No: follow the process described in Section G 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 G 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 total bilirubin) in isolation 
or in combination, or a clinically relevant change in associated symptoms. The determination 
of whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty. 

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G 8 
Laboratory Tests 
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended. When using a central laboratory, all recommended tests will be completed. 
When using a local laboratory, the list may be modified based on clinical judgment. 
Hy’s Law Laboratory Kit for Central Laboratories  
Additional standard chemistry and coagulation tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV 
HbsAg 
IgM and IgG anti-HBc 
HBV DNA a 
IgG anti-HCV 
HCV RNA b 
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM & IgG anti-CMV 
IgM & IgG anti-HSV 
IgM & IgG anti-Epstein-Barr virus 
Alcoholic hepatitis 
Carbohydrate deficient transferrin (CD-transferrin)c 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab (Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin c 
Transferrin saturation 
a 
HBV DNA is only recommended when IgG anti-HBc is positive 
b 
HCV RNA is only recommended when IgG anti-HCV is positive or inconclusive  
c 
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly 
CMV: cytomegalovirus; GGT: gamma-glutamyl transferase; HAV: hepatitis A virus; HBc: hepatitis B core 
antigen; HbsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HEV: hepatitis E 
virus; HSV: herpes simplex virus; IgG: immunoglobulin G; IgM: immunoglobulin M; INR: international 
normalized ratio; LDH: lactate dehydrogenase. 
 

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G 9 
References 
(Aithal et al 2011, FDA 2009) 
Aithal et al, 2011A ithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815. 

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Appendix H Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis 
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from AstraZeneca. 
H 1 
Reconsent of Study Participants During Study Interruptions  
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on-site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Consent for the alternative 
means of carrying our visits and assessments will be obtained at study entry. 
H 2 
Rescreening of Participants to Reconfirm Study Eligibility 
Rescreening for screen failure due to study disruption can be performed in previously 
screened participants; refer to Section 5.4. The Investigator should confirm this with the 
designated Study Physician. 
H 3 
Telemedicine Visit to Replace On-site Visit (Where Applicable) 
In this appendix, the term telemedicine visit refers to remote contact with the participants 
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices. 
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow adverse events and concomitant medications to be reported 
and documented. 
H 4 
Data Capture During Telemedicine or Home/Remote Visits 
Data collected during telemedicine or home/remote visits will be captured by the qualified 
healthcare professional from the study site or third-party vendor service in the source 
documents, or by the participant themselves. 

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H 5 
Schedule of Activities 
For further details on the Schedule of Activities, refer to Section 1.3. 

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Appendix I 
Dosing Modification and Toxicity Management Guidelines 
for Sabestomig Monotherapy 
Version 24 March 2022 
The Toxicity Management Guidelines (TMGs) have been developed to assist Investigators 
with the recognition and management of toxicities associated with use of sabestomig in 
monotherapy and in combination with other anticancer drugs (ie, antineoplastic 
chemotherapy, targeted agents) which are administered concurrently or sequentially as part of 
a protocol-specific treatment regimen. The TMGs provide information for the management of 
immune-mediated reactions, infusion-related reactions, and non-immune-mediated reactions 
that may be observed with monotherapy or combination checkpoint inhibitor regimens, with 
specific instructions for checkpoint inhibitor-specific treatment modifications (including 
discontinuation) and treatment interventions. Investigators are advised however to use local 
practice guidelines and consult local references, incl. the product labels for the management of 
toxicities observed with other anticancer treatment. 
Toxicity management for immune-mediated, infusion-related, and non-immune–mediated 
reactions associated with the use of sabestomig in monotherapy and in combination with other 
anticancer drugs (ie, antineoplastic chemotherapy, targeted agents) administered concurrently 
or sequentially – should therefore be performed in accordance with this Annex to Protocol, 
which for the purposes of submission and approval of substantial updates is maintained as a 
standalone document. The TMG updates are iterated by date and should be used in accordance 
with the CTCAE version specified in the Clinical Study Protocol (CSP). 
Although the TMG versioning is independent of the CSP, the TMG Annex to the CSP should 
be read in conjunction with the CSP, where if applicable additional references for the 
management of toxicities observed with other anticancer treatment are included in the specific 
section of the CSP. 

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Dosing Modification and Toxicity Management Guidelines (TMGs) for Sabestomig  
General Considerations Regarding Immune-Mediated Reactions 
These guidelines are provided as a recommendation to support Investigators in the management of potential imAEs. 
 
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible immune-mediated reactions. Investigators are 
advised to take into consideration the appropriate practice guidelines and other society guidelines (eg, NCCN, ESMO) in the management of these events. Refer to the 
section of the table titled “Other -Immune-Mediated Reactions” for general guidance on imAEs not noted in the “Specific Immune-Mediated Reactions” section. 
Early identification and management of imAEs are essential to ensure safe use of the study intervention. Monitor patients closely for symptoms and signs that may be 
clinical manifestations of underlying imAEs. Patients with suspected imAEs should be thoroughly evaluated to rule out any alternative etiologies (eg, disease progression, 
concomitant medications, infections). In the absence of a clear alternative etiology, all such events should be managed as if they were immune-mediated. Institute medical 
management promptly, including specialty consultation as appropriate. In general, withhold investigational drug(s) for severe (Grade 3) imAEs. Permanently discontinue 
investigational drug(s) for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs that require systemic immunosuppressive treatment, or an inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.  
 
Based on the severity of the imAE, treatment with sabestomig should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid should 
be tapered over ≥ 28 days. More potent immunosuppressive agents such as TNF inhibitors (eg, infliximab) should be considered for events not responding to systemic 
steroids. Alternative immunosuppressive agents not listed in this guideline may be considered at the discretion of the Investigator based on clinical practice and relevant 
guidelines. With long-term steroid and other immunosuppressive use, consider need for Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis carinii 
pneumonia) prophylaxis, gastrointestinal protection, and glucose monitoring. 
 
 
AE: Adverse event; ESMO: European Society for Medical Oncology; imAE: immune-mediated adverse event; NCCN: National Comprehensive Cancer Network; TNF: tumor 
necrosis factor. 
 
 
 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event  
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial Lung 
Disease (ILD) 
Any Grade 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity) 
General Guidance 
For Any Grade 
− 
Monitor patients for signs and symptoms of 
pneumonitis or ILD (new onset or worsening 
shortness of breath or cough). Evaluate patients with 
imaging and pulmonary function tests, including other 
diagnostic procedures as described below. 
− 
Suspected pneumonitis should be confirmed with 
radiographic imaging and other infectious and 
disease-related aetiologies excluded and managed as 
described below. 
− 
Initial work-up may include clinical evaluation, 
monitoring of oxygenation via pulse oximetry (resting 
and exertion), laboratory work-up, and 
high-resolution CT scan. 
− 
Consider Pulmonary and Infectious Diseases consults. 
− 
For diagnosis of pneumonitis/ILD follow local 
clinical guidance in consultation with pulmonologist. 
Grade 1 
 
No dose modifications required. 
However, consider holding 
investigational drug(s) as clinically 
appropriate and during diagnostic 
work-up for other etiologies. 
For Grade 1  
− 
Monitor and closely follow up in 2 to 4 days for 
clinical symptoms, pulse oximetry (resting and 
exertion), and laboratory work-up, and then as 
clinically indicated. 
Grade 2 
 
Hold investigational drug(s) until 
Grade 2 resolution to Grade ≤ 1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade 
≤ 1, then the decision to 
reinitiate investigational drug(s) 
will be based upon treating 
physician’s clinical judgment 
For Grade 2 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (eg, prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
− 
Reimage as clinically indicated, consider chest CT 
with contrast and repeat in 3 to 4 weeks. 
− 
If no improvement within 2 to 3 days, additional 
workup should be considered and prompt treatment 
with IV methylprednisolone 2 to 4 mg/kg/day started. 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event  
Dose Modifications 
Toxicity Management 
and after completion of steroid 
taper. 
− 
If no improvement within 2 to 3 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly 
start immunosuppressive therapy such as TNF 
inhibitors (eg, infliximab at 5 mg/kg IV once, may be 
repeated at 2 and 6 weeks after initial dose at the 
discretion of the treating provider). Caution: It is 
important to rule out sepsis and refer to infliximab 
label for general guidance before using infliximab. 
Consider, as necessary, discussing with study 
physician. 
Grade 3 or 4 
 
 
Permanently discontinue 
investigational drug(s). 
For Grade 3 or 4 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain Pulmonary and Infectious Diseases Consults; 
consider discussing with study physician, as needed. 
− 
Hospitalize the patient. 
− 
Supportive care (eg, oxygen). 
− 
If no improvement within 2 to 3 days, additional 
workup should be considered and prompt treatment 
with additional immunosuppressive therapy such as 
TNF inhibitors (eg, infliximab at 5 mg/kg IV, may be 
repeated at 2 and 6 weeks after initial dose at the 
discretion of the treating provider). Caution: rule out 
sepsis and refer to infliximab label for general 
guidance before using infliximab. 
Diarrhea/Colitis 
 
 
 
Any Grade 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity) 
General Guidance 
For Any Grade 
− 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or 
changes in bowel habits such as increased frequency 
over baseline or blood in stool) or related to bowel 
perforation (such as sepsis, peritoneal signs, and 
ileus). 
− 
WHEN SYMPTOMS OR EVALUATION 
INDICATE AN INTESTINAL PERFORATION 
IS SUSPECTED, CONSULT A SURGEON 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event  
Dose Modifications 
Toxicity Management 
EXPERIENCED IN ABDOMINAL SURGERY 
IMMEDIATELY WITHOUT ANY DELAY.  
− 
PERMANENTLY DISCONTINUE STUDY 
INTERVENTION FOR ANY GRADE OF 
INTESTINAL PERFORATION. 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (eg, disease progression, 
other medications, or infections), including testing for 
Clostridium difficile toxin, etc. 
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in 
order to prevent potential progression to higher grade 
events, including intestinal perforation.  
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
 
No dose modifications. 
For Grade 1 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, 
American Dietetic Association colitis diet), 
loperamide, and other supportive care measures.  
− 
If symptoms persist, consider checking lactoferrin; if 
positive, treat as Grade 2 below. If negative and no 
infection, continue Grade 1 management. 
Grade 2 
 
Hold investigational drug(s) until 
resolution to Grade ≤ 1 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade 
≤ 1, then investigational drug(s) 
can be resumed after 
completion of steroid taper. 
For Grade 2 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, 
American Dietetic Association colitis diet), and 
loperamide and/or budesonide. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 2 to 3 days or 
worsens despite prednisone at 1 to 2 mg/kg/day PO or 
IV equivalent, consult a GI specialist for 
consideration of further workup, such as imaging 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event  
Dose Modifications 
Toxicity Management 
and/or colonoscopy, to confirm colitis and rule out 
perforation. 
− 
If still no improvement within 2 to 3 days despite 1 to 
2 mg/kg IV methylprednisolone, promptly start 
immunosuppressants such as infliximab at 5 mg/kg 
IV, may be repeated at 2 and 6 weeks after initial dose 
at the discretion of the treating provider. a Caution: it 
is important to rule out bowel perforation and refer to 
infliximab label for general guidance before using 
infliximab. 
− 
Consider, as necessary, discussing with study 
physician if no resolution to Grade ≤1 in 3 to 4 days. 
Grade 3 or 4 
 
 
Grade 3 
• 
Hold investigational 
drug(s) until resolution to 
Grade ≤ 1; investigational 
drug(s) can be resumed 
after completion of steroid 
taper. Permanently 
discontinue 
investigational drug(s) for 
Grade 3 if toxicity does 
not improve to Grade ≤ 1 
within 14 days. 
• 
Permanently discontinue 
investigational drug(s) for 
any grade of intestinal 
perforation in any patient 
treated with study 
intervention. 
For Grade 3 or 4 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain 
hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 2 days, continue 
steroids and promptly add further 
immunosuppressants (eg, infliximab at 5 mg/kg IV, 
may be repeated at 2 and 6 weeks after initial dose at 
the discretion of the treating provider). Caution: 
Ensure GI consult to rule out bowel perforation and 
refer to infliximab label for general guidance before 
using infliximab.  
− 
If perforation is suspected, consult a surgeon 
experienced in abdominal surgery immediately 
without any delay. 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event  
Dose Modifications 
Toxicity Management 
• 
Permanently discontinue 
investigational drug(s) for 
recurrent ≥ Grade 3 colitis 
 
 
Grade 4  
Permanently discontinue  
investigational drug(s). 
 
Nephritis or renal 
dysfunction 
(elevated serum creatinine) 
Any Grade 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity) 
General Guidance 
For Any Grade 
− 
Consult a nephrologist. 
− 
Monitor for signs and symptoms that may be related 
to changes in renal function (eg, routine urinalysis, 
elevated serum BUN and creatinine, decreased 
creatinine clearance, electrolyte imbalance, decreased 
urine output, or proteinuria). 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (eg, disease progression, 
infections, recent IV contrast, medications, fluid 
status). 
− 
Consider using steroids in the absence of a clear 
alternative etiology even for low-grade events 
(Grade 2), in order to prevent potential progression to 
higher grade events. 
Grade 1 
 
No dose modifications. 
For Grade 1 
− 
Monitor serum creatinine weekly and any 
accompanying symptoms. 
• 
If creatinine returns to baseline, resume its 
regular monitoring per study protocol. 
• 
If creatinine worsens, depending on the 
severity, treat as Grade 2, 3, or 4. 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event  
Dose Modifications 
Toxicity Management 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
Grade 2 
 
Hold investigational drug(s) until 
resolution to Grade ≤ 1 or baseline.  
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
If toxicity improves to 
Grade ≤ 1 or baseline, then 
resume investigational drug(s) 
after completion of steroid 
taper. 
For Grade 2 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days 
and as clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if 
clinically indicated. 
− 
If event is persistent beyond 3 to 5 days or worsens, 
promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or 
worsens despite prednisone at 1 to 2 mg/kg/day PO or 
IV equivalent, consider additional workup. When 
event returns to baseline, resume investigational 
drug(s) and routine serum creatinine monitoring per 
study protocol. 
Grade 3 or 4 
 
 
Permanently discontinue 
investigational drug(s). 
For Grade 3 or 4 
− 
Carefully monitor serum creatinine daily. 
− 
Consult nephrologist and consider renal biopsy if 
clinically indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or 
worsens despite prednisone at 1 to 2 mg/kg/day PO or 
IV equivalent, consider additional workup and prompt 
treatment with an immunosuppressant in consultation 
with a nephrologist. 
Rash or Dermatitis 
 
Any Grade 
(Refer to NCI CTCAE applicable 
version in study protocol for 
General Guidance 
For Any Grade 
− 
Monitor for signs and symptoms of dermatitis (rash 
and pruritus). 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event  
Dose Modifications 
Toxicity Management 
(Including Pemphigoid) 
definition of severity/grade 
depending on type of skin rash) 
− 
HOLD INVESTIGATIONAL DRUG(S) IF 
STEVENS-JOHNSON SYNDROME (SJS), 
TOXIC EPIDERMAL NECROLYSIS (TEN), OR 
OTHER SEVERE CUTANEOUS ADVERSE 
REACTION (SCAR) IS SUSPECTED.  
− 
PERMANENTLY DISCONTINUE 
INVESTIGATIONAL DRUG(S) FOR ANY 
GRADE OF CONFIRMED SJS, TEN, OR SCAR. 
Grade 1 
No dose modifications. 
For Grade 1 
− 
Consider symptomatic treatment, including oral 
antipruritics (eg, diphenhydramine or hydroxyzine) 
and topical therapy (eg, normalize, lotion, or 
institutional standard). 
Grade 2 
For persistent (> 1 week) Grade 2 
events, hold investigational drug(s) 
until resolution to Grade ≤ 1 or 
baseline. 
• 
If toxicity worsens, then treat 
as Grade 3. 
• 
If toxicity improves to Grade 
≤ 1 or baseline, then resume 
investigational drug(s) after 
completion of steroid taper. 
For Grade 2 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, including oral 
antipruritics (eg, diphenhydramine or hydroxyzine) 
and topical therapy. 
− 
Consider moderate-strength topical steroid. 
− 
If no improvement of rash/skin lesions occurs within 
3 days or is worsening despite symptomatic treatment 
and/or use of moderate strength topical steroid, 
consider discussing with study physician, as needed, 
and promptly start systemic steroids such as 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Consider skin biopsy if the event persists for >1 week 
or recurs. 
Grade 3 or 4 
For Grade 3 
• 
Hold investigational drug(s) 
until resolution to Grade ≤ 1 or 
baseline. 
For Grade 3 or 4 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the Event  
Dose Modifications 
Toxicity Management 
• 
If toxicity improves to Grade 
≤ 1 or baseline, then resume 
investigational drug(s) after 
completion of steroid taper. 
• 
If toxicity worsens, then treat as 
Grade 4. 
 
For Grade 4 
Permanently discontinue 
investigational drug(s). 
− 
Consider skin biopsy (preferably more than 1) as 
clinically feasible. Consider, as necessary, discussing 
with study physician. 
Endocrinopathy 
(eg, hyperthyroidism, 
thyroiditis, hypothyroidism, 
type 1 diabetes mellitus, 
hypophysitis, hypopituitarism, 
and adrenal insufficiency) 
 
Any Grade 
(Depending on the type of 
endocrinopathy, refer to NCI 
CTCAE applicable version in 
study protocol for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade 
− 
Consider consulting an endocrinologist for endocrine 
events. 
− 
Consider discussing with study physician, as needed. 
− 
Monitor patients for signs and symptoms of 
endocrinopathies. Non-specific symptoms include 
headache, fatigue, behaviour changes, mental status 
changes, photophobia, visual field cuts, vertigo, 
abdominal pain, unusual bowel habits, polydipsia, 
polyuria, hypotension, and weakness. 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (eg, disease progression 
including brain metastases, or infections). 
− 
Depending on the suspected endocrinopathy, monitor 
and evaluate thyroid function tests: TSH, free T3 and 
free T4 and other relevant endocrine and related labs 
(eg, blood glucose and ketone levels, HgA1c).If a 
patient experiences an AE that is thought to be 
possibly of autoimmune nature (eg, thyroiditis, 
pancreatitis, hypophysitis, or diabetes insipidus), the 
Investigator should send a blood sample for 
appropriate autoimmune antibody testing. 

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− 
Investigators should ask participants with 
endocrinopathies who may require prolonged or 
continued hormonal replacement, to consult their 
primary care physicians or endocrinologists about 
further monitoring and treatment after completion of 
the study. 
Grade 1 
No dose modifications. 
For Grade 1 
− 
Monitor patient with appropriate endocrine function 
tests. 
− 
For suspected hypophysitis/hypopituitarism, consider 
consulting an endocrinologist to guide assessment of 
early-morning ACTH, cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, and prolactin 
levels, as well as cosyntropin stimulation test (though 
it may not be useful in diagnosing early secondary 
adrenal insufficiency). 
− 
If TSH < 0.5 x LLN, or TSH > 2 x ULN, or 
consistently out of range in 2 subsequent 
measurements, include free T4 at subsequent cycles 
as clinically indicated and consider consultation of an 
endocrinologist. 
Grade 2, 3, or 4 
• 
For Grade 2 to 4 
endocrinopathies other than 
hypothyroidism and type 1 
diabetes mellitus, consider 
holding investigational drug(s) 
dose until acute symptoms 
resolve. 
• 
Investigational drug(s) can be 
resumed once patient stabilizes 
and after completion of steroid 
taper. 
For Grade 2, 3, or 4  
− 
Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by suspected 
endocrinopathy and as clinically indicated, consider 
pituitary scan. 
− 
For all patients with abnormal endocrine work up, 
except those with isolated hypothyroidism or type 1 
DM, and as guided by an endocrinologist, consider 
short-term corticosteroids (eg, 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and prompt 
initiation of treatment with relevant hormone 
replacement (eg, hydrocortisone, sex hormones). 

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• 
Patients with endocrinopathies 
who may require prolonged or 
continued steroid replacement 
(eg, adrenal insufficiency) can 
be retreated with investigational 
drug(s) if the patient is 
clinically stable as per 
Investigator or treating 
physician’s clinical judgement. 
• 
If toxicity worsens, then treat 
based on severity. 
 
− 
Isolated hypothyroidism may be treated with 
replacement therapy, without investigational drugs 
interruption, and without corticosteroids. 
− 
Isolated type 1 diabetes mellitus (DM) may be treated 
with appropriate diabetic therapy, and without 
corticosteroids. Only hold investigational drug(s) in 
setting of hyperglycemia when diagnostic workup 
is positive for diabetic ketoacidosis.  
− 
For patients with normal endocrine workup 
(laboratory assessment or MRI scans), repeat 
laboratory assessments/MRI as clinically indicated. 
Amylase/Lipase increased 
 
Any Grade 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity) 
General Guidance 
For Any Grade 
− 
For modest asymptomatic elevations in serum 
amylase and lipase, corticosteroid treatment is not 
indicated as long as there are no other signs or 
symptoms of pancreatic inflammation.  
− 
Assess for signs/symptoms of pancreatitis.  
− 
Consider appropriate diagnostic testing (eg, 
abdominal CT with contrast, MRCP if clinical 
suspicion of pancreatitis and no radiologic evidence 
on CT). 
− 
If isolated elevation of enzymes without evidence of 
pancreatitis, continue immunotherapy. Consider other 
causes of elevated amylase/lipase. 
− 
If evidence of pancreatitis, manage according to 
pancreatitis recommendations.  
 
Grade 1 
No dose modifications. 
 
Grade 2, 3, or 4 
For Grade 2, 3, or 4 
In consultation with relevant 
pancreatic specialist consider 
continuing investigational drug(s) if 
no clinical/radiologic evidence of 
pancreatitis ± improvement in 
amylase/lipase. 
Acute Pancreatitis 
Any Grade 
General Guidance 
For Any Grade 
− 
Consider Gastroenterology referral.  

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defining the CTC grade/severity) 
 
Grade 1 
No dose modifications. 
For Grade 1 
− 
IV hydration. 
− 
Manage as per amylase/lipase increased 
(asymptomatic). 
 
Grade 2, 3, or 4 
For Grade 2 
Hold investigational drug(s) until 
resolution to Grade ≤ 1. 
For Grade 3 or 4 
Permanently discontinue 
investigational drug(s). 
For Grade 2, 3, or 4 
− 
Promptly start systemic steroids prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
− 
IV hydration. 
Neurotoxicity 
(to include but not limited to 
non-infectious meningitis, non-
infectious encephalitis, and 
autonomic neuropathy, 
excluding Myasthenia Gravis 
and Guillain-Barre) 
Any Grade 
(Depending on the type of 
neurotoxicity, refer to NCI 
CTCAE applicable version in 
study protocol for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade 
− 
Patients should be evaluated to rule out any 
alternative etiology (eg, disease progression, 
infections, metabolic syndromes, or medications). 
− 
Monitor patient for general symptoms (headache, 
nausea, vertigo, behavior change, or weakness). 
− 
Consider appropriate diagnostic testing 
(eg, electromyogram and nerve conduction 
investigations). 
− 
Perform symptomatic treatment with neurological 
consult as appropriate. 
− 
FOR TRANSVERSE MYELITIS OR 
MENINGOENCEPHALITIS, PERMANENTLY 
DISCONTINUE INVESTIGATIONAL DRUG(S) 
FOR ANY GRADE. 

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Grade 1 
No dose modifications. 
For Grade 1 
− 
See “Any Grade” recommendations above. 
Grade 2 
• 
For acute motor neuropathies or 
neurotoxicity, hold 
investigational drug(s) until 
resolution to Grade ≤ 1. 
• 
For sensory 
neuropathy/neuropathic pain, 
consider holding investigational 
drug(s) until resolution to 
Grade ≤ 1. 
• 
Permanently discontinue 
investigational drug(s) if Grade 
2 imAE does not resolve to 
Grade ≤ 1 within 30 days. 
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
For Grade 2 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (eg, gabapentin 
or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
− 
If no improvement within 2 to 3 days despite 1 to 
2 mg/kg/day prednisone PO or IV equivalent, 
consider additional workup and promptly treat with 
an additional immunosuppressant (eg, IV IG or other 
immunosuppressant depending on the specific imAE). 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue 
investigational drug(s). 
For Grade 3 or 4 
− 
Consider, as necessary, discussing with study 
physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 2 to 3 days despite IV 
corticosteroids, consider additional workup and 
promptly treat with an additional immunosuppressant 
(eg, IV IG or other immunosuppressant depending on 
the specific imAE). 

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− 
Once stable, gradually taper steroids over ≥ 28 days. 
Peripheral neuromotor 
syndromes 
 
Any Grade 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity) 
General Guidance 
For Any Grade 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain 
patients may unpredictably experience acute 
decompensations that can result in substantial 
morbidity or in the worst case, death. Special care 
should be taken for certain sentinel symptoms that 
may predict a more severe outcome, such as 
prominent dysphagia, rapidly progressive weakness, 
and signs of respiratory insufficiency or autonomic 
instability. 
− 
Patients should be evaluated to rule out any 
alternative etiology (eg, disease progression, 
infections, metabolic syndromes or medications). It 
should be noted that the diagnosis of 
immune-mediated peripheral neuromotor syndromes 
can be particularly challenging in patients with 
underlying cancer, due to the multiple potential 
confounding effects of cancer (and its treatments) 
throughout the neuraxis. Given the importance of 
prompt and accurate diagnosis, it is essential to have a 
low threshold to obtain a neurological consult. 
− 
Neurophysiologic diagnostic testing 
(eg, electromyogram and nerve conduction 
investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon 
suspicion of such conditions and may be best 
facilitated by means of a neurology consultation. 
− 
It is important to consider that the use of steroids as 
the primary treatment of Guillain-Barre is not 
typically considered effective. Patients requiring 
treatment should be started with IV IG and followed 
by plasmapheresis if not responsive to IV IG. 
− 
FOR CONFIRMED MYASTENIC 
SYNDROME/MYASTHENIA GRAVIS, 
GUILLAIN-BARRE SYNDROME 

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PERMANENTLY DISCONTINUE 
INVESTIGATIONAL DRUG(S) FOR ANY 
GRADE. 
Grade 1 
No dose modifications. 
For Grade 1 
− 
Consider discussing with the study physician, as 
needed. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above. 
− 
Consult a neurologist. 
Grade 2 
Hold investigational drug(s) until 
resolution to Grade ≤ 1. 
Permanently discontinue 
investigational drug(s) if it does not 
resolve to Grade ≤ 1 within 30 days 
or if there are signs of respiratory 
insufficiency or autonomic 
instability. 
PERMANENTLY 
DISCONTINUE 
INVESTIGATIONAL DRUG(S) 
FOR CONFIRMED 
MYASTENIC 
SYNDROME/MYASTHENIA 
GRAVIS OR GUILLAIN-
BARRE OF ANY GRADE. 
For Grade 2 
− 
Consider discussing with the study physician, as 
needed. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above. 
− 
Consult a neurologist. 
− 
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (eg, gabapentin 
or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. It is important to 
consider that steroid therapy (especially 
with high doses) may result in transient 
worsening of myasthenia and should 
typically be administered in a monitored 
setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with 
plasmapheresis or IV IG. Such decisions are 
best made in consultation with a 

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neurologist, taking into account the unique 
needs of each patient. 
o 
If myasthenia gravis-like neurotoxicity is 
present, consider starting AchE inhibitor 
therapy in addition to steroids. Such 
therapy, if successful, can also serve to 
reinforce the diagnosis. 
o 
Avoid medications that can worsen 
myasthenia gravis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use 
of steroids as the primary treatment of 
Guillain-Barre is not typically considered 
effective. 
o 
Patients requiring treatment should be 
started with IV IG and followed by 
plasmapheresis if not responsive to IV IG. 
Grade 3 or 4 
For Grade 3 
• 
Hold investigational drug(s) 
until resolution to Grade ≤ 1. 
• 
Permanently discontinue 
investigational drug(s) if Grade 
3 imAE does not resolve to 
Grade ≤ 1 within 30 days or if 
there are signs of respiratory 
insufficiency or autonomic 
instability. 
 
For Grade 4 
For Grade 3 or 4  
− 
Consider discussing with study physician, as needed. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and consult a neurologist. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. They should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with 
plasmapheresis or IV IG. 
o 
If myasthenia gravis-like neurotoxicity 
present, consider starting AchE inhibitor 
therapy in addition to steroids. Such 
therapy, if successful, can also serve to 
reinforce the diagnosis. 

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Permanently discontinue 
investigational drug(s). 
PERMANENTLY 
DISCONTINUE 
INVESTIGATIONAL DRUG(S) 
FOR CONFIRMED 
MYASTENIC 
SYNDROME/MYASTHENIA 
GRAVIS OR GUILLAIN-
BARRE OF ANY GRADE. 
o 
Avoid medications that can worsen 
myasthenia gravis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use 
of steroids as the primary treatment of 
Guillain-Barre is not typically considered 
effective. 
o 
Patients requiring treatment should be 
started with IV IG and followed by 
plasmapheresis if not responsive to IV IG. 
 
Myocarditis 
For patients with asymptomatic 
laboratory (eg, elevated 
troponin or N-terminal pro-
hormone BNP (NT-proBNP) / 
brain natriuretic peptide (BNP) 
> ULN) or cardiac imaging 
abnormalities (including 
patients with elevated troponin 
at baseline who have any 
further increase after dosing), 
follow the guidelines as for 
Grade 1. 
Any Grade 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity) 
General Guidance 
 
For Any Grade 
− 
The prompt diagnosis of immune-mediated 
myocarditis is important, particularly in patients with 
baseline cardiopulmonary disease and reduced cardiac 
function.  
− 
Consider discussing with the study physician/medical 
monitor, as needed. 
− 
Monitor patients for signs and symptoms of 
myocarditis (new onset or worsening chest pain, 
arrhythmia, shortness of breath, peripheral edema). 
As some symptoms can overlap with lung toxicities, 
simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (eg, pulmonary 
embolism, congestive heart failure, malignant 
pericardial effusion).  
− 
Consult a cardiologist early, to promptly assess 
whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
− 
Initial work-up should include clinical evaluation, 
troponin, NT-proBNP/BNP, CPK, CK-MB, ECG, 
ECHO, monitoring of oxygenation via pulse oximetry 
(resting and exertion), and additional laboratory 
work-up as indicated. Consider cardiac MRI with 

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T1/T2 mapping to assess for the presence of 
myocardial edema, and/or endomyocardial biopsy to 
make an accurate diagnosis when it is possible, and 
the clinical condition of the patient allows. 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (eg, disease progression, 
other medications, or infections). 
 
Grade 1 
 
Hold investigational drug during 
diagnostic work-up for other 
etiologies. 
If investigational drug is held, 
resume if all diagnostic work-up is 
negative and no persistent 
worsening of elevated troponin is 
noted. 
For Grade 1 (no definitive findings) 
- 
Consider cardiology consult.  
- 
Consider diagnostic work-up coordinated with 
cardiologist that may include evaluation for clinical 
symptoms, NT-proBNP/BNP, serial measurement of 
CPK, CK-MB, and troponin at 6 and 12 hours to 
evaluate for acute coronary syndrome, ECG, ECHO 
and/or cardiac MRI, pulse oximetry (resting and 
exertion), and other laboratory work-up as clinically 
indicated.  
- 
Consider using steroids if clinical suspicion is high.  
- 
Monitor and closely follow up in 24 to 48 hours with 
repeat NT-proBNP, CPK, CK-MB, troponin, ECG, 
and other work-up as clinically indicated. 
 
Grade 2 
 
Hold investigational drug during 
diagnostic workup. If immune 
mediated myocarditis is confirmed, 
therapy may be re-initiated once the 
participant has recovered and where 
the benefit risk balance is deemed 
positive following consultation 
between Investigator and 
cardiologist. Upon re-initiation it is 
highly recommended that the 
− 
Monitor symptoms daily, hospitalize. 
− 
Supportive care (eg, oxygen).  
− 
Consider laboratory workup and imaging as described 
under general guidance for all grades of myocarditis.  
− 
Consider cardiology consult to determine if and when 
to complete diagnostic procedures including a cardiac 
biopsy.  
− 
Promptly start high-dose pulse IV methylprednisolone 
1 gram/day for 3 days and then 2 mg/kg prednisone 
daily.  
− 
If no improvement within 2 to 3 days despite IV 
methylprednisolone at 1 gram/day, promptly start 
additional immunosuppressives (eg, tacrolimus, 
mycophenolate mofetil, or TNF inhibitors such as 

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participant is assessed by a 
cardiologist on a regular basis. 
 
infliximab at 5 mg/kg IV which may be repeated at 
2 and 6 weeks after initial dose at the discretion of the 
treating provider). Caution: It is important to rule out 
sepsis and refer to infliximab label for general 
guidance before using infliximab. Infliximab is 
contraindicated for patients who have heart failure.  
− 
Close monitoring for worsening symptoms or signs of 
myocarditis needs to be performed before and during 
the tapering of corticosteroid or other 
immunosuppressive. 
− 
If patient continues to worsen, treat as Grade 3/4. 
 
Grade 3 or 4 
 
 
 
• 
Permanently discontinue 
investigational drug. 
− 
Monitor symptoms daily, hospitalize. 
− 
Supportive intensive care (eg, oxygen, circulatory 
support including hemodynamic, temporary pacing, 
arrhythmia treatment as needed).  
− 
Consider laboratory workup and imaging as described 
under general guidance for all grades of myocarditis. 
− 
Consider urgent cardiology consultation to determine 
if and when to complete diagnostic procedures, 
including a cardiac biopsy. 
− 
Promptly start high-dose pulse high-dose IV 
methylprednisolone 1 gram/day for 3 days and then 
2 mg/kg prednisone daily. Consider initiation ACE 
inhibitors or ARBs for LV dysfunction, if clinically 
appropriate.  
− 
If no improvement within 3 to 5 days despite IV 
methylprednisolone, consider starting additional 
immunosuppressives such as tacrolimus or 
mycophenolate mofetil. In unstable patients who do 
not respond to corticosteroids, consider antithymocyte 
globulin or IV immunoglobulin.  
− 
Close monitoring for worsening symptoms or signs of 
myocarditis needs to be performed before and during 
the tapering of corticosteroid or other 
immunosuppressive. 

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 Myositis/ Polymyositis  
Any Grade 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity) 
General Guidance 
For Any Grade 
− 
Monitor patients for signs and symptoms of 
poly/myositis. Typically, muscle weakness/pain 
occurs in proximal muscles including upper arms, 
thighs, shoulders, hips, neck and back, but rarely 
affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing 
can occur and progress rapidly. Increased general 
feelings of tiredness and fatigue may occur, and there 
can be new-onset falling, difficulty getting up from a 
fall, and trouble climbing stairs, standing up from a 
seated position, and/or reaching up. 
− 
If poly/myositis is suspected, a neurology 
consultation should be obtained early, with prompt 
guidance on diagnostic procedures. Myocarditis may 
co-occur with poly/myositis; refer to guidance under 
Myocarditis. Given breathing complications, refer to 
guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously 
unknown) autoimmune disorder, consider 
Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
Initial work-up should include clinical evaluation, 
creatine kinase, aldolase, LDH, BUN/creatinine, 
erythrocyte sedimentation rate or C-reactive protein 
level, urine myoglobin, and additional laboratory 
work-up as indicated, including a number of possible 
rheumatological/antibody tests (ie, consider whether a 
rheumatologist consultation is indicated and could 
guide need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase [such as 
anti-Jo-1], and/or signal-recognition particle 
antibodies). Confirmatory testing may include 
electromyography, nerve conduction studies, MRI of 
the muscles, and/or a muscle biopsy. Consider 

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Barium swallow for evaluation of dysphagia or 
dysphonia. 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (eg, disease progression, 
other medications, or infections). 
 
Grade 1 
 
• 
No dose modifications. 
For Grade 1 
− 
Monitor and closely follow up in 2 to 4 days for 
clinical symptoms and initiate evaluation as clinically 
indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the study 
physician. 
 
Grade 2 
 
• 
Hold investigational drug(s) 
until resolution to Grade ≤ 1. 
• 
Permanently discontinue 
investigational drug(s) if it does 
not resolve to Grade ≤ 1 within 
30 days or if there are signs of 
respiratory insufficiency. 
For Grade 2 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), 
promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with receiving 
input from Neurology consultant.  
− 
If clinical course is not rapidly progressive, start 
systemic steroids (eg, prednisone 1 to 2 mg/kg/day 
PO or IV equivalent); if no improvement within 2 to 
3 days, continue additional work up and start 
treatment with IV methylprednisolone 2 to 
4 mg/kg/day. 
− 
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 2 to 
3 days, consider starting another immunosuppressive 
therapy such as a TNF inhibitor (eg, infliximab at 
5 mg/kg IV, may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the treating provider). 

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Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance 
before using infliximab. 
 
Grade 3 or 4 
 
For Grade 3 
• 
Hold investigational drug(s) 
until resolution to Grade ≤ 1. 
• 
Permanently discontinue 
investigational drug(s) if Grade 
3 imAE does not resolve to 
Grade ≤ 1 within 30 days or if 
there are signs of respiratory 
insufficiency. 
• 
Permanently discontinue 
investigational drug(s) for 
recurrent ≥ Grade 3 myositis 
 
 
For Grade 4 
• 
Permanently discontinue 
investigational drug(s). 
For Grade 3 or 4  
− 
Monitor symptoms closely; recommend 
hospitalization. 
− 
Obtain Neurology consult 
− 
Consider discussing with the study physician, as 
needed. 
− 
Promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with receiving 
input from Neurology consultant. 
− 
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 2 to 
3 days, consider starting another immunosuppressive 
therapy such as a TNF inhibitor (eg, infliximab at 
5 mg/kg IV, may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the treating provider). 
Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance 
before using infliximab. 
− 
Consider whether patient may require IV IG, 
plasmapheresis. 
a ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
b FDA Liver Guidance Document 2009 Guidance for Industry: Drug-induced Liver Injury – Premarketing Clinical Evaluation. 
c NCCN Clinical Practice Guidelines in Oncology “Management of Immunotherapy-Related Toxicities” Version 1.2020 – December 2019. 
AchE: Acetylcholine esterase; ACTH: adrenocorticotropic hormone; ADL: Activities of daily living; AE: Adverse event; ALP: Alkaline phosphatase test; ALT: Alanine 
aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; CK-MB: creatinine kinase isoenzyme MB; CT: Computed tomography; CTC: Common 
Terminology Criteria; CTCAE: Common Terminology Criteria for Adverse Events; ILD: Interstitial lung disease; imAE: immune-mediated adverse event; IG: Immunoglobulin; 
IV: Intravenous; GI: Gastrointestinal; LFT: Liver function tests; LLN: Lower limit of normal; MRI: Magnetic resonance imaging; NCI: National Cancer Institute; NCCN: National 
Comprehensive Cancer Network; PJP: Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO: per os (taken orally); T3: Triiodothyronine; 
T4: Thyroxine; TBL: Total bilirubin; TNF: Tumor necrosis factor; TSH: Thyroid-stimulating hormone; ULN: Upper limit of normal. 
 

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Management of immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI) 
 
Recommended management of treatment-emergent abnormal hepatic biochemical tests in clinical trials with sabestomig (patients with normal baseline 
ALT, ASTa) 
 
Treatment 
Emergent ALT/AST 
Elevations 
TBLb Values at Time of Treatment 
Emergent ALT Elevation 
Investigational drugs treatment 
adjustment and additional therapy 
Monitoring and evaluation 
Normal 
Isolated total blood bilirubin 
elevation > 3 × ULN 
Discontinue investigational drug. 
Repeat blood testsd within 2 to 3 days. Initiate close 
monitoring and evaluatione. 
≤ 3 x ULN 
Normal.  
Patients with Gilbert’s syndrome: No 
change in baseline TBL. 
Continue treatment. 
 
Repeat blood testsc within 1 to 2 weeks. 
> 3 x ULN 
 
Normal.  
 
Patients with Gilbert’s syndrome: No 
change in baseline TBL. 
Withhold investigational drug. 
If rising ALT/AST when re-checked, start 
prednisone/prednisolone 1 mg/kg/df. 
If ALT/AST improve to ≤ 3.0 x ULN, 
resume treatment after completion of 
steroid taper to equivalent of 
prednisone ≤ 10 mg/day. 
Repeat blood testsd within 2 to5 days. Initiate close 
monitoring and evaluatione. 
TBL > 2 x ULN. 
 
Patients with Gilbert’s syndrome: 
Doubling of direct bilirubin.  
Discontinue investigational drug. 
Start prednisone/prednisolone 1 to 2 
mg/kg/df. 
Repeat blood testsd within 2 to 3 days. Initiate close 
monitoring and evaluatione. 
> 5 x ULN 
Normal.  
 
Patients with Gilbert’s syndrome: No 
change in baseline TBL. 
Withhold investigational drug.  
Start prednisone/prednisolone 1 to 2 
mg/kg/df. 
 
Resume treatment if elevations downgrade 
to AST and ALT ≤ 3.0 x ULN within 14 
days, and after completion of steroid taper 
to equivalent of prednisone ≤ 10 mg/day. 
Otherwise discontinue investigational drug 
permanently. 
Repeat blood testsd within 2 to 3 days. Initiate close 
monitoring and evaluatione. 
 
Treatment shall only resume following consultation with a 
hepatologist and based on a benefit/risk assessment for the 
affected participant. 
> 10 x ULN  
Normal or elevated. 
Discontinue investigational drug. 
Start prednisone/prednisolone 1 to 2 
mg/kg/dg. 
Repeat blood testsd within 2 to 3 days. Initiate close 
monitoring and evaluatione. 

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Recommended management of treatment-emergent abnormal hepatic biochemical tests in clinical trials with sabestomig (patients with abnormal baseline 
ALT, ASTa) 
 
Treatment 
Emergent ALT/AST 
Elevations 
TBLb Values at Time of Treatment 
Emergent ALT Elevation 
Investigational drugs treatment 
adjustment and additional therapy 
Monitoring and evaluation 
> bsl 
Normal.  
Patients with Gilbert’s syndrome: No 
change in baseline TBL. 
Continue treatment. 
Repeat blood testsc within 1 to 2 weeks. 
> 2 x bsl  
Normal.  
 
Patients with Gilbert’s syndrome: No 
change in baseline TBL. 
Withhold investigational drug. 
If rising ALT/AST when re-checked, 
start prednisone/prednisolone 
1 mg/kg/df. 
If ALT/AST improve to ≤ 2 x bsl, 
resume treatment after completion of 
steroid taper to equivalent of 
prednisone ≤ 10 mg/day. 
Repeat blood testsd within 2 to 5 days. Initiate close monitoring 
and evaluatione. 
TBL >2 x ULN. 
 
Patients with Gilbert’s syndrome: 
Doubling of direct bilirubin  
Discontinue investigational drug. 
Start prednisone/prednisolone 1 to 
2 mg/kg/df. 
Repeat blood testsd within 2 to 3 days. Initiate close monitoring 
and evaluatione. 
> 3 x bsl 
Normal.  
 
Patients with Gilbert’s syndrome: No 
change in baseline TBL. 
Withhold investigational drug. 
Start prednisone/prednisolone 1 to 
2 mg/kg/df. 
Resume treatment if elevations 
downgrade to AST and ALT ≤ 2 x bsl 
within 14 days, and after completion 
of steroid taper to equivalent of 
prednisone ≤ 10 mg/day. 
Otherwise discontinue investigational 
drug permanently. 
Repeat blood testsd within 2 to 3 days. Initiate close monitoring 
and evaluatione. 
> 5 x bsl 
Normal or elevated. 
Discontinue investigational drug. 
Start prednisone/prednisolone 1 to 2 
mg/kg/dg. 
Repeat blood testsd within 2 to 3 days. Initiate close monitoring 
and evaluatione. 
 

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a. 
Use of serum ALT is preferred over AST due to its higher hepatic specificity. ALP is not included in this table as isolated ALP elevation is often related to the underlying 
malignancy and uncommonly related to ILICI. Furthermore, there are limited published data regarding management of ILICI in patients who develop isolated ALP elevation 
during ICI treatment.  
b. 
Measurement of total and conjugated (or direct) bilirubin is recommended to help identify patients with indirect hyperbilirubinemia due to Gilbert’s syndrome or hemolysis 
versus liver injury.  
c. 
Recommended blood tests include ALT, AST, ALP, GGT, TBL.  
d. 
Recommended blood tests include: ALT, AST, ALP, GGT, TBL, DBL, CK, INR.  
e. 
Initial monitoring should be 2–3 times a week. Frequency of monitoring may be adjusted based on clinical scenario and severity of injury. Monitoring should continue until 
ALT/AST levels return to ≤ 3 x ULN, regardless of whether or not the investigational drugs have been discontinued. For recommendations on diagnostic follow-up and 
evaluation of potential alternative etiologies see Table 1 below. 
f. 
Oral prednisone/prednisolone: if hepatic biochemical tests worsen on oral prednisone/prednisolone, change to IV (methyl)prednisolone. Once ALT/AST return to ≤ 3 x ULN, 
corticosteroids can be weaned over 2–4 weeks. Treatment with investigational drug(s) may be resumed with close monitoring, once prednisone/ prednisolone dose ≤ 10 
mg/day.  
g. 
IV (methyl)prednisolone: if worsening continues on IV (methyl)prednisolone, consider adding MMF 500–1000 mg twice daily. Once hepatic biochemical tests return to 
Grade 1, corticosteroids can be weaned over 4 weeks. Treatment with investigational drug(s) may be resumed with close monitoring, once prednisone/prednisolone dose ≤ 10 
mg/day.  
 
Abbreviations: bsl: baseline; CK creatinine kinase; DBL direct Bilirubin; GGT Gamma-glutamyl transferase; INR international normalized ratio; IV: intravenous; PO: per os 
(taken orally); ULN upper limit of normal 
 
Table 1 – Recommended evaluation of patients with treatment-emergent ALT elevation during a clinical trial with immune checkpoint 
inhibitorsa 
Recommended evaluation 
Competing causes of abnormal liver tests 
1st Line Testing 
Thorough history of symptoms, co-existing medical conditions, 
concomitant medications, dietary and nutritional supplements, 
excessive exercise or muscle injury, alcohol consumption, illicit 
substances. 
Systemic infection/sepsis; ischemic/congestive hepatic injury; gallstone 
disease; 
alcoholic 
liver 
disease; 
muscle 
injury/rhabdomyolysis; 
acetaminophen toxicity; DILI due to another drug, herbal or dietary 
supplement. 
Serum CK 
Muscle injury/rhabdomyolysisb 
Anti-HAV (IgM) 
Acute HAV infection 
HbsAg 
• Anti-HBc IgG, IgM, HBV DNA 
Acute hepatitis B; Exacerbation of chronic hepatitis B 
Anti-HCV 
• HCV RNA (PCR) 
Acute hepatitis C 
Exacerbation of chronic hepatitis Cc 

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Anti-HEV (IgG, IgM); HEV RNAd 
Acute hepatitis E 
ANA, ASMA 
• Quantitative immunoglobulins (IgG, IgM, IgA) 
Autoimmune hepatitise 
Hepatobiliary imaging (ultrasonography, CT scan, MRI, MRCP)f 
Biliary obstruction; pancreatitis; gallstones; portal-vein/hepatic vein 
thrombosis; hepatic metastasis 
2nd Line Testing 
Serological tests for EBV, CMV, HSV. 
• May need to obtain acute and convalescent serological tests 
• EBV-DNA, CMV-DNA, HSV-DNA by PCR. Liver biopsy 
needed to confirm HSV 
Hepatic injury caused by CMV, EBV, HSV 
Additional Testsg 
Anti-LKM-1 
Autoimmune hepatitis 
Serum EtOH 
• Urinary ethyl-glucuronide and ethyl-sulfateh, Serum 
phosphatidylethanoli 
Alcohol related liver disease 
Serum acetaminophen level; Acetaminophen protein adducts 
Acetaminophen toxicity 
Review of blood pressure, pulse, electrocardiogram, 
echocardiogram, cardiology consult 
Ischemic or congestive hepatic injury 
Urine toxicology screen 
Hepatotoxicity due to cocaine, amphetamines, opiates and other illicit 
substances 
Anti-HDV 
Hepatitis D 
Blood or urine cultures 
Systemic infection, sepsis 
Blood ceruloplasmin, serum copper 
• Slit lamp eye examination for Kayser-Fleischer rings, genetic 
testing 
Wilson’s disease 

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Abbreviations used: CMV, Cytomegalovirus; CK, creatine kinase; DILI, drug-induced liver injury; EBV, Epstein Bar Virus; HBV, hepatitis B virus, 
HbsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; HSV; Herpes Simplex Virus; LKM-1, 
liver kidney microsomal type 1. 
Adapted from Arie Regev, et al., Journal of Autoimmunity, https://doi.org/10.1016/j.jaut.2020.102514 
a 
Extent and type of work-up may vary by patient’s history, severity of liver injury, underlying disease, and geography. 
b 
Serum AST typically (although not always) is higher than ALT. 
c 
Acute hepatitis C may be anti-HCV negative but HCV RNA positive. 
d 
If anti-HEV IgM positive, consider confirmation with HEV RNA by nested PCR. 
e 
A liver biopsy is needed to confirm a diagnosis of AIH. 
f 
If cholestatic injury, magnetic resonance cholangiopancreatography may be recommended. 
g 
Based on medical history and clinical judgment. 
h 
Alcohol consumption in past 3 to 5 days. 
i 
Alcohol consumption in past 3 weeks. 
 
 

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Other–Immune-Mediated Reactions (incl. hypersensitivity reactions) 
Severity Grade of the Event 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all 
organs, some of them are not noted specifically in these 
guidelines (eg, immune thrombocytopenia, haemolytic 
anaemia, uveitis, vasculitis). 
− 
The study physician may be contacted for immune-mediated 
reactions not listed in the “specific immune-mediated 
reactions” section. 
− 
Thorough evaluation to rule out any alternative etiology 
(eg,, disease progression, concomitant medications, and 
infections). 
− 
Consultation with relevant specialist. 
− 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Monitor as clinically indicated 
Grade 2 
• 
Hold investigational drug(s) until resolution to 
≤ Grade 1 or baseline. 
• 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
• 
Investigational drug(s) can be resumed once event 
stabilizes to Grade ≤ 1 after completion of steroid 
taper. 
• 
Consider whether investigational drug(s) 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 
with systemic steroids and following full taper. 
For Grade 2, 3, or 4 
Treat accordingly, as per institutional standard, appropriate 
clinical practice guidelines, and other society guidelines (eg, 
NCCN, ESMO).  
Grade 3 
Hold investigational drug(s).  
Grade 4 
Permanently discontinue investigational drug(s).  
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE: Adverse event; CTCAE: Common Terminology Criteria for Adverse Events; NCI: National Cancer Institute. 
 

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Infusion-Related Reactions 
Severity Grade of the Event 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the CTC 
grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance. 
For Any Grade 
− 
Manage per institutional standard at the discretion of Investigator. 
− 
Monitor patients for signs and symptoms of infusion-related 
reactions (eg, fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (eg, generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1 
The infusion rate of investigational drug(s) may be 
decreased by 50% or temporarily interrupted until 
resolution of the event. 
 
For Grade 2 
• 
The infusion rate of investigational drug(s) may be 
decreased 50% or temporarily interrupted until 
resolution of the event. 
• 
Subsequent infusions may be given at 50% of the 
initial infusion rate. 
For Grade 1 or 2 
− 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the Investigator. 
− 
Consider premedication per institutional standard prior to 
subsequent doses. 
− 
Steroids should not be used for routine premedication of 
Grade ≤ 2 infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue investigational drug(s). 
For Grade 3 or 4 
− 
Manage severe infusion-related reactions per institutional 
standards (eg, IM epinephrine, followed by IV diphenhydramine 
and famotidine, and IV glucocorticoid). 
CTCAE: Common Terminology Criteria for Adverse Events; IM: intramuscular; IV: intravenous; NCI: National Cancer Institute. 
 
 

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Cytokine Release Syndrome (CRS) 
NOTE: Dose modification (ie, hold and discontinuation) and toxicity management guidelines for CRS are provided based on 2018 
CRS Consensus Grading by Lee et al1. 
CRS is a systemic inflammatory response caused by the release of cytokines, chemokines and interferon (IFN)-inducible genes that 
are expected to induce both innate and adaptive immunity. Clinically, CRS consists of a constellation of symptoms that may include 
fever, nausea, headaches, flushing, flu-like symptoms, tachypnea, hypoxemia, tachycardia, hypotension, confusion, etc, along with 
possible laboratory changes in the cell blood count, liver function tests, C-reactive protein, and ferritin. Because these symptoms can 
progress quickly to become potentially life-threatening, suggested guidelines for the management of sabestomig-related CRS are 
provided below. These general guidelines are to assist the investigator in the diagnosis and management of the potential immune-
mediated/CRS events and are not meant to supplant discussions with the Medical Monitor. Accordingly, please notify the Medical 
Monitor as soon as possible for all AEs consistent with CRS.  
1 Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk 
Manag. 2019;15:323-35. 
 

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Cytokine Release Syndrome 
Severity Grade of the Event  
Dose Modifications 
Toxicity Management 
Grade 1  
Fever (≥ 100 ºF or ≥ 38ºC)* 
No dose modifications. 
Immediately inform Medical Monitor. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology. 
− 
Symptomatic treatment (eg, antipyretics). 
− 
Close monitoring of the vital parameters and 
of biologic lab tests (including CBC, LFTs, CRP, and 
ferritin) should be performed until resolution of symptoms. 
Grade 2 
Fever (≥ 100 ºF or ≥ 38ºC)* with 
hypotension not requiring vasopressors 
and/or hypoxia requiring low-flow 
nasal cannula or blow-by oxygen 
Hold sabestomig until resolution to Grade ≤ 1. 
• 
If toxicity worsens, then treat as Grade 3 or 4. 
• 
If toxicity does not improve to Grade ≤ 1 within 
48 hours, then permanently discontinue 
sabestomig. 
• 
If toxicity improves to Grade ≤ 1 within 48 hours, 
then sabestomig can be resumed under the 
following conditions: 
− 
The event stabilizes and is controlled. 
− 
The patient is clinically stable as per 
investigator or treating physician’s clinical 
judgement. 
− 
Prednisone equivalent dose is ≤ 10 mg/day. 
− 
Immediately inform Medical Monitor. 
− 
Recommend hospitalization for management and 
observation until recovery. 
− 
Close monitoring of the vital parameters and of biologic lab 
tests including CBC, LFTs, CRP and ferritin should be 
performed until the resolution of the symptoms. 
− 
Aggressive supportive care including fluid and electrolyte 
replacement.  
− 
Systemic corticosteroids (1-2 mg/kg/day of 
methylprednisolone IV) should be considered. 
− 
Tocilizumab may be considered per the Investigator’s 
institutional SOPs. 
− 
If the symptoms do not improve within 48 hours despite 
appropriate medical management, proceed with measures 
applicable to Grade 3. 
Grade 3 
Fever (≥ 100 ºF or ≥ 38ºC)* with 
hypotension requiring one vasopressor 
with or without vasopressin and/or 
hypoxia requiring high-flow nasal 
cannula, facemask, non-rebreather 
mask, or Venturi mask not attributable 
to any other cause 
Permanently discontinue investigational drug(s). 
- 
Immediately inform Medical Monitor. 
- 
Proceed with the CRS management related to Grade 2. 
- 
Consider higher dose corticosteroids of 1-2 mg/kg every 
12 hours of methylprednisolone IV (ie, 2-4 mg/kg/day). 

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Cytokine Release Syndrome 
Severity Grade of the Event  
Dose Modifications 
Toxicity Management 
Grade 4 
Fever (≥ 100 ºF or ≥ 38ºC)* with 
hypotension requiring multiple 
vasopressors (excluding vasopressin) 
and/or hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, intubation, 
and mechanical ventilation) not 
attributable to any other cause 
Permanently discontinue sabestomig. 
Immediately inform Medical Monitor. 
Proceed with the CRS management related to Grade 3. 
*In patients who have CRS then receive tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension 
and/or hypoxia. BiPAP, bilevel positive airway pressure; CBC, complete blood count; CPAP, continuous positive airway pressure; CRP, C-reactive protein; CRS, cytokine release 
syndrome; IV, intravenous; LFT, liver function test; SOP, standard operating procedure. 
 

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Non-Immune-Mediated Reactions 
Severity Grade of the Event 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the CTC 
grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study intervention (ie, events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold investigational drug(s) until resolution to ≤ Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold investigational drug(s) until resolution to ≤ Grade 1 or 
baseline. 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume investigational 
drug(s) administration. Otherwise, discontinue investigational 
drug(s). 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue investigational drugs (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with AstraZeneca). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE: Adverse event; CTCAE: Common Terminology Criteria for Adverse Events; NCI: National Cancer Institute. 
 
 

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J 1 
National Cancer Institute Patient Reported Outcomes-Common 
Terminology Criteria for Adverse Events  
Figure 5 
NCI PRO-CTCAE Questionnaire Example  
 

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Basch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer Institute's patient-reported outcomes version of 
the common terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst 2014;106(9). Available at: 
https://healthcaredelivery.cancer.gov/pro-ctcae/. Accessed 27 January 2020.  

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J 2 
National Cancer Institute Pediatric Patient Reported Outcomes-
Common Terminology Criteria for Adverse Events  
Figure 6 
NCI Peds-PRO-CTCAE Questionnaire Example  
 
 

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J 6 
Patient Global Impression of Treatment Tolerability  
Figure 10 
PGI-TT questionnaire  
 
 

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Appendix K  Abbreviations 
Abbreviation or special term 
Explanation 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody  
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AML 
acute myeloid leukemia 
ANSM 
French National Agency for the Safety of Medicines and Health 
Products 
ASCT 
autologous stem cell transplant 
AST 
aspartate aminotransferase 
ATD 
accelerated titration design 
AUC 
area under the concentration curve 
BICR 
blinded independent central review 
BOR 
best overall response 
BUN 
blood urea nitrogen 
CAPA 
corrective and preventive action 
CAR-T 
Chimeric Antigen Receptor T cell 
cHL 
Classical Hodgkin Lymphoma 
CI 
confidence interval 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CR 
Complete Response 
CRO 
Contract Research Organization 
CRR 
Complete Response Rate 
CRS 
Cytokine Release Syndrome 
CSP 
clinical study protocol 
CSTD 
closed system transfer device 
CSR 
clinical study report 
CT 
computed tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
CTFG 
Clinical Trials Facilitation Group 
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Abbreviation or special term 
Explanation 
CTIS 
Clinical Trials Information System 
CTLA-4 
cytotoxic T-lymphocyte associated protein 4 
CTR 
Clinical Trials Regulation 
CTT 
Clinical Trial Transparency 
DCO 
data cut-off  
DEHP 
Di (2-ethylhexyl) phthalate 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid  
DoCR 
Duration of Complete Response 
DoR 
Duration of Response 
DU 
current dose is unacceptably toxic 
EBV 
Epstein Bar Virus 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
 
 
 
 
EMA 
European Medicines Agency 
EOI 
end of infusion 
EORTC IL 
European Organization for Research and Treatment of Cancer Item List 
EoS 
end of study 
EoT 
end of treatment 
ePRO 
electronic device and patient-reported outcome instruments 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
FAS 
full analysis set 
Fc 
fragment crystallizable 
FDA 
US Food and Drug Administration 
FDG 
18F-fluorodeoxyglucose 
FEV1 
Forced Expiratory Volume in the 1st second 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FIH 
first-in-human 
FVC 
forced vital capacity 
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Abbreviation or special term 
Explanation 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GRAD 
Global Retention and Disposal 
HAV 
hepatitis A virus 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HEV 
hepatitis E virus 
HIV 
human immunodeficiency virus 
HL 
Hy’s Law 
HR-MDS 
high risk myelodysplastic syndrome 
HRQoL 
health-related quality of life 
HRS 
Hodgkin Reed-Sternberg 
HSCT 
hematopoietic stem cell transplantation 
HSV 
herpes simplex virus 
IC 
immune checkpoint 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IgG1 
immunoglobulin G1 
IgM 
Immunoglobulin M 
IHC 
immunohistochemistry 
IL 
Interleukin 
ILD 
Interstitial Lung Disease 
ILICI 
immune-mediated liver injury caused by immune checkpoint inhibitors 
IM 
intramuscular 
imAE 
immune-mediated adverse event 
IMP 
investigational medicinal product 
IO 
Immuno-oncology 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRT/RTSM 
Interactive Response Technology System/ Randomization and Trial 
Supply Management 
IV 
intravenous(ly) 

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Abbreviation or special term 
Explanation 
PK/PD 
pharmacokinetics / pharmacodynamics 
PO 
per os (taken orally) 
PP 
polypropylene 
PVC 
polyvinylchloride 
PR 
partial response 
PRO 
patient-reported outcomes 
PRO-CTCAE 
Patient-Reported Outcomes version of the Common Terminology 
Criteria for Adverse Events 
PTAP 
Post-trial Access Program 
Q1W 
every week 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
Q6W 
every 6 weeks 
QL2 
2-item global HRQoL 
QTcF 
Corrected QT interval, using Fridericia’s formula 
RECIL 
Response-evaluation Criteria in Lymphoma 
RNA 
ribonucleic acid 
RP2D 
recommended phase 2 dose 
r/r 
relapsed/refractory 
RT 
radiation therapy 
SAE 
serious adverse event  
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SDi 
shortest diameter 
SLD 
sum of longest diameters 
SJS 
Stevens-Johnson syndrome 
SoA 
schedule of activities 
SoC 
standard of care 
SOI 
start of infusion 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
sWFI 
sterile water for injection 
t½ 
terminal elimination half-life 
TB 
Tuberculosis 
TBL 
total bilirubin 

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Abbreviation or special term 
Explanation 
TCR 
T cell receptor 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
TH1 
T helper 1 
TIM-3 
T cell immunoglobulin and mucin domain-containing protein-3 
TMDD 
Target-mediated drug disposition 
TME 
tumor microenvironment 
TMG 
toxicity management guidelines 
TNF 
Tumor Necrosis Factor 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
V 
Visit 
w/v 
Weight/volume 

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Appendix L Protocol Version History 
The Protocol Version Summary of Changes Table for the current version is located directly 
before the Table of Contents in this document. 
Version 4 (11 July 2023) 
This modification is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
and in the EU Clinical Trial Regulation Article 2, 2 (13).  
Overall Rationale for the Modification: 
The primary rationale for the changes implemented in this protocol modification was to 
introduce the new liquid formulation, implement EU CTR language, and introduce the 
endpoint of quality of life. Further changes were made for clarification and to address 
inconsistencies.  
List of Substantial Modifications 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints – Table 6 and 
Table 7 
Included objectives for quality of life / 
PRO assessments. 
Additional metrics assessing 
impact of AZD7789 on quality of 
life/patient reported outcomes to 
further improve the risk/benefit 
assessment. 
Section 1.1 Synopsis, 
Section 4.1.2 Part B: Dose 
Expansion, and Section 5.1 
Inclusion Criteria #10a 
Changed eligibility of Cohort B1 from at 
least 3 to 2 prior cycles of anti-PD-1/ 
PD-L1 based therapy. 
To expand the participant 
population 
Section 1.3 Schedule of 
Activities – Tables 3 and 4 
Added PRO-CTCAE (or Peds-PRO-
CTCAE), PGI-TT, 
 (or 
a), 
 
To provide schedule of quality of 
life / patient reported outcomes 
assessments 
Section 5.2 Exclusion 
criteria #2 
Added peripheral neuropathy to the list of 
acceptable ongoing ≥ Grade 2 toxicities 
from prior therapies unless 
immune-mediated. 
Accounting for propensity for 
participants to have peripheral 
neuropathy based on prior 
treatment. 
Section 5.2 Exclusion 
criteria #3 
Added list of acceptable unresolved 
imAE ≥ Grade 2  
To account for immune-mediated 
conditions where there would be 
an unreasonable expectation for 
resolution to < Grade 2 given 
pathophysiology of conditions. 
Section 5.2 Exclusion 
Criteria #18b 
Modified the definition of washout period 
to 28 days. 
To account for extended half-lives 
of certain monoclonal antibodies 
while ensuring agents with short-
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Section # and Name 
Description of Change 
Brief Rationale 
half lives have shorter washout 
periods. 
Section 6.1.1 Investigational 
Products – Table 10, and 
Section 6.1.2 Identity of 
Investigational Product(s)  
Added description of 
 formulation.  
New 
formulation added. 
Section 6.2.1 AZD7789 
Infusion Preparation and 
Administration 
Added preparation and administration 
guidance for 
 formulation. 
New
 formulation added. 
Section 8.1.4 Patient-
Reported Outcomes, Section 
9.4.3 Safety Analyses, and 
Section 9.4.4.4 Patient-
Reported Outcomes  
Added description of quality of life / PRO 
secondary and exploratory endpoints to 
be included in Part B of study.  
To acquire additional information 
regarding the impact of AZD7789 
on PRO to support development 
of therapy for r/r cHL population. 
cHL: classical Hodgkin Lymphoma; 
 
; 
; imAE: immune-
mediated adverse event; PD-1: programmed cell death protein-1; PD-L1: programmed cell death ligand-1; r/r: 
relapsed or refractory; Peds: Pediatric; PGI-TT: Patient Global Impression of Treatment Tolerability; 
: 
; 
; PRO: patient-
reported outcomes; PRO-CTCAE: Patient-Reported Outcomes version of the Common Terminology Criteria 
for Adverse Events. 
 
List of Non-substantial Modifications 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Administrative change: 
The version numbering was updated. 
Typos were corrected and minor 
clarifications made. 
Editorial updates 
Title Page 
Added EU CT number 
Update required to comply 
with EU CTR. 
Section 1.1 Synopsis, and 
Section 9.3 Populations for 
Analyses – Table 21 
Updated definition of interim 
response-evaluable population. 
Update to be in consistent with 
planned response assessment 
for Cycle 3. 
Section 1.3 Schedule of 
Activities – Table 1 
COVID-19 testing added to screening 
procedures and footnote added.  
COVID testing is required at 
screening per eligibility 
criteria; updating SoA to align. 
Section 1.3 Schedule of 
Activities – Tables 1, 2, 3 
Moved biomarker evaluation for Genomics 
Initiative from Screening to Cycle 1 Day 1  
Participants must fulfill 
eligibility criteria for inclusion 
in the genetic research 
Section 1.3 Schedule of 
Activities – Tables 1, 2, 3, 4, 
and Section 8.2.7 Clinical 
Clarified when free thyroxine and free 
triiodothyronine testing is indicated and 
footnote added. 
For consistency with 
description of clinical safety 
laboratory variables 
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Section # and Name 
Description of Change 
Brief Rationale 
Safety Laboratory 
Assessments – Table 17 
Section 1.3 Schedule of 
Activities – Tables 2, 3, 4 
Clarified timing of imaging disease 
assessment relative to AZD7789 
administration. 
Improve consistency and 
provide clearer guidance 
Section 1.3 Schedule of 
Activities – Table 2 
Aligned PK schedule and footnote to ADA 
sampling cycle 8 onwards in Part A 
Match PK sampling to ADA 
scheduling 
Section 1.3 Schedule of 
Activities – Table 3 
Added footnote b to C2D8. 
Improve clarity of ECG 
schedule 
Section 1.3 Schedule of 
Activities – Table 3 
Clarified in footnotes that Day 8 ECG 
assessment is only to be performed if 
cardiac signal is detected in Part A. 
Corrected error 
Section 1.3 Schedule of 
Activities – Table 3 
Footnotes and text added to clarify PK 
sample collection for mainland China. 
To correct the PK sampling 
frequency to match Part A 
Section 1.3 Schedule of 
Activities – Table 3 
Clarified in footnotes differences in 
disease response assessment between 
Investigator and BICR review.  
BICR will only assess 
according to Modified Lugano.  
Section 1.3 Schedule of 
Activities – Table 4 
Table formatting mistake fixed. 
No ECHO/MUGA testing 
during remote survival 
follow-up. 
Section 1.3 Schedule of 
Activities – Table 4 
PK timepoint removed at Day 90 post 
treatment 
Reduce sampling where 
appropriate.  
Section 4.2.1 Rationale for 
Endpoints, and Section 8.1 
Disease Response Assessment 
Clarified that Investigator response 
assessment using the Modified Lugano and 
RECIL criteria during Parts A and B were 
secondary endpoints. 
Correcting description of 
analysis. 
Section 4.4 End of Study 
Definition  
Clarified definition of the end of study 
according to European Union and Food 
and Drug Administration requirements. 
For consistency and alignment 
with how study results are 
shared. 
Section 6.1 Study 
Intervention(s) Administered, 
and Section 6.2 
Preparation/Handling/Storage/
Accountability 
Updated language for lyophilized product 
to match current lyophilized product 
template 
For consistency and alignment 
across development program.  
Section 6.1.1 Investigational 
Products 
Added 
 to list of commercially 
available products to be supplied by each 
site. 
Clarified study resourcing 
Section 6.2.1 AZD7789 
Infusion Preparation for 
Administration 
Updated description of AZD7789 product 
preparation and administration.  
Guidance provided for new 
 formulation.  
Section 6.10 Treatment of 
Overdose 
Update of AstraZeneca standard text to 
include new section on the treatment of 
overdose  
Update of AstraZeneca 
standard text 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.1 B-symptoms 
B-symptoms moved from the safety 
section to efficacy assessments 
B-symptoms assessment is not 
a safety measure but is part of 
the disease assessment 
Section 8.1.2 Efficacy 
Assessment Types 
Added description of radiological 
assessment schedule if treatment 
discontinued prior to Year 1 
Clarified assessment schedule 
Section 8.3.13 Medication 
Error, Drug Abuse and Drug 
Misuse 
Added Drug Abuse and Drug Misuse 
definition. 
Update required due to CT-3 
Regulation and corporate 
safety CAPA. 
Section 8.4 Reporting of 
Overdose 
Update of AstraZeneca standard text to 
include new section on the treatment of 
overdose. 
Update of AstraZeneca 
standard text. 
Section 8.6.2.1 Tumor Tissue 
Sample – Table 18 
Adjusted labeling in rows for Part A of the 
study 
To clarify that baseline 
biopsies are required in the 
mTPI portion of the study  
Appendix A 1 Regulatory and 
Ethical Considerations 
Added sub-heading “Regulatory Reporting 
Requirements for Serious Breaches.” 
Update required to comply 
with regulatory requirement 
(eg, EU CTR) and global 
company requirement. 
Appendix A 6 Dissemination 
of Clinical Study Data 
Updated information about timelines for 
submission of trial results summaries to 
EU CTIS. 
Update required to comply 
with EU CTR. 
Appendix A 7 Data Quality 
Assurance 
Updated information about retention 
timelines of records and documents to 
minimum of 25 years after study archiving 
or as required by local regulations.  
Update required to comply 
with EU CTR and global 
company requirement. 
Appendix D 4 Medication 
Error, Drug Abuse, and Drug 
Misuse 
Added detailed Drug Abuse and Drug 
Misuse definition and examples. 
Update required due to CT-3 
Regulation and corporate 
safety CAPA. 
Appendix J Clinical Outcome 
Assessment Questionnaires 
Added example copies of PRO assessment 
questionnaires 
To provide information on 
content of questionnaires. 
BICR: blinded independent central review; C: cycle; CAPA: corrective and preventive action; COVID-19: 
coronavirus disease 2019; CTIS: Clinical Trials Information System; CTR: Clinical Trials Regulation; D: day; 
ECG: electrocardiogram; ECHO: echocardiogram; EU: European Union; IV: intravenous; mTPI: modified 
toxicity probability interval; MUGA: multigated acquisition scan; PK: pharmacokinetic; PRO: patient-reported 
outcomes; RECIL: Response evaluation Criteria in Lymphoma; SoA: schedule of activities. 
 
Version 3 (1 November 2022) 
This modification is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.  

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Summary of Changes: 
List of Substantial Modifications 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, and 
4.1.1 Part A: Dose 
Escalation 
Amended to clarify when a cohort (eg, 
Cohort A5, A6, A7 or A8) could fill their 
roster of up to 12 participants 
independently of each other. 
To clarify the timing of opening a 
mini expansion once a dose level 
cohort is declared safe.  
Section 1.1 Synopsis, 4.1 
Overall Design, and 4.2 
Scientific Rationale for 
Study Design, 9.2 Sample 
Size Determination, 9.3 
Populations for Analysis, 
and Appendix A 3 Informed 
Consent Process 
Added wording associated with 
collecting agreement from a young adult 
participant or their legally authorized 
representative for participation in the 
study, and updated instances of “adult” 
to adult/young adult".  
To align with changes in Section 
5.1 Inclusion Criteria to lower the 
age range of participants from 18 
to 16 years. 
Section 1.3 Schedule of 
Activities – Table 2 
Reduction of PK sampling at later 
timepoints in Part A Dose Escalation. 
To reduce participant burden of 
PK sampling at later timepoints. 
Section 1.3 Schedule of 
Activities – Table 4 
Addition of AZD7789 PK and ADA 
samples at EoT. 
To align with collection of other 
samples at EoT. 
Section 4.5 
Study Stopping Criteria 
The study stopping criteria were further 
clarified for each phase of the study by 
adding frequency and severity of the 
AEs. Some details in this section were 
also removed to avoid redundancy while 
a paragraph was moved to the more 
relevant Section 6.6.7 "Safety Review 
Committee" as the information was 
related to the SRC meeting schedule. 
To address a request from the 
ANSM - amended to clarify the 
study stopping rules, applying to 
the study as a whole and to its 
different phases. 
Section 5.1 Inclusion 
Criteria - #1, #2, and #4. 
Age range of participants lowered from 
18 to 16 years. Addition of text 
specifying that participants between 16 
and 18 years old need to provide assent, 
if required per local regulations, and their 
legally authorized representative must 
give signed written informed consent.  
To increase the therapeutic 
options available for young adults 
with r/r cHL, who otherwise have 
limited treatment alternatives. 
Section 5.1 Inclusion 
Criteria - #7 
“after the last line of therapy” was added. 
Amended to clarify when 
measurable disease was required.   
Section 5.1 Inclusion 
Criteria - #8 
Amended the minimum threshold left 
ventricular ejection fraction as part of the 
inclusion criteria. Added a footnote to 
Table 9 to state that if clinically 
indicated, and at the Investigator’s 
discretion, a consultation with 
cardiologist is recommended for follow-
up.   
Allow patients with mild cardiac 
dysfunction to be included in this 
trial so as not to exclude previous 
heavily pre-treated patients who 
might have mild cardiac 
dysfunction but who could have 
clinical benefit being treated with 
the study drug. 

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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion 
Criteria - #18 
Addition of criterion for minimum body 
weight ≥ 40 kg for all participants. 
Introducing a minimum weight 
will guarantee that participants 
will receive an adequate flat dose 
per current protocol, as 40 kg is 
considered the girls’ 0.4th 
percentile weight at 18 years, 
which means a ≥ 16-year-old 
participant weighing at least 40kg 
will have similar PK/PD and 
metabolism to the adult 
population (≥ 18 years old) 
already being studied in this trial. 
Additionally, the minimum 
threshold weight of 40kg is 
aligned with the inclusion of 
young adult participants per 2019 
FDA guidance (Inclusion of 
Adolescent Patients in Adult 
Oncology Clinical Trials), which 
states that adolescent participants 
weighing at least 40 kg can 
receive the same fixed dose 
administered in adults. 
Section 5.2 Exclusion 
Criteria - #11 
Bold text was added to the exclusion 
criteria as follows: 
“Active or prior documented 
pathologically confirmed autoimmune or 
inflammatory disorders, including 
inflammatory bowel disease (eg, colitis 
or Crohn’s disease), diverticulitis (with 
the exception of diverticulosis)” 
Clarification of the exclusion 
criterion specifying participants 
with pathologically confirmed 
autoimmune or inflammatory 
disorders will be excluded from 
this trial.   
Section 5.2 Exclusion 
Criteria - #3 
Addition of “prior checkpoint inhibitor” 
to clarify which immunotherapy. 
To limit the type of 
immunotherapy to checkpoint 
inhibitors. 
Section 5.2 – Exclusion 
Criteria - #7f 
Specified for participants with 
COVID-19 infection in the last 
3 months, a negative PCR test is needed 
within 72 hours prior to first dose.  
Clarification on timeframe 
regarding testing requirement in 
the event of previous COVID-19 
infection prior to dosing. 
Section 5.2 – Exclusion 
Criteria - #18b 
Washout period timeframe “whichever is 
shorter” updated to “whichever is 
longer”. 
Correction 
Section 6.6.1.2 Modified 
Toxicity Probability 
Interval, and Table 15 
Decreased the upper limit of the target 
toxicity interval from 35% to 33%. 
Table 15 was updated to align with the 
new upper limit and include an 
To address a request from the 
MHRA - amended to provide a 
more conservative Modified 

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Section # and Name 
Description of Change 
Brief Rationale 
additional rule of exception when a 
single dose-limiting toxicity is observed 
among the first 3 participants. 
Toxicity Probability Interval dose 
setting design. 
Section 6.6.3 Definition of 
Dose-limiting Toxicity 
The DLT definition was amended to 
include Grade 4 anemia not related to the 
underlying disease or any extraneous 
cause (eg, bleeding). 
To address a request from the 
ANSM - amended as Grade 4 
anemia is with life-threatening 
consequences and needs urgent 
intervention as per CTCAE v5.0. 
Section 6.7 Dose Delay 
Consideration added as regards dose 
delay.  
Clarification on acceptable timing 
to delay/resume AZD7789 dosing.  
Section 6.8 Treatment 
Beyond Progression 
A subsection was added to provide 
guidance in case pseudo-progression (eg, 
tumor flare due to immunomodulatory 
agent therapy) occurs during treatment 
with the study drug. 
Additional guidance was provided 
to prevent premature treatment 
discontinuation.  
Section 7.1 Discontinuation 
of Study Intervention 
Additional text in terms of efficacy 
assessments during follow-up for 
participants discontinuing study 
intervention due to PD versus participant 
discontinuing the study drug while in 
response (CR, PR) or with stable disease.  
Further clarification to clearly 
specify participants in response 
who discontinue treatment should 
continue efficacy assessments 
until death, PD or start of new 
treatment (whichever occurs first). 
Section 8.1.1 Efficacy 
Assessment Types, Table 
16, Section 1.3 Schedule of 
Activities Table 2, 3 and 4 
Text was added and Table 16 modified to 
clarify timing of imaging based on 
disease response. 
Modification of PET-CT 
frequency requirement to limit the 
exposure of the participant to 
unnecessary radiation.  
Section 8.3.8 Disease 
Progression 
Added text to specify when disease 
progression should be reported as a SAE/ 
SUSAR. 
To address a request from the 
MHRA - amended to include the 
possibility that an IMP enhances 
disease progression, and that an 
investigator may consider that 
disease progression is IMP related 
and as such should be a 
SAE/SUSAR. 
Appendix I Dosing 
Modification and Toxicity 
Management Guidelines for 
AZD7789 Monotherapy 
Revision of the study drug 
discontinuation criteria in the following 
sections: colitis; rash/dermatitis; 
neurotoxicity; peripheral neuromotor 
syndromes; myositis; immune-mediated 
liver injury; cytokine release syndrome 
To address a request from the 
MHRA - amended to add 
permanent study drug 
discontinuation guidance for 
selected high-grade AEs. 
AE: adverse event; ADA: anti-drug antibodies; ANSM: Agence Nationale de Sécurité du Médicament et des 
Produits de Santé (National Security Agency of Medicines and Health Products); cHL: classical Hodgkin 
Lymphoma; CR: complete response; COVID-19: coronavirus disease 2019; CTCAE: Common Terminology 
Criteria for Adverse Events; DLT: dose-limiting toxicity; EoT: end of treatment; FDA: United States Food 
and Drug Administration; IMP: investigational medicinal product; MHRA: Medicines and Healthcare 
products Regulatory Agency; PCR: polymerase chain reaction; PD: progressive disease; PET-CT: positron 

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Section # and Name 
Description of Change 
Brief Rationale 
emission tomography-computed tomography; PK: pharmacokinetic; PK/PD: pharmacokinetics/ 
pharmacodynamics; PR: partial response; r/r: relapsed or refractory; SAE: serious adverse event; SRC: Safety 
Review Committee; SUSAR: suspected unexpected serious adverse reaction. 
 
List of Non-substantial Modifications 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Administrative change: 
The version numbering was updated. 
Typos were corrected and minor 
clarifications made. 
‘The Sponsor’ has been changed to 
‘AstraZeneca’.  
Editorial updates. 
Update of AstraZeneca 
standard text and changed 
globally for consistency. 
Section 1.1 Synopsis, and 
Section 9.5 Interim Analysis 
Clarification of timing and details of 
interim safety and efficacy analysis. 
Amended to differentiate 
timepoints for interim safety 
and efficacy analysis 
(previously described in 
Section 4.5 only) as not 
necessarily both analyses will 
occur at the same time.  
Section 1.1 Synopsis, and 
Section 9.3 Populations for 
Analyses 
Clarified the definition of the interim 
safety and efficacy evaluable populations. 
Amended to remove ambiguity 
of analysis set definition. 
Section 1.1 Synopsis, and 
Section 9.5 Interim Analyses 
Updated text for subsequent interim 
analyses from “will be performed after 
every 20 additional participants” to “may 
be performed after every 20 additional 
participants”. Clarified role of Part A 
participants for interim efficacy analyses 
in synopsis per Section 9.5. 
For operational flexibility, and 
clarification in the synopsis. 
Section 1.1 Synopsis – 
Figure 1 
Figure updated to amend “total n = 
” to 
"total n = up to
" for cohorts A5-A8, and 
text added to clarify total numbers of 
participants in Parts A and B. 
For clarification and 
consistency with updates in 
other sections of the protocol. 
Section 1.3 Schedule of 
Activities – Table 1, Table 3; 
Section 5.1 Inclusion criteria - 
#13; Section 8.5 Human 
Biological Samples; Section 
8.6. Collection of Mandatory 
Samples for Biomarker 
Analysis1; Section 8.6.2.1 
Tumor Tissue Samples; 
Section 8.6.2.2 Non-tumor 
Tissue Biopsy at Toxicity; 
Footnotes and text added to clarify sample 
collection requirements for mainland 
China. 
To conform with 
country-specific sample 
collection requirements 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.6.3 Collection of 
Optional Biomarker Samples; 
Section 8.7 Optional 
Genomics Initiative Sample 
Section 1.3 Schedule of 
Activities – Table 1 
Urine pregnancy test added to the 
screening procedure with footnote 
specifying that in the event of a positive 
urine test, a serum test should be 
performed for confirmation.  
Alignment with Section 8.2.8 
Section 1.3 Schedule of 
Activities – Table 1 
Additional instructions provided for the 
collection of tumor archival tissue to be 
obtained within 4 months of study 
participation. 
Alignment with 
Section 8.6.2.1 
Section 1.3 Schedule of 
Activities – Table 2 and 
Table 3 
Removed “Study Day” row from the SoA. 
Removed to simplify as 
“Cycle Number and Day” are 
already provided in the table. 
Section 1.3 Schedule of 
Activities – Table 2 and 
Table 3 
Removed column for “After EOI” at C1D1 
and added footnotes in ECG and vital 
signs rows. 
For clarity, as EOI collection 
of ECGs, vital signs and PK 
samples are already detailed in 
the footnotes of the table. The 
hematology EOI sample was 
removed as it was not an 
informative assessment. 
Section 1.3 Schedule of 
Activities – Table 2 
Anti-drug antibody sample collection 
added in the schedule of activities for 
C2D8. 
Alignment between the 
clinical study protocol and the 
laboratory manual 
Section 1.3 Schedule of 
Activities – Table 2, Table 3, 
Table 4 
Clarifications made for assessment and 
sampling timepoints.  
 
To avoid confusion around 
collection timings for samples. 
Section 1.3 Schedule of 
Activities – Table 3, Table 4 
Addition of soluble TIM-3 assessments to 
Tables 3 and 4. 
To correct previous omission 
of TIM-3 assessments in 
Tables 3 and 4. 
Section 3 Objectives and 
Endpoints – Table 7 
Exploratory endpoint
 
 
. Formatting of list of 
secondary endpoints for Part A Dose 
Escalation and Part B Dose Expansion 
updated. 
Removed as this was a 
duplication of the secondary 
endpoint for Part A and Part B. 
Formatting improved to clarify 
which footnotes pertain to 
which endpoints. 
Section 4.2 Scientific 
Rationale for Study Design 
Update from 1 to 2 prior lines of therapy. 
Correction of typo to be 
aligned with inclusion 
criterion #9 
Section 4.5 Study Stopping 
Criteria, and Section 6.6.7 
Safety Review Committee 
The paragraph describing SRC safety 
review milestones during Part A of the 
study was moved for clarity from Section 
Moved for clarity since the 
paragraph pertains to SRC 
safety review milestones 
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Section # and Name 
Description of Change 
Brief Rationale 
4.5 "Study Stopping Criteria" to the more 
relevant Section 6.6.7 "Safety Review 
Committee". 
during Part A of the study and 
not to study stopping criteria. 
Section 5.1 Inclusion Criteria - 
#8 
Removed “measured within 7 days prior to 
first dose” 
The values in Table 9 pertain 
to study entry levels, so this 
text is not needed. 
Addition of a footnote to Table 9 to 
explain that from cycle 2 onwards, 
thresholds for adequate marrow, renal and 
liver function must be met. 
For clarification and 
completeness. 
Section 6.1.1 Investigational 
Products 
“within 1 to 3 days prior to infusion” 
amended to “within 3 days prior to 
infusion” 
Amended to provide flexibility 
in logistics and scheduling at 
site 
Section 6.2.3 AZD7789 IV 
Bag or Syringe Preparation for 
IV Administration 
Timepoints for vital signs checks replaced 
by reference to schedule of assessments 
Table 2 and Table 3  
Clarification to provide all 
timepoints in one single place  
Section 6.3 Measures to 
Minimize Bias: 
Randomization and Blinding  
Text “or B1 and B2” removed. Text 
“starting with the highest dose that has 
been declared safe by the SRC. However, 
prioritization may be given to cohorts 
where potential clinical activity has been 
observed” added. 
Cohort assignment was 
inaccurately defined, and 
clarification was provided as 
follows for: 
• 
Cohorts B1 and B2, text 
was not applicable as 
study entry is not 
randomly assigned but is 
dependent on prior 
anti-PD-1 exposure 
• 
Cohorts A5 to A8, 
clarification on cohort 
assignment in the event 
mini dose expansions are 
opened in parallel. 
Section 6.5.1 Premedication 
Removed dose specification for 
acetaminophen. 
Clarification. 
Section 6.5.2 Rescue 
Medicine – Table 13 
The recommended timing for COVID-19 
vaccination was clarified for the first 2 
cycles. Text related to cycle 2 was 
removed. 
Clarification as cycle 2 occurs 
within the 28 days DLT 
period, during which 
COVID-19 vaccination is not 
recommended. 
Section 6.6.1 Starting Dose, 
Dose Escalation Scheme, and 
Stopping Criteria – Table 14 
Removed footnote “a”. 
Correction – footnote was not 
required in the table. 
Section 6.6.5 Definition of 
Optimal Biological Dose 
Clarified that RP2D will be selected by 
AstraZeneca in discussion with members 
of the Study Steering Committee. 
Clarification. 

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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.6.6 Definition of 
DLT-evaluable Participants 
Re-wording to indicate 28 days is the 
DLT-evaluation period. 
Clarification and to align with 
other sections of the protocol 
Section 8.1.1 Efficacy 
Assessment Types – Table 16, 
and Section 1.3 Schedule of 
Activities Tables 2, 3, and 4 
Text added to describe options for imaging 
modalities and that the modality selected at 
baseline should remain consistent during 
the study. 
To clarify the definition of 
diagnostic quality and what to 
do in the event of contrast 
shortage. 
Section 8.1.2 Blinded 
Independent Review 
Committee Assessment 
Addition of subsection describing central 
review of radiological imaging by BICR in 
Part B of the study, and that in Part A, 
imaging must be archived and transferred 
to the BICR vendor to allow retrospective 
disease response assessment in participants 
treated at a potential RP2D. 
Guidelines on transfer and 
archiving of disease 
assessment imaging reports 
were added because 
participants treated with the 
RP2D at Part A will be 
included in the Part B analysis.  
Section 8.2.7 B-symptoms 
Clarification that presence of B-symptoms 
should not be used in the overall response 
assessment as per Lugano 2014. 
B-symptoms assessment is not 
part of the overall disease 
response criteria as per Lugano 
2014. 
Section 8.2.8 Clinical Safety 
Laboratory Assessment 
Table 17 
Creatinine clearance added to the list of 
parameters to tested for biochemistry 
To be consistent with inclusion 
criterion #8, Table 9.  
Section 8.3.1 Time Period and 
Frequency for Collecting AE 
and SAE Information 
“Serious AEs will be recorded from the 
time of signing of ICF.” was modified to 
“Serious AEs will be collected from the 
time of signing of ICF until the end of the 
study.” 
To address a request from the 
German Clinical Ethics 
Committee - amended to 
clarify that SAEs are recorded 
throughout the entire duration 
of the clinical trial. 
Section 8.6.1 Collection of 
Mandatory Samples for 
Biomarker Analysis 
Sampling timepoints for tumor tissue 
samples removed, and text mentioning 
 serum samples added. 
Alignment with timeframes 
outlined in Table 18, and to 
clarify there are 2 serum 
biomarker samples 
(exploratory analysis and 
). 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.6.2.1 Tumor Tissue 
Samples, and Table 18 
The following instructions were added to 
the section for the collection of tumor 
archival tissue to be obtained within 4 
months prior to initiating of study 
intervention: “participant must not have 
received any anti-cHL treatment within 
that time period otherwise fresh tissue 
required”.  
Additionally, in Table 18 it was clarified 
that the instructions for tumor tissue 
collection apply to the entire dose 
escalation regardless of the design and 
therefore “accelerated titration design 
segment” was removed to avoid confusion.  
Additional instruction 
provided as archival tissue 
prior to study entry will 
utilised as baseline and any 
treatment intervention 
in-between will interfere with 
the biology of the tumor.  
Section 9 Statistical 
Considerations 
Clarification of interim safety population, 
timing of primary, safety, and efficacy 
analysis, other minor clarifications, and a 
correction to the heading of Table 23. 
Amended for clarification and 
consistency with other 
protocol sections. Table 23 
heading corrected to refer to 
Cohort B2. 
Section 9.4.4.1 
Pharmacokinetics and 
Pharmacodynamics 
Updated text to indicate analysis of PK/PD 
data will be described in a separate 
document. 
Clarification of potential 
exploratory analysis of PK/PD. 
Section 9.5 Interim Analyses 
Language amended to specify Investigator 
assessment will be used for interim 
analysis assessment and, as appropriate, 
BICR assessment may complement. 
For clarification of endpoints 
considered for interim efficacy 
analyses to enable timely 
evaluation of emerging data. 
Appendix C Response 
Evaluation Using the 
Modified Lugano (Cheson et 
al, JCO 2014) and RECIL 
(Younes et al, Ann Oncol 
2017) Criteria 
Additional guidance provided in the 
appendix to perform disease assessment as 
per Modified Lugano 2014 and as per 
RECIL. The Deauville 5-point scale was 
updated per Cheson et al 2014. 
For clarification and 
completeness.  
Appendix K Protocol Version 
History 
Added Protocol Version History Appendix  Appendix was added to 
include previous version 
summaries of changes. 
Appendix J Abbreviations 
Abbreviations added/removed. 
To align with revisions. 
Missing abbreviations added. 
AE: adverse event; BICR: blinded independent central review; C: cycle; cHL: classical Hodgkin Lymphoma; 
COVID-19:  coronavirus disease 2019; D: day; DLT: dose-limiting toxicity; ECG: electrocardiogram; EOI: end 
of infusion; ICF: informed consent form; IV: intravenous; PD-1: programmed cell death protein-1; PK: 
pharmacokinetic; PK/PD: pharmacokinetics/pharmacodynamics; RECIL: Response Evaluation Criteria in 
Lymphoma; RP2D: recommended phase 2 dose; SAE: serious adverse event; SOA: Summary of Assessments; 
SRC: Safety Review Committee; TIM-3: T cell immunoglobulin and mucin domain-containing protein-3. 

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Version 2 (24 September 2021) 
This modification is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Modification: 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
Section 1.1 
Synopsis 
The synopsis was revised to 
align with revisions in the 
CSP sections. 
Revisions were made for 
consistency. 
Non-substantial 
Section 1.2 
Schema 
The schema was revised to 
align with revisions in 
Sections 6.6.1 and 9.2. 
Revisions were made for 
consistency. 
Non-substantial 
Section 1.3 
Schedule of Activities 
In Table 2 and Table 3, ADA 
sample timepoints were 
revised. 
Amended in response to 
request from FDA. 
Non-substantial 
Table 2 and Table 3 were 
aligned with revisions in 
Sections 6.2.3, 6.5.1 (newly 
added) and 6.6.1.1. 
Revisions were made for 
consistency. 
Non-substantial 
Section 4.1 
Overall Design 
Part A and Part B were 
described in more detail and 
the number of participants to 
be enrolled was updated. The 
participants to be included in 
the analysis in Cohort B1 was 
clarified. 
Amended in response to 
request from FDA. 
Non-substantial 
Section 4.2.1 
Rationale for Endpoints 
Added text to clarify that the 
selection of the RP2D will be 
made by the Study Steering 
Committee, based on the 
OBD. 
Amended in response to 
request from FDA. 
Non-substantial 
Section 4.5 
Study Stopping Criteria 
The stopping criteria were 
expanded and described in 
more detail. 
Amended in response to 
request from FDA. 
Substantial 
Section 5.1 Inclusion 
criteria 
Inclusion criterion 9 for 
Part A was modified to 
require that participants failed 
at least 2 prior lines of 
systemic therapy (instead of 
2 prior lines of therapy) and 
received at least 3 cycles of 
anti-PD-1/PD-L1 based 
therapy (instead of 1 cycle) 
Amended in response to 
request from FDA. 
Substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
Section 6.1.1 
Investigational Products 
Added text to describe dosing 
criteria for Cycles ≥ 2. 
Amended in response to 
request from FDA. 
Substantial 
Section 6.2.3 
AZD7789 IV Bag or 
Syringe Preparation for 
IV Administration 
Added text to clarify how 
participants will be monitored 
during and after infusions, on 
Cycle 1 Day 1 and for 
subsequent doses. 
Amended in response to 
request from FDA. 
Substantial 
Section 6.5.1 
(Premedication) 
This section was added to 
discuss premedication to be 
administered 30 minutes prior 
to each dose. 
Amended in response to 
request from FDA. 
Substantial 
Section 6.5.2 
Rescue Medication 
(previously 
Section 6.5.1) 
Table 12 was updated to 
include a reference to the text 
added in Section 6.5.1. In 
addition, existing text was 
updated for clarification. 
Revisions were made for 
consistency. 
Non-substantial 
Section 6.6.1 
Starting Dose, Dose 
Escalation Scheme, and 
Stopping Criteria 
Added text to explain that the 
planned dose levels may need 
to be adjusted depending on 
reported AEs and DLTs. 
Amended in response to 
request from FDA. 
Substantial 
Section 6.6.1.2 
Modified Toxicity 
Probability Interval 
Added text to specify that the 
posterior distribution for all 
dose levels is Beta(1+a, 1+b), 
where a and b are the number 
of participants with and 
without a DLT at the current 
dose level, respectively.  
The criteria for an unsafe dose 
level and dose escalation/de-
escalation decision rules were 
adjusted. 
Amended in response to 
request from FDA. 
Substantial 
Section 6.6.3 
Definition of 
Dose-limiting Toxicity 
The DLT evaluation period 
was changed from 21 to 
28 days from the first dose of 
AZD7789 on Cycle 1 Day 1. 
Amended in response to 
request from FDA. 
Substantial 
Updated conditions to be 
considered as DLTs: 
Conditions for 
thrombocytopenia were 
updated and conditions for 
CRS were added. 
Amended in response to 
request from FDA. 
Substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
Section 6.6.6 
Definition of DLT-
evaluable Participants 
The definition for an 
evaluable participant was 
aligned with revised 
definition of the DLT 
evaluation period in 
Section 6.6.3. 
Revisions were made for 
consistency. 
Substantial 
Section 8.6.2.1 Tumor 
Tissue Samples 
Table 18 was corrected to 
indicate that Cycle 1 Day 8 
biopsy during Part B is not 
mandatory if medically 
contraindicated. 
Correction of a typo. 
Non-substantial 
Section 9.2 
Sample Size 
Determination 
The total number of 
participants to be enrolled in 
the study and the number of 
participants to be enrolled in 
Part B were updated. 
Amended in response to 
request from FDA. 
Substantial 
Section 9.3 
Populations for 
Analyses  
In Table 21, the definition for 
an evaluable participant was 
aligned with revised 
definition of the DLT 
evaluation period in 
Section 6.6.3. 
Revisions were made for 
consistency. 
Substantial 
Section 9.4.2.2 
Secondary Endpoint(s) 
It was clarified that, for 
progression-free survival, 
additional 
supportive/sensitivity 
analyses will be provided in 
the SAP. 
Amended in response to 
request from FDA. 
Non-substantial 
Section 9.4.3.1 
Maximum Tolerated 
Dose Evaluation 
Changed the probability 
percentage for dose level 
considered to be unsafe. 
Amended in response to 
request from FDA. 
Substantial 
Section 9.5 
Interim Analyses 
It was clarified that 
participants treated at the 
RP2D in Part A will be 
included in Cohort B1. 
Amended in response to 
request from FDA. 
Substantial 
Section 9.5.1 Relapsed 
or Refractory cHL, 
Anti-PD-1/PD-L1 
Exposed  
Defined No-Go and false No-
Go criteria. 
Amended in response to 
request from FDA. 
Substantial 
Section 9.5.2 
Relapsed or Refractory 
cHL, Anti-PD-
1/PD-L1-naïve 
Defined No-Go and false No-
Go criteria. 
Amended in response to 
request from FDA. 
Substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
Appendix I 
Added section for Cytokine 
Release Syndrome (CRS). 
 Amended in response to 
request from FDA. 
Substantial 
Appendix J 
Added abbreviations to align 
with revisions. 
Revisions were made for 
consistency. 
Non-substantial 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore have not 
been summarized. 
Non-substantial 
 
 

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