Conditions: Acute Myeloid Leukemia
Keywords: Sabatolimab MBG453 TIM-3 Azacitidine Acute Myeloid Leukemia AML Allogeneic Hematopoietic Stem Cell Transplantation aHSCT Measurable Residual Disease MRD Phase Ib/II Acute myeloid leukemia Hematopoietic stem cell transplantation
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 24
Healthy volunteers: no

Brief summary:
The primary purpose of this study was to test the hypothesis that preemptive treatment with sabatolimab, alone or in combination with azacitidine, when administered to participants with Acute myeloid leukemia (AML)/secondary AML who were in complete remission with positive measurable residual disease post-allogeneic hematopoietic stem cell transplantation (Minimal residual disease (MRD)+ post- Allogeneic hematopoietic stem cell transplantation (aHSCT)), could enhance the graft versus leukemia (GvL) response and prevent or delay hematologic relapse without an unacceptable level of treatment-emergent toxicities, including clinically significant acute and/or chronic graft-versus-host disease (GvHD) and immune-related adverse events

Detailed description:
This is a phase Ib/II, open label, multi-center study of sabatolimab as monotherapy and in combination with azacitidine, in participants with AML/secondary AML who had received one aHSCT and achieved complete remission but MRD+, by local assessment, anytime at \>= Day 60 after aHSCT and at least 2 weeks after immunosuppressive medications had been tapered off.

The study was planned to enroll approximately 59 participants and be conducted in two parts:

Part 1 was a Safety Run-in of approximately 20 participants, to assess whether sabatolimab as monotherapy at the two tested dose levels (400 mg and 800 mg intravenously Q4W) was safe when administered in the post-aHSCT setting. For each dose level, once the required number of evaluable participants had been confirmed, enrollment would be halted until participants had completed the dose limiting toxicities (DLT) observation period (≥ 8 weeks following the first dose). Following the observation period for DLTs, a Safety Review Meeting was to be conducted after each dose level to assess safety and determine the recommended dose for expansion to proceed with enrollment of additional cohorts in Part 2 of the study.

Part 2 consisted of sabatolimab monotherapy expansion cohort of approximately 13 participants, sabatolimab in combination with azacitidine cohort of approximately 20 participants, and an adolescent cohort of approximately 6 participants (≥ 12 years but \< 18 years of age) with sabatolimab as monotherapy. Sabatolimab was to be administered at the recommended dose for expansion determined in Part 1.

After initiating Part 2, Novartis took the decision to put enrollment in permanent halt and terminate the sabatolimab program. This decision was not driven by any safety concerns.

Arms:
arm 1: Safety cohort 1: Participants in this arm will receive sabatolimab 400mg intravenously every 4 weeks. arm 2: Safety cohort 2: Participants in this arm will receive sabatolimab 800mg intravenously every 4 weeks. arm 3: Expansion cohort 3: Participants in this arm will receive sabatolimab at the recommended dose for expansion in combination with azacitidine. arm 4: Expansion cohort 4: Participants in this arm will receive sabatolimab at the recommended dose for expansion. arm 5: Adolescent safety cohort (cohort 5): ≥12 to \< 18 year old adolescent participants in this arm will receive sabatolimab at the recommended dose for expansion.

Interventions: intervention 1: Sabatolimab intervention 2: Azacitidine
Intervention descriptions: intervention 1: Sabatolimab is a solution in vial for IV infusion intervention 2: Azacitidine comes in Vial for IV infusion or subcutaneous administration

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
MBG453 
Clinical Trial Protocol CMBG453F12201 / NCT04623216
A phase Ib/II, open label study of sabatolimab as a 
treatment for patients with acute myeloid leukemia and 
presence of measurable residual disease after 
allogeneic stem cell transplantation 
Document type: 
Amended Clinical Trial Protocol  
EUDRACT number: 
2020-000869-17  
Version number: 
02 (Clean) 
Clinical Trial Phase: 
I/II 
Release date: 
24-Mar-2022
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents .................................................................................................... 2 
List of tables ........................................................................................................... 5 
List of figures ......................................................................................................... 6 
List of abbreviations ............................................................................................... 7 
Glossary of terms .................................................................................................. 11 
Amendment 2 (24-Mar-2022) .............................................................................. 14 
Amendment 1 (16-Apr-2021) ............................................................................... 16 
Protocol summary ................................................................................................. 18 
1 
Introduction .......................................................................................................... 22 
1.1 
Background ............................................................................................... 22 
1.2 
Purpose ..................................................................................................... 26 
2 
Objectives, endpoints and estimands .................................................................... 27 
2.1 
Primary estimands .................................................................................... 29 
2.2 
Secondary estimands ................................................................................ 32 
3 
Study design ......................................................................................................... 32 
4 
Rationale ............................................................................................................... 36 
4.1 
Rationale for study design ........................................................................ 36 
4.2 
Rationale for dose/regimen and duration of treatment ............................. 36 
4.3 
Rationale for choice and dose of combination drugs ................................ 39 
4.4 
Rationale for MRD assessments 
 .................. 40 
4.4.1 
Rationale for MRD assessments .............................................. 40 
 
 41 
4.5 
Purpose and timing of interim analyses/design adaptations ..................... 41 
4.6 
Risks and benefits ..................................................................................... 42 
5 
Study Population .................................................................................................. 43 
5.1 
Inclusion criteria ....................................................................................... 43 
5.2 
Exclusion criteria ...................................................................................... 44 
6 
Treatment .............................................................................................................. 46 
6.1 
Study treatment ......................................................................................... 46 
6.1.1 
Investigational and control drugs ............................................. 47 
6.1.2 
Additional study treatments ..................................................... 48 
6.1.3 
Treatment arms/group .............................................................. 48 
6.1.4 
Guidelines for continuation of treatment ................................. 48 
6.1.5 
Treatment duration ................................................................... 48 
6.2 
Other treatment(s) ..................................................................................... 49 
6.2.1 
Concomitant therapy ................................................................ 49 
6.2.2 
Prohibited medication .............................................................. 50 
6.3 
Participant numbering, treatment assignment, randomization ................. 50 


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6.3.1 
Participant numbering .............................................................. 50 
6.3.2 
Treatment assignment, randomization ..................................... 51 
6.4 
Treatment blinding ................................................................................... 52 
6.5 
Dose escalation and dose modification..................................................... 52 
6.5.1 
Dose escalation guidelines ....................................................... 52 
6.5.2 
Guidelines for determination of the recommended dose for 
expansion (RDE) ...................................................................... 52 
6.5.3 
Definitions of dose limiting toxicities (DLTs) ......................... 53 
6.5.4 
Dose modifications ................................................................... 55 
6.5.5 
Follow-up for toxicities ............................................................ 59 
6.6 
Additional treatment guidance .................................................................. 62 
6.6.1 
Treatment compliance .............................................................. 62 
6.7 
Preparation and dispensation .................................................................... 62 
6.7.1 
Handling of study treatment and additional treatment ............. 63 
6.7.2 
Instruction for prescribing and taking study treatment ............ 64 
7 
Informed consent procedures ............................................................................... 64 
8 
Visit schedule and assessments ............................................................................ 65 
8.1 
Screening .................................................................................................. 84 
8.1.1 
Eligibility screening ................................................................. 85 
8.1.2 
Information to be collected on screening failures .................... 85 
8.2 
Participant demographics/other baseline characteristics .......................... 85 
8.3 
Efficacy ..................................................................................................... 86 
8.3.1 
Efficacy response assessment .................................................. 86 
8.3.2 
Efficacy assessment: MRD by MFC ........................................ 88 
8.3.3 
Appropriateness of efficacy assessments ................................. 89 
8.4 
Safety ........................................................................................................ 90 
8.4.1 
Laboratory evaluations ............................................................. 92 
8.4.2 
Electrocardiogram (ECG) ........................................................ 93 
8.4.3 
Pregnancy and assessments of fertility .................................... 94 
8.4.4 
Other safety evaluations ........................................................... 95 
8.4.5 
Appropriateness of safety measurements ................................. 96 
8.5 
Additional assessments ............................................................................. 96 
8.5.1 
Clinical Outcome Assessments (COAs) .................................. 96 
8.5.2 
Pharmacokinetics ..................................................................... 97 
8.5.3 
Biomarkers ............................................................................... 99 
9 
Study discontinuation and completion ............................................................... 101 
9.1 
Discontinuation and completion ............................................................. 101 
9.1.1 
Study treatment discontinuation and study discontinuation... 101 


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9.1.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples .......................................................... 103 
9.1.3 
Lost to follow-up .................................................................... 104 
9.1.4 
Early study termination by the sponsor .................................. 104 
9.2 
Study completion and post-study treatment ........................................... 105 
10 Safety monitoring and reporting ......................................................................... 105 
10.1 
Definition of adverse events and reporting requirements ....................... 105 
10.1.1 
Adverse events ....................................................................... 105 
10.1.2 
Serious adverse events ........................................................... 107 
10.1.3 
SAE reporting......................................................................... 108 
10.1.4 
Pregnancy reporting ............................................................... 109 
10.1.5 
Infection reporting .................................................................. 110 
10.1.6 
Reporting of study treatment errors including misuse/abuse . 110 
10.2 
Additional Safety Monitoring ................................................................. 110 
11 Data Collection and Database management ....................................................... 111 
11.1 
Data collection ........................................................................................ 111 
11.2 
Database management and quality control ............................................. 111 
11.3 
Site monitoring ....................................................................................... 112 
12 Data analysis and statistical methods ................................................................. 112 
12.1 
Analysis sets ........................................................................................... 113 
12.2 
Participant demographics and other baseline characteristics .................. 113 
12.3 
Treatments .............................................................................................. 114 
12.4 
Analysis supporting primary objectives ................................................. 114 
12.4.1 
Definition of primary endpoint(s) .......................................... 114 
12.4.2 
Statistical model, hypothesis, and method of analysis ........... 114 
12.4.3 
Handling of intercurrent events of primary estimand ............ 116 
12.4.4 
Handling of missing values not related to intercurrent event 116 
12.4.5 
Sensitivity analyses ................................................................ 116 
12.4.6 
Supplementary analysis .......................................................... 117 
12.4.7 
Supportive analyses ................................................................ 117 
12.5 
Analysis supporting secondary objectives .............................................. 117 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) ..................... 117 
12.5.2 
Safety endpoints ..................................................................... 118 
12.5.3 
Pharmacokinetics ................................................................... 119 
 
 120 
 
 120 
 
 120 
12.7 
Interim analyses ...................................................................................... 121 
12.8 
Sample size calculation........................................................................... 122 


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12.8.1 
Primary endpoint(s) ................................................................ 122 
13 Ethical considerations and administrative procedures ....................................... 127 
13.1 
Regulatory and ethical compliance ......................................................... 127 
13.2 
Responsibilities of the investigator and IRB/IEC ................................... 128 
13.3 
Publication of study protocol and results................................................ 128 
13.4 
Quality Control and Quality Assurance .................................................. 128 
14 Protocol adherence ............................................................................................. 128 
14.1 
Protocol amendments.............................................................................. 129 
15 References .......................................................................................................... 130 
16 Appendices ......................................................................................................... 135 
16.1 
Appendix 1: Acute GvHD Staging Criteria (Harris et al 2016) ............. 135 
16.2 
Appendix 2: Grading of Chronic GvHD (NIH Consensus Criteria) ...... 137 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-
up ............................................................................................................ 141 
16.4 
Appendix 4: Infection Severity Grading................................................. 143 
16.5 
Appendix 5: Patient Past History and Disease Characteristics ............... 148 
16.6 
Appendix 6: Statistical details on the Bayesian Logistic Regression Model 
(BLRM) .................................................................................................. 151 
List of tables 
Table 2-1 
Objectives and related endpoints ............................................. 27 
Table 6-1 
Investigational and control drug ............................................... 47 
Table 6-2 
Criteria for Dose Limiting Toxicities (DLTs) .......................... 54 
Table 6-3 
Criteria for dose interruption, re-initiation and discontinuation 
of sabatolimab due to adverse drugs reactions ......................... 55 
Table 6-4 
Criteria for dose interruption, re-initiation and discontinuation 
of study treatment due to GvHD .............................................. 58 
Table 6-5 
Follow-up of abnormal liver chemistry results ........................ 60 
Table 6-6 
Action required for isolated total bilirubin elevation ............... 61 
Table 8-1 
Assessment Schedule, Sabatolimab monotherapy cohort ........ 66 
Table 8-2 
Assessment Schedule, Sabatolimab in combination with 
Azacitidine ............................................................................... 74 
Table 8-3 
Response classification in AML at a given evaluation time 
(based on IWG Cheson et al 2003, ELN 2017 Döhner et al 
2017) ........................................................................................ 88 
Table 8-4 
BMA for MRD by flow cytometry .......................................... 89 
Table 8-5 
Assessments & Specifications.................................................. 90 
Table 8-6 
ECOG performance status ........................................................ 90 
Table 8-7 
Karnofsky/Lansky Performance Scales ................................... 91 
Table 8-8 
Local clinical laboratory parameters collection plan ............... 92 
Table 8-9 
Central clinical laboratory parameters collection plan ............. 93 


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Table 8-10 
ECG collection plan ................................................................. 93 
Table 8-11 
Blood (serum) collection schedule for PK, 
 for 
sabatolimab monotherapy (All cohorts except Cohort 3) ........ 97 
Table 8-12 
Blood (serum) collection schedule for PK, 
 for 
sabatolimab in combination with azacitidine (Cohort 3) ......... 98 
Table 8-13 
BMA for Biomarkers for all cohorts ...................................... 100 
 
 101 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................... 110 
Table 12-1 
Probability of unacceptable toxicity for different hypothetical 
scenarios ................................................................................. 122 
Table 12-2 
Data scenarios, inferential results and decisions for different 
values of the proportion of participants with no hematologic 
relapse in the sabatolimab monotherapy arm (n=25) ............. 124 
Table 12-3 
Data scenarios, inferential results, and decisions for different 
values of the proportion of participants with no hematologic 
relapse in the combination arm (sabatolimab + azacitidine) 
(n=20) ..................................................................................... 126 
Table 16-1 
Acute GvHD Staging Criteria (Harris et al 2016) .................. 135 
Table 16-2 
NIH global severity of chronic GvHD ................................... 139 
Table 16-3 
Specific Renal Alert Criteria and Actions .............................. 141 
Table 16-4 
Renal Event Follow Up .......................................................... 142 
Table 16-5 
Severity grading table and recurrence interval definitions .... 143 
Table 16-6 
Four age groups relevant to HCT ........................................... 146 
Table 16-7 
2016 WHO AML classification ............................................. 148 
Table 16-8 
2017 ELN risk stratification by genetics ................................ 149 
Table 16-9 
Prior distribution .................................................................... 151 
Table 16-10 
Summary of prior distribution of DLT rates .......................... 151 
Table 16-11 
Probability of unacceptable toxicity for different hypothetical 
scenarios ................................................................................. 152 
Table 16-12 
Operating characteristics for different true values of DLT rate
 ................................................................................................ 152 
List of figures 
Figure 3-1 
Study design ............................................................................. 33 
Figure 3-2 
Study Flow ............................................................................... 35 
Figure 12-1 
Operating characteristics for the proportion of participants with 
no hematologic relapse in the sabatolimab monotherapy arm 125 
Figure 12-2 
Operating characteristics for the proportion of participants with 
no hematologic relapse in the combination arm (sabatolimab + 
azacitidine) ............................................................................. 127 
 


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List of abbreviations 
 
 
ADL 
Activities of daily living 
AE 
Adverse Event 
aGvHD 
acute Graft versus Host Disease 
aHSCT 
allogeneic Hematopoietic Stem Cell Transplantation 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the curve 
AV 
Atrioventricular 
AZA 
Azacitidine 
BLRM 
Bayesian Logistic Regression Model 
BM 
Bone marrow 
BMA 
Bone marrow aspirate 
BMB 
Bone marrow biopsy 
BMT CTN 
Blood and Marrow Transplant Clinical Trials Network 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary artery bypass graft 
cGvHD 
chronic Graft versus Host Disease 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CIR 
Cumulative incidence of relapse 
CK 
Creatinine Kinase 
Cmax 
Maximum plasma concentration 
Cmin 
Minimum plasma concentration 
CMO&PS  
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 
COVID-19 
Coronavirus disease 2019 
CR 
Complete remission 
CRA 
Contract research associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRi 
Complete remission with incomplete hematologic recovery 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CSA 
Cyclosporin A 
CSR 
Clinical study report 


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CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
CTT 
Clinical trial team 
CV 
coefficient of variation 
DDE 
Direct Data Entry 
DDS 
Dose determining set 
DFS 
Disease free survival 
DILI 
Drug-Induced Liver Injury  
DLI 
Donor lymphocyte infusion 
DLT 
Dose Limiting Toxicity 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EFS 
Event free survival 
ELISA 
Enzyme-linked immunosorbent assay 
ELN 
European Leukemia Network 
EMD 
Extramedullary disease 
EOT 
End of treatment 
eSource 
Electronic Source 
EU 
European union 
EWOC 
Escalation with overdose control 
FAS 
Full Analysis Set 
FEV1 
Forced expiratory volume in 1 second 
FISH 
Fluorescence in situ hybridization 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GLDH 
Glutamate dehydrogenase  
GRFS 
GvHD-free/relapse-free survival 
GvHD 
Graft versus Host Disease 
GvL 
Graft versus Leukemia  
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
Hgb 
Hemoglobin 
HHV6 
Human Herpes Virus 6 
HIV 
Human immunodeficiency virus 
HLA 
Human Leukocyte Antigen 
HMA 
Hypomethylating agent 
HR 
Hazard ratio 
HR-MDS 
High-risk myelodysplastic syndrome 
hrs 
Hour 
HSCT 
Hematopoietic Stem Cell Transplantation 


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HSV 
Herpes simplex virus 
HZV 
Herpes Zoster Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IFN 
interferon-gamma 
 
 
IL 
Interleukin 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IO 
Immuno-oncology 
iPSP 
initial Pediatric Study Plan 
irAE 
immune-related adverse events 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IST 
Immunosuppressive treatment 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IV 
Intravenous 
IWG 
International Working Group 
LAIP 
Leukemia associated immunophenotype 
LC-MS 
Liquid chromatography mass spectrometry 
LDH 
lactate dehydrogenase 
LFS 
leukemia-free survival 
LFT 
Liver function test  
LLOQ 
lower limit of quantification 
LMWH 
Low molecular weight heparin 
LUC 
Large unstained cells 
MDRD 
Modification of diet in renal disease 
MedDRA 
Medical dictionary for regulatory activities  
MFC 
Multiparameter flow cytometry 
mg 
milligram(s) 
MI 
Myocardial infarction 
mL 
milliliter(s) 
MLFS 
Morphologic leukemia-free state 
MRD 
Measurable Residual Disease 
MUGA 
Multiplied-Gated Acquisition 
NCI 
National Cancer Institute 
NGS 
Next Generation Sequencing 
NIH 
National Institutes Health 
NK 
Natural killer 
NTproBNP 
N-terminal prohormone brain natriuretic peptide  
OS 
Overall survival 
PB 
Peripheral blood 
PCR 
Polymerase Chain Reaction 


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PD 
Pharmacodynamic 
PD-1 
Programmed cell death protein 1 
PK 
Pharmacokinetic(s) 
PS 
Performance status 
Q4W 
Every 4 weeks 
QMS  
Quality Management System 
qPCR 
Quantitative polymerase chain reaction 
QTcF 
QT interval corrected by Fridericia’s formula 
RDE 
Recommended dose for expansion 
RFS 
Relapse free survival 
RSV 
Respiratory Syncytial Virus 
SAE 
Serious Adverse Event 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous 
sCR 
serum creatinine 
SD 
standard deviation 
SJS 
Stevens-Johnson syndrome 
SOP 
Standard operating procedures 
 
 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBIL 
Total Bilirubin 
TEN 
Toxic epidermal necrolysis 
TIM-3 
T-cell immunoglobulin domain and mucin domain-3 
TKD 
Tyrosine kinase domain 
TNF 
Tumor necrosis factor 
Tregs 
T regulatory 
TSH 
Thyroid-Stimulating Hormone 
ULN 
upper limit of normal 
USA 
United States of America 
VES 
Visit evaluation schedule 
VZV 
Varicella Zoster Virus 
WBC 
White Blood Cells 
WHO 
World Health Organization  
WoC 
Withdrawal of study Consent 
WOCBP 
Women of child-bearing potential 
 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as 
described in the protocol, but not as an investigational medicinal 
product (e.g. any background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study participant  
Coded Data 
Personal Data which has been de-identified by the investigative center 
team by replacing personal identifiers with a code 
Cohort 
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess 
internal study validity, and/or evaluate comparative effects of the 
investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days) 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 
100 mg once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from source 
data/documents used at the point of care 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last 
participant.  
Enrollment 
Point/time of participant entry into the study at which informed consent 
must be obtained. The action of enrolling one or more participants.   
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
combines source documents and case report forms (eCRFs) into one 
application, allowing for the real time collection of clinical trial 
information to sponsors and other oversight authorities, as appropriate 
Estimand  
As defined in the ICH E9(R1) addendum, estimand is a precise 
description of the treatment effect reflecting the clinical question posed 
by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same participants under different treatment 
conditions being compared. Attributes of an estimand include the 
population, variable (or endpoint) and treatment of interest, as well as 
the specification of how the remaining intercurrent events are 
addressed and a population-level summary for the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with the 
clinical question of interest. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy) 


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Part  
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single 
dose part and a multiple dose part, or a part in participants with 
established disease and in those with newly diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the 
informed consent. This number is the definitive, unique identifier for the 
participant and should be used to identify the participant throughout the 
study for all data collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually 
in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data 
includes participant identifier information, study information and 
biological samples. 
Premature participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this 
time all study drug administration is discontinued, and no further 
assessments are planned 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias 
Randomization 
number 
A unique identifier assigned to each randomized participant 
Re-screening 
If a participant fails the initial screening and is considered as a Screen 
Failure, he/she can be invited once for a new Screening visit after 
medical judgment and as specified by the protocol. 
Screen Failure 
A participant who did not meet one or more criteria that were required 
for participation in the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant 
Study treatment 
Any drug or combination of drugs   or intervention administered to the 
study participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) 
prior to the defined study treatment completion date (if any) for any 
reason; may or may not also be the point/time of study discontinuation  
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the 
combination and may consist of 1 or more cohorts. 
Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment 
to which comparison will be made. These might be individual 
interventions, combinations of interventions administered concurrently, 
e.g. as add-on to standard of care, or might consist of an overall 
regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of 
interest, which might or might not be the same as the study treatment. 


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Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is 
required to address the clinical question. The specification of the 
variable might include whether the participant experiences an 
intercurrent event. 
Withdrawal of study 
consent (WoC) / 
Opposition to use of 
data /biological 
samples 
Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer wishes 
to receive study treatment AND does not agree to further protocol 
required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation. 
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different 
legal reason than consent.   


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Amendment 2 (24-Mar-2022)  
Amendment rationale  
At the time of release of this amendment, nine sites have been initiated, twelve patients have 
been pre-screened and/or screened and four (4) patients have been enrolled into safety run-
in cohort 1. One (1) patient is currently receiving study treatment in this trial. 
The main purpose of this amendment is to modify some of the inclusion/exclusion criteria 
that are considered too restrictive and causing slow recruitment rate, per feedback from 
Principal Investigators on the study. The inclusion/exclusion criteria selected for the 
amendment were assessed to have no substantial impact on the study design or primary 
objectives, including safety and preliminary efficacy assessments.  
In addition, determination of eligibility for enrollment based on central MRD assay where 
required (e.g., USA) was added.   
Furthermore, format and grammatical corrections as well as removing redundancies are 
made throughout the protocol to improve flow and consistency. 
Changes to the protocol 
 Protocol Summary, Section 2.1, Section 3: Updated to allow for MRD positivity 
window any time at ≥ Day 60 after aHSCT.  
 Section 5.1: Updated Inclusion Criteria 4 of eligibility time window based on 
MRD positivity to [any time at ≥ Day 60 after aHSCT], which will allow earlier 
eligibility (Day 100 was changed to Day 60) and to remove the Day 365 
restriction.   
 Section 5.2: Updated Exclusion criteria 8 to allow for participants with history 
of another malignancy who are receiving adjuvant therapy, such as hormone 
therapy, to enter the study. 
 Section 5.2: Updated Exclusion criteria 18 to allow prior use of “prophylactic” 
donor lymphocyte infusion (DLI) with or without hypomethylating agent 
(HMA), if DLI was completed ≥ 3 months and HMA was completed ≥ 4 weeks 
prior to start of study treatment.    
 Section 6.2.2: Added to clarify that DLI and other cellular therapies are 
prohibited while on study. 
 Table 6-2: Modified DLT definition in regard to the duration of grade 4 
cytopenias based on FDA feedback. 
 Table 6-4: Corrected an error in the lower right cell of the table replacing “grade 
I” with “mild” for chronic GvHD.  
 Section 8.1: Addition of central MRD assessment where required (e.g., USA) 
and wording modified for more clarity. 
 Table 8-1 and Table 8.2: Added DLI and other cellular therapies and updated 
footnotes for more clarity 
 Section 8.2: “Demographics and other baseline characteristics” with the 
requirement for data collection to capture “prior antineoplastic therapies”, prior 


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to and post-aHSCT, including prior prophylactic DLI(s) with or without 
hypomethylating agents. 
 Table 8-4: Added BMA for MRD by Flow Cytometry unscheduled collection 
timepoint. 
 Section 8.5.3, Table 8-13, Table 8-14: Added Biomarker unscheduled collection 
timepoint. 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
In addition, the changes herein affect the Informed Consent. Sites are required to update and 
submit for approval the revised Informed Consents, which takes into account the changes 
described in this amended protocol.  
 
 


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Amendment 1 (16-Apr-2021)  
Amendment rationale  
At the time of release of this amendment, no sites have been initiated, and no subject has 
been screened or has received study treatment in this trial. 
The main purpose of this amendment is:  
- 
To modify the list of inclusion and exclusion criteria to include requirements for 
minimum hemoglobin level and restrictions for prior cancer-directed treatments or 
investigational modalities, and for patient with BCR-ABL mutations eligible for 
post-transplant tyrosine kinase inhibitor therapies, respectively, as requested by 
health authorities.   
- 
To provide further clarification on the dose to be used for cohorts 3-5 in the study 
design schema, how DLTs will be defined and how dose modifications for 
sabatolimab will be handled, as requested by health authorities.  
Other changes include:  
- 
To add/correct visit windows and specify collection of antineoplastic 
therapies/medications since discontinuation (previously included in collection 
concomitant medication and therapies) in visit schedule assessments tables 
 
 
 
 
- 
New Novartis standard language, has been added to update to the most recent version 
of the Novartis protocol CTP template v4.0 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
 List of Abbreviations / Glossary of Terms: Updated based on changes to the CTP 
template v4.0 
 Section 2 / Section 12.4 / Section 12.4.1 / Section 12.4.3 / Section 12.4.5 / Section 
12.5: Updated section title to match CTP template v4.0 
 Table 2-1: Rearranged the order of primary objectives to align with the order in 
which the study cohorts will be conducted  
 Figure 3-1: Study design schema was updated to provide further clarification on 
the dose to be used in cohorts 3-5 
 Section 4.6: Updated to include risks and benefits related to COVID-19 
vaccination 
 Section 5.1: Inclusion criteria #15 for minimum hemoglobin level added 
 Section 5.2: Added Exclusion criteria #18 for prior cancer-directed treatments or 
investigational modalities. 


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 Section 5.2: Added exclusion criteria #19 for participants with BCR-ABL 
mutations eligible for post-transplant tyrosine kinase therapies 
 Section 6.2.1: Updated to provide a window of when concomitant medication 
data should be collected. 
 Section 6.5.3: Removed text related to DLT definition to provide further clarity 
 Table 6-2: Updated DLT criteria in the table to include febrile neutropenia ≥ 
CTCAE Grade 3 and thrombocytopenia ≥ CTCAE Grade 3 with clinically 
significant bleeding  
 Section 6.5.4: Additional language added to provide further clarity on guidelines 
for dose modifications for sabatolimab  
 Section 7 / Section 9.1.2 / Section 9.1.3 / Section 10.1.3 / Section 10.1.4: Added 
wording to match CTP template v4.0 
 Table 8-1 and Table 8-2: Added visit window +/- 3 days after Cycle 1 Day 1 as 
stated in Section 8 during the treatment period, added antineoplastic therapy 
assessment during safety and post-treatment follow-up period. 
 Table 8-1 and Table 8-2: Added a check at the screening visit for the collection 
of the efficacy bone marrow aspirate or biopsy assessment to align with Section 
8.3.1. 
 Section 8.2: Modified language regarding race/ethnicity baseline characteristics 
to match CTP template v4.0 
 Table 8-11 and Table 8-12: check removed at Day 1 Cycle 24 end of sabatolimab 
infusion for participants enrolled in monotherapy cohorts (cohorts 1, 2, 4 and 5) 
and at Day 5 Cycle 24 end of sabatolimab infusion for participants enrolled in 
combination cohort 3. 
 
 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  


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Protocol summary 
Protocol number 
CMBG453F12201 
Full Title 
A phase Ib/II, open label study of sabatolimab as a treatment for patients 
with acute myeloid leukemia and presence of measurable residual 
disease after allogeneic stem cell transplantation. 
Brief title 
A prospective study of sabatolimab alone or in combination with 
azacitidine preemptive therapy in patients with acute myeloid leukemia 
(AML) after allogeneic stem cell transplantation. 
Sponsor and 
Clinical Phase 
Novartis 
Phase Ib/II 
Investigation type 
Drug: Biological 
Study type 
Interventional 
Purpose and 
rationale 
The primary purpose of this study is to test the hypothesis that 
preemptive treatment with sabatolimab, alone or in combination with 
azacitidine, when administered to participants with AML/secondary AML 
who are in complete remission with positive measurable residual disease 
post-allogeneic hematopoietic stem cell transplantation (MRD+ post-
aHSCT), can enhance the graft versus leukemia (GvL) response and 
prevent or delay hematologic relapse without an unacceptable level of 
treatment-emergent toxicities, including clinically significant acute and/or 
chronic graft-versus-host disease (GvHD) and immune-related adverse 
events. 
Primary 
Objective(s)  
 
Safety - for adults only in the Safety Run-in part: to determine 
whether sabatolimab as monotherapy at the two tested dose levels 
[400 mg and 800 mg every 4 weeks (Q4W)] leads to an unacceptable 
level of toxicity when administered post-aHSCT, as measured by the 
incidence of treatment-emergent dose limiting toxicities (DLTs) during 
the first 2 cycles of study treatment. 
 
Efficacy- for adults only in both Safety Run-in and expansion parts: to 
evaluate preliminary efficacy of sabatolimab (at the recommended 
dose for expansion) as monotherapy and in combination with 
azacitidine on prevention of hematologic relapse, as measured by the 
proportion of adult participants with AML and  MRD+ post-aHSCT for 
whom no evidence of hematologic relapse (no evidence of bone 
marrow blasts ≥5%; no evidence of reappearance of blasts in the 
blood; no evidence of development of extramedullary disease) have 
been documented after 6 cycles of study treatment (per investigator 
assessment). 
 
Safety - for adolescents after completion of the Safety Run-in in 
adults: to determine whether sabatolimab as monotherapy at the 
recommended dose level for adults leads to an unacceptable level of 
toxicity when administered to adolescent participants post-aHSCT, as 
measured by the incidence of treatment-emergent dose limiting 
toxicities during the first 2 cycles of study treatment. 
Secondary 
Objectives 
 
Incidence of grade III or IV acute GvHD and moderate to severe 
chronic GvHD. 
 
Pharmacokinetics (PK) of sabatolimab. 
 
GvHD-free/relapse-free survival. 
 
Relapse-Free Survival. 
 
Safety and tolerability of sabatolimab. 
 
Incidence of severe immune-related adverse events not attributed to 
GvHD. 


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 
The proportion of participants with centrally confirmed MRD+ at 
screening who become MRD negative during the first 6 cycles of 
study treatment. 
Study design 
This is a phase Ib/II, open label, multi-center study of sabatolimab as 
monotherapy and in combination with azacitidine, in participants with 
AML/secondary AML who have received one aHSCT and achieved 
complete remission but MRD+ any time at ≥ Day 60 after aHSCT and at 
least 2 weeks after immunosuppressive medications have been tapered 
off. 
The study will enroll approximately 59 participants and will be conducted in 
two parts: 
Part 1 is a Safety Run-in of approximately 20 participants, to assess 
whether sabatolimab as monotherapy at the two tested dose levels (400 
mg and 800 mg intravenously Q4W) is safe when administered in the post 
aHSCT setting. For each dose level, once the required number of evaluable 
participants has been confirmed, enrollment will be halted until participants 
have completed the DLT observation period (≥ 8 weeks following the first 
dose). Following the observation period for DLTs, a Safety Review Meeting 
will be conducted after each dose level to assess safety and determine the 
recommended dose for expansion to proceed with enrollment of additional 
cohorts in Part 2 of the study. 
Part 2 consists of sabatolimab monotherapy expansion cohort of 
approximately 13 participants, sabatolimab in combination with azacitidine 
cohort of approximately 20 participants, and an adolescent cohort of 
approximately 6 participants (≥ 12 years but < 18 years of age) with 
sabatolimab as monotherapy. Sabatolimab will be administered at the 
recommended dose for expansion determined in Part 1. 
Study population 
The study population will enroll approximately 59 participants with de 
novo AML or secondary AML, who have achieved complete remission 
after aHSCT and are at high risk for relapse defined by the presence of 
MRD any time at ≥ Day 60  post-transplant after tapering off 
immunosuppressive therapy. 
Key Inclusion 
criteria 
 
At the date of signing the informed consent form (ICF), eligible 
participants must be ≥ 18 years for the adult cohorts; and ≥ 12 years 
old but < 18 years old for the adolescent cohort, which will open after 
completion of Safety Run-in. 
 
Diagnosis of AML/secondary AML and received one prior aHSCT 
performed to control AML   
 
Participants are eligible irrespective of response or MRD status 
at time of aHSCT 
 
Participants in complete remission (< 5% bone marrow blasts, 
absence of circulating blasts in the blood, and no extramedullary 
disease) with MRD positivity (by local assessment or central 
assessment where required (e.g. in US)), any time at ≥ Day 60 after 
aHSCT. 
 
Ability to provide a fresh bone marrow aspirate sample collected 
within 28 days from enrollment/randomization, and immediately 
shipped to a Novartis designated central laboratory for MRD testing. 
 
Systemic GvHD prophylaxis or treatment [immunosuppressive 
treatment (IST)] completely tapered for at least two weeks prior to 
study entry. Prednisone dose ≤ 5 mg/day or equivalent corticosteroid 
dose is allowed. 


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 
Participants who are found with MRD positivity while still on or 
tapering systemic GvHD prophylaxis or treatment, MRD positivity 
must be re-confirmed at least 2 weeks after the last dose of IST. 
 
For the adult cohorts, participants must have an Eastern Cooperative 
Oncology Group (ECOG) performance status of 0, 1 or 2. For the 
adolescent cohort, participants must have a Karnofsky (age ≥ 16 
years) or Lansky (age < 16 years) performance status score of ≥ 50% 
Key Exclusion 
criteria 
 
Prior exposure to TIM-3 directed therapy at any time. 
 
History of severe hypersensitivity reactions to any ingredient of study 
drug(s) (azacitidine, sabatolimab) or monoclonal antibodies (mAbs) 
and/or their excipients. 
 
Active acute GvHD grade III-IV [according to Harris et al 2016 criteria 
(Appendix 1)]. 
 
Active moderate chronic GvHD of the lungs [according to the 2014 
NIH consensus criteria (Appendix 2)]. 
 
Active severe chronic GvHD [according to the 2014 NIH consensus 
criteria (Appendix 2)]. 
 
Active autoimmune disease requiring systemic therapy (e.g. 
corticosteroids). Topical, inhaled, nasal and ophthalmic steroids are 
not prohibited. Replacement corticosteroids therapy is allowed and 
not considered a form of systemic treatment 
 
Live vaccine administered within 30 days prior to the first day of study 
treatment (C1D1) 
Study treatment 
Sabatolimab monotherapy 
Sabatolimab + azacitidine 
Efficacy 
assessments 
 
Response evaluation will be per Investigator's assessment, based on 
standardized criteria as proposed by the European LeukemiaNet 
(ELN) and International Working Group (IWG) for AML 
(Cheson et al 2003, Döhner et al 2017) 
 
Disease assessment at baseline and evaluation of response during 
study treatment will rely on bone marrow and peripheral blood 
assessments. 
 
Disease response (bone marrow assessment, hematology) will be 
assessed locally at any time as clinically indicated. 
Pharmacokinetic 
assessments  
Pharmacokinetic (PK) samples will be obtained and evaluated in all 
participants. 
Key safety 
assessments 
 
Acute graft-versus-host disease. 
 
Chronic graft-versus host disease. 
 
Immune-mediated adverse events. 
 
Incidence and severity of adverse events and serious adverse events. 
 
Changes in vital signs. 
 
Changes in laboratory values. 
Other 
assessments  
Biomarker Assessments: 
Bone marrow aspirate, peripheral blood and plasma samples will be 
collected for biomarker assays. These include MRD measurements by 
multiparameter flow cytometry 
; 
 
 
 
Samples will be collected at baseline and at regular intervals during the 
course of the study as defined in the schedule of assessments. 


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Data analysis 
For adults participants included in the Safety Run-in part of the study, and 
for the adolescent cohort, the assessment of the acceptable level of 
toxicity with sabatolimab in monotherapy will be guided by a Bayesian 
Logistic Regression Model (BLRM). The probability that the true Dose 
Limiting Toxicity (DLT) rate exceeds 50% should be lower than 25% to 
declare that sabatolimab in monotherapy is reaching an acceptable level 
of toxicity. 
Efficacy of sabatolimab will be assessed based on the proportion of adult 
participants treated with sabatolimab at the recommended dose for 
expansion, as monotherapy or in combination with azacitidine, who remain 
with no evidence of hematologic relapse after 6 cycles of study treatment 
as per investigator assessment and using a Bayesian dual-criterion design: 
 
Adult participants treated with sabatolimab monotherapy: At least 8 
participants with no evidence of hematologic relapse after 6 cycles of 
treatment out of 25 participants are required for success  
 
Statistical decision rule: the posterior probability that the 
proportion of adult participants who remain with no evidence of 
hematologic relapse after 6 cycles of study treatment ≥ 15% is at 
least 97.5% (statistical significance at 2.5% level, 1-sided) 
 
Clinical decision rule: the posterior median for the proportion of 
adult participants who remain with no evidence of hematologic 
relapse is ≥ 30%. 
 
Adult participants treated with sabatolimab in combination with 
azacitidine: At least 11 participants with no evidence of hematologic 
relapse after 6 cycles of treatment out of 20 participants are required 
for success  
 
Statistical decision rule:  the posterior probability that the 
proportion of adult participants who remain with no evidence of 
hematologic relapse after 6 cycles of study treatment ≥ 30% is at 
least 97.5% (statistical significance at 2.5% level, 1-sided) 
 
Clinical decision rule: the posterior median for the proportion of 
adult participants who remain with no evidence of hematologic 
relapse is ≥ 50%. 
Key words 
Phase Ib/II, sabatolimab, TIM-3, azacitidine, Acute Myeloid Leukemia, 
allogeneic hematopoietic stem cell transplantation, measurable residual 
disease. 


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1 
Introduction 
1.1 
Background 
Acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation and graft-
versus-host disease / graft-versus-leukemia:  
Acute myeloid leukemia (AML) is a malignant disease characterized by the clonal 
expansion of myeloid blasts in the bone marrow, peripheral blood and extramedullary 
tissues. AML is the most common form of acute leukemia in adults; an estimated 21,450 
new cases of AML and 10,920 deaths from the disease will occur in the United States, in 
2019 (American Cancer Society 2019). Intensive chemotherapy is standard of care for first 
line treatment, which achieves complete remission (CR) in a majority of cases; however, 
most participants will experience relapse without additional therapy. Post-remission 
allogeneic hematopoietic stem cell transplantation (aHSCT) is the only curative treatment 
for most participants with AML. 
aHSCT is a potentially curative treatment for AML. The anti-leukemia effect of aHSCT 
depends on the cytotoxicity of the pretransplant conditioning therapy and the posttransplant 
graft-versus-leukemia (GvL) effect (Dickinson et al 2017). 
However, clinically significant acute and chronic graft-versus-host disease (GvHD) occur 
following aHSCT, with reported incidence rates ranging from 9% to 50% for acute GvHD 
(aGvHD) and from 30% to 70% for chronic GvHD (cGvHD) (Jagasia et al 2012, Lee et al 
2013) (Flowers et al 2002, Lee and Flowers 2008, Flowers et al 2011, Flowers and Martin 
2015, Jagasia et al 2015, Vaughn et al 2015). 
The incidence of GvHD varies based on several factors, including but not limited to degree 
of human leukocyte antigen (HLA) matching between the donor and recipient, graft source, 
conditioning regimen, and GvHD prophylaxis. 
GvHD remains a serious and common complication, contributing to post-aHSCT morbidity 
and mortality. However, a retrospective analysis of data reported to the Center for 
International Blood and Marrow Transplant Research (CIBMTR) registry on 2905 
participants who developed grade II-IV aGvHD following aHSCT for hematological 
malignancies (56% AML) between 1999 and 2012, demonstrated a shift in maximal grade 
of aGvHD and a decrease in the proportion of grade III-IV disease over time [56%, 47%, 
and 37% for 1999-2001, 2002-2005, and 2006-2012, respectively]. In addition, the overall 
survival and treatment related mortality improved significantly overtime with a decline in 
deaths from organ failure and infection (Khoury et al 2017). 
Notably, analysis of the impact of cGvHD and its severity indicates a close relationship 
between cGvHD and the immune-mediated GvL effect; as demonstrated with a lower risk 
of relapse translating into improved disease free survival (DFS) with mild or moderate 
cGvHD compared to no cGvHD (Mo et al 2015). 
Relapse post-aHSCT:  
Unfortunately, 30-40% of participants with AML will relapse after transplant and this is the 
major cause of treatment failure (Thekkudan et al 2020). The outcomes for participants 
relapsing after aHSCT are poor with limited therapeutic options and no standard of care. 
Bejanyan et al. published the outcome data reported to the CIBMTR from 1788 participants 
(age range, <1 to 76 years) with AML who relapsed after aHSCT during first or second 
complete remission/response (CR). Median time to post-aHSCT relapse was 7 months 


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(range, 1 to 177). Relapses post-aHSCT occurred within <6 months in 43% of participants, 
between 6 months-2 years in 39%, between 2-3 years in 8%, and within ≥ 3 years post-
aHSCT in 10%. At relapse, participants received intensive therapy, including chemotherapy 
alone, donor lymphocyte infusion (DLI) +/- chemotherapy, or second aHSCT +/- 
chemotherapy +/- DLI, with subsequent CR rates of 29%. Survival for all participants was 
23% at 1 year after relapse; however, 3-year overall survival (OS) correlated with time from 
aHSCT to relapse with dismal survival with early disease relapse post-aHSCT (4% for 
relapse during the 1- to 6-month period, 12% during the 6-month to 2-year period, 26% 
during the 2- to 3-year period, and 38% for ≥3 years) (Bejanyan et al 2015).  
Measurable residual disease (MRD) post-aHSCT and relapse:  
Several studies reported that detection of MRD post-aHSCT [by multiparameter flow 
cytometry (MFC), polymerase chain reaction (PCR), next generation sequencing (NGS), 
levels of mixed chimerism (as a surrogate), interphase fluorescence in situ hybridization 
(FISH) or conventional cytogenetics] identifies participants at high risk for subsequent 
relapse, poor outcome and survival. (Fang et al 2012, Appelbaum 2013, Campana and Leung 
2013, Hourigan and Karp 2013, Zhou et al 2016, Liu et al 2019, Thol et al 2019). 
Liu et al. retrospectively reported the relationship between MRD by multicolor flow 
cytometry and transplant outcomes in 460 participants with AML who received 
haploidentical aHSCT in first or second complete remission. Compared to participants with 
negative MRD post-aHSCT, participants with detectable MRD+ post-aHSCT had 
statistically significantly higher cumulative incidence of relapse (100.0% vs 8.3%), lower 
3-year probabilities of overall survival (OS) (16.9% vs 78.2%) and leukemia-free survival 
(LFS) (0% vs 76.5%). These results indicate that MRD assessment may be useful for risk 
stratification (Liu et al 2019). 
Thol et al. also reported on the prognostic impact of MRD by next generation sequencing 
(NGS) in participants with AML who achieved complete remission following aHSCT, using 
peripheral blood samples in the majority of the analyses. MRD positivity by NGS on day 90 
and/or day 180 post-aHSCT was detected in 16% and 20.3% of participants with the limited 
(1-2 markers per patient) and extended (2-4 markers per patient) marker approach, 
respectively. MRD by NGS was predictive for cumulative incidence of relapse (CIR) (58% 
in for participants with MRD+ and 27% with MRD negative with the extended marker 
approach) and OS; which remained significant in multivariate analysis for CIR (HR 4.75; 
CI 2.66-8.50; P=<0.001) and OS (HR 2.56; CI 1.26-5.20; P<0.009) (Thol et al 2019). 
TIM-3 blockade and sabatolimab: 
T-cell immunoglobulin and mucin domain-containing 3 (TIM-3; also known as hepatitis A 
virus cellular receptor 2) has a widespread and complex role in immune system regulation, 
with published roles in both the adaptive immune responses (CD4+ and CD8+ T effector 
cells, regulatory T cells) and innate immune responses (macrophages, dendritic cells, NK 
cells). TIM-3 was initially described as an inhibitory protein expressed on activated T helper 
(Th) 1 CD4+ and cytotoxic CD8+ T cells that secrete interferon-gamma (IFN-γ) (Monney 
et al 2002, Sánchez-Fueyo et al 2003). TIM-3 is enriched on FoxP3+ Tregs and 
constitutively 
expressed 
on 
DCs, 
monocytes/macrophages, 
and 
NK 
cells (Anderson et al 2007, Ndhlovu et al 2012). Further, TIM-3 has also been identified as 
an acute myeloid leukemia (AML) stem cell antigen that is present in leukemic blasts but 
not normal hematopoietic stem cells, and anti-TIM-3 antibody treatment has shown efficacy 
in 
blocking 
engraftment 
of 
AML 
in 
a 
mouse 
xenotransplantation 
model 


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(Kikushige et al 2010). Promising preclinical and clinical anti-cancer activity has been 
reported for TIM-3 blockade (Kikushige et al 2010, Sakuishi et al 2010, Ngiow et al 2011, 
Sakuishi et al 2011, Jing et al 2015, Asayama et al 2017). 
Sabatolimab, a novel monoclonal antibody inhibitor of TIM-3, has shown preliminary 
evidence of clinical activity as a single-agent in participants with relapsed/refractory AML, 
and promising evidence of efficacy, including durable CRs of up to 24 months, when 
administered in combination with HMAs to participants with newly diagnosed AML and 
high-risk MDS. 
Immunomodulation and enhancement of GvL:  
Immunomodulatory agents and/or checkpoint inhibitors, including sabatolimab, may 
represent an effective maintenance or preemptive intervention to prevent or delay 
hematological relapse in the post-aHSCT by enhancing GvL effect and potentially 
restoring/improving immune surveillance and destruction of malignant cells by alloreactive 
donor T cells. However, interventions aiming at enhancing GvL effect of the allogeneic graft 
may be associated with increased risk or worsening of acute and chronic GvHD, which are 
major causes of non-relapse mortality after aHSCT. 
Therefore, a sabatolimab-mediated enhancement of GvL could potentially exacerbate 
GvHD, an immune-mediated toxicity and a principal safety concern in the aHSCT setting. 
There are no reported data on the safety of sabatolimab in the post-aHSCT setting. However, 
preliminary available data on sabatolimab-associated irAEs appear to be limited and less 
frequent compared to PD-1 blockade.  
Recent report on 15 participants treated with sabatolimab in combination with HMA for 
MDS and AML successfully proceeded to aHSCT within a median of 29 days (range 10-
145 days) from the last dose of sabatolimab until transplant. No sabatolimab was 
administered post-aHSCT. Limited toxicities related to GVHD were reported [6 participants 
with grade I-II acute GVHD (skin, n=6; upper GI, n=1), no grade III or higher GVHD and 
3 participants with chronic GVHD: 2 had liver involvement, both responsive to steroids, and 
one had ocular and oral cGVHD] (Brunner et al 2020). 
Azacitidine:  
Azacitidine (AZA), a pyrimidine analog and HMA, with antineoplastic effects. 
Azacitidine has been shown to have effects on the activation and proliferation of T cells 
suggesting a role in GVL and GVHD. AZA and other HMAs, upregulate silenced minor 
histocompatibility and tumor antigens on leukemic blasts, potentially augmenting the GVL 
response. It is also noted that azacitidine facilitates T regulatory cell (Tregs) reconstitution, 
which may reduce GVHD risk. 
The safety of azacitidine at 75 mg/m2 SC or IV x 7 days of every 28-day cycle in 
combination with sabatolimab at 800 mg IV Q4W has been evaluated in MDS and AML 
population and found to be safe and tolerable. 
Azacitidine is not yet approved in the post aHSCT setting. However, azacitidine has been 
tested at different doses and schedules in various clinical studies in the post-aHSCT setting 
as preemptive or maintenance therapy of AML or MDS (Thekkudan et al 2020). 
A dose and schedule finding study of azacitidine was conducted by de Lima et 
al (de Lima et al 2010) with different dose levels (8, 16, 24, 32, or 40 mg/m2) for 5 days for 
one to four 30-day cycles, in 45 participants with high-risk MDS/AML starting from the 
sixth week after aHSCT. The dose of 32 mg/m2 was chosen as optimal, as further dose 


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escalation was limited by thrombocytopenia. Their results suggested that azacitidine may 
prolong event-free survival (EFS) and overall survival (OS). However, there was no 
significant association between the azacitidine dose and OS or EFS. 
In addition, the RICAZA phase I/II study (Craddock et al 2016, Goodyear et al 2012) 
analyzed the impact of maintenance with azacitidine at a dose of 36 mg/m2 SC for 5 days, 
every 28 days, starting on day+ 42 post-aHSCT [median of 54 days (range, 40 to 194 days)], 
for up to 1 year post-aHSCT in participants with AML (n=37). Azacitidine was well-
tolerated in the majority of participants. The 1-year and 2-year relapse-free survival (RFS) 
were 57% and 49%, respectively. Induction of CD8+ T cell response to tumor antigens, one 
of the proposed mechanisms of graft-vs-leukemia (GvL) augmentation by azacitidine, was 
associated with a reduced risk of disease relapse (hazard ratio 0.30; 95% confidence interval 
[CI], 0.10 to 0.85; P= 0.02) and improved relapse-free survival (HR, 0.29; 95% CI, 0.10 to 
0.83; P= 0.02). This GvL augmentation was not associated with increased risk of GvHD, 
likely due to azacitidine-induced T regulatory cell expansion. Of interest, the dose of 
azacitidine observed to induce a CD8+ T cell response in this study is approximately one-
half that utilized in the treatment of participants with de novo AML or MDS, consistent with 
the hypothesis that the observed reduction in relapse is consequent upon manipulation of the 
alloreactive response and maybe achieved with low doses of azacitidine. 
The phase II RELAZA trial (Platzbecker et al 2012, Platzbecker et al 2018) reported on 20 
participants treated with preemptive azacitidine for decreasing CD34 cell chimerism, at a 
dose of 75 mg/m2/day SC, for 7 days, for 4 cycles every 28 days while still in complete 
remission post-aHCST. About 80% (16/20) of participants had either increasing CD34+ 
donor chimerism to ≥80% or stabilization of chimerism, in the absence of relapse. In those 
who ultimately relapsed (13 participants, 65%), there was a considerable 7-month delay 
after initial decrease of CD34 donor chimerism to <80%. However, grade 3-4 neutropenia 
and thrombocytopenia were common. 
Additional data were reported with the RELAZA2 phase II study (Platzbecker et al 2018) 
in 53 participants with advanced MDS or AML, who had achieved a complete remission 
after conventional chemotherapy (n= 29) or after aHSCT (n= 24), and treated with 
azacitidine preemptively when presented with a detectable minimal residual disease (MRD) 
by quantitative PCR for mutant NPM1, leukemia-specific fusion genes (DEK–NUP214, 
RUNX1–RUNX1T1, CBFb–MYH11), or by decreasing CD34 cell chimerism after aHSCT. 
The azacitidine dose was 75 mg/m2 per day SC for 7 days of a 29-day cycle for 24 cycles. 
After 6 cycles, participants with MRD negativity responses were eligible for a treatment de-
escalation. Of the 24 participant post-aHSCT, 17 participants (71%) were relapse-free and 
alive 6 months after the start of azacitidine and 7 participants had no response. At the data 
cutoff, 12 of the 17 responding participants were alive and in ongoing remission. Among all 
treated participants, the most common (grade 3–4) adverse event was neutropenia, occurring 
in 45 (85%) of 53 participants. One participant with neutropenia died because of an infection 
considered possibly related to study treatment. 
Therefore, the dual activity of azacitidine as an antileukemic agent and inhibitor of GvHD, 
and the availability of published data on the use of azacitidine in the post-aHSCT setting, 
make it an attractive partner for combination with sabatolimab post-aHSCT to mitigate the 
potential risk of inducing or worsening of GvHD. 


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1.2 
Purpose 
The primary purpose of the current study is to test the hypothesis that preemptive treatment 
with sabatolimab, alone or in combination with azacitidine, when administered to 
participants with AML/secondary AML who are in complete remission with MRD+ post-
aHSCT, can enhance the GvL response and prevent or delay hematologic relapse [ie, 
maintenance of complete remission (CR) or CR with incomplete hematologic recovery 
(CRi) without development of hematologic relapse (no evidence of bone marrow blasts 
≥5%; no evidence of reappearance of blasts in the blood; no evidence development of 
extramedullary disease) after 6 cycles of study treatment]. 
MRD for participant selection and enrichment:  
Despite the challenges in standardizing definitions of assay-specific and AML-specific 
thresholds of MRD and the lack of one universal modality or target, there is now evidence 
that MRD monitoring can improve relapse risk stratification and detection in 
AML (Hourigan and Karp 2013, Schuurhuis et al 2018a), and see Section 1.1 MRD post-
aHSCT and relapse. 
MRD positivity post-aHSCT identifies patients at high risk for subsequent relapse, poor 
outcome and survival (See Section 1.1). Therefore, positive MRD may serve as a predictor 
for disease recurrence, enrich for trial population and provide a setting to test various post 
transplantation preemptive therapies in patients with AML post-aHSCT. Harnessing the 
immune system to enhance the GvL effect is one of the intervention aim in the setting of 
post-aHSCT with MRD+. 
Safety Run-in of sabatolimab monotherapy:  
A sabatolimab-mediated enhancement of GvL could potentially exacerbate GvHD, an 
immune-mediated toxicity and constitutes the principal safety concern in the post-aHSCT 
setting. There are no reported data on the safety of sabatolimab in the post-aHSCT 
setting; therefore, an important safety objective will be to assess the occurrence and severity 
of treatment-emergent aGvHD and cGvHD, immune-related and other adverse events. 
The study will start with a Safety Run-in to assess whether sabatolimab can be administered 
in the post-aHSCT setting without unacceptable levels of treatment-emergent toxicities 
(dose limiting toxicities, ie; primary safety objective), including increased or worsening risk 
of treatment emergent aGvHD or cGvHD, as well as severe immune-related toxicity during 
the first2 cycles of study treatment. The Safety Run-in will be conducted starting with a 
lower MBG453 dose (ie, 400 mg IV Q4W) than what is currently being used in the MDS 
and AML setting outside of aHSCT setting (ie, 800 mg IV Q4W). If unacceptable toxicities 
are not observed, a new cohort of participants treated at 800 mg IV Q4W will subsequently 
be evaluated.  
Details on dose escalation guidelines and determination of the recommended dose for 
expansion are provided in Section 6.5. 
Sabatolimab will then be evaluated at the recommended dose for expansion during Safety 
Run-in as monotherapy as well as in combination with azacitidine.  
Combination with azacitidine:  
Azacitidine is not yet approved in the post aHSCT setting, however, it has been tested at 
different doses and schedules in various clinical studies in the post-aHSCT setting as 
preemptive or maintenance therapy of AML or MDS (See Section 1.1). Based on the 


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available published data on the safety and efficacy of various dosing regimens of 
azacitidine in the post-aHSCT setting, lower doses of azacitidine were selected (50 mg/m2 
SC x 5 days of every 28-day cycle) aiming to improve the tolerability of treatment with 
likely less hematological toxicities and infectious complications after aHSCT; enhance the 
adherence to treatment schedule and protocol compliance by reducing the burden of 
frequent 
hospital 
visits; and 
increase 
the 
likelihood 
of 
a 
greater 
efficacy 
with the an administration of more cycles of azacitidine. For further details, please 
see Section 1.1.  
The dual activity of azacitidine as an antileukemic agent and inhibitor of GvHD, and the 
availability of published data on the use of azacitidine in the post-aHSCT setting, make it 
an attractive partner for combination with sabatolimab post-aHSCT to mitigate the potential 
risk of inducing or worsening of GvHD. 
Adolescent cohort:  
In addition to the adult cohorts, a cohort of approximately 6 adolescent participants who are 
≥ 12 years old but <18 years old and meet eligibility for this study will be enrolled. Data 
(PK, safety and preliminary response assessment) obtained from adults and the additional 
cohort of adolescent participants in this study will be used to inform the design and doses 
for the evaluation of the initial pediatric study plan (iPSP) through modelling and 
simulation. 
2 
Objectives, endpoints and estimands 
All secondary 
 objectives will be applicable in adult and adolescent 
participants separately, unless otherwise specified. 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
 
For adults only (from the safety run-in part): To 
determine whether sabatolimab as 
monotherapy at the two tested dose levels 
(400 mg and 800 mg Q4W) leads to an 
unacceptable level of toxicity when 
administered to adult participants with AML 
who are in complete remission but are MRD+ 
post-aHSCT. 
 
Incidence of treatment-emergent dose 
limiting toxicities (DLTs), including 
aGvHD and cGvHD during the first 2 
cycles of study treatment. 
 
For adults only (from both safety run-in and 
expansion parts): To evaluate preliminary 
efficacy of sabatolimab (at the recommended 
dose level for expansion) as monotherapy and 
in combination with azacitidine on prevention 
of hematologic relapse by assessing the 
proportion of adult participants with AML and 
MRD+ post-aHSCT,) who remain with no 
evidence of hematologic relapse after 6 cycles 
of study treatment. 
 
The proportion of adult participants for 
whom no evidence of hematologic 
relapse (no evidence of bone marrow 
blasts ≥5%; no evidence of 
reappearance of blasts in the blood; 
no evidence of development of 
extramedullary disease) have been 
documented after 6 cycles of study 
treatment (per investigator 
assessment).   
 
For adolescents only: To determine whether 
sabatolimab as monotherapy at the 
recommended dose level for adults leads to an 
unacceptable level of toxicity when 
 
Incidence of treatment-emergent dose 
limiting toxicities (DLTs), 
including aGvHD and cGvHD during 
the first 2 cycles of study treatment. 


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Objective(s) 
Endpoint(s) 
administered to adolescent participants with 
AML who are in complete remission but are 
MRD+ post-aHSCT. 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
 
To assess the incidence of grade III or IV 
aGvHD and moderate to severe cGvHD. 
 
Incidence of treatment 
emergent grade III or grade IV 
aGvHD. 
 
Incidence of treatment emergent 
moderate to severe cGvHD. 
 
To characterize the pharmacokinetics (PK) of 
sabatolimab. 
 
Summary of serum concentrations 
(pre-dose samples) and 
pharmacokinetic parameters (the 
minimum observed plasma or serum 
drug concentration: Cmin) for 
sabatolimab. 
 
To assess GvHD-free/relapse-free survival 
(GRFS). 
 
Time from start of treatment to the 
date of first documented occurrence or 
worsening of treatment emergent 
grade III or IV aGvHD or moderate to 
severe cGvHD requiring initiation of 
systemic treatment, hematologic 
relapse, or death due to any cause, 
whichever occurs first. 
 
To assess Relapse-Free Survival (RFS). 
 
Time from start of treatment to the 
date of first documented hematologic 
relapse or death due to any cause, 
whichever occurs first. 
 
To determine the safety and tolerability of 
sabatolimab in monotherapy and in 
combination with azacitidine. 
 
Incidence and severity of AEs and 
SAEs, changes in laboratory values 
and vital signs. 
 
To assess severe immune-related adverse 
events not attributed to GvHD. 
 
Incidence of treatment-emergent ≥ 
grade 3 immune-related adverse 
events not attributed to GvHD. 
 
To assess the proportion of participants with 
centrally confirmed MRD+ at screening who 
become MRD- during the first 6 cycles of study 
treatment. 
 
Proportion of participants with centrally 
confirmed MRD+ status at baseline 
converting to MRD- within the first 6 
cycles of study treatment (see 
Section 8.3.2). 


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2.1 
Primary estimands 
For adults participants included in this study, there are two primary clinical questions: 
 Safety: Does sabatolimab, administered as monotherapy at 400 mg and 800 mg Q4W 
dose levels, lead to an unacceptable level of toxicity [dose-limiting toxicity (DLT)], 
when given to treat participants with acute myeloid leukemia (AML) who have received 
an allogeneic hematopoietic stem cell transplantation (aHSCT), and are in complete 
remission but are MRD+?  
 Efficacy: What is the effect of sabatolimab at the RDE, as monotherapy and in 
combination with azacitidine, on prevention of hematologic relapse (ie, no evidence of 
bone marrow blasts ≥5%, no evidence of reappearance of blasts in the blood, no evidence 
of development of extramedullary disease) [i.e., maintenance of complete remission 
(CR) or CR with incomplete hematologic recovery (CRi)] in participants with AML at 
high risk of relapse (MRD positivity) after aHSCT regardless of treatment interruption 
or discontinuation during study and until use of donor lymphocyte  infusion (DLI) or 
other new antineoplastic therapies? 
For adolescent participants included in this study, there is one primary clinical question: 
 Safety: Does sabatolimab administered as monotherapy at the recommended dose level 
for adults, lead to an unacceptable level of toxicity (DLT), when given to 
treat adolescents with AML who have received an aHSCT, have been tapered off 
of systemic immunosuppressive therapy at enrollment, and are in complete 
remission but are MRD+? 
Justification: In this proof-of-concept study, the primary purpose is to determine whether or 
not the risk of developing GvHD, immune-related toxicities and other unacceptable 
toxicities is not exacerbated when sabatolimab is administered in the post-transplant setting. 
The activity of sabatolimab is assessed based on the absence of hematologic relapse (no 


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evidence of any of the following: bone marrow blasts ≥5%; reappearance of blasts in the 
blood; or development of extramedullary disease), which is the most clinically meaningful 
endpoint in this post-transplant setting where complete hematologic recovery may be 
delayed early post-transplant. 
The primary safety estimand for adult participants included in this study is described by 
the following attributes: 
1. Population: Adult participants with AML who are in CR after aHSCT and are at high 
risk of relapse defined as positive MRD any time at ≥ Day 60 after aHSCT (with a 
confirmed MRD positivity at least 2 weeks after systemic immunosuppression has been 
tapered off) and who are exposed to study treatment for at least 2 cycles (minimum 
exposure criterion defined in Section 12.1) or who experienced a DLT within the DLT 
observation period. 
2. Primary variable: Proportion of adult participants who experience at least one dose 
limiting toxicity (DLT) (see Table 6-2) including but not limited to aGvHD and cGvHD 
as per investigator assessment between Cycle 1 Day 1 (first administration of 
sabatolimab) and end of Cycle 2 (Day 28). 
3. Treatment of interest: Treatment with sabatolimab as monotherapy at 400 mg and 800 
mg Q4W dose levels taken for the entire study duration post aHSCT. 
4. Handling of remaining intercurrent events:  
 Delay to start Cycle 3 due to any reason: a DLT that will occur after Day 28 of 
Cycle 2 and before starting Cycle 3 will be considered in the analysis (treatment 
policy strategy).  
 Failure to start Cycle 3 due to any reason: a DLT that will occur up to the theoretical 
last day of Cycle 2 (Cycle 2 Day 28) will be considered in the analysis regardless 
of permanent discontinuation after the dose of sabatolimab in Cycle 2 (treatment 
policy strategy). 
5. Summary 
measure for 
the 
primary 
safety 
estimand is 
the 
proportion 
of 
participants with treatment-emergent dose limiting toxicity as per investigator 
assessment reported during the first 2 cycles.  
The primary efficacy estimands for adult participants included in this study are 
described by the following attributes:  
1. Population: Adult participants with AML who are in CR after aHSCT and are at high 
risk of relapse defined as positive MRD at baseline any time at ≥ Day 60 after aHSCT 
(with a confirmed MRD positivity at least 2 weeks after systemic immunosuppression 
has been tapered off). 
2. Primary variable: Proportion of adult participants who remain with no evidence of 
hematologic relapse (no evidence of any of the following: bone marrow blasts ≥5%; 
reappearance of leukemic blasts in the blood; or development of extramedullary 
disease) as per investigator assessment after 6 cycles of the study treatment. 
3. Treatment of interest: Treatment with sabatolimab or sabatolimab in combination with 
azacitidine taken for the entire study duration post aHSCT. One estimand for each of the 
two treatments of interest (sabatolimab in monotherapy and sabatolimab in combination 
with azacitidine) will be considered. 
4. Handling of remaining intercurrent events:  


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 Failure to complete 6 cycles of treatment due to death for any reason or relapse: a 
participant who dies or has a relapse before completing 6 cycles of treatment will 
be considered as a non-responder (composite variable strategy). 
 Failure to complete 6 cycles of treatment due to reasons other than relapse and death 
for any reason (including due to adverse events, graft vs host disease for example): 
all participants with an adequate response assessment (other than "unknown" 
response) will be taken into account regardless of any study treatment interruption 
or permanent discontinuation; for a participant who stops the study due to reasons 
other than relapse or death, we will ask the participant to perform a response 
assessment 6 months after starting study treatment; a participant with no evidence 
of hematologic relapse 6 months after starting treatment will be considered as a 
responder (treatment policy strategy). 
 Start of donor leucocytes infusions (DLI) or a new anti-neoplastic therapy before 
completing 6 cycles of study treatment: a participant who starts a DLI or a new 
antineoplastic therapy before completing 6 cycles of treatment will be considered 
as a non-responder (composite variable strategy). 
5. Summary measure for the primary efficacy estimand is the proportion of participants 
with no evidence of hematologic relapse with its exact 95% confidence interval for each 
of the two study treatments of interest: sabatolimab in monotherapy and sabatolimab in 
combination with azacitidine. The trial will be successful if at least one of the treatments 
of interest (sabatolimab in monotherapy or sabatolimab in combination with azacitidine) 
meets both statistical and clinical significance (Section 12.4.2). 
The primary safety estimand for adolescent participants included in this study is 
described by the following attributes: 
1. Population: Adolescent participants with AML who are in CR after aHSCT and at high 
risk of relapse defined as positive MRD any time at ≥ Day 60 after aHSCT (with a 
confirmed MRD positivity at least 2 weeks after systemic immunosuppression has been 
tapered off) and who are exposed to study treatment for at least 2 cycles (minimum 
exposure criterion defined in Section 12.1) or who experienced a DLT within the DLT 
observation period. 
2. Primary variable: Proportion of adolescent participants who experience at least one dose 
limiting toxicity (DLT) (see Table 6-2) including but not limited to aGvHD and cGvHD 
as per investigator assessment between Cycle 1 Day 1 (first administration of MBG453) 
and end of Cycle 2 (Day 28). 
3. Treatment of interest: Treatment with sabatolimab as monotherapy at the recommended 
dose for adults taken for the entire study duration post aHSCT. 
4. Handling of remaining intercurrent events:  
 Delay to start Cycle 3 due to any reason: a DLT that will occur after Day 28 of 
Cycle 2 and before starting Cycle 3 will be considered in the analysis (treatment 
policy strategy).  
 Failure to start Cycle 3 due to any reason: a DLT that will occur up to the theoretical 
last day of Cycle 2 (Cycle 2 Day 28) will be considered in the analysis regardless 
of permanent discontinuation after the dose of sabatolimab in Cycle 2 (treatment 
policy strategy). 
5. Summary measure for the primary safety estimand is the proportion of 
participants with treatment-emergent dose limiting toxicity as per investigator 
assessment reported in the first 2 cycles. 


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2.2 
Secondary estimands 
Not applicable. 
3 
Study design 
This is a Phase Ib/II open label, multi-center study of sabatolimab, as monotherapy and in 
combination with azacitidine, in participants with AML/secondary AML who have received 
one aHSCT and who are in CR (bone marrow blasts < 5% and no extramedullary disease) 
but MRD+, any time at ≥ Day 60 after aHSCT (MRD positivity confirmed at least 2 weeks 
after immunosuppressive medications tapered off). 
Study treatment will be administered in 28-day treatment cycles. The study will enroll a 
total of approximately 59 participants [20 participants in safety run-in (Cohorts 1 and 2), 13 
in sabatolimab monotherapy expansion cohort (Cohort 4), 20 in the combination cohort 
(Cohort 3), 6 in the adolescent cohort (Cohort 5)] and will be conducted in two parts 
(Figure 3-1). 
Part 1 is a Safety Run-in to assess whether sabatolimab is safe in the post-aHSCT setting 
when administered as a single agent at two dose levels, 400 mg and 800 mg, on a Q4W 
regimen on Day 1 of every 28-day cycle. Sabatolimab has been demonstrated to be safe and 
well tolerated as a single agent and in combination with HMAs in previous studies. 
However, sabatolimab has not been explored in the post-aHSCT setting; therefore, the 
principal assessment of safety will be based on the rate of unacceptable level of toxicity [ie, 
treatment-emergent dose limiting toxicities (DLTs) including but not limited to aGvHD and 
cGvHD] during the first 2 cycles of study treatment (Table 6-2). 
A total of approximately 20 participants will be enrolled to Part 1 across the two dose levels. 
Approximately 8 participants will be enrolled at the starting dose level, 400 mg Q4W IV in 
order to obtain at least 6 evaluable participants. If the observed DLTs rate does not exceed 
the acceptable threshold at this starting dose, then approximately 12 participants will be 
enrolled in a second cohort of Safety Run-in and treated with sabatolimab monotherapy at 
dose level 800 mg Q4W in order to obtain at least 9 evaluable participants. For each dose 
level, once the required number of evaluable participants has been confirmed, enrollment 
will be halted until participants have completed the DLT observation period (≥ 56 days 
following the first dose) (Section 6.5.3). If no safety concerns were identified at either 
sabatolimab dose level, the preferred dose level for sabatolimab will be 800 mg IV Q4W. 
Part 2 will assess efficacy as well as safety, PK, and MRD status when sabatolimab is 
administered at the recommended dose for expansion determined in Part 1 as monotherapy 
and/or in combination with azacitidine. Part 2 will enroll a total of approximately 13 
participants in the monotherapy expansion [to obtain a total of 25 participants from the 
combined Safety Run-in (Cohort 2) and monotherapy expansion cohort (Cohort 4)]; and 20 
participants in the combination cohort (Cohort 3). Participants will be randomized to one of 
these two cohorts in Part 2 - combination cohort (Cohort 3) or monotherapy expansion 
cohort (Cohort 4) - and the randomization ratio will depend on the number of participants 
from the Safety-Run in part (Part 1) already treated with sabatolimab at the selected dose 
level for expansion (See Section 6.3.2). 
In the monotherapy expansion cohort (Cohort 4), sabatolimab will be administered as a 
single agent on Day 1 (Q4W) of every 28-day cycle. 


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In the combination cohort (Cohort 3) of sabatolimab with azacitidine, sabatolimab will be 
administered on Day 5 (+3 days) of every 28-day cycle IV on a Q4W regimen. 
Azacitidine will be administered IV or SC at 50 mg/m2 on Days 1 to 5 for 5 days per cycle. 
In the combination cohort (Cohort 3), participants unable to tolerate one of the study 
drugs may continue on study receiving only the tolerated study drug. 
In addition, based on Part 1 Safety Run-in results, an additional cohort of 6 adolescent 
participants (Cohort 5) will be opened (if no unacceptable rate of toxicities is observed in 
adults) to include participants who are 12 years or older but less than 18 years old and meet 
eligibility for this study. This cohort will be conducted in aHSCT site(s) that treat 
participants at this age group. 
The decision to open the combination cohort (Cohort 3) and the adolescent cohort (Cohort 
5) will be based principally on safety data obtained in Part 1. The decision to open the 
sabatolimab monotherapy expansion cohort (Cohort 4) will be based on an overall 
assessment of available safety, preliminary response assessment, PK, and MRD 
assessments. 
Throughout the study, the decision whether or when to open an additional cohort(s) will be 
based on the overall safety, PK, tolerability, and preliminary response assessment.  
Figure 3-1 
Study design 
  
 


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* Criteria to proceed with sabatolimab dose increase or Go/No Go for Cohort 2: based on DLTs 
during the first 2 cycles of study treatment in Cohort 1. 
** Go criteria for potential expansion monotherapy cohort, combination cohort and adolescent 
cohort at the recommended dose for expansion determined by Safety Run-in: Based on an overall 
assessment of all available data, including safety, preliminary response assessment, clinical 
pharmacology, tolerability, and recommendations from participating investigators  
 R: participants will be randomized to Cohort 3 or Cohort 4 
Study treatment will be administered for up to a maximum of 24 cycles or until a participant 
experiences hematologic relapse (bone marrow blasts ≥5%; or reappearance of blasts in the 
blood; or development of extramedullary disease) as defined by ELN 2017 
(Döhner et al 2017); or unacceptable toxicity, whichever is earlier. For participants who 
achieve negative MRD and maintain MRD negativity for 12 consecutive cycles, study 
treatment (sabatolimab monotherapy or sabatolimab in combination with azacitidine) may 
be discontinued earlier at investigator's discretion. 
In each cohort, response status will be evaluated by standard hematologic/morphologic 
criteria per investigator's assessment after each cycle up to Cycle 3, then after every 3 cycles 
of study treatment up to cycle 12, and then after every 6 cycles for up to a total of 24 cycles 
(post cycle 1, 2, 3, 6, 9, 12, 18, 24). 
For participants with MRD+ centrally assessed at baseline (defined as at time of enrollment 
prior to starting treatment), MRD status will be evaluated by Novartis central laboratory at 
the same schedule as the hematologic/morphologic disease assessment after cycles 1, 2 and 
3 and then after every 3 cycles of study treatment up to cycle 12, and then after every 6 
cycles for up to a total of 24 cycles (post cycle 1, 2, 3, 6, 9, 12, 18, 24). In addition, 
MRD status will be assessed locally at the same schedule as the hematologic/morphologic 
disease assessment after cycles 1, 2 and 3 and then after every 3 cycles of study treatment 
up to cycle 12, and then after every 6 cycles for up to a total of 24 cycles (post cycle 1, 2, 3, 
6, 9, 12, 18, 24). 
After completion of the treatment period, all participants will enter post-treatment follow-
up until hematologic relapse or start of new therapy. 
 
 
After the end of study treatment, all participants must be followed for adverse events (AEs) 
for 150 days following the last dose of sabatolimab, or 30 days following the last dose of 
azacitidine, whichever is later. All participants who discontinued study treatment while in 
remission with absence of hematologic relapse will enter a long-term follow-up for efficacy 
as described in the study flow diagram below (Figure 3-2) and outlined in Section 9.1.  


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Study flow 
Figure 3-2 
Study Flow 
  
*All participants will enter safety follow-up. After completion of the treatment period, all participants 
who discontinued study treatment while in remission with no evidence of hematologic relapse will 
enter post-treatment follow-up until hematologic relapse or start of new therapy. Additionally, 
participants with MRD- status at end of treatment will continue to be assessed for MRD until MRD+ 
or for 12 months after end of study treatment, whichever is earlier. 
The study flow is comprised of 4 periods (Figure 3-2): prescreening, pretreatment 
(Screening), treatment, and follow up. 
Participants will undergo safety assessments during screening and periodically during 
treatment and follow-up as outlined in Table 8-1 and Table 8-2. 
An end of treatment visit will be performed when participants permanently discontinue 
study treatment. participants will then enter safety/post-treatment follow-up as shown in 
Figure 3-2 (see also Section 9.1.1). 


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Based on safety and efficacy in previous cohorts, option, via protocol amendment, for 
expansion cohorts or additional treatment cohorts combining sabatolimab with e.g. donor 
lymphocyte infusions (DLI) or other novel combinations will be considered. 
4 
Rationale 
4.1 
Rationale for study design 
The rationale for the design of this phase Ib/II, multicenter, open-label, proof-of-concept 
study is to assess the safety and preliminary efficacy of sabatolimab monotherapy and 
sabatolimab combination with azacitidine for preventing/delaying disease relapse in 
participants with AML/secondary AML post-aHSCT who achieved complete remission but 
with MRD positivity, indicating increased risk for disease relapse. 
A sabatolimab-mediated enhancement of GvL could potentially exacerbate GvHD and 
immune-related adverse events, therefore, the study employs a 2-part Safety Run-in to 
assess whether sabatolimab is safe at two dose levels with a halt between cohort 1 (at 400 
mg Q4W) and cohort 2 (at 800 mg Q4W) prior to dose escalation and a Safety Review 
Meeting at each dose level. The occurrence and severity of treatment-emergent aGvHD and 
cGvHD, immune-related and other adverse drug reactions on sabatolimab as monotherapy 
post-aHSCT after the completion of at least 2 cycles of study treatment will be assessed. As 
the start of GvHD and/or immune-related adverse events induced by immunomodulatory 
agents and/or checkpoint inhibitors, may be delayed, a minimum of 2 cycles with at least 8 
weeks following the first dose of sabatolimab was designated. 
The timing of efficacy assessment, as measured by the proportion of adult participants who 
remain with no evidence of hematologic relapse (no evidence of bone marrow blasts ≥5%; 
no evidence of reappearance of blasts in the blood; no evidence development of 
extramedullary disease) after 6 cycles of the study treatment, is based on the reported timing 
of AML hematologic relapse post-aHSCT (median time to relapse 7 months (range, 1 to 
177), with 43% of relapses within <6 months). For details, refer to Background Section 1.1 
(Bejanyan et al 2015). 
The study treatment will be open-label without blinding as this is a proof-of-concept study 
in participant population at high risk for relapse. However, in Part 2 of the study, participants 
will be randomized to be enrolled in either the combination cohort (Cohort 3) or 
the monotherapy expansion cohort (Cohort 4) to minimize selection bias. 
Rationale for inclusion of the adolescent cohort: In addition to data obtained from adult 
participants (PK, safety and preliminary response assessment), enrollment of the adolescent 
cohort will enable obtaining additional information from this age group to inform the design 
and doses for the evaluation of the initial pediatric study plan (iPSP) through modelling and 
simulation. 
4.2 
Rationale for dose/regimen and duration of treatment 
Immunomodulatory agents and/or checkpoint inhibitors may represent an effective 
maintenance or preemptive intervention to prevent or delay hematological relapse in the 
post-aHSCT by enhancing GvL effect and potentially restoring/improving immune 
surveillance and destruction of malignant cells by alloreactive donor T cells 
(Thekkudan et al 2020). However, interventions aiming at enhancing GvL effect of the 


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allogeneic graft may be associated with increased risk or worsening of acute and chronic 
GvHD, which are major causes of non-relapse mortality after aHSCT. 
T-cell immunoglobulin and mucin domain-containing 3 (TIM-3; also known as hepatitis A 
virus cellular receptor 2) is a negative regulator of T cells. TIM-3 was initially described as 
an inhibitory protein expressed on activated T helper (Th) 1 CD4+ and cytotoxic CD8+ T 
cells 
that 
secrete 
interferon-gamma 
(IFN-
γ) (Monney et al 2002, Sánchez-Fueyo et al 2003). TIM-3 is enriched on FoxP3+ Tregs and 
constitutively 
expressed 
on 
DCs, 
monocytes/macrophages, 
and 
NK 
cells (Anderson et al 2007, Ndhlovu et al 2012). Further, TIM-3 has also been identified as 
an acute myeloid leukemia (AML) stem cell antigen that is present in leukemic blasts but 
not normal hematopoietic stem cells, and anti-TIM-3 antibody treatment has shown efficacy 
in 
blocking 
engraftment 
of 
AML 
in 
a 
mouse 
xenotransplantation 
model 
(Kikushige et al 2010). Promising preclinical and clinical anti-cancer activity has been 
reported for TIM-3 blockade (Kikushige et al 2010, Sakuishi et al 2010, Ngiow et al 2011, 
Sakuishi et al 2011, Jing et al 2015, Asayama et al 2017). 
A sabatolimab-mediated enhancement of GvL could potentially exacerbate GvHD, an 
immune-mediated toxicity and the principal safety concern in the aHSCT setting. There are 
no reported data on the safety of sabatolimab in the post-aHSCT setting; therefore, an 
important safety objective is to assess the incidence and severity of treatment-emergent 
aGvHD and cGvHD, immune-related and other adverse events. 
However, preliminary available data on sabatolimab indicate that associated irAEs appear 
to be limited and less frequent compared to PD-1 blockade.  
This study will start with a Safety Run-in to assess whether sabatolimab can be administered 
in the post-aHSCT setting without unacceptable levels of treatment-emergent toxicities 
(dose limiting toxicities, ie; primary safety objective), including increased or worsening the 
risk of treatment emergent aGvHD or cGvHD, as well as severe immune-related toxicity 
during the first 2 cycles of study treatment. 
The Safety Run-in will be conducted starting with a lower sabatolimab dose (400 mg IV 
Q4W) than what is currently being used in the MDS and AML setting outside of aHSCT 
setting (800 mg IV Q4W). If unacceptable toxicities are not observed, a new cohort of 
participants treated at 800 mg IV Q4W will subsequently be evaluated. Sabatolimab will 
then be evaluated at the recommended dose for expansion during Safety Run-in as 
monotherapy as well as in combination with azacitidine (See Section 4.3). 
The preferred sabatolimab dose level for evaluation of efficacy in the study is 800 mg Q4W 
based on data accumulated from 2 phase 1 studies, [CMBG453X2101] and 
[CPDR001X2105] (Refer to Clinical Pharmacology, Clinical Efficacy, Clinical Safety, and 
Predicted Target Engagement below). 
For further details, please refer to Section 1.1 and Section 1.2. 
Clinical Pharmacology: 
The 
pharmacokinetics 
(PK) 
of 
sabatolimab 
were 
similar 
between 
studies 
[CMBG453X2101] in solid tumor patients and [CPDR001X2105] in AML and high risk 
MDS patients.  At lower doses (at 80 mg and below for Q2W dosing or at 240 mg and below 
for Q4W dosing), the PK was nonlinear, with faster elimination at lower concentrations. PK 
appeared linear with an approximate proportional dose-exposure (AUC and Cmax) 
relationship at doses of 240 mg and above for Q2W dosing and at doses of 800 mg and 


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above for Q4W dosing. Accumulation of sabatolimab was observed with repeated 
administrations, and for the Q2W regimen, AUCtau during cycle 3 ranged between 1.01-
2.78 fold higher than during cycle 1. A dose of 800 mg Q4W has similar AUCtau as 400 
mg Q2W at the steady state. 
Clinical Efficacy: 
In study [CPDR001X2105], clinical benefit was seen across 3 dose levels tested (at 240 mg 
Q2W, 400 mg Q2W, 800 mg Q4W in combination with decitabine) with CR or marrow CR 
in high risk MDS participants and CR or CRi in newly diagnosed AML participants. Among 
participants who obtained CR, there were durable responses as long as 15 months (as of cut-
off date of 10-Nov-2018). No obvious dose-response relationship was observed. In a 
preliminary exposure-response analysis, there was also no clear relationship between 
exposure and response, using a steady state exposure metrics of AUCtau or Ctrough and 
efficacy metrics of clinical benefit (CR/marrow CR/CRi) or percent of blast reduction. 
Clinical Safety: 
Sabatolimab was found to be safe and well tolerated across all dose levels tested in both 
studies. In study [CMBG453X2101], as of 25-Jul-2019, a total of 133 participants with solid 
tumors have been treated with sabatolimab single agent therapy. There were no adverse 
events attributed to study treatment with an incidence >10%. The most frequently reported 
adverse events attributed to study treatment included fatigue (9%), followed by decreased 
appetite and nausea (5% each). There were no DLTs during the first cycle. No participants 
discontinued study treatment due to treatment-related AEs. 
In study [CPDR001X2105], as of 26-Jul-2019, a total of 123 participants with hematological 
malignancies have been treated with sabatolimab as a single agent (n=26) or in combination 
with decitabine (n=81) or azacitidine (n=16). In the 26 participants treated with sabatolimab 
single agent, there were no adverse events attributed to study treatment with an incidence 
>10%. The most frequently reported adverse event attributed to study treatment was a rash 
in two participants (8%). All other adverse events attributed to study treatment were single 
occurrences. There were no DLTs during the first cycle. No participants discontinued study 
treatment due to treatment-related AEs. In the 81 participants treated with sabatolimab in 
combination with decitabine, the most frequent adverse events (all grades, >10%) attributed 
to study treatment have included thrombocytopenia, anemia, neutropenia, nausea, and 
fatigue. One participant experienced a DLT during the first 2 cycles, which consisted of 
hepatitis manifesting as Grade 3 ALT increase. One participant discontinued study treatment 
due to a treatment-related adverse event (AE) of possible hemophagocytic 
lymphohistiocytosis. In the 16 participants treated with sabatolimab in combination with 
azacitidine, the most frequent adverse events (all grades, >10%) attributed to study treatment 
have included nausea, vomiting, anemia, constipation, neutrophil count decrease and 
platelet count decrease. There were no DLTs during the first 2 cycles. No participants 
discontinued study treatment due to treatment-related AEs. No study treatment-related 
deaths were observed in any of the studies mentioned above. 
Preliminary analysis revealed no relationship between dose, incidence and severity of 
adverse events across the different treatment groups. No relationship was observed between 
Cmax and the incidence of potential immune related adverse events, providing additional 
support for 800 mg Q4W regimen, which has the highest Cmax among the doses tested. 
Please refer to the Investigator's Brochure for additional information of AEs reported in 


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participants with solid tumors or with hematologic malignancies treated with sabatolimab 
as a single agent or in combination with other drugs. 
Predicted Target Engagement:  
A population pharmacokinetic model of sabatolimab concentration was fit to all participants 
from [CPDR001X2105] and [CMBG453X2101] studies. This model was used to simulate 
the TIM-3 occupancy in the bone marrow by making assumptions about sabatolimab 
biodistribution to the bone marrow and binding affinity to TIM-3. Using trial simulation, 
this model predicted that the 800 mg Q4Wdose would give at least 95% receptor occupancy 
in at least 95% of participants at steady state Ctrough. This high degree of target engagement 
is also supported by a plateau in the accumulated soluble TIM-3 that is observed at doses of 
240 mg Q2W and above, and at 800 mg Q4W and above. 
In summary, given the excellent safety and tolerability seen across all doses and schedules 
in [CMBG453X2101] and [CPDR001X2105], the activity seen at all three doses tested in 
study [CPDR001X2105]; the predicted saturation of TIM-3 from the soluble TIM-3 data 
and the receptor occupancy model; and the lack of clear dose-response or exposure-response 
relationship for sabatolimab, 800 mg Q4W was selected as the target dose regimen for this 
study. 
Rationale for duration of treatment: 
The proposed duration of treatment in this study is up to a maximum of 24 cycles, or until 
hematologic relapse, or unacceptable toxicity, whichever is earlier.  
This is consistent with the RELAZA2 study where azacitidine was given for 24 cycles. After 
6 cycles, participants with MRD negativity response (major response) were eligible for a 
treatment de-escalation (Platzbecker et al 2018).  
This is also supported by the reported time to relapse post aHSCT in 1788 participants with 
AML with the majority of relapses occurring within the first 2 years post-aHSCT (median 
time to post-aHSCT relapse 7 months with 43% within <6 months and 39% between 6 
months-2 years, and 18% beyond 2 years post-aHSCT) (Bejanyan et al 2015). 
Although the optimal duration of therapy remains to be determined, the proposed 24 cycles 
would theoretically ensure maintenance of augmented GvL and suppression of residual 
leukemic cell growth for a prolonged period during the time post-aHSCT with the highest 
risk for relapse. 
For participants who achieve and maintain MRD negativity for 12 consecutive cycles, study 
treatment may be discontinued earlier at investigator's discretion. 
4.3 
Rationale for choice and dose of combination drugs 
After the completion of Safety Run-in and determination of the recommended dose for 
expansion, sabatolimab will be evaluated as monotherapy as well as in combination with 
azacitidine.  
Azacitidine: 
The dual activity of azacitidine as an antileukemic agent and inhibitor of GvHD makes it an 
attractive partner for combination with sabatolimab post-aHSCT to mitigate the potential 
risk of inducing or worsening of GvHD. 


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Azacitidine at 75 mg/m2 SC or IV x 7 days of every 28-day cycle in combination with 
sabatolimab at 800 mg IV Q4W has been evaluated in MDS and AML population and was 
found to be safe and tolerable (Borate et al 2020).  
Azacitidine is currently not approved in the post aHSCT setting. However, azacitidine has 
been tested at different doses and schedules in various clinical studies in the post-aHSCT 
setting as preemptive or maintenance therapy of AML or MDS (see Section 1.1). 
Based on the available published data on the safety and efficacy of various dosing regimens 
of azacitidine in the post-aHSCT setting (for further details, please see Section 1.1, 
azacitidine), lower doses of azacitidine were selected (50 mg/m2 SC x 5 days of every 28-
day cycle) aiming to improve the tolerability of treatment with likely less hematological 
toxicities and infectious complications after aHSCT, enhance the adherence to treatment 
schedule and protocol compliance by reducing the burden of frequent hospital visits and 
increase the likelihood of a greater efficacy with the administration of more cycles of 
azacitidine (de Lima et al 2010, Goodyear et al 2012, Platzbecker et al 2012, Craddock et al 
2016, Platzbecker et al 2018). 
Of note, azacitidine dosing schedule of 50 mg/m2 SC x 5 days every 4 weeks has been 
studied in maintenance trials of AML after intensive chemotherapy (Griffin et al 2015, 
Huls et al 2019). 
4.4 
Rationale for MRD assessments 
 
4.4.1 
Rationale for MRD assessments 
Measurable Residual Disease (MRD) in AML refers to the presence of leukemic blasts at a 
sensitivity of detection below the threshold of conventional morphologic methods. 
participants who experience a CR according to morphologic assessments (<5% blasts in the 
bone marrow) can still harbor a large number of leukemic cells in the bone marrow, which 
confers poor outcome. Detection of MRD in AML has shown prognostic relevance in 
several 
studies 
(Freeman et al 2013, 
Terwijn et al 2013, 
Ivey et al 2016, 
Freeman et al 2018), indicating that the depth of leukemic clearance should be considered 
as a relevant prognostic endpoint in this setting. 
The significance of MRD in hematopoietic stem cell transplantation is well recognized in 
AML. Indeed, there is a growing evidence that post-transplant MRD positivity is a 
prognostic biomarker of high-risk of relapse (Fang et al 2012, Appelbaum 2013, 
Zhou et al 2016, Shah et al 2018, Liu et al 2019, , Thol et al 2019). Furthermore, even pre-
transplant MRD assessment by either MFC or molecular techniques can be used for risk 
stratification at the time of HSCT following either myeloablative or reduced intensity 
conditioning 
(Walter et al 2011, 
Buckley et al 2017, 
Canaani et al 2018, 
Gilleece et al 2018, Thol et al 2018). 
To investigate in detail the depth of leukemic clearance, we will perform central MRD 
assessments using both phenotypic 
 methods. At present, Multiparameter 
Flow Cytometry (MFC) represents the most adequate, clinically validated technology to 
robustly monitor MRD in the large majority of AML participants (~90%), and 
recommended in the European Leukemia Net (ELN) 2018 MRD guidelines 
(Schuurhuis et al 2018b). For this reason, we plan to use MFC-MRD data as a secondary 
efficacy endpoint. 


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4.5 
Purpose and timing of interim analyses/design adaptations 
Interim analyses are planned for the monitoring of safety data (see Section 12.7). 
The study design foresees that during and at the conclusion of Part 1 (Safety Run-in), 
decisions based on emerging data are made at safety review meetings following completion 
of enrollment at each dose level (or earlier if required) and prior to starting Part 2. The 
decision to escalate to the 800 mg Q4W dose level in Part 1 and the selection of the preferred 


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dose level for Part 2, will be based, principally, on the occurrence of dose limiting toxicities 
(DLTs) (see Table 6-2). The decision to open the combination cohort (cohort 3), the 
expansion monotherapy cohort (cohort 4) and the adolescent cohort (cohort 5) will be based 
on an overall assessment of all available data, including safety, preliminary response 
assessment, clinical pharmacology, tolerability, and recommendations from participating 
investigators. All the decisions will be guided by a Bayesian Logistic Regression Model 
(BLRM) to assess the relationship between the dose of MBG453 and the incidence of DLTs. 
If the probability that the true Dose Limiting Toxicity (DLT) rate exceeds 50% is less than 
25%, the BLRM will recommend pursuing the recruitment and open a new cohort (see 
Section 6.5.2 for details on guidelines for determination of the recommended dose for 
expansion). These decisions will be communicated to investigators. 
Details of this procedure and the process for communication with investigators are provided 
in Section 6.5.1 and Section 6.5.2. 
The primary efficacy analysis will be performed after all participants of cohorts 3 and 4 have 
completed at least 6 cycles of study treatment or have been followed for at least 6 months 
after the first dose of study treatment or have discontinued from the study earlier. See 
Section 12.7. 
Throughout the study, the decision whether or when to open an additional cohort(s) will be 
based on the overall safety, PK, tolerability, and preliminary response assessment. 
4.6 
Risks and benefits 
The risk to participants in this trial will be minimized by compliance with the eligibility 
criteria and study procedures, as well as close clinical monitoring. Further, dose 
modifications are recommended and must be applied per protocol based on clinical or 
laboratory findings (see Section 6.5.4). 
Occurrence of an immune-related adverse event is an anticipated risk in participants treated 
with immune-oncology drugs such as sabatolimab. In the case of an immune-related event, 
there are dose modification and management guidelines, including detailed plans for follow-
up of toxicities. In addition, the protocol references and requires adherence to the recent 
American Society of Clinical Oncology (ASCO) practices guidelines for the management 
of 
immune-related 
adverse 
events 
in 
patients 
treated 
with 
checkpoint 
inhibitors (Brahmer et al 2018) (see Section 6.5.5 and Section 6.5.5.2).  
Based on the currently available data, there are no known significant overlapping toxicities 
between azacitidine and sabatolimab. However, this novel combination treatment may have 
unforeseen risks, which could be serious. In particular, there is a potential for an increased 
toxicity secondary to cytokine release syndrome due to activation of T cells and 
macrophages, and there may also be changes in immune function that could lead to 
autoimmunity or other immune-related adverse events, as well as increased risk of infection. 
All participants enrolled will be monitored closely for these potential toxicities. 
Furthermore, as the safety of sabatolimab monotherapy has not been assessed previously in 
the post- aHSCT setting, the protocol stipulates that consecutive safety run-in cohorts at 400 
mg Q4W and 800 mg Q4W will be observed for at least 2 treatment cycles followed by a 
Safety Review Meeting, before opening enrollment to a larger participant population in Part 
2 with a combination cohort (sabatolimab+ azacitidine) (Cohort 3), an expansion 
monotherapy cohort (Cohort 4) and an adolescent cohort (Cohort 5).   


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Sexually active males treated with azacitidine, and all women of child bearing potential 
enrolled in the study, must be informed that taking the study treatment may involve 
unknown risks to the fetus if a pregnancy were to occur during the study and must agree that 
in order to participate in the study they must adhere to the contraception requirements 
outlined in the exclusion criteria . If there is any question that the participant will not reliably 
comply, they should not be entered or continue in the study. 
SARS-CoV-2 and COVID-19 pandemic: No additional risk to participants' safety due to the 
SARS-CoV-2 virus and the COVID-19 pandemic has been identified with sabatolimab 
based on the available knowledge at this time, and therefore the benefit- risk remains 
unchanged. There is no contraindication for the use of an inactivated, viral-vector, or mRNA 
based SARS-CoV-2 vaccine in cancer patients on sabatolimab therapy.  
COVID-19 vaccines have not been tested in patients treated with MBG453, therefore any 
additional risks are unknown. Before receiving any vaccine, the risks and benefits should be 
evaluated by the investigator. In case of active COVID-19 infection, a careful benefit- risk 
evaluation to be performed to determine whether participants can remain on study 
medication or not. 
5 
Study Population 
The study population will include adult and adolescent participants with de novo AML or 
secondary AML, who have achieved complete remission (i.e., <5% bone marrow blasts, 
absence of circulating blasts in the blood, and absence of extramedullary disease) after 
aHSCT and at high risk of relapse defined by the presence of MRD (MRD+), any time at ≥ 
Day 60 after aHSCT.  
Prior to enrollment, participants must have systemic GvHD prophylaxis or treatment 
[immunosuppressive treatment (IST)] completely tapered for at least two weeks prior to 
study entry, without any active grade III or IV acute GvHD, or moderate lung chronic 
GvHD, or any severe chronic GvHD. Prednisone dose ≤ 5 mg/day or equivalent 
corticosteroid dose is allowed. 
A total of approximately 59 participants will be enrolled; including adults ≥ 18 years and a 
cohort of approximately 6 adolescent participants who are 12 years or older but less than 18 
years old. 
The exact number of participants enrolled will be determined by results obtained during the 
course of the study.  
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. At the date of signing the informed consent form (ICF), eligible participants must be ≥ 
18 years for the adult cohorts; and ≥ 12 years old but < 18 years old for the adolescent 
cohort (cohort 5), which will open after completion of Safety Run-in. 
3. Diagnosis of AML/secondary AML and received one prior aHSCT performed to control 
AML 
 Participants are eligible irrespective of response or MRD status at time of aHSCT 
4. Participants in complete remission (< 5% bone marrow blasts, absence of circulating 
blasts, and absence of extramedullary disease) with MRD positivity by local assessment 


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or by central assessment where required (e.g., USA sites), any time at ≥ Day 60 after 
aHSCT.  
5. Ability to provide a fresh bone marrow aspirate sample collected within 28 days from 
enrollment/randomization, and immediately shipped to a Novartis designated central 
laboratory for MRD testing.  
6. Systemic GvHD prophylaxis or treatment [immunosuppressive treatment (IST)] 
completely tapered for at least two weeks prior to study entry. Prednisone dose ≤ 5 
mg/day or equivalent corticosteroid dose is allowed. 
7. Participants who are found with MRD positivity while still on or tapering systemic 
GvHD prophylaxis or treatment, MRD positivity must be re-confirmed at least 2 weeks 
after the last dose of IST 
8. For the adult cohorts, participants must have an Eastern Cooperative Oncology Group 
(ECOG) performance status of 0, 1 or 2. 
For the adolescent cohort, participants must have a Karnofsky (age ≥ 16 years) or Lansky 
(age < 16 years) performance status score ≥ 50%. 
9. AST and ALT ≤ 3 × upper limit of normal (ULN) 
10.  Total bilirubin ≤ 1.5 × ULN (except in the setting of isolated Gilbert syndrome, in which 
case higher total bilirubin is allowed provided that conjugated bilirubin is ≤ 1.5 x ULN) 
11. Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73 m2 (calculated, based 
on local laboratory, using the Modification of Diet in Renal Disease (MDRD) formula 
in adults, and using the bedside Schwartz formula in the adolescent cohort). 
12. ANC ≥ 1.0x109/L 
13. Platelet count ≥ 75x109/L 
14. Written informed consent, willingness and ability to comply with all study procedures. 
15. Haemoglobin level of ≥ 8 g/dL 
 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Prior exposure to TIM-3 directed therapy at any time. 
2. History of severe hypersensitivity reactions to any ingredient of study drug(s) 
(azacitidine, sabatolimab) or monoclonal antibodies (mAbs) and/or their excipients 
3. Human immunodeficiency virus (HIV) infection not controlled by standard therapy 
and/or with known history of opportunistic infection. For countries where HIV status is 
mandatory: HIV status will be tested during screening using a local test. 
4. Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Participants whose disease is 
controlled under antiviral therapy should not be excluded. 
5. Active acute GvHD grade III-IV according to standard criteria (Appendix 1). 
6. Active moderate chronic GvHD of the lungs according to NIH consensus criteria 
(Appendix 2). 
Active severe chronic GvHD according to NIH consensus criteria. 
7. Psychiatric disorder that interferes with ability to understand the study and give informed 
consent or patient information assent for adolescent, and/or impacts study participation 
or follow-up. 


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8. History of another primary malignancy that is currently clinically significant or currently 
requires active intervention. Participants who are receiving adjuvant therapy, such as 
hormone therapy, are eligible. 
9. Any concurrent severe and/or active uncontrolled infection requiring parenteral 
antibacterial, antiviral or antifungal therapy (such as severe pneumonia, meningitis, or 
septicemia) 
10. Other concurrent severe and/or uncontrolled medical conditions (e.g. uncontrolled 
diabetes mellitus, chronic obstructive or chronic restrictive pulmonary disease including 
dyspnoea at rest from any cause) or history of serious organ dysfunction or disease 
involving the heart, kidney, or liver. 
11. Other co-morbidity that, in the opinion of the investigator, predisposes the participant to 
high risk of noncompliance with the protocol. 
12. Active autoimmune disease requiring systemic therapy (e.g. corticosteroids). Topical, 
inhaled, nasal and ophthalmic steroids are not prohibited. Replacement corticosteroids 
therapy is allowed and not considered a form of systemic treatment 
13. Live vaccine administered within 30 days prior to the first day of study treatment (C1D1) 
14. Cardiac or cardiac repolarization abnormality, including but not limited to any of the 
following: 
a) History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft 
(CABG) within 6 months prior to starting study treatment 
b) Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and 
third-degree AV block)  
15. Female is pregnant or breastfeeding. Negative serum pregnancy test is required for 
women of child-bearing potential (WOCBP). 
16. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during study treatment and for 90 days after the last dose of azacitidine (or as per the 
respective local label, whichever is longer) and 150 days after the last dose of 
sabatolimab. Highly effective contraception methods include: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment 
 Male sterilization (at least 6 months prior to screening/baseline). For female 
participants on the study the vasectomized male partner should be the sole partner 
 Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device (IUD) or 
intrauterine system (IUS) or other forms of hormonal contraception that have 
comparable efficacy (failure rate <1%), for example hormone vaginal ring or 
transdermal hormone contraception 
In case of use of oral contraception women should have been stable on the same pill for 
a minimum of 3 months before taking study treatment. 


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Women of non-childbearing potential, defined as women who are physiologically and/or 
anatomically incapable of becoming pregnant, as now further described: 
 They are post-menopausal as evidenced by 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (i.e., age-appropriate history of 
vasomotor symptoms), or, 
 they have had bilateral surgical oophorectomy (with or without hysterectomy), total 
hysterectomy or bilateral tubal ligation at least 6 weeks prior to first dose. In the 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment, is she considered not of 
childbearing potential. 
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF. 
17. Sexually active males unless they use a condom during intercourse while taking 
azacitidine and for 3 months after stopping this drug. They should not father a child in 
this period. A condom is required to be used also by vasectomized men in order to 
prevent delivery of the drug via seminal fluid. In addition, male participants must not 
donate sperm for the time period specified above. 
18. Prior systemic AML/cancer-directed treatments given at any time after aHSCT; or 
investigational modalities ≤ 5 half-lives or 4 weeks prior to starting study, whichever is 
shorter. Prior prophylactic use of DLI with or without hypomethylating agent (HMA) is 
permitted, if DLI is completed ≥ 3 months, and HMA is completed ≥ 4 weeks prior to 
start of study treatment.  
19. Participants with BCR-ABL mutant AML who are eligible for post-transplant tyrosine 
kinase inhibitor therapy as per investigator clinical assessment and local practice 
guidelines  
 
6 
Treatment 
6.1 
Study treatment 
In this study, the term “investigational drug” refers to the Novartis study drug, sabatolimab 
(MBG453). 
The term “study treatment” refers to the combination of study drugs: sabatolimab plus 
azacitidine or sabatolimab alone. 
All doses prescribed, dispensed to the participant and all dose changes during the study 
including the reason must be recorded on the appropriate electronic case report form (eCRF) 
page. 


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6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigatio
nal/ Control 
Drug  
(Name and 
Strength) 
Dose for 
Administ
ration 
Frequency
/Regimen 
Pharmace
utical 
Dosage 
Form 
Route of 
Administr
ation 
Supply 
Type 
Sponsor 
(global or 
local) 
Sabatolimab 
400 mg/4ml 
400 mg 
Q4W 
Solution in 
vial for IV 
infusion 
Intravenou
s use 
Open label  
Sponsor 
(global) 
800 mg 
Azacitidine* 
100 mg 
as per local 
/global 
supply 
50 mg/m2 
Days 1-5 of 
each cycle 
Vial for IV 
infusion or 
subcutane
ous 
administrati
on$ 
Intravenou
s or 
subcutane
ous 
administrati
on$ 
Open label 
Sponsor 
(global) 
or provided 
locally 
* Azacitidine will be used only in the Combination cohort. 
$ Intravenous or subcutaneous azacitidine should not be substituted by oral azacitidine (CC-
486, Onureg®). The indications and dosing regimen for intravenous or subcutaneous azacitidine 
differ from that of oral azacitidine (CC-486, Onureg®). 
Sabatolimab 
Sabatolimab will be administered at an assigned dose level, 400 mg or 800 mg, via IV 
infusion over 30 minutes (up to 2 hours, if clinically indicated) on Day 1 of each 28-day 
treatment cycle for participants in the sabatolimab monotherapy cohorts; and on Day 5 (+/- 
3 days except for Cycle 1 where sabatolimab should not be administered earlier than Day 5, 
after the participant has received at least 5 doses of azacitidine) of each 28-day treatment 
cycle in the combination cohort. There should be a period of at least 1 hour after the infusion 
whereby the participant requires close observation. 
On days of co-administration of azacitidine and sabatolimab (e.g. on Day 5 of a cycle), the 
azacitidine should be administered first followed by sabatolimab. A minimum of one hour 
break between azacitidine administration (IV or SC) must be applied before starting the 
sabatolimab infusion. 
Further instructions for the preparation and dispensation of sabatolimab is described in the 
Pharmacy Manual. 
Azacitidine (Combination Cohort 3 only) 
Azacitidine will be administered at a dose of 50 mg/m2; body surface area (BSA) in m2 = 
[height (cm) x weight (kg)/3600]0.5), SC or IV every day for five consecutive days on 
Days 1-5 out of a 28 days cycle (for further details except the dose and schedule, see local 
azacitidine prescribing information or (Vidaza (Azacitadine) USPI 2008). 
The azacitidine regimen used in this protocol was selected based on the available data from 
various clinical studies testing azacitidine at different doses and schedules in the post-
aHSCT setting as preemptive or maintenance therapy of AML or MDS (de Lima et al 2010, 
Goodyear et al 2012, Platzbecker et al 2012, Craddock et al 2016, Platzbecker et al 2018). 
Please refer to Section 1.1, Section 1.2 and Section 4.3 for background, purpose 
and rationale. Lower doses of azacitidine (50 mg/m2 SC x 5 days of every 28-day cycle) 


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were selected in attempt to improve tolerability of treatment with likely less hematological 
toxicities and infectious complications after aHSCT; and to enhance adherence to schedule 
and protocol compliance by reducing the burden of frequent hospital visits.  
Intravenous or subcutaneous azacitidine should not be substituted by oral azacitidine (CC-
486, 
Onureg®). 
The 
indications 
and 
dosing 
regimen 
for 
intravenous 
or 
subcutaneous azacitidine differ from that of oral azacitidine (CC-486, Onureg®). 
6.1.2 
Additional study treatments 
No other study treatment beyond investigational drugs (sabatolimab and azacitidine) is 
included in this trial. 
6.1.3 
Treatment arms/group 
In Part 1 (Safety Run-in), participants enrolled in cohort 1 will receive sabatolimab 400 mg 
Q4W, and participants enrolled in cohort 2 will receive sabatolimab 800 mg Q4W. 
Participants enrolled in Part 2 will receive sabatolimab in monotherapy at the recommended 
dose for expansion determined in the Safety Run-in (either 400 mg Q4W or 800 mg Q4W) 
in cohorts 4 and 5 (monotherapy expansion cohort and adolescent cohort respectively), or 
sabatolimab in combination with azacitidine in cohort 3 (combination cohort). 
6.1.4 
Guidelines for continuation of treatment 
Per protocol, dose modifications, including dose interruptions, for toxicities are permitted 
and outlined in Section 6.5. 
6.1.5 
Treatment duration 
Study treatment will be administered for up to a maximum of 24 cycles or until a participant 
experiences hematologic relapse (bone marrow blasts ≥5%; or reappearance of blasts in the 
blood; 
or 
development 
of 
extramedullary 
disease) 
as 
defined 
by 
ELN 
2017 (Döhner et al 2017); or any of the following events, whichever is earlier: 
 unacceptable toxicity 
 initiation of a treatment cycle is delayed due to toxicities by more than 28 days 
(measured from the intended start date of the new cycle (i.e. measured from Day 29 of 
the previous cycle) 
 withdrawal of consent 
 physician decision 
 lost to follow up 
 pregnancy 
 death 
For participants who achieve negative MRD and maintain MRD negativity for 12 
consecutive cycles, study treatment (sabatolimab monotherapy or sabatolimab in 
combination with azacitidine) can be discontinued earlier, at the discretion of the PI. 
6.1.5.1 
Treatment beyond disease progression 
Treatment beyond hematologic relapse is not permitted. 


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6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
In general, the use of any concomitant medication/therapy deemed necessary for the care of 
the participant (e.g., such as anti-emetics, anti-diarrheal) is permitted (see Section 6.2.1.1), 
except when specifically prohibited (see Section 6.2.2). The participant must be told to 
notify the investigational site about any new medications he/she takes after the start of the 
study drug. 
Participants should not receive pre-medication to prevent infusion reaction before the first 
infusion of sabatolimab. If a participant experiences an infusion reaction, he/she may receive 
pre-medication on subsequent dosing days. The pre-medication should be chosen per 
institutional standard of care, at the discretion of the treating physician. If a participant 
experiences a Grade 3 infusion reaction (which does not resolve within 72 hrs) or Grade 4 
infusion reaction, the investigational drug (sabatolimab) should be discontinued (see 
Table 6-3). 
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal 
cardiopulmonary 
status. 
If 
a 
participant 
experiences 
a 
Grade 
3 
anaphylactic/anaphylactoid reaction, the participant will be discontinued from the study 
treatment. 
Sabatolimab should be administered in a facility equipped for cardiopulmonary 
resuscitation. Appropriate resuscitation equipment should be available at the bedside and a 
physician readily available. 
Participants should receive appropriate prophylaxis (e.g. antiemetics) for azacitidine as per 
local practice. 
For participants enrolled all medications, procedures, and significant non-drug 
therapies/procedures (including physical therapy) taken within the 28 days of screening 
until 150 days after the last dose of sabatolimab or 30 days after the last dose of azacitidine 
administered, whichever is later, or until start of a new antineoplastic therapy must be 
recorded in the appropriate Case Report Forms. Concomitant medication administered to 
treat AE/SAEs suspected to be related to study treatment will continue to be collected up to 
the end of the safety follow-up period. 
The approved drug labels for azacitidine should be consulted for guidance on concomitant 
therapies. 
Each concomitant drug must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt, the investigator should contact the Novartis 
medical monitor before enrolling a participant or allowing a new medication to be started. 
If the participant is already enrolled, contact Novartis medical monitor to determine if the 
participant should continue study treatment. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Anticoagulation therapy is permitted if the participants are already at stable dose of warfarin 
or stable doses of low molecular weight heparin (LMWH) for ˃ 2 weeks at time of first dose 
and International Normalized Ratio (INR) should be monitored as clinically indicated per 
investigator’s discretion. Participants who develop a new requirement for anticoagulant 


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therapy during the conduct of the study may remain on study after documented discussion 
with the Novartis medical monitor. However, ongoing anticoagulant therapy should be 
temporarily discontinued to allow bone marrow sampling according to the institutional 
guidelines. 
Anti-hypertensive therapy is allowed as concomitant medications; however, because 
transient hypotension has occurred during infusions of monoclonal antibodies, consideration 
should be given to withholding anti-hypertensive medications for 12 hours prior to infusion 
with sabatolimab. 
6.2.2 
Prohibited medication 
During the course of study treatment, participants must not receive additional investigational 
drugs or devices, chemotherapy, DLI, other cellular therapies or any other therapies that 
may be active against cancer or modulate the immune response. Post treatment efficacy 
follow-up period will end, once a participant develops a hematologic relapse, or start of new 
therapy for AML. 
Additionally, the use of systemic corticosteroids and/or immunosuppressive medications is 
not allowed while on study treatment unless given for the management of infusion-related 
reaction, treatment-emergent immune-related adverse events (irAEs), aGvHD and/or 
cGvHD. 
Systemic corticosteroids required for control of infusion-related reactions or irAEs must be 
tapered and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent 
corticosteroid dose) before the next study administration. If more than 10 mg/day prednisone 
is used, sabatolimab should be interrupted until the participant receives 10 mg/day or less 
of prednisone. Topical, inhaled, non-absorbable, nasal and ophthalmic steroids are allowed. 
For aGvHD and/or cGvHD, refer to Table 6-4. 
The use of systemic steroids and/or other immunosuppressive drugs may be administered 
for prophylaxis against imaging contrast dye allergy (providing this is ≤ 10 mg/day 
prednisone or equivalent corticosteroid dose), or replacement-dose steroids in the setting of 
adrenal insufficiency, or for the management of transient exacerbation of other underlying 
diseases such as chronic obstructive pulmonary disease requiring treatment for ≤ 3 weeks. 
The use of live vaccines is not allowed through the duration of the study treatment and 150 
days after the last dose of sabatolimab. Inactivated vaccines, subunit, recombinant, 
polysaccharide and conjugate vaccines and toxoid vaccines are allowed. 
In addition, prohibited medication related to azacitidine will apply according to local/global 
label. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for prescreening (if applicable) or screening and is 
retained for the participant throughout his/her participation in the trial. A new Participant 
No. will be assigned at every subsequent enrollment if the participant is re-screened. The 
Participant No. consists of the Center Number (Center No.) (as assigned by Novartis to the 
investigative site) with a sequential participant number suffixed to it, so that each 


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participant’s participation is numbered uniquely across the entire database. Upon signing 
the informed consent form, the participant is assigned to the next sequential Participant No. 
available. 
The investigator or designated staff will contact the Interactive Response Technology (IRT) 
and provide the requested identifying information to register the participant. Once assigned, 
the participant No. must not be reused for any other participant and the participant No. for 
that individual must not be changed unless the participant is re-screened. If the participant 
fails to be randomized or start treatment for any reason, the reason will be entered into the 
appropriate eCRF page and IRT should be notified as soon as possible.  Re-screening is 
allowed once for participants that were initially screen failures for any reason. All eligibility 
criteria must be re-checked and met prior to enrollment of the participant into the study. A 
new participant No. should be assigned for all re-screened participants. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant 
after a participant has screen failed, and the participant will be assigned a new Participant 
No. 
6.3.2 
Treatment assignment, randomization 
This phase Ib/II trial is an open label study. 
 In the Part 1 (safety run-in part), the study is non-randomized, and participants will be 
treated with sabatolimab in monotherapy 
 In the Part 2, adult participants will be randomized to one of the two cohorts: 
combination cohort (Cohort 3 with sabatolimab + azacitidine as study treatment) and 
expansion monotherapy cohort (Cohort 4 with sabatolimab monotherapy as study 
treatment). The randomization ratio will depend on the number of participants from the 
safety-run in part (Part 1) already treated with sabatolimab at the selected dose level for 
expansion. If the sabatolimab dose selected for expansion is the 800 mg dose level and 
if 12 participants are included in the safety run-in part at that dose level, participants will 
be randomized in a 1:1.5 ratio to one of the two adult cohorts in Part 2. Thus, 25 
participants will be treated with sabatolimab in monotherapy at the selected dose level 
(12 participants from the safety run-in cohorts and 13 participants from the expansion 
monotherapy cohort) and 20 participants will be treated with sabatolimab at the selected 
dose given in combination with azacitidine (20 participants from the combination 
cohort). 
 In Part 2, adolescent participants will be enrolled in Cohort 5 with sabatolimab 
monotherapy. 
For the randomization part (Cohort 3 and Cohort 4): 
Following completion of screening procedures and prior to receive the first dose of study 
treatment, all eligible participants will be randomized via Interactive Response Technology 
(IRT) to one of the two cohorts: Cohort 3 with the combination sabatolimab + azacitidine 
or Cohort 4 with sabatolimab in monotherapy. The investigator or his/her delegate will 
contact the IRT after confirming that the participant fulfills all the inclusion/exclusion 
criteria. The IRT will assign a randomization number to the participant, which will be used 
to link the participant to a treatment and will specify a unique medication number for the 
first package of sabatolimab to be dispensed to the participant. Study treatment azacitidine 
will be supplied by Sponsor (global) or sourced locally for participants randomized in 
Cohort 3. 


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The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Global Clinical Supply (GCS) using a validated system that 
automates the random assignment of medication numbers to packs containing the study 
treatment. 
The randomization scheme for participants will be reviewed and approved by a member of 
the Randomization Office. 
6.4 
Treatment blinding 
Treatment will be open to participants, investigator staff, persons performing the 
assessments, and the CTT. 
6.5 
Dose escalation and dose modification 
Two dose levels of sabatolimab, 400mg Q4W and 800mg Q4W will be evaluated. Intra-
participant dose escalation is not permitted at any time during the study. Guidance for dose 
modifications is provided in Section 6.5. 
6.5.1 
Dose escalation guidelines 
Sabatolimab will be given at 400 mg IV every 4 weeks in the first cohort including 
approximately 8 participants (to obtain at least 6 evaluable participants). If there is no 
unacceptable level of toxicity during the first 2 cycles at this dose level, sabatolimab will be 
given at 800 mg IV every 4 weeks in the second cohort including approximately 12 
participants (to obtain at least 9 evaluable participants). 
The level of toxicity will be assessed by the number of dose-limiting toxicities as defined in 
Table 6-2. 
Guidelines for dose escalation and for determination of the recommended dose for 
expansion are presented in Section 6.5.2. 
In case of safety concerns and/or based on pharmacokinetic/pharmacodynamic data during 
the safety run-in part of the study (Part 1), the following changes may be considered: 
 To include additional participants at the current dose level 
 To not escalate to the next planned dose (sabatolimab 800 mg Q4W) 
6.5.2 
Guidelines for determination of the recommended dose for 
expansion (RDE) 
The recommended dose for expansion (RDE) of sabatolimab will be the highest dose level 
between 400 mg and 800 mg Q4W that is not expected to cause an unacceptable level of 
toxicity (DLT) including aGvHD and cGvHD in more than 50% of the treated participants 
during the DLT evaluation period (See Table 6-2). 
Notably, the curative efficacy of aHSCT is attributable to GvL, which inherently maybe 
associated with risk of GvHD, with reported incidence rates of clinically significant aGvHD 
ranging from 9% to 50%, and cGvHD from 30% to 70% (see Section 1.1). Therefore, post-


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aHSCT immunomodulatory interventions, including sabatolimab, that promote GvL could 
potentially induce GvHD and other immune-related adverse events.  
However, the assessment of whether GvHD or unacceptable level of toxicity is possibly 
treatment-related, and therefore a DLT, will be confounded by the inherent background 
incidence of GvHD associated with aHSCT. As the reported incidence of acute and chronic 
GvHD is similar to or in some cases higher than the standard threshold for incidence of DLT 
in phase I studies (i.e. DLT rate < 33.3%), a higher threshold (DLT rate of 50%) was selected 
for the Bayesian model to determine if sabatolimab given as monotherapy is not meeting an 
unacceptable level of toxicity. 
However, all toxicities ≥ grade 2 will be individually reviewed to evaluate safety data 
of each cohort from the Safety Run-in part. 
In the first cohort, approximately 8 participants (to obtain at least 6 evaluable participants) 
will be treated with the starting dose of sabatolimab 400 mg every 4 weeks. 
In the second cohort, approximately 12 participants (to obtain at least 9 evaluable 
participants) will be treated with sabatolimab 800 mg every 4 weeks. 
For both cohorts, participants must complete a minimum of 2 cycles of treatment with the 
minimum safety evaluation and drug exposure or have had at least one dose-limiting toxicity 
(DLT) including aGvHD and cGvHD within the first 2 cycles of treatment to be considered 
evaluable for dose escalation/expansion decisions. Dose escalation/expansion decisions will 
occur when the cohort of participants have met these criteria. 
Dose escalation/expansion decisions will be made by Investigators and Novartis study 
personnel (including the study physician and statistician) during a dose decision meeting by 
teleconference. Decisions will be based on a synthesis of all relevant data available from all 
dose levels evaluated in the ongoing study including safety information, incidence and 
severity of aGvHD and cGvHD, incidence of DLTs, all Common Terminology Criteria for 
Adverse Events (CTCAE) Grade ≥ 2 toxicity data during the first two cycles, available PK 
and PD data from evaluable participants. 
The recommended dose for the next cohort of participants (second cohort in the safety run-
in part, expansion cohort, combination cohort and adolescent cohort) will be guided by a 
Bayesian logistic regression model (BLRM) and by applying the following principle: the 
risk to have ≥ 50% DLTs including GvHD must be below 25%. This adaptive Bayesian 
methodology has the advantage to incorporate information gained at the preceding dose 
levels. Thus, additional participants may be enrolled at this dose level or a higher dose level 
as agreed by Investigators and Novartis personnel and if the BLRM predicts that the risk to 
have ≥ 50% dose limiting toxicities (DLTs) including GvHD remains below 25%. 
Sabatolimab administration at the next higher dose level (sabatolimab 800 mg Q4W) or 
starting the recruitment of the Part 2 of the study (monotherapy expansion cohort, 
combination cohort and adolescent cohort) may not proceed until the investigator receives 
written confirmation from Novartis indicating that the results of the previous cohort were 
evaluated and that it is permissible to proceed to open a new cohort. 
6.5.3 
Definitions of dose limiting toxicities (DLTs) 
Dose-limiting toxicities will be collected and evaluated in participants enrolled to the Safety 
Run-in part and adolescent cohort.  


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A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
considered by the Investigator to be at least possibly related to sabatolimab as a single 
contributor that occurs during the DLT observation period [during the first 2 cycles, ie, 
Cycle 1 Day 1 (starting from the first infusion of sabatolimab) to the end of Cycle 2 of 
treatment with sabatolimab monotherapy in Safety Run-in] and meets any of the criteria 
included in Table 6-2. The National Cancer Institute Common Terminology Criteria for 
Adverse events (NCI CTCAE) version 5.0 will be used for all grading, except for GvHD 
(Harris et al 2016 for aGvHD and NIH consensus criteria for cGvHD). For the purpose of 
dose-escalation decisions, DLTs will be considered and included in the BLRM. 
If a participant experiences a DLT (during the DLT observation period) then study treatment 
must be interrupted and may be permanently discontinued depending on the severity of the 
DLT. If the DLT (other than GvHD) resolves to CTCAE Grade 1 or baseline value, the 
participant may continue to receive study treatment following consultation with the Novartis 
medical monitor.  
For aGvHD and/or cGvHD that meet DLT criteria, refer to Table 6-4 for study treatment 
interruption, re-initiation and/or discontinuation. 
The investigator must notify the sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. 
Table 6-2 
Criteria for Dose Limiting Toxicities (DLTs) 
Toxicity 
DLT Criteria 
DLTs considered related to graft vs host disease (GvHD) by the Investigator assessment 
Acute GvHD 
Grade IV acute GvHD 
Stage ≥3 lower GI acute GvHD (consistent with Grade III 
acute GvHD) 
Stage ≥3 liver acute GvHD (consistent with Grade III GvHD) 
Chronic GvHD 
Moderate chronic GvHD of the lungs 
Severe chronic GvHD 
Other DLTs excluding acute or chronic GvHD by the investigator assessment 
Immune-related adverse 
events (irAEs) 
- irAEs ≥ CTCAE Grade 3 persisting > 7 days after starting 
appropriate treatment (e.g. with corticosteroids) 
- Pneumonitis ≥ CTCAE Grade 2 persisting > 7 days despite 
treatment with corticosteroids 
- Pneumonitis ≥ CTCAE Grade 3 
Hematology 
- Febrile neutropenia ≥ CTCAE Grade 3 in the absence of 
leukemic involvement in the marrow 
- Thrombocytopenia ≥ CTCAE Grade 3 with clinically 
significant bleeding in the absence of leukemic involvement in 
the marrow  
- Grade 4 neutropenia, thrombocytopenia, and pancytopenia, 
not related to leukemic infiltration, and do not respond to 
growth factor or transfusion support within 14 days will be 
considered to be a DLT (BM evaluation may be required to 
determine if marrow aplasia is due to leukemia). 
Infusion related reactions 
Infusion reaction CTCAE Grade 3 that does not resolve to 
Grade 1 within 72 hours or CTCAE grade 4 of any duration. 


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Toxicity 
DLT Criteria 
Other 
Any other unacceptable non-hematological toxicity 
encountered by a participant as determined by the 
Investigators and Novartis. 
6.5.4 
Dose modifications 
For participants who do not tolerate the protocol-specified dosing schedule, dose 
interruptions are required to allow participants to continue the study treatment. 
Dose modifications for sabatolimab 
Dose modifications for sabatolimab will be done according to ASCO guidelines for 
management of immune-related AEs including hematological AEs. (Brahmer et al 2018) 
Additionally, the guidance indicated in Table 6-3 below, provides instructions for infusion 
reaction, immune-related adverse events not covered by ASCO guidelines and a general 
guideline for non-hematologic non-immune-related toxicities that are clinically significant 
per investigator judgement and possibly attributable to the investigational drug. This general 
guideline will not apply in case of non-hematologic non-immune-related toxicities that are 
attributable to azacitidine and its complications. 
Deviations to dose interruptions, reductions and/or permanent discontinuations outlined in 
Table 6-3 are not allowed. 
Administration of sabatolimab may be delayed due to toxicities. A scheduled dose may be 
delayed within a cycle by up to 14 days. If a dose cannot be administered within the planned 
window within the cycle, then the dose should be skipped. Next scheduled dosing may 
resume once the adverse event has resolved to ≤ Grade 1 or baseline per the next planned 
treatment cycle. Dose reductions for sabatolimab are not allowed. 
Overall, for adverse events of potential immune-related etiology (other than GvHD) that do 
not recover to ≤ Grade 1 or baseline and be maintained at a dose of immunosuppression of 
≤ 10 mg/day prednisone or equivalent (or as indicated in Table 6-3 within 12 weeks after 
initiation of immunosuppressive therapy), sabatolimab must be permanently discontinued. 
For acute and/or chronic GvHD, refer to Table 6-4 for study treatment interruption, re-
initiation and/or permanent discontinuation. 
Dose interruption at the start of a new treatment cycle (Combination cohort) 
In participants who have Grade 4 neutropenia and/or Grade 4 thrombocytopenia dosing of 
azacitidine should be interrupted until resolution to ≤ Grade 2. Sabatolimab should not be 
administered during azacitidine dose interruption. After resolution, dosing of azacitidine 
may be resumed on the same day. The first day dosing is resumed will be considered as D1 
of the new treatment cycle and sabatolimab will be administered on Day 5 of the new cycle. 
In participants who achieved CRi or MLFS, azacitidine has been permanently discontinued, 
remain on sabatolimab, but have Grade 4 neutropenia and/or Grade 4 thrombocytopenia; 
dosing of sabatolimab should be interrupted until resolution to ≤ Grade 2. The first day 
dosing with sabatolimab is resumed will be considered D5 of the new cycle. 
For study treatment interruption for acute and/or chronic GvHD, refer to Table 6-4. 


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Table 6-3 
Criteria for dose interruption, re-initiation and discontinuation of 
sabatolimab due to adverse drugs reactions 
Worst Toxicity Grade 
(CTCAE v5.0) 
Recommended Dose Modifications 
Infusion Reaction 
Grade 1 
Decrease infusion rate until recovery 
Grade 2 
Stop infusion 
Before restarting – pre-medicate according to local institutional 
guidelines. 
Restart infusion at 50% of previous rate under continuous 
observation. Ensure that there is a minimum observation period of 1 
hour prior to restarting the infusion(s)If the AE recurs at the 
reinitiated slow rate of infusion, and despite oral pre-medication*, 
then discontinue MBG453 
Grade 3 
Stop infusion 
If the AE resolves to ≤ Grade 1 within 72hrs: 
ꞏ At next scheduled treatment visit, pre-medicate according to local 
institutional guidelines. 
ꞏ Restart infusion at 50% of previous rate under continuous 
observation. Ensure that there is a minimum observation period of 1 
hour 
ꞏ If the AE recurs despite slow rate of infusion and pre-medication*, 
then discontinue sabatolimab 
If the AE does not resolve to ≤ Grade 1 within 72hrs: 
ꞏ Discontinue sabatolimab 
Grade 4 
Discontinue sabatolimab 
For adverse events thought to be immune-related and not covered in the ASCO 
Guidelines for the management of immune-related adverse events in participants treated 
with immune checkpoint inhibitor therapy (Brahmer et al 2018)  
Grade 1 
Continue treatment with sabatolimab 
Grade 2 or Grade 3 ≤ 7 
days 
Delay treatment with sabatolimab until resolved to ≤ Grade 1 or 
baseline 
Grade 3 lasting > 7 days 
but < 21 days 
1st and 2nd occurrence: 
Delay study treatment until resolved to ≤ Grade 1 or baseline 
3rd occurrence: 
Discontinue study treatment 
Grade 3 lasting ≥ 21 
days Or Grade 4 
Discontinue study treatment 
Dermatological toxicities 
Grade 1 
Maintain sabatolimab. Use topical steroids, antihistamines, topical 
emollients. 
Grade 2 
Consider interrupting sabatolimab. 
Use topical or oral steroids, antihistamines. 
If sabatolimab is interrupted and resolution to ≤ Grade 1, restart 
sabatolimab. 
Grade 3 or 4 
Interrupt sabatolimab. 
Manage per institutional practice. 
After resolution to ≤ Grade 1, consider restarting sabatolimab. 
Bullous dermatitis 
Grade 1, 2, and 3: Interrupt sabatolimab. Consult with dermatologist 
for appropriateness to restart sabatolimab. 


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Worst Toxicity Grade 
(CTCAE v5.0) 
Recommended Dose Modifications 
Grade 4: Permanently discontinue sabatolimab. 
Stevens-Johnson 
syndrome (SJS) or Lyell 
syndrome/toxic 
epidermal necrolysis 
(TEN) 
Permanently discontinue sabatolimab. 
For non-hematological, non-immune related adverse events clinically significant** and 
possible attributable to the investigational drug (NCI CTCAE v5.0) 
(The guideline does not apply to for toxicities attributable to azacitidine or the underlying 
AML including its complications) 
Grade 1 and Grade 2 
tolerable 
Continue treatment with sabatolimab 
Grade 2 intolerable and 
Grade 3 
1st or 2nd occurrence: 
ꞏ Interrupt sabatolimab until toxicity recovers to ≤ Grade 1 or 
baseline 
ꞏ Once recovered to ≤ Grade 1 or baseline restart sabatolimab at the 
same dose level and schedule 
AE resolution to ≤ Grade 1 or baseline must occur within a maximum 
period of 56 days since interruption, otherwise sabatolimab must be 
permanently discontinued. 
3rd occurrence:  
ꞏ Permanently discontinue sabatolimab 
Grade 4 
Discontinue sabatolimab 
All dose modifications should be based on the available information and worst preceding toxicity 
*Prophylaxis regimens will include both paracetamol/acetaminophen and an antihistamine. 
**Per investigator judgement 
Dose modifications for azacitidine (Combination cohort) 
If azacitidine is deemed by the investigator to possibly have contributed to an observed 
adverse event, the dose or schedule of azacitidine may be modified within a cycle and/or for 
subsequent cycles, or temporarily interrupted, or permanently discontinued. 
Permanent discontinuation of sabatolimab and azacitidine (Combination cohort) 
If the study treatment (sabatolimab + azacitidine) is interrupted for toxicities other than 
GvHD and the start of the subsequent study treatment cycle is delayed for more than 28 
consecutive days from the intended start date of cycle (Day 29 of the previous cycle) the 
participant should be discontinued from study treatment. For permanent discontinuation of 
study treatment due to acute and/or chronic GvHD, refer to Table 6-4. 
Permanent discontinuation of only one component sabatolimab (or azacitidine - 
Combination cohort) 
If one component only of the study treatment (azacitidine or sabatolimab) is discontinued 
for toxicities (other than GvHD), then the treatment may continue with the other component 
of study treatment alone (sabatolimab alone or azacitidine alone) as long as the participant 
benefits per investigator's judgement.  
These dose changes must be recorded on the appropriate CRF. 


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Table 6-4 
Criteria for dose interruption, re-initiation and discontinuation of 
study treatment due to GvHD 
  
Interrupt study 
treatment£ (sabatoli
mab monotherapy 
or in combination 
with azacitidine)  
Resume study 
treatment 
(sabatolimab 
monotherapy or in 
combination with 
azacitidine)  
Discontinue study 
treatment 
permanently 
(sabatolimab 
monotherapy or in 
combination with 
azacitidine)  
Acute GvHD 
(aGvHD) 
 
New onset grade 
II requiring 
systemic therapy 
 
New onset grade 
III 
 
Baseline grade I 
or II worsening to 
grade III 
 
If aGvHD 
improved to ≤ 
grade I or to 
baseline prior to 
starting study 
treatment within ≤ 
8 weeks of 
observation from 
onset or 
exacerbation of 
aGvHD 
 
The following are 
allowed at time of 
resumption of 
study treatment:  
 
Topical, non-
absorbable 
or inhaled 
steroids 
 
Systemic 
doses of 
steroids ≤ 10 
mg 
prednisone 
or equivalent 
 
Tacrolimus 
with trough 
levels <5 
ng/mL OR 
CSA with 
trough levels 
<200 ng/mL  
(indicating 
continuous 
IST taper) 
 
Grade IV aGvHD 
 
Recurrence or 
exacerbation of 
aGvHD to ≥ grade 
III after resuming 
study treatment 
 
Steroid-refractory 
aGvHD 
 
No improvement 
to ≤ grade I or to 
baseline prior to 
starting study 
treatment after 8 
weeks of 
observation from 
onset or 
exacerbation of 
aGvHD 
Chronic GvHD 
(cGvHD) 
 
New onset 
moderate cGvHD 
ONLY if requires 
systemic therapy 
with > 5 mg 
prednisone or 
equivalent 
 
If cGvHD 
improved to ≤ 
mild cGvHD or to 
baseline prior to 
starting study 
treatment 
within ≤ 8 weeks 
of observation 
from onset or 
exacerbation of 
aGvHD 
 
Severe cGvHD 
 
Moderate cGvHD 
of the lungs 
 
Baseline 
moderate cGvHD 
worsening to 
severe cGvHD 
 
Recurrence or 
exacerbation of 
cGvHD to 


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Interrupt study 
treatment£ (sabatoli
mab monotherapy 
or in combination 
with azacitidine)  
Resume study 
treatment 
(sabatolimab 
monotherapy or in 
combination with 
azacitidine)  
Discontinue study 
treatment 
permanently 
(sabatolimab 
monotherapy or in 
combination with 
azacitidine)  
 
The followings 
are allowed at 
time of 
resumption of 
study treatment:  
 
Topical, non-
absorbable 
or inhaled 
steroids 
 
Systemic 
doses of 
steroids ≤ 10 
mg 
prednisone 
or equivalent 
 
Tacrolimus 
with trough 
levels <5 
ng/mL OR 
CSA with 
trough levels 
<200 ng/mL  
(indicating 
continuous 
IST taper) 
moderate cGvHD 
that requires 
systemic therapy 
with > 5 mg 
prednisone or 
equivalent; 
severe cGvHD; or 
moderate cGvHD 
of the lung after 
resuming study 
treatment 
 
Steroid refractory 
cGvHD 
 
No improvement 
to ≤ mild or to 
baseline prior to 
starting study 
treatment after 8 
weeks of 
observation from 
onset or 
exacerbation of 
cGvHD 
£Treatment of GvHD at the discretion of the treating investigator 
6.5.5 
Follow-up for toxicities 
Participants whose treatment is interrupted or permanently discontinued due to an AE or 
clinically significant laboratory value, must be followed-up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed 
necessary.  
All participants in Safety Run-in, expansion monotherapy, and adolescent cohorts must be 
followed up for AEs (including but not limited to acute and chronic GvHD, irAEs and SAEs) 
for 150 days following the last dose of sabatolimab. 
All participants in combination cohort must be followed up for AEs (including but not 
limited to acute and chronic GvHD, irAEs and SAEs) for 30 days following the last dose of 
azacitidine and 150 days following the last dose of sabatolimab, whichever is later.  
In addition to the instructions provided in this section, please refer to Section 16.3 
(Appendix 3) for further guidance on renal alert criteria, actions and events follow up. 


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6.5.5.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Guidelines for follow-up on potential DILI cases are described in Table 6-5 and Table 6-6. 
Table 6-5 
Follow-up of abnormal liver chemistry results 
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
If normal at baseline: 
ALT > 3 x ULN 
Normal 
For participants with 
Gilbert’s syndrome: 
No change in 
baseline TBL 
None 
- No change to study 
treatment 
- Measure alanine 
aminotransferase 
(ALT), aspartate 
aminotransferase 
(AST), alkaline 
phosphatase (ALP), 
gamma-glutamyl 
transferase (GGT), 
TBIL, INR, albumin, 
lactate 
dehydrogenase 
(LDH), CK, and 
glutamate 
dehydrogenase 
(GLDH) in 48-72 
hours. 
- Follow-up for 
symptoms 
If elevated at 
baseline: 
ALT > 2 x baseline or 
> 200 U/L (whichever 
occurs first) 
If normal at baseline: 
ALT > 5 x ULN for 
more than two weeks 
Normal 
For participants with 
Gilbert’s syndrome: 
No change in 
baseline TBL 
None   
- Interrupt study drug 
- Measure ALT, AST, 
ALP, GGT, TBIL, INR, 
albumin, LDH, CK, 
and GLDH in 48-72 
hours. 
- Follow-up for 
symptoms. 
- Initiate close 
monitoring and 
workup for competing 
etiologies. 
- Study drug can be 
restarted only if 
another etiology is 
identified, and liver 
enzymes return to 
baseline. 
If elevated at 
baseline: 
ALT > 3 x baseline or 
> 300 U/L (whichever 
occurs first) for more 
than two weeks 
If normal at baseline: 
ALT > 8 x ULN 
Normal   
None 
ALT increase with bilirubin increase: 
If normal at baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN (or 
INR > 1.5) 
For participants with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 x baseline or 
> 200 U/L (whichever 
occurs first) 
If normal at baseline: 
ALT > 3 x ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
right upper quadrant 
pain 
If elevated at 
baseline: 
ALT > 2 x baseline or 
> 200 U/L (whichever 
occurs first) 


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Table 6-6 
Action required for isolated total bilirubin elevation 
Abnormality 
Action required 
Any elevation > ULN 
Fractionate bilirubin, evaluate for cholestatic liver injury (ALP) or 
alternative causes of bilirubin elevation. Treat alternative causes 
according to local institutional guidelines 
Grade 2 (>1.5 - 3.0 
ULN) 
Maintain treatment. Repeat LFTs within 48-72 hours, then monitor 
LFTs weekly until resolution to ≤ Grade 1 or to baseline 
Grade 3 (>3.0 – 10 
ULN) 
Interrupt treatment. Repeat LFTs within 48-72 hours, then monitor 
LFTs weekly until resolution to ≤ Grade 1 or to baseline 
Grade 4 (> 10 x ULN) 
Discontinue study treatment 
If abnormalities are confirmed, close observation and follow-up are required: 
1. A detailed assessment of potential treatment emergent GvHD of liver (acute or 
chronic) should be performed by the Investigator 
2. A detailed history, including relevant information, such as cardiac disease, history of 
any pre-existing liver conditions or risk factors, blood transfusions, IV drug abuse, 
travel, work, alcohol intake, and full clinical examination for evidence of acute or 
chronic liver disease, cardiac disease and infection etc. should be performed. 
3. Review of concomitant medications, including nonprescription medications and herbal 
and dietary supplement preparations, alcohol use, recreational drug use, special diets, 
and chemicals exposed to within one month of the onset of the liver injury. 
4. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
5. Obtain an unscheduled PK sample, as close as possible to last dose of study treatment. 
Additional testing for other hepatotropic viral infection (EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist. 
6.5.5.2 
Follow-up for immune -related AEs 
The emergence of Immune-Related AE (irAE) may be anticipated based on general 
experience in clinical studies with similar class of compounds that block the negative 
immune regulators. 
An irAE is any clinically significant AE affecting any organ that is associated with study 
drug exposure, is consistent with an immune-mediated mechanism, and where alternative 
explanations have been investigated and ruled out or are considered to be unlikely. 
Serologic, histologic and immunological assessments should be performed as deemed 
appropriate by the Investigator, to verify the immune related nature of the AE. An empiric 
trial of corticosteroids may also contribute to understanding the etiology of a potential irAE. 
However, in the post-aHSCT setting, acute and chronic GvHD manifestations may overlap 
and be challenging to distinguish from irAEs [eg, skin rash, liver (hyperbilirubinemia, 
cholestasis, transaminitis), diarrhea, pneumonitis, etc.]. 
All participants with signs or symptoms of irAEs not attributed to acute or chronic GvHD 
should be monitored and managed following the ASCO Guidelines for the management of 
immune-related adverse events in participants treated with immune checkpoint inhibitor 
therapy (Brahmer et al 2018). For irAEs not covered by ASCO guidelines, please refer to 
Table 6-3. 


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In case of a suspected irAE not attributed to acute or chronic GvHD, the relevant 
immunological assessments (e.g. rheumatoid factor, anti-DNA Ab, etc.) should be 
performed. In case of a toxicity suspected to be a cytokine release syndrome, the cytokine 
assessments outlined in Table 8-9 must be performed. 
Participants should be monitored carefully for any skin toxicity or mucositis and study 
treatment should be discontinued for any suspected case of SJS/TEN. 
6.5.5.3 
Follow-up for QTcF Prolongation 
In case of QTcF >480 ms (or QTcF prolongation >60 ms from baseline): 
 Assess the quality of the ECG recording.  Collect two additional ECGs as soon as 
possible.  
 Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia, 
hypocalcemia). If abnormal, correct abnormalities.  
 Review concomitant medication use for possible causes for QT prolongation (refer to 
crediblemedicines.org). Record all concomitant medications in the appropriate eCRF 
page. 
 Monitor ECG per the institutional standards. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Every time the investigational treatment sabatolimab is to be administered, IRT must be 
accessed to assign a medication (kit) number to the participants. The date and time of all 
study treatment administration sabatolimab during the study and any deviations from the 
protocol treatment schedule will be captured by the investigator staff and reviewed by field 
monitor on the appropriate study treatment dispensing form. Compliance with the study 
treatment will be assessed by the field monitor at each visit and information provided by the 
pharmacist or by the investigator. All study treatment dispensed, returned or destroyed as 
per local regulation must be recorded in the Drug Accountability Log. 
Pharmacokinetic parameters will be determined in all participants as detailed in the 
pharmacokinetics Section 8.5.2. 
All dosages for sabatolimab as well as azacitidine (Combination cohort) prescribed to the 
participant and all dose changes during the study must be recorded on the corresponding 
Dosage Administration Record.  
6.7 
Preparation and dispensation 
The investigator or responsible site personnel must instruct the participant or caregiver to 
take the study treatment as per protocol. Study drug(s) will be dispensed to the participant 
by authorized site personnel only. A unique medication number is printed on the study 
medication label. All dosages for study treatment sabatolimab prescribed to the participant 
and all dose changes during the study must be recorded on the Dosage Administration 
Record eCRF. 


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Sabatolimab 
Each study site will be supplied by Novartis with the investigational drug sabatolimab as 
global clinical open supply and will be packed and labelled under the responsibility of 
Novartis. Investigator staff will identify the study medication kits to dispense to the 
participant by contacting the IRT and obtaining the medication number(s). The study 
medication has a 2-part label (base plus tear-off label or peel off label), immediately before 
dispensing the medication kit to the participant, site personnel will detach the outer part of 
the label from the packaging and affix it to the source document. Sabatolimab will be 
administered IV. Further instructions for the preparation and dispensation of sabatolimab 
are described in the Pharmacy Manual. 
Azacitidine (Combination cohort) 
Each study site will be supplied by Novartis with the study treatment azacitidine as global 
or local clinical open supply and will be packed and labelled under the responsibility of 
Novartis. Investigator staff will identify the study medication kits to dispense to the 
participant by contacting the IRT and obtaining the medication number(s). The study 
medication has a 2-part label (base plus tear-off label or peel off label), immediately before 
dispensing the medication kit to the participant, site personnel will detach the outer part of 
the label from the packaging and affix it to the source document. Azacitidine may be 
administered i.v. or subcutaneously. For details on preparation refer to the country-specific 
label instructions and/or azacitidine package insert. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, all study treatment must be stored 
according to the instructions specified on the labels and in the Investigator's Brochure. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical 
complaints are to be reported to the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no 
information about the participant except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed 
by monitors during site visits or remotely and at the completion of the trial. Participants will 
be asked to return all unused study treatment and packaging at the end of the study or at the 
time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site. 
6.7.1.2 
Handling of additional treatment 
Not applicable. 


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6.7.2 
Instruction for prescribing and taking study treatment 
Refer to Section 6.1.1 
All kits of study treatment assigned by the IRT will be recorded in the IRT system if sourced 
globally. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board/Independent Ethics Committee 
(IRB/IEC)-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the 
extent possible given his/her level of understanding. If the participant is capable of doing 
so, he/she must indicate agreement by personally signing and dating the written informed 
consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. 
all of the procedures described in the protocol). The process of obtaining informed consent 
must be documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form, an assent form for adolescents below 18 years old at the time of enrollment, and an 
informed consent for parent legal guardians, that complies with the ICH E6 GCP guidelines 
and regulatory requirements and is considered appropriate for this study. Any changes to 
the proposed consent form suggested by the investigator must be agreed by Novartis before 
submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can 
be found in the Investigator's Brochure (IB). This information will be included in the 
participant informed consent and should be discussed with the participant during the study 
as needed. Any new information regarding the safety profile of the investigational drug that 
is identified between IB updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the participant. 
The following informed consents are included in this study: 
 Main study consent, which also includes:  
 A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during 
this study 
 As applicable, Pregnancy Outcomes Reporting Consent for female participants  
 A molecular pre-screening informed consent to allow shipping of local bone marrow 
aspirate collected as per routine practice to a designated central laboratory for central 
analysis 
Women of childbearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree 
that in order to participate in the study, they must adhere to the contraception requirements. 


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A copy of the approved version of all consent forms must be provided to Novartis after 
IRB/IEC approval. 
8 
Visit schedule and assessments 
Assessment schedule Table 8-1 and Table 8-2 lists all of the assessments when they are 
performed. All data obtained from these assessments must be supported in the participant’s 
source documentation. 
 Each treatment cycle is 28 days. 
 Screening evaluations should be performed within ≤ 28 days of Cycle 1 Day 1 (except 
for the pregnancy test which has to be performed within 72 hours before the first dose). 
Lab tests results must be provided within a maximum of 7 days prior to start of 
treatment. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1 and Table 8-2) or as close to the designated day/time as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Participants who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At 
this final visit, all dispensed investigational product should be reconciled, and the adverse 
event and concomitant medications recorded on the CRF. 
During the course of the study visits, test and/or procedures should occur on schedule 
whenever possible. A visit window of +/- 3 days is allowed for study procedures (including 
treatment administration after C1D1). See Section 6.1 and Section 6.5 for details on study 
treatment, dosing and permitted dose delays. A visit window of +/- 7 days will be allowed 
for BMA procedures. Further, a maximum of 7 days is allowed between BMA efficacy, 
hematology assessments, and extramedullary disease assessments (if applicable) of the same 
visit.  
Note: If a treatment cycle is delayed at any time during the study, all study visits and safety 
and efficacy assessments should continue according to the appropriate number of calendar 
days measured from Day 1 of the previous cycle, or more often if clinically indicated. In the 
combination cohort, when treatment is resumed, the first day of azacitidine administration 
will be considered as D1 of the new treatment cycle and visit schedule will be shifted 
accordingly. If sabatolimab administration on Day 5 is delayed within a cycle due to 
toxicities, visit assessments for Day 5 should be shifted accordingly. 
On PK
 collection days the windows and time points are provided in Section 8.5.2. 
Participants who discontinue the study treatment for any reason should be scheduled for an 
end of treatment (EOT) visit within 14 days from the decision to permanently discontinue 
study treatment, at which time all of the assessments listed for the EOT visit will be 
performed.  
For post-treatment follow-up information, please refer to Section 9.1.1.2. 


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Table 8-1 
Assessment Schedule, Sabatolimab monotherapy cohort 
Period 
Pre-
Screening Screening 
Treatment 
EOT 
Safety 
Follow-up 
Post-Treatment 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 7 (and subsequent cycles 
up to Cycle 24) 
 
 
 
Days 
NA 
-28 to -1 
D1 D15 D1 
±3 
D15 
 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
EOT 
30,90,150 
days 
Every 12 weeks 
Pre-screening 
Informed Consent 
1 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed consent 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
IRT Registration 
X 
X 
X 
  
  
  
  
  
  
  
  
X 
  
  
Demography 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / 
Exclusion criteria 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
AML Disease 
History [aHSCT 
and GvHD (acute 
and chronic) 
history] 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
MRD History2 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Other relevant 
Medical History 
/Current medical 
conditions 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Prior medications 
(including prior 
antineoplastic 
therapies, 
prophylactic DLI), 
surgery, and 
medical 
procedures 
  
X 
continuous 
X 
  


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Period 
Pre-
Screening Screening 
Treatment 
EOT 
Safety 
Follow-up 
Post-Treatment 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 7 (and subsequent cycles 
up to Cycle 24) 
 
 
 
Days 
NA 
-28 to -1 
D1 D15 D1 
±3 
D15 
 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
EOT 
30,90,150 
days 
Every 12 weeks 
Physical 
Examination 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
  
  
Vital Signs 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Body Height 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Body Weight 
  
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
  
  
Performance 
Status Score3 
  
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
  
  
Hematology 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
at Day1 of every cycle, and 
unscheduled as clinically indicated 
X 
  
every 12 weeks 
(aligned with the 
response 
assessments and 
as clinically 
indicated) 
Chemistry 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
at Day1 of every cycle and 
unscheduled as clinically indicated 
X 
  
  
Uric acid 
  
X 
if clinically indicated 
  
  
  
Coagulation 
  
X 
X 
  
  
  
X 
  
  
X 
Day 1 of every 3rd cycle starting with 
Cycle 9 D1.  Unscheduled as 
clinically indicated at any time. 
X 
  
  
Cytogenetics 4 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Urinalysis 
(dipstick or as per 
local practice)  
  
S 
if clinically indicated 
  
  
Thyroid function5 
  
X 
  
  
  
  
X 
  
  
X 
at Cycle 9 Day 1 then every 3 cycles 
(Day 1) thereafter and as clinically 
indicated 
X 
  
  


Novartis 
Confidential 
Page 68 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EOT 
Safety 
Follow-up 
Post-Treatment 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 7 (and subsequent cycles 
up to Cycle 24) 
 
 
 
Days 
NA 
-28 to -1 
D1 D15 D1 
±3 
D15 
 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
EOT 
30,90,150 
days 
Every 12 weeks 
Cytokines for 
safety (IFN-γ; IL-
6, IL-1,TNF-α) 
  
X 
anytime for a suspected cytokine release syndrome, immediately after the AE, and one 
week after occurrence of AE 
  
  
Virology hepatitis 
B and C 
  
S 
  
  
  
  
  
  
  
  
  
  
  
  
HIV serology 
(only if required 
per local 
regulation) 
  
S 
  
  
  
  
  
  
  
  
  
  
  
  
Additional hepatic 
tests in case of 
DILI6 
  
X7 
If clinically indicated 
  
  
Serum Pregnancy 
test 8 
  
S 
S9 
  
  
  
  
  
  
  
  
S 
  
  
Urine Pregnancy 
Test OR Serum 
Pregnancy Test8 
  
  
  
  
S 
  
S 
S 
S 
S 
S 
  
S 
(monthly)10 
  
12-Lead ECG 
(triplicates) 
  
S 
if clinically indicated 
S 
  
  
Echocardiogram 
or MUGA11 
  
X 
if clinically indicated 
  
  
Adverse Events 
  
X 
continuous 
X 
  
aGVHD 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cycle 7 Day 1 and every 2 cycles 
(Day1) thereafter and as clinically 
indicated 
X 
X 
  


Novartis 
Confidential 
Page 69 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EOT 
Safety 
Follow-up 
Post-Treatment 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 7 (and subsequent cycles 
up to Cycle 24) 
 
 
 
Days 
NA 
-28 to -1 
D1 D15 D1 
±3 
D15 
 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
EOT 
30,90,150 
days 
Every 12 weeks 
cGVHD 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cycle 7 Day 1 and every 2 cycles 
(Day 1) thereafter and as clinically 
indicated 
X 
X 
every 12 weeks 
(aligned with the 
response 
assessment and as 
clinically indicated) 
IRT - drug 
dispensation 
(sabatolimab) 
  
  
X 
  
X 
  
X 
X 
X 
X 
at Day 1 of each cycle until C24 
  
  
  
Sabatolimab 
infusion 
  
  
X 
  
X 
  
X 
X 
X 
X 
at Day 1 of each cycle until C24 
  
  
  
Efficacy - Bone 
marrow aspirate 
or biopsy 
  
 X 
  
  
X 
  
X 
X 
  
  
 Cycle 7 Day 1 then every 3 cycles until Cycle 13 Day 1 and then every 6 
cycles including EOT until relapse or start of new therapy and as clinically 
indicated 
Efficacy - 
Extramedullary 
disease 
assessment12 
  
X 
  
  
X 
  
X 
X 
  
  
 Cycle 7 Day 1 then every 3 cycles until Cycle 13 Day 1 and then every 6 
cycles including EOT until relapse or start of new therapy and as clinically 
indicated 
Efficacy - 
response 
assessment 
  
X13 
  
  
X 
  
X 
X 
  
  
 Cycle 7 Day 1 then every 3 cycles until Cycle 13 Day 1 and then every 6 
cycles including EOT until relapse or start of new therapy and as clinically 
indicated 
Biomarker - Bone 
marrow aspirate 
for MRD/MFC 
(central) 
X14 
  
  
X 
  
X 
X 
  
  
 Cycle 7 Day 1 then every 3 cycles until Cycle 13 Day 1 and then every 6 
cycles including EOT until relapse or start of new therapy and as clinically 
indicated 


Novartis 
Confidential 
Page 70 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EOT 
Safety 
Follow-up 
Post-Treatment 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 7 (and subsequent cycles 
up to Cycle 24) 
 
 
 
Days 
NA 
-28 to -1 
D1 D15 D1 
±3 
D15 
 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
EOT 
30,90,150 
days 
Every 12 weeks 
Biomarker - Bone 
marrow aspirate 
for phenotypic 
 
 
  
X14 
  
  
X 
  
X 
X 
  
  
 Cycle 7 Day 1 then every 3 cycles until Cycle 13 Day 1 and then every 6 
cycles including EOT until relapse or start of new therapy and as clinically 
indicated 
Biomarker - 
Peripheral blood 
for phenotypic 
 
 
  
  
X 
  
X 
  
  
X 
  
  
Cycle 7 Day 1 
  
  
  


Novartis 
Confidential 
Page 71 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EOT 
Safety 
Follow-up 
Post-Treatment 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 7 (and subsequent cycles 
up to Cycle 24) 
 
 
 
Days 
NA 
-28 to -1 
D1 D15 D1 
±3 
D15 
 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
EOT 
30,90,150 
days 
Every 12 weeks 
Pharmacokinetic 
(PK) sampling19 
  
  
X 
  
X 
  
X 
  
  
X 
at Day 1 of cycles 9, 12, 18, 24 
X 
at 30 and 
150 days (if 
visit is 
conducted at 
site)  
  
Antineoplastic 
therapy since 
discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Disposition 
  
X 
  
  
  
  
  
  
  
  
X 
X 
  
X 


Novartis 
Confidential 
Page 72 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EOT 
Safety 
Follow-up 
Post-Treatment 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 7 (and subsequent cycles 
up to Cycle 24) 
 
 
 
Days 
NA 
-28 to -1 
D1 D15 D1 
±3 
D15 
 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
EOT 
30,90,150 
days 
Every 12 weeks 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Pre-screening ICF will only be applicable for participants who will be monitored by MRD testing as part of their standard of care. 
2 All local MRD assessments from BMA or peripheral blood prior to enrollment should be recorded, if available, including pre-transplant MRD 
assessment and post-transplant assessments until   assessment used for screening.    
3 ECOG PS scale will be used for the adult cohort, Karnofsky Scale will be used for adolescents ≥ 16 years, and Lansky Scale will be used for 
adolescents < 16 years. Refer to Table 8-6 and Table 8-7. 
4 Cytogenetic status at diagnosis is to be recorded in the clinical database (eCRF) 
5 Any deficiency should be corrected before the start of Study Treatment. refer to Table 8-7 for details on analytes to be tested  
6 Refer to Section 6.5.5.1 for DILI follow -up  
7 Only GLDH to be tested at baseline- see Table 8-8 
8 This test will be performed only for women with child bearing  potential  
9 Does not need to be performed, if it was done in screening within 72 hours before first dose 
10 Pregnancy testing for women of childbearing potential should be performed monthly during the safety follow-up period (urine or serum test may be 
performed, depending on local regulations 
11 A pre-existing assessment may be used if done within 6 months prior to enrollment 
12 Extramedullary disease is to be assessed via physical examination. Additional evaluation [eg, imaging, procedures (tissue biopsy, lumbar puncture), 
etc.] will be performed as clinically indicated per the investigator's assessment. 
13 A pre-existing assessment done as part of standard of care can used, if done within 28 days from enrollment/randomization 
14 Pre-existing bone marrow aspirate collected locally can be used, if collected within 28 days of enrollment/randomization 
15 Cryopreserved (preferred) or frozen BMA samples from initial diagnosis and pretransplant should be submitted, if available 
 
 
 
 
 
 
 
 
19 For adult participants PK samples will be collected only at Cycles 1, 3, 6, 24,EOT and 30 days and 150 days of the safety follow-up. For adolescent 
participants, additional samples will be collected at Cycles 2, 9, 12 and 18. 


Novartis 
Confidential 
Page 73 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EOT 
Safety 
Follow-up 
Post-Treatment 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 7 (and subsequent cycles 
up to Cycle 24) 
 
 
 
Days 
NA 
-28 to -1 
D1 D15 D1 
±3 
D15 
 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
D1 
±3 
EOT 
30,90,150 
days 
Every 12 weeks 
 
 


Novartis 
Confidential 
Page 74 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Table 8-2 
Assessment Schedule, Sabatolimab in combination with Azacitidine 
Period 
Pre-
Screening Screening 
Treatment 
EO
T 
Safety 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 Cycle 4 Cycle 5 
Cycle 6 
Cycle 7 (and subsequent 
cycles until C24) 
 
 
Days 
NA 
-28 to -1 D1 
D5 
±3 
D15 
±3 
D1 D5 
±3 
D15 
±3 
D1 D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
EO
T 
30,90,150 
days 
Pre-screening 
Informed 
Consent 1 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed 
consent 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT Registration 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Demography 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / 
Exclusion criteria 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AML Disease 
History [aHSCT 
and GvHD 
(acute and 
chronic) history] 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
MRD History2 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Other relevant 
Medical History 
/Current medical 
conditions 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


Novartis 
Confidential 
Page 75 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EO
T 
Safety 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 Cycle 4 Cycle 5 
Cycle 6 
Cycle 7 (and subsequent 
cycles until C24) 
 
 
Days 
NA 
-28 to -1 D1 
D5 
±3 
D15 
±3 
D1 D5 
±3 
D15 
±3 
D1 D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
EO
T 
30,90,150 
days 
Prior 
medications 
(including prior 
antineoplastic 
therapies, 
prophylactic 
DLI), surgery, 
and medical 
procedures 
  
X 
continuous 
X 
Physical 
Examination 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
  
Vital Signs 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Body Height 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
BSA (use height 
from screening) 
  
  
X 
  
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Body Weight 
  
X 
X 
  
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Performance 
Status Score3 
  
X 
X 
  
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Hematology 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
at Day 1 and 5 of every cycle 
and unscheduled as clinically 
indicated 
X 
  
Chemistry 
  
X 
X 
  
X 
X 
  
X 
X 
  
X 
  
X 
  
X 
  
at Day 1 of 
every cycle 
and 
unscheduled 
as clinically 
indicated 
  
X 
  
Uric acid 
  
X 
if clinically indicated 
  
  


Novartis 
Confidential 
Page 76 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EO
T 
Safety 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 Cycle 4 Cycle 5 
Cycle 6 
Cycle 7 (and subsequent 
cycles until C24) 
 
 
Days 
NA 
-28 to -1 D1 
D5 
±3 
D15 
±3 
D1 D5 
±3 
D15 
±3 
D1 D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
EO
T 
30,90,150 
days 
Coagulation 
  
X 
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
Day 1 of every 
3rd cycle 
starting with 
Cycle 9 D1.  
Unscheduled 
as clinically 
indicated at 
any time. 
  
X 
  
Cytogenetics 4 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Urinalysis 
(dipstick or as 
per local 
practice)  
  
S 
if clinically indicated 
  
Thyroid function5 
  
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
at Cycle 9 Day 
1 then every 3 
cycles (Day 1) 
thereafter and 
as clinically 
indicated 
  
X 
  
Cytokines for 
safety (IFN-γ; IL-
6, IL-1, TNF-α) 
  
X 
anytime for a suspected cytokine release syndrome, immediately after the AE, and one week after occurrence of 
AE 
  
Virology hepatitis 
B and C 
  
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
HIV serology 
(only if required 
per local 
regulation) 
  
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


Novartis 
Confidential 
Page 77 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EO
T 
Safety 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 Cycle 4 Cycle 5 
Cycle 6 
Cycle 7 (and subsequent 
cycles until C24) 
 
 
Days 
NA 
-28 to -1 D1 
D5 
±3 
D15 
±3 
D1 D5 
±3 
D15 
±3 
D1 D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
EO
T 
30,90,150 
days 
Additional 
hepatic tests in 
case of DILI6 
  
X7 
If clinically indicated 
  
Serum 
Pregnancy test 8 
  
S 
S9 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
S 
  
Urine Pregnancy 
Test OR Serum 
Pregnancy Test8 
  
  
  
  
  
S 
  
  
S 
  
S 
  
S 
  
S 
  
S 
  
  
S 
(monthly)10 
12-Lead ECG 
(triplicates) 
  
S 
if clinically indicated 
S 
  
Echocardiogram 
or MUGA11 
  
X 
if clinically indicated 
  
Adverse Events 
  
X 
continuous 
X 
aGVHD 
  
X 
X 
  
X 
X 
  
X 
X 
  
X 
  
X 
  
X 
  
Cycle 7 Day 1 
and every 2 
cycles (Day 1) 
thereafter and 
as clinically 
indicated 
  
X 
X 
cGVHD 
  
X 
X 
  
X 
X 
  
X 
X 
  
X 
  
X 
  
X 
  
Cycle 7 Day 1 
and every 2 
cycles (Day 1) 
thereafter and 
as clinically 
indicated 
  
X 
X 
IRT - drug 
dispensation 
(sabatolimab) 
  
  
  
X 
  
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
at Day 5 of 
each cycle 
until C24 
  
  


Novartis 
Confidential 
Page 78 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EO
T 
Safety 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 Cycle 4 Cycle 5 
Cycle 6 
Cycle 7 (and subsequent 
cycles until C24) 
 
 
Days 
NA 
-28 to -1 D1 
D5 
±3 
D15 
±3 
D1 D5 
±3 
D15 
±3 
D1 D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
EO
T 
30,90,150 
days 
Sabatolimab 
infusion 
  
  
  
X 
  
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
at Day 5 of 
each cycle 
until C24 
  
  
IRT - drug 
dispensation 
(azacitidine) 
  
  
Days 1-5 of each cycle until C24 
  
  
Azacitidine 
infusion 
  
  
 Days 1-5 prior to sabatolimab of each cycle until C24 
  
  
Efficacy - Bone 
marrow aspirate 
or biopsy 
  
X  
  
  
  
X 
  
  
X 
  
X 
  
  
  
  
  
  Cycle 7 Day 1 then every 3 cycles until Cycle 
13 Day 1 and then every 6 cycles including EOT 
until relapse or start of new therapy and as 
clinically indicated 
Efficacy - 
Extramedullary 
disease 
assessment12 
  
X 
  
  
  
X 
  
  
X 
  
X 
  
  
  
  
  
  Cycle 7 Day 1 then every 3 cycles until Cycle 
13 Day 1 and then every 6 cycles including EOT 
until relapse or start of new therapy and as 
clinically indicated 
Efficacy - 
response 
assessment 
  
X13 
  
  
  
X 
  
  
X 
  
X 
  
  
  
  
  
  Cycle 7 Day 1 then every 3 cycles until Cycle 
13 Day 1 and then every 6 cycles including EOT 
until relapse or start of new therapy and as 
clinically indicated 
Biomarker - 
Bone marrow 
aspirate for 
MRD/MFC 
(central) 
X14 
  
  
  
X 
  
  
X 
  
X 
  
  
  
  
  
  Cycle 7 Day 1 then every 3 cycles until Cycle 
13 Day 1 and then every 6 cycles including EOT 
until relapse or start of new therapy and as 
clinically indicated 


Novartis 
Confidential 
Page 79 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EO
T 
Safety 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 Cycle 4 Cycle 5 
Cycle 6 
Cycle 7 (and subsequent 
cycles until C24) 
 
 
Days 
NA 
-28 to -1 D1 
D5 
±3 
D15 
±3 
D1 D5 
±3 
D15 
±3 
D1 D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
EO
T 
30,90,150 
days 
Biomarker - 
Bone marrow 
aspirate for 
phenotypic 
 
 
  
X14 
  
  
  
X 
  
  
X 
  
X 
  
  
  
  
  
  Cycle 7 Day 1 then every 3 cycles until Cycle 
13 Day 1 and then every 6 cycles including EOT 
until relapse or start of new therapy and as 
clinically indicated 
Biomarker - 
Peripheral blood 
for phenotypic 
 
 
  
  
X 
  
  
X 
  
  
  
  
X 
  
  
  
  
  
Cycle 7 Day 1 
  
  
  


Novartis 
Confidential 
Page 80 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Pre-
Screening Screening 
Treatment 
EO
T 
Safety 
Follow-up 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 Cycle 4 Cycle 5 
Cycle 6 
Cycle 7 (and subsequent 
cycles until C24) 
 
 
Days 
NA 
-28 to -1 D1 
D5 
±3 
D15 
±3 
D1 D5 
±3 
D15 
±3 
D1 D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
D1 D5 
±3 
D1 
D5 
±3 
EO
T 
30,90,150 
days 
PK sampling for 
sabatolimab 
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
at Day 5 of 
cycle 24 
X 
at Day 30 
and 150 (if 
visit is 
conducted 
at site) 
Antineoplastic 
therapy since 
discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Disposition 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
 
 
Period 
Post-Treatment Follow-up 
Cycle 
 
Days 
Every 12 weeks 
Pre-screening Informed Consent 1 
  
Informed consent 
  
IRT Registration 
  
Demography 
  
Inclusion / Exclusion criteria 
  


Novartis 
Confidential 
Page 81 of 153 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CMBG453F12201 
 
 
 
Period 
Post-Treatment Follow-up 
Cycle 
 
Days 
Every 12 weeks 
AML Disease History [aHSCT and GvHD (acute and chronic) 
history] 
  
MRD History2 
  
Other relevant Medical History /Current medical conditions 
  
Prior medications (including prior antineoplastic therapies, 
prophylactic DLI), surgery, and medical procedures 
  
Physical Examination 
  
Vital Signs 
  
Body Height 
  
BSA (use height from screening) 
  
Body Weight 
  
Performance Status Score3 
  
Hematology 
every 12 weeks (aligned with the response assessments and as clinically indicated) 
Chemistry 
  
Uric acid 
  
Coagulation 
  
Cytogenetics 4 
  
Urinalysis (dipstick or as per local practice)  
  
Thyroid function5 
  
Cytokines for safety (IFN-γ; IL-6, IL-1, TNF-α) 
  
Virology hepatitis B and C 
  
HIV serology (only if required per local regulation) 
  
Additional hepatic tests in case of DILI6 
  
Serum Pregnancy test 8 
  
Urine Pregnancy Test OR Serum Pregnancy Test8 
  
12-Lead ECG (triplicates) 
  
Echocardiogram or MUGA11 
  


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Period 
Post-Treatment Follow-up 
Cycle 
 
Days 
Every 12 weeks 
Adverse Events 
  
aGVHD 
  
cGVHD 
every 12 weeks (aligned with the response assessment and as clinically indicated) 
IRT - drug dispensation (sabatolimab) 
  
Sabatolimab infusion 
  
IRT - drug dispensation (azacitidine) 
  
Azacitidine infusion 
  
Efficacy - Bone marrow aspirate or biopsy 
  Cycle 7 Day 1 then every 3 cycles until Cycle 13 Day 1 and then every 6 cycles including EOT until 
relapse or start of new therapy and as clinically indicated 
Efficacy - Extramedullary disease assessment12 
  Cycle 7 Day 1 then every 3 cycles until Cycle 13 Day 1 and then every 6 cycles including EOT until 
relapse or start of new therapy and as clinically indicated 
Efficacy - response assessment 
  Cycle 7 Day 1 then every 3 cycles until Cycle 13 Day 1 and then every 6 cycles including EOT until 
relapse or start of new therapy and as clinically indicated 
Biomarker - Bone marrow aspirate for MRD / MFC (central) 
  Cycle 7 Day 1 then every 3 cycles until Cycle 13 Day 1 and then every 6 cycles including EOT until 
relapse or start of new therapy and as clinically indicated 
Biomarker- Collection of archival BMA sample for retrospective 
MRD analysis 
  
Biomarker - Bone marrow aspirate for phenotypic 
 
 
  Cycle 7 Day 1 then every 3 cycles until Cycle 13 Day 1 and then every 6 cycles including EOT until 
relapse or start of new therapy and as clinically indicated 
Biomarker - Peripheral blood for phenotypic 
 
 
  
PK sampling for sabatolimab 
  


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Period 
Post-Treatment Follow-up 
Cycle 
 
Days 
Every 12 weeks 
Antineoplastic therapy since discontinuation 
X 
Disposition 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Pre-screening ICF will only be applicable for participants who will be monitored by MRD testing as part of their standard of care. 
2 All local MRD assessments from BMA or peripheral blood prior to enrollment should be recorded, if available, including pre-transplant MRD assessment and post-
transplant assessments until   assessment used for screening.    
3 ECOG PS scale will be used for the adult cohort, Karnofsky Scale will be used for adolescents ≥ 16 years, and Lansky Scale will be used for adolescents < 16 years. 
Refer to Table 8-6 and Table 8-7. 
4 Cytogenetic status at diagnosis is to be recorded in the clinical database (eCRF) 
5 Any deficiency should be corrected before the start of Study Treatment. Refer to Table 8-7 for details on analytes to be tested. 
6 Refer to Section 6.5.5.1 for DILI follow-up 
7 Only GLDH to be tested at baseline - see Table 8-8 
8 This test will be performed only for women with child bearing potential 
9 Does not need to be performed, if it was done in screening within 72 hours before first dose 
10 Pregnancy testing for women of childbearing potential should be performed monthly during the safety follow-up period (urine or serum test may be performed, 
depending on local regulations 
11 A pre-existing assessment may be used if done within 6 months of enrollment 
12 Extramedullary disease is to be assessed via physical examination. Additional evaluation [e.g., imaging, procedures (tissue biopsy, lumbar puncture), etc.] will be 
performed as clinically indicated per the investigator's assessment. 
13 A pre-existing assessment done as part of standard of care can used, if done within 28 days from enrollment/randomization 
14 Pre-existing bone marrow aspirate collected locally can be used, if collected within 28 days of enrollment/randomization 
15 Cryopreserved (preferred) or frozen BMA samples from initial diagnosis and pretransplant should be submitted, if available 
 
 


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8.1 
Screening 
Pre-screening sample collection 
MRD testing is considered routine standard of care practice for post-transplant participants, and 
therefore it is expected that these tests would be performed irrespective of participant’s trial 
participation. 
The participants enrolled on this study will have undergone post-transplant MRD testing on 
blood or bone marrow aspirate samples and participant's eligibility for the study will be based 
on the MRD results from the site local laboratory (or central assessment where required (e.g 
US)). A bone marrow aspirate (BMA) sample must be provided for central MRD testing for all 
participants entering the study. The collection and shipment of this BMA sample for central 
MRD testing may occur before screening (= pre-screening collection) or during screening (= 
screening collection). 
 Pre-screening collection occurs when a BMA sample is collected and shipped before local 
MRD status is known (e.g. in order to avoid repeating unnecessarily the bone marrow 
aspiration procedure, the BMA samples for local and central MRD tests can be collected 
during the same procedure and the BMA sample for central MRD testing can be shipped 
straight away, before local MRD status is known, this is in order to preserve sample 
integrity). In this case, the participant will have to sign the pre-screening ICF before the 
sample is collected and shipped to the central laboratory and the participant will then have 
the opportunity to sign the screening ICF if the local MRD status is confirmed as positive. 
Note that it is possible that, under the pre-screening ICF, a participant will go through 
several local MRD tests (and hence potentially several collections and shipments of BMA 
sample for central MRD testing) before a positive MRD status is obtained locally.  
 Screening collection occurs when a BMA sample for central MRD testing is shipped after 
the MRD positive status was obtained by local assessment (e.g. local MRD positive status 
was obtained on blood and the BMA collection/shipment occurs thereafter, during 
screening). In this case, the participant will not sign the pre-screening ICF but will sign the 
screening ICF directly after MRD positivity was confirmed locally. 
For sites in the USA where central assessment is required, screening collection occurs when 
a BMA sample for central MRD testing is shipped directly to the central lab. 
Screening 
All participants must provide signed ICFs prior to performing any study specific procedures. 
Screening assessments to confirm eligibility should be performed as per the schedule of 
assessments detailed in Table 8-1 and Table 8-2. participants will be evaluated against all study 
inclusion and exclusion criteria and safety assessments which must be completed within 28 days 
prior to the start of study treatment (C1D1), with the exception of the local serum pregnancy 
test (for women of child-bearing potential) which must be conducted and confirmed as negative 
within 72 hrs prior to the start of study treatment. Lab test results must be provided within a 
maximum of 7 days prior to study treatment. Laboratory parameters may be retested within the 


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28-day screening period. If the repeat value remains outside of the specified ranges, the 
participant will be considered a screen failure. 
An individual participant may only be re-screened once for the study. A new ICF will need to 
be signed if the investigator chooses to re-screen the participant. Any re-screened participant 
should receive a new participant No., and the original participant number must be noted on the 
Re-Screening CRF. All required screening activities must be performed when the participant is 
re-screened for participation in the study. 
8.1.1 
Eligibility screening 
Following registering in the IRT for screening, participant eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual. 
8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to administration of study treatment (C1D1) will be considered a screen failure. The reason for 
screen failure should be recorded on the appropriate Case Report Form (CRF). The 
demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for screen failure participants. No other data will be entered into the clinical database 
for participants who are screen failures, unless the participant experienced a serious adverse 
event during the screening phase (see Section 10.1.3 for reporting details). If the participant is 
screen failed or will not be treated, the IRT is to be notified within 2 days e that the participant 
was not enrolled. 
8.2 
Participant demographics/other baseline characteristics 
Demographics and other baseline characteristics data to be collected on all participants include: 
 Disease history, including date of diagnosis, 2016 World Health Organization (WHO) AML 
classification (Arber et al 2016), ELN cytogenetic risk stratification (Döhner et al 2017), 
and any additional molecular markers (FLT3-TKD, isocitrate dehydrogenase 1 and 2 
(IDH1/2), DNMT3A, c-KIT, and others) (National Comprehensive Cancer 2020). Refer to 
Appendix 5 Section 16.5 for details. 
 Prior antineoplastic therapies [prior to aHSCT and post-aHSCT (before start of study 
treatment) including prophylactic donor lymphocyte infusion(s) with or without HMAs].  
 aHSCT characteristics, conditioning regimen intensity, disease remission status at 
transplant (e.g., CR with undetectable MRD, CR with detectable MRD, active disease), 
timing of transplant (e.g., first CR, second CR, outside of CR2, refractory / induction 
failure), prior and current history of aGvHD or cGvHD, immunosuppressive therapy 
(systemic GvHD prophylaxis or treatment, date of completion). 
 Race/ethnicity (participant race /ethnicity are collected and analyzed to identify variations 
in safety or efficacy due to these factors as well as to assess the diversity of the study 
population as required by Health Authorities) 
 All prior and concomitant medications and medical procedure 
 Results, timing, and methods used for local MRD assessment. 


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Other assessments will be completed for the purpose of determining eligibility for inclusion in 
the study as reported in Table 8-1 and Table 8-2. 
Assessments to be performed at screening include: 
 After all study ICFs are signed the participant will be registered with the IRT 
 Inclusion/exclusion criteria 
 Medical history/current medical conditions 
 Disposition 
 Physical examination 
 ECOG Performance Status, body height, weight, vital signs (blood pressure (supine position 
preferred when ECGs are collected) and pulse, and body temperature). 
 Laboratory - hematology, blood chemistry, uric acid, coagulation, urinalysis, serum 
pregnancy test for women of child-bearing potential, thyroid function, virology hepatitis B 
and C, HIV serology (only if required per local regulation) 
 Triplicate 12-lead local ECG 
 Echocardiogram/MUGA, if not performed within 6 months of enrollment 
 Bone marrow aspirate collection for MRD and other biomarkers (if no sample was collected 
at pre-screening) 
 MRD history- methodology [Flow cytometry, NGS, qPCR, chimerism] and source 
(BM/PB) date and results 
 Bone marrow biopsy / aspirate for efficacy assessment (if no sample was collected at pre-
screening) 
 Extramedullary disease assessment (See Section 8.3.1) 
 Blood sample for Cytokines 
 Adverse events 
 Blood should be collected for phenotypic assessment 
8.3 
Efficacy 
8.3.1 
Efficacy response assessment 
Response assessments (bone marrow aspirate (BMA)/bone marrow biopsies (BMB)), 
peripheral blood, hematology assessments, extramedullary disease assessments) will be 
performed locally, by the Investigator, according to the assessment schedule depicted in 
Table 8-1 and Table 8-2 for assessment of relapse; complete remission, or complete remission 
with incomplete hematologic recovery. 
Bone marrow assessments will be performed at screening, and pre-dose on C2D1, C3D1, C4D1 
and C7D1 and every 3 cycles D1 until Cycle 13 D1 and then every 6 months and as clinically 
indicated until relapse, start of a new anti-neoplastic treatment, death, lost to follow-up or 
withdrawal of consent. 
For sabatolimab monotherapy cohort participants, hematology assessments will be performed 
at screening, and pre-dose on D1 and D15 for the two first cycles and thereafter at D1 of each 


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cycle, at the end of treatment visit, at unscheduled visit as clinically indicated, and every 12 
weeks for participants who enter post-treatment follow-up. 
For sabatolimab in combination with azacitidine cohort participants, hematology 
assessments will be performed at screening, and pre-dose on D1, D5 and D15 for the two first 
cycles and thereafter on D1 and D5 of each cycle, at the end of treatment visit, at unscheduled 
visit as clinically indicated, and every 12 weeks for participants who enter post-treatment 
follow-up. 
Response evaluation will be based on the Investigator’s assessment based on standardized 
criteria as proposed by the International Working Group (IWG) and European Leukemia 
Network (ELN) for AML (Cheson et al 2003, Döhner et al 2017) (see Table 8-1 and Table 8-2). 
Disease classification at baseline and evaluation of response during study treatment will rely on 
bone marrow, peripheral blood assessment, as well as the presence or absence of extramedullary 
disease. For disease characterization at baseline, the last assessment of bone marrow (within 28 
days before study treatment starts) and peripheral blood counts (within 14 days before study 
treatment starts) at the screening visit should be used. In case of missing data for the full 
assessment required to qualify for a given response, the overall assessment “unknown” will be 
assigned unless relapse was seen in at least one compartment (i.e. bone marrow or blood, or 
appearance of extramedullary disease). 
Extramedullary disease assessment is performed via physical examination. Additional 
evaluation for extramedullary disease [eg, imaging, procedures (tissue biopsy, lumbar 
puncture), etc.] will be performed as clinically indicated per the investigator's assessment. 
Cerebrospinal fluid assessment and relevant imaging techniques may be performed, as 
clinically appropriate at the investigator's discretion, in case of symptoms suggestive of 
meningeosis leukemia, and/or prior history of central nervous system involvement with AML. 
In case of extramedullary disease (re-) appearance during the study, the lesions should be 
considered for confirmation by imaging or biopsy if technically and/or clinically feasible. 
Assessment for the presence or absence of extramedullary disease will be performed at 
screening, and pre-dose on C2D1, C3D1, C4D1 and C7D1 and every 3 cycles D1 until Cycle 
13 D1 and then every 6 months and as clinically indicated until relapse, start of a new anti-
neoplastic treatment, death, lost to follow-up or withdrawal of consent. The presence or absence 
and physical location of extramedullary disease are to be recorded on the CRFs.  
Participants can be assessed for disease response (bone marrow assessment, hematology, 
extramedullary disease assessment) at any time if clinically indicated, for example in case of 
suspicion of relapse. Therefore, more frequent efficacy assessments may be performed at the 
investigator’s discretion, if medically indicated, and recorded as an unscheduled visit in the 
eCRFs. Clinical suspicion of relapse at any time will require an evaluation promptly, rather than 
waiting for the next scheduled assessment. In case of an unscheduled or delayed disease 
evaluation of any reason, subsequent assessments should be performed according to the 
originally planned schedule. 
More frequent efficacy assessments, performed at the Investigator’s discretion, should be 
recorded on the Unscheduled Visit CRFs. All assessments will be analyzed. 


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Table 8-3 
Response classification in AML at a given evaluation time (based on 
IWG Cheson et al 2003, ELN 2017 Döhner et al 2017) 
Response Category 
Definition1 
Complete Remission 
 
Bone marrow: blasts < 5% 
 
Peripheral blood: No circulating blasts or blasts with Auer rods 
 
No evidence of extramedullary disease (such as CNS or soft tissue 
involvement) 
 
Neutrophils ≥ 1.0x109/L 
 
Platelets ≥ 100x109/L 
Complete remission with 
incomplete hematologic 
recovery (CRi) 
 
Bone marrow: blasts < 5% 
 
Peripheral blood: No circulating blasts or blasts with Auer rods 
 
No evidence of extramedullary disease (such as CNS or soft tissue 
involvement) 
 
Neutrophils < 1.0x109/L or platelets < 100x109/L 
Hematologic relapse 
(from CR or CRi) 
Only in participants with CR or CRi. Any of the following: 
 
Reappearance of blasts in peripheral blood 
OR 
 
Bone marrow blasts ≥ 5% 
OR 
 
Development of extramedullary disease 
Unknown 
In case the response assessment was not done, or the assessment 
was incomplete 
1 If not defined otherwise, all of these criteria apply 
Post treatment efficacy follow up 
Participants who discontinue treatment for reasons other than documented relapse from 
CR/CRi, death, lost to follow-up, or withdrawal of consent, will enter the post-treatment follow-
up phase (Section 9.2). Hematology assessments must continue to be performed every 3 
months, response should be assessed at least every 6 months, and bone marrow assessment 
should be done at least every 6 months until relapse or start of new therapy per Table 8-1 and 
Table 8-2, or as clinically indicated any time in case relapse is suspected. 
The post-treatment follow-up period will last until participant's documented relapse (per ELN 
criteria (Döhner et al 2017), see Table 8-1 and Table 8-2, start of new therapy, death, lost to 
follow-up, or withdrawal of consent or the end of study whichever comes first.  
8.3.2 
Efficacy assessment: MRD by MFC 
MRD in bone marrow will be assessed by central multi-parameter flow cytometry (MFC). 
Assessments will be performed at baseline, and during the treatment period until relapse, as 
indicated in the table below. The first volume aspirated from the bone marrow should be 
provided for this assessment, when possible.   
MRD-negative will be defined based on the detection of Leukemia associated 
immunophenotype (LAIP), at a threshold defined by the AML-MRD flow cytometry assay. 


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A cryopreserved bone marrow aspirate sample performed at diagnostic and prior aHSCT is 
requested for retrospective MRD analysis (if available). The sample should be submitted at 
C1D1 after the participant is confirmed to have received his/her first dose. The BMA samples 
will be used to determine the presence of LAIP at diagnostic and prior aHSCT, as well as 
additional relevant biomarkers and genetic alterations related to AML. 
Table 8-4 
BMA for MRD by flow cytometry 
Volume of BMA / visit 
Visit* 
Time Point 
Cryopreserved / frozen archival 
diagnostic sample** 
Screening** 
Anytime 
Cryopreserved / frozen archival 
pre-transplant sample** 
Screening** 
Anytime 
4mL 
(First BMA draw should be 
provided for this assessment) 
Screening or prescreening*** 
Anytime 
C2D1 
Pre-study treatment dose 
C3D1 
Pre-study treatment dose 
C4D1 
Pre-study treatment dose 
C7D1 
Pre-study treatment dose 
C10D1 
Pre-study treatment dose 
C13D1 
Pre-study treatment dose 
Every 6 cycles after cycle 13 
D1 (including EOT and post-
treatment follow up) until 
relapse**** or start of new 
therapy and as clinically 
indicated 
Pre-study treatment dose, if 
applicable 
 
Unscheduled***** 
Anytime 
* Collection of BMA samples for biomarkers should be performed at same time as bone marrow 
collection for disease assessment/efficacy at the indicated timepoints. 
** If available, sites should provide archival cryopreserved (preferred) / frozen bone 
marrow aspirate MRD samples collected at initial diagnosis and prior to aHSCT. For further details on 
sample collection please refer to the [CMBG453F12201 Laboratory Manual]. 
*** Prescreening fresh BMA sample can be used, if collected within 28 days from 
randomization/enrollment. 
****If a participant is MRD+ at end of study treatment no MRD collection will be required during post-
treatment follow up.  
***** In rare occasions scheduled samples and/or additional samples can be collected outside of 
planned visits. 
 
8.3.3 
Appropriateness of efficacy assessments 
The assessment of response to study treatment is based on standardized criteria as proposed by 
the European LeukemiaNet (ELN) and the International Working Group (IWG) 
(Cheson et al 2003, Döhner et al 2017) in Table 8-3. 


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8.4 
Safety 
Safety assessments are specified in Table 8-5 below with the assessment schedule detailing 
when each assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. 
Table 8-5 
Assessments & Specifications 
Assessment 
Specification 
Physical examination 
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological. If indicated based on medical history and/or symptoms, rectal, 
external genitalia, breast, and pelvic exams will be performed. 
A complete physical examination is required at screening, D1 and D15 for 
the first 2 cycles (C1 and C2) and thereafter at D1 of each cycle until EOT. 
For sabatolimab in combination with azacitidine Cohort: At screening, 
D5 and D15 for the 2 first cycles (C1 and C2) and thereafter at D1 of each 
cycle until EOT. 
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present 
prior to signing informed consent must be recorded on the appropriate CRF 
that captures medical history. Significant findings made after signing 
informed consent which meet the definition of an Adverse Event must be 
recorded as an adverse event. 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, and body temperature are collected at 
screening, D1 and D15 for the first 2 cycles (C1 and C2) and thereafter at 
D1 of each cycle until EOT (Cohort 1)  
For sabatolimab in combination with azacitidine Cohort  vital signs will 
be collected at screening, D1, D5 and D15 for the two first cycles (C1 and 
C2) and thereafter at D1 and D5 of each cycle until EOT. 
Height and weight 
Height in centimeters (cm) will be measured at Screening. Body weight (to 
the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be 
measured at screening and at subsequent time points as specified in 
Table 8-1 and Table 8-2 
Performance status: 
ECOG Performance status scale will be used for the adult cohort as described in Table 8-6, and 
Karnofsky/Lansky Performance Scales will be used for the adolescent cohort as described in 
Table 8-7. 
Table 8-6 
ECOG performance status 
Grade 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., 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 


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Grade 
ECOG Status 
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 
Death 
Table 8-7 
Karnofsky/Lansky Performance Scales 
Karnofsky Scale (age ≥ 16 years) 
Lansky Scale (age < 16 years) 
Able to carry on normal activity and to work; no 
special care needed. 
Able to carry on normal activity; no special care 
is needed 
100 
Normal no complaints; 
no evidence of disease 
100 
Fully active 
90 
Able to carry on 
normal activity; minor 
signs or symptoms of 
disease 
90 
Minor restriction in 
physically strenuous 
play 
80 
Normal activity with 
effort; some signs or 
symptoms of disease 
80 
Restricted in strenuous 
play, tires more easily, 
otherwise active 
Unable to work; able to live at home and care for 
most personal needs; varying amount of 
assistance needed. 
Mild to moderate restriction 
70 
Cares for self; unable 
to carry on normal 
activity or to do active 
work 
70 
Both greater 
restrictions of, and less 
time spent in active 
play 
60 
Requires occasional 
assistance, but is able 
to care for most of his 
personal needs 
60 
Ambulatory up to 50% 
of the time, limited 
active play with 
assistance/supervision 
50 
Requires considerable 
assistance and 
frequent medical care 
50 
Considerable 
assistance required for 
any active play, fully 
able to engage in quiet 
play 
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
Moderate to severe restriction 
40 
Disabled; requires 
special care and 
assistance 
40 
Able to initiate quiet 
activities 
30 
Severely disabled; 
hospital admission is 
indicated although 
death not imminent 
30 
Needs considerable 
assistance for quiet 
activity 
20 
Very sick; hospital 
admission necessary; 
active supportive 
treatment necessary 
20 
Limited to very passive 
activity initiated by 
others (e.g. television) 


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Karnofsky Scale (age ≥ 16 years) 
Lansky Scale (age < 16 years) 
10 
Moribund; fatal 
processes progressing 
rapidly 
10 
Completely disabled, 
not even passive play 
0 
Dead 
0 
Unresponsive 
8.4.1 
Laboratory evaluations 
Local clinical laboratory parameters will be used for the analysis of scheduled hematology, 
chemistry and other blood specimens collected as part of safety monitoring (as detailed 
in Table 8-1 and Table 8-2 and Table 8-8) and the results will be collected in the eCRF. 
Unscheduled assessments of these parameters can be performed more often as clinically 
indicated. It is preferable to use the same laboratory for all the assessments performed, 
especially for the hematology assessments. 
A central laboratory will be used for the parameters listed in Table 8-9 and as per the schedule 
in Table 8-1 and Table 8-2. 
Laboratory values obtained during the Screening phase will be used to assess participant’s 
eligibility. 
Novartis must be provided with a copy of the certification and a tabulation of the normal ranges 
and units for all local laboratories used to in the trial. 
Table 8-8 
Local clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hemoglobin (Hgb), white blood cells (WBC), differential (including basophils, 
eosinophils, lymphocytes, monocytes, neutrophils, bands, metamyelocytes, 
myelocytes, promyelocytes, blasts), atypical cells (e.g. LUC, erythroblasts), 
platelets 
(absolute value preferred, %s are acceptable) 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphorus, Sodium, 
Potassium, Bicarbonate, Creatinine, Creatine kinase, Total Bilirubin, (Indirect 
Bilirubin, Direct Bilirubin) *, Total Cholesterol, Total Protein, Blood Urea Nitrogen 
(BUN) or Urea, Amylase, Lipase, Glucose (fasting), Troponin-T or Troponin I, 
CRP, NTproBNP** 
Chemistry 
Uric acid 
Virology*** 
HBsAg, HBcAb, HBV DNA (in participants positive for HBcAb), HCV RNA (PCR) 
HIV (Only if required by local regulation) 
Coagulation 
International normalized ratio [INR]), Activated partial thromboplastin time 
(APTT), fibrinogen 
Thyroid 
At baseline: TSH, Free-T3 and Free-T4. 
During treatment: TSH at time points indicated in Table 8-1 and Table 8-2 and 
as clinically indicated. If TSH is abnormal, then test free-T3 and free-T4 
Urinalysis*** 
(dipstick and 
sediment) 
Dipstick examination includes specific gravity, pH, glucose, protein, blood, 
bilirubin, ketones and WBC as clinically indicated. 


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Test Category 
Test Name 
Pregnancy 
Test*** 
Serum / Urine pregnancy test (refer to Section 8.4.3) 'Pregnancy and 
assessments of fertility' 
 
* Indirect and direct bilirubin only required if total bilirubin is abnormal 
** NTproBNP may be required as an additional test upon signs/symptoms and based on cardiology 
consult 
*** Virology, urinalysis, and pregnancy test will only be reported in the source documentation 
Table 8-9 
Central clinical laboratory parameters collection plan 
Test Category 
Test Name 
Cytokines 
IFN-γ, IL-6, IL-1, TNF-α 
Chemistry for DILI1 
Glutamate dehydrogenase (GLDH) 
1 at baseline and as clinically indicated for follow-up of DILI per Section 6.5.5.1 
8.4.2 
Electrocardiogram (ECG) 
Standard triplicate 12 lead ECG recording will be performed according to Table 8-10. The 
Fridericia QT correction formula (QTcF) should be used for clinical decisions. 
The ECGs are to be collected with local ECG machines at the time points indicated in the ECG 
collection plan Table 8-10 . 
Table 8-10 
ECG collection plan 
Cycle 
Day 
Time point 
Screening 
Day -28 to Day -1 
Anytime 
EOT 
N/A 
Anytime 
Unscheduled 
Any 
As clinically indicated1 
* all ECGs to be collected in 12-lead triplicate 
1 ECG collection prior to any study drug dosing 
All ECGs must be recorded using the local machine. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated and reported as unscheduled time points. 
Interpretation of the tracing must be made by a qualified physician and documented in the 
source documents. Each ECG tracing should be labeled with the study number, participant 
initials (where regulations permit), participant number, date, and kept in the source documents 
at the study site. 
Clinically significant abnormalities present at screening should reported on the Medical History 
CRF. New or worsened clinically significant findings occurring after informed consent must be 
recorded as adverse events. 
In case of QTcF prolongation, please refer to Section 6.5.5.3. 


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8.4.2.1 
Echocardiogram or MUGA 
The left ventricular cardiac function will be evaluated by echocardiogram or MUGA at baseline 
according to the visit schedule in Table 8-1 and Table 8-2 and if clinically indicated. 
8.4.3 
Pregnancy and assessments of fertility 
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female pediatric participants who are menarchal or who 
become menarchal during the study. 
All menarchal girls and their parents/caregivers should be informed about the potential risks of 
pregnancy and the need to prevent pregnancy during the study. 
It is important to be sensitive in introducing this issue, as understanding and comprehension of 
puberty, sexual activity, pregnancy and contraception is influenced by age, as well as factors 
such as precocity, socio (educational) economic and familial background. These discussions 
with the participant and her parents/caregivers are therefore best performed by investigators 
familiar with the pediatric participant and her family and should be guided by requirements of 
the local regulatory authorities. These discussions should take into account the socio-economic, 
cultural factors and religious beliefs of the adolescent participant and her family. The 
investigator should also discuss the management of the pregnancy test results with the 
participant and her parents/caregivers. The privacy of the participant should be considered in 
accordance with the local law and ethics. 
Participants becoming pregnant must be discontinued from study drug. 
However, a participant may choose to remain in the study should she become pregnant and be 
followed according to the protocol-defined study visits. 
Serum pregnancy test will be performed for all females of child-bearing potential according to 
the protocol assessment schedule below: 
At screening, a serum pregnancy test (serum ß-HCG) must be performed within 3 days before 
the first dose. 
During the study, a urine/serum pregnancy test should be performed at Day 1 of each cycle 
(except Cycle 1 if a pregnancy test had been performed within 72 hours of the first dose) and a 
serum pregnancy test at EOT visit. Pregnancy testing (urine/serum) should occur at monthly 
intervals during the 150-day safety follow-up period. Refer to Table 8-1 and Table 8-2 for 
pregnancy testing schedule. Additional pregnancy testing might be performed if requested by 
local requirements or at investigators discretion. A positive urine pregnancy needs to be 
confirmed with a serum test. Confirmed positive pregnancy test requires immediate 
discontinuation of study treatment and discontinuation from study. See Section 10.1.4 for 
pregnancy reporting. The pregnancy tests will be recorded only in the source documentation, 
not in the CRF. 
Assessments of fertility 
Women of childbearing potential should employ the use of highly effective contraception 
during study treatment for 150 days after the last dose of sabatolimab and 90 days after the last 


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dose of azacitidine (sabatolimab with azacitidine combination Cohort). Highly effective 
contraception methods are defined in Section 5.2. 
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner while taking 
azacitidine and for 3 months after stopping this drug (Combination cohort). In addition, male 
participants should not donate sperm for the time period specified above. 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline. 
8.4.4 
Other safety evaluations 
8.4.4.1 
aGvHD assessment 
aGvHD staging and grading will be performed by the Investigator at screening, every 2 weeks 
for the first two cycles, at Day 1 visit of every cycle up to Cycle 7, then at Day 1 visit every 2 
cycles during the treatment period, at EOT visit, at the Safety Follow-up visits, and as clinically 
indicated thereafter as outlined in Table 8-1 and Table 8-2. 
aGvHD will be performed using standard criteria (Harris et al 2016): measures of body surface 
area aGvHD skin rash, stool volumes or frequency per 24h time period, and serum bilirubin 
levels, staging by organ (skin; liver; upper GI; lower GI) and overall grading at the time of the 
evaluation should be reported according to Appendix 1. 
The data should be entered in the appropriate CRFs. 
In addition, Investigator should record and report any management action of aGvHD in 
appropriate CRF(s).   
Note: Additional aGvHD assessments (including biopsy of the organ involved) may be done as 
per institutional guidelines at investigator’s discretion. aGvHD assessments performed at 
unscheduled visit and leading to a change in patient's management after the last dose of study 
treatment should be recorded in the CRF. 
8.4.4.2 
cGvHD assessment 
Occurrence of definitive and possible manifestations of cGvHD will be assessed by the 
Investigator at screening, every two weeks for the first two cycles, at Day 1 visit of every cycle 
up to Cycle 7, then at Day 1 visit every 2 cycles during the treatment period, and at EOT visit. 
After EOT, participants will be assessed for occurrence of cGvHD at the Safety Follow-Up 
visit, and at Day 30, at Day 90 and at Day 150 and every 12 weeks during the Post Treatment 


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follow-up period (see Table 8-1 and Table 8-2). Occurrence of cGvHD will be reported on 
appropriate specific CRF. 
Investigator will assess cGvHD as per NIH consensus guidelines for cGvHD (Appendix 2): 
overall grading (mild, moderate, severe) at the time of cGvHD diagnosis which will be reported 
in corresponding CRF. 
Additional cGvHD assessments (including biopsy of the organ involved) may be done as per 
institutional guidelines at investigator’s discretion.  
In addition, Investigator should indicate if a systemic treatment is initiated for cGvHD in 
appropriate CRF(s).  
8.4.5 
Appropriateness of safety measurements 
Overall, the safety assessments selected are standard for this indication/participant population.  
Additionally, given the unique clinical setting and limited information about the use of 
sabatolimab in the post-aHSCT setting, additional evaluations are required: 
The primary purpose of the current study is to test the hypothesis whether preemptive treatment 
with sabatolimab, alone or in combination, when administered to participants with 
AML/secondary AML who are in complete remission with MRD+ post-aHSCT, can enhance 
the GvL response and prevent or delay hematologic relapse. However, a sabatolimab-mediated 
enhancement of GvL could potentially exacerbate GvHD, an immune-mediated toxicity and a 
principal safety concern in the aHSCT setting. 
There are no reported data on the safety of sabatolimab in the post-aHSCT setting, therefore a 
key primary safety objective will be to assess the occurrence and severity of treatment-emergent 
aGvHD and cGvHD, immune-related and other adverse events. 
The study will start with a Safety Run-in to assess whether sabatolimab can be administered in 
the post-aHSCT setting without unacceptable levels of treatment-emergent toxicities (dose 
limiting toxicities, i.e.; primary safety objective), including increased or worsening the risk of 
treatment emergent aGvHD or cGvHD, as well as severe immune-related toxicity after 2 cycles 
of study treatment. The Safety Run-in will be conducted starting with a lower sabatolimab dose 
(i.e., 400 mg IV Q4W) than what is currently being used in the MDS and AML setting outside 
of aHSCT setting (i.e., 800 mg IV Q4W). If unacceptable toxicities were not observed, dose 
escalation at 800 mg IV Q4W will subsequently be evaluated. Details on dose escalation 
guidelines and determination of the recommended dose for expansion are provided in 
Section 6.5. 
Sabatolimab will then be evaluated in Part 2 at the determined dose as monotherapy and in 
combination with azacitidine, as well as in adolescent participants.  
8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
Not applicable 


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8.5.2 
Pharmacokinetics 
Pharmacokinetic (PK), 
 samples will be 
obtained and evaluated in all participants. Please refer to Table 8-11 and Table 8-12 for details 
on PK, 
 sample collections. If participants experience an SAE or an AE leading 
to the discontinuation of the study treatment, an unscheduled PK blood sample should be 
obtained as close as possible to the event occurrence. The date and time of the last dose and the 
time of PK blood draw should be recorded.
8.5.2.1 
Pharmacokinetic blood collection and handling 
Sabatolimab PK, 
 blood sampling schedule is outlined in Table 8-11 and 
Table 8-12. Blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein opposite to the arm used for infusion. A single blood sample of 
approximately 5 mL will be collected. After clotting, the resulting serum will be separated in 
aliquots and will be stored frozen until analysis. The exact date and clock times of drug 
administration and blood draw for PK, 
 assessment will be recorded on the 
appropriate eCRF. 
After permanent discontinuation of sabatolimab, the samples scheduled for pre-sabatolimab 
infusion and end of sabatolimab infusion (within 2 hours) should no longer be collected. 
Refer to the [CMBG453F12101 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK, 
 samples. 
Table 8-11 
Blood (serum) collection schedule for PK, 
 for 
sabatolimab monotherapy (All cohorts except Cohort 3) 
 Cycle 
Day 
Scheduled 
Time Point 
PK sample 
1 
1 
Pre-
sabatolimab 
infusion/0h 
x 
1 
1 
End of 
sabatolimab 
infusion 
(within 2 
hours) 
x 
2* 
1 
Pre-
sabatolimab 
infusion 
x 
3 
1 
Pre-
sabatolimab 
infusion 
x 


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 Cycle 
Day 
Scheduled 
Time Point 
PK sample 
3 
1 
End of 
sabatolimab 
infusion 
(within 2 
hours) 
x 
6 
1 
Pre-
sabatolimab 
infusion 
x 
9* 
1 
Pre-
sabatolimab 
infusion 
x 
12* 
1 
Pre-
sabatolimab 
infusion 
x 
18* 
1 
Pre-
sabatolimab 
infusion 
x 
24 
1 
Pre-
sabatolimab 
infusion 
x 
24 
1 
End 
of sabatolima
b infusion 
(within 2 
hours) 
x 
EOT 
  
Anytime 
x 
Unscheduled 
or Unplanned 
  
Anytime 
x 
Follow-up day 
30 
  
Anytime 
x 
Follow-up day 
150 
  
Anytime 
x 
* Additional samples to be collected only for adolescent participants (Cycles 2, 9, 12 and 18) 
Table 8-12 
Blood (serum) collection schedule for PK, 
 for 
sabatolimab in combination with azacitidine (Cohort 3) 
 Cycle 
Day 
Scheduled 
Time Point 
PK sample 
1 
1 
Pre-HMA 
infusion 
  
1 
5 
Pre-
sabatolimab 
infusion/0h 
x 


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 Cycle 
Day 
Scheduled 
Time Point 
PK sample 
1 
5 
End of 
sabatolimab 
infusion 
(within 2 
hours) 
x 
3 
5 
Pre-
sabatolimab 
infusion 
x 
3 
5 
End of 
sabatolimab 
infusion 
(within 2 
hours) 
x 
6 
5 
Pre-
sabatolimab 
infusion 
x 
24 
5 
Pre-
sabatolimab 
infusion 
x 
24 
5 
End of 
sabatolimab 
infusion 
(within 2 
hours) 
x 
EOT 
  
Anytime 
x 
Unscheduled 
or Unplanned 
  
Anytime 
x 
Follow-up day 
30 
  
Anytime 
x 
Follow-up day 
150 
  
Anytime 
x 
8.5.2.2 
Analytical method 
Bioanalysis for pharmacokinetic studies will employ several validated assays: 
 The assay to quantify sabatolimab will be a validated liquid chromatography mass 
spectrometry (LC-MS) assay. 
 
 
 
 
 
 For further details on sample collection and processing please refer to the 
[CMBG453F12201 Laboratory Manual]. 
8.5.3 
Biomarkers 
The biomarker strategy for this study is (i) to monitor the persistence of malignancy at orders 
of magnitude below the limit of conventional morphologic detection (Section 8.3.2); (ii) to 


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explore mechanisms of action of sabatolimab; (iii) and finally to enhance the understanding of 
the biology behind the treatment response. 
 
 
 
 
 
Samples will be collected at baseline, during treatment, at EOT and anytime during treatment 
and/or follow up period as clinically indicated, as defined in the VES (Table 8-1 and Table 8-2) 
and Table 8-13. BMA samples for biomarkers should always be collected at the same time as 
investigator assessment of disease and should preferentially be part of the first or the second 
draw to ensure sufficient and adequate material for analysis. All assessments will be performed 
at Novartis designated laboratories. In addition, the biomarker samples may be used to develop 
a biological test (such as a test to assess residual disease). Instructions for collection, preparation 
and shipment of all biomarker samples can be found in the laboratory manual. Required sample 
collection information must be entered on the requisition forms.  
Table 8-13 
BMA for Biomarkers for all cohorts 
Volume of BMA for 
phenotypic 
 
assessments / visit 
Visit* 
Time Point 
4 mL 
 
Screening**  
Anytime 
C2D1 
Pre-dose 
C3D1 
Pre-dose 
C4D1 
Pre-dose 
C7D1 
Pre-dose 
Every 3 cycles D1 after C7D1 
until C13D1 
Pre-dose 
Every 6 cycles D1 after cycle 
13 D1 until relapse*** or start of 
new therapy (including 
posttreatment follow up) 
Pre-dose, where applicable 
EOT 
Anytime 
As clinically indicated (At same 
time as BM collection for 
efficacy) 
Anytime 
Unscheduled**** 
Anytime 
*Collection of BMA samples for biomarkers should be performed at same time as bone marrow 
collection for disease assessment/efficacy at the indicated time points.  
** Pre-exitisting sample collected within 28 days of enrollment/randomization is acceptable 
*** If a participant is MRD+ at end of study treatment no MRD collection will be required. 
**** In rare occasions scheduled samples and/or additional samples can be collected outside of 
planned visits. 


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9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment will occur when a participant has documented relapse from 
CR/CRi or until for any of the reasons described below, and can be initiated by either the 
participant or the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
 participant/guardian decision 
 Pregnancy 


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 Use of prohibited treatment as per recommendations in the prohibited treatment 
(Section 6.2.2) 
 Any situation in which study participation might result in a safety risk to the participant 
 Any adverse events or laboratory abnormalities that in the judgment of the 
investigator, taking into consideration the participant’s overall status, prevents the 
participant from continuing the study treatment 
 Protocol-defined reasons for treatment discontinuation (see 
Section 6.1.4 and Section 6.1.5) 
 Termination of the study by Novartis 
If discontinuation of study treatment occurs due to circumstances other that the protocol defined 
criteria in Section 6.1.4 and Section 6.1.5, the investigator should make a reasonable effort to 
understand the primary reason for the participant’s premature discontinuation of study treatment 
and record this information. 
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' Section 9.1.2). Where possible, they 
should return for the assessments indicated in the Assessment Schedule. If they fail to 
return for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) 
should be made to contact the participant/pre-designated contact as specified in the lost to 
follow-up section. This contact should preferably be done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
 Concomitant treatment 
 Adverse events/ Serious Adverse Events 
For details on AE/SAE reporting, please refer to Section 10.1.1. Information about concomitant 
treatment should be collected for up to 30 days after last dose of any study treatment. 
In addition, for women with child-bearing potential, a serum or urine pregnancy test must be 
performed as indicated in Section 8.4.3. 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
If discontinuation of study treatment occurs due to protocol defined reasons, participants will 
be followed for efficacy and safety as detailed in Section 9.1.1.1 and Section 9.1.1.2 
9.1.1.1 
Safety Follow-up 
All participants must be followed for safety for 150 days after the last dose of sabatolimab or 
30 days after the last dose of azacitidine (Combination cohort) whichever is longer. 


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After the 30-day on-site safety follow-up visit, participants will be followed via telephone call 
(or onsite visit if participant happens to be visiting the site) at 90 and 150 days after the last 
dose of sabatolimab. All safety assessments should be completed as per Table 8-1 and Table 8-2 
(Section 10.1.2). However, if the participant begins new anti-neoplastic medication before the 
end of the safety follow-up period the collection of new SAEs and AEs unrelated to study 
medication will stop and thereafter only suspected AEs and suspected SAEs will continue to be 
collected up to the end of the safety follow-up period. Suspected SAEs will continue to be 
collected beyond the 150-Day safety visit (in Post-Treatment follow-up) see. For female 
participants of childbearing potential, a pregnancy test will be performed at the time points 
listed in Table 8-1 and Table 8-2. 
9.1.1.2 
Post-Treatment Follow-up 
All participants who discontinued study treatment while in remission without evidence of 
hematologic relapse will enter a post-treatment follow-up until hematologic relapse or start of 
new therapy. Additionally, participants with MRD- status at end of treatment will continue to 
be assessed for MRD until MRD+ or for 12 months after end of study treatment, whichever is 
earlier. Efficacy assessments must continue to be performed as per the assessment schedule 
(Table 8-1 and Table 8-2) with hematological assessments every 3 months (12 weeks), cGvHD 
assessments every 3 months (12 weeks), and bone marrow assessments every 6 months. 
9.1.1.3 
Replacement policy 
Participants will not be replaced on study. However, if a participant is considered as non-
evaluable for the safety run-in (see Section 6.5.1), enrolment of a new participant to the safety 
run-in will be considered if there are less than the required number of evaluable participants. 
9.1.2 
Withdrawal of informed consent/Opposition to use data/biological 
samples 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent/opposition to use data/biological samples occurs only when a 
participant: 
 Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
 No longer wishes to receive study treatment 
and 
 Does not want any further visits or assessments (including further study related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent/ 
opposition to use data/biological samples and record this information. 


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Where consent to the use of Personal and Coded Data is not required in a certain country’s legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued, and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study discontinuation. If the 
participant agrees, a final evaluation at the time of the participant’s study discontinuation and 
withdrawal of consent/ opposition to use data/biological samples should be made as detailed in 
the assessment table (Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/ opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the participant welfare and safety. Should early termination be 
necessary, participants must be seen as soon as possible to perform their End of Treatment Visit 
(EOT) and the assessments for EOT as described in Section 8 and will be treated as a 
prematurely withdrawn participant. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
participant’s interests. The investigator or sponsor depending on the local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial. 
In the event that the study is terminated prematurely, e.g., due investigator recommendation at 
the safety review meeting or Novartis decision, participants still receiving study treatment and 
who, according to investigator assessment, continue to benefit from the treatment, will be 
offered to continue study treatment as per protocol or through an alternative setting (see 
Section 9.2). 


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9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision.  
Following completion of the treatment period all participants will complete the safety follow 
up period, and in addition participants who are in CR/CRi will be followed for efficacy during 
the post-treatment follow up period for up to 12 months or until relapse, whichever occurs 
earlier (see Section 9.1.1.2). 
The information collected is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3. Documentation of attempts to contact 
the participant should be recorded in the source documentation.  
The primary CR rate analysis will be conducted after the last participant enrolled has 
completed 6 cycles of treatment. Following the cut-off date for the analysis reported in the 
primary Clinical Study Report (CSR), the study will remain open and ongoing participants will 
continue to receive study treatment and be followed per the schedule of assessments until 
discontinuation criteria is met per Section 9.1.1. 
The end of study is defined as all participants having completed the safety and posttreatment 
follow up (if applicable), or having died, been lost to follow-up or having withdrawn consent 
to further participation in the study. 
At the end of the study, every effort will be made to continue the provision of sabatolimab 
outside this study through an alternative setting for participants who are still receiving treatment 
with sabatolimab and deriving clinical benefit in the opinion of the investigator; safety will be 
monitored and reported to Health Authorities as per regulatory requirements. 
The final analysis will occur at the end of the study. All available data from all participants up 
to this cut-off date will be analyzed and summarized in a final CSR. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a participant 
or clinical investigation participant after providing written informed consent for participation 
in the study. Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 


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The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The Common Toxicity Criteria (CTC) AE grade (CTCAE version 5.0) will be used for 
grading of all adverse events except for GvHD (Harris 2016 for aGvHD and NIH 
consensus criteria for cGvHD). 
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
 Dose not changed 
 Dose reduced/increased 
 Drug interrupted/withdrawn 
6. its outcome  
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. 
For grade 3 and 4 adverse events only, if improvement to a lower grade is determined a new 
entry for this event should be reported in the CRF noting the start date when the event improved 
from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse event monitoring should be continued for at least 
 150 days after the last administration of sabatolimab, or 30 days after the last 
administration of azacitidine, whichever is later. 
OR 


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 Until the start of a new post treatment antineoplastic medication if sooner than the 150 
days mentioned above. If a participant starts post treatment antineoplastic medication, then 
only adverse events suspected to be related to study treatment should be collected, up to 
150 days after discontinuation of sabatolimab. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as separate 
adverse event. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Disease hematologic relapse / progression (including fatal outcomes), if documented by use of 
appropriate method [for example, as per ELN 2017 (Döhner et al 2017)], should not be reported 
as an adverse event. Adverse events separate from the disease hematologic relapse / progression 
(i.e., deep vein thrombosis at the time of hematologic relapse / progression or hemoptysis 
concurrent with finding of disease hematologic relapse / progression) will be reported as per 
usual guidelines used for such events with proper attribution regarding relatedness to the drug. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
 they induce clinical signs or symptoms 
 they are considered clinically significant 
 they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participants 
with the underlying disease. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
 fatal 
 life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
 results in persistent or significant disability/incapacity 


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 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
events irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until the end of the safety follow-up period (Section 9.1.1.1 
must be reported to Novartis safety immediately, without undue delay, under no circumstances 
later than within 24 hours of learning of its occurrence. Detailed instructions regarding the 
submission process and requirements are to be found in the investigator folder provided to each 
site. Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. 
SAE reporting timeframes:  
1. Screen Failures (e.g., a participant who is screened but is not treated or randomized): All 
SAEs occurring after the participant has provided informed consent until the time the 
participant is deemed a Screen Failure must be reported to Novartis. 


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2. Treated participants (including randomized participants in the Randomized Part): SAEs 
collected between time participant signs ICF until 30 days after the participant has 
discontinued or stopped azacitidine or 150 days after stopping sabatolimab, whichever is 
later. If a participant starts post treatment antineoplastic medication, then only SAEs 
suspected to be related to study treatment should be collected, up to 150 days or beyond 
after discontinuation of sabatolimab. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. A SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office & patient 
Safety (CMO & PS) Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the participants have completed the safety follow-up period should 
only be reported to Novartis Safety if the investigator suspects a causal relationship to study 
treatment, unless otherwise specified by local law/regulations. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the Study Doctor to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
Pregnancy data will not be collected from the female partners of any male participants who took 
study treatment in this study. 


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For all pregnancies with live birth and/or unknown outcome the newborn has to be followed up 
to obtain infant health status and development up to twelve months after delivery. 
10.1.5 
Infection reporting 
Infections will be reported as adverse events and the AE severity grade will be assessed 
according to CTCAE grading as defined in Section 10.1. 
In addition, Investigators will detail the type of infection as well as the method of diagnosis and 
assess the event according to the Infection Severity grading (BMT CTN 2013) (Appendix 4). 
10.1.6 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
Implementation of safety monitoring committees will not be required for this study considering 
that it is an open-label study. However, close monitoring of safety is planned; 
specifically, Novartis and the study investigators involved in the safety run-in will conduct at 
least one safety review meeting for safety run-in cohorts 1, 2 and 5 : once all evaluable 
participants in that cohort are observed for at least 2 cycles of treatment or experienced a DLT, 
whichever occurs first, in order to review and discuss safety data, including adverse events, 
dose interruptions and dose modifications, as well as available pharmacokinetic data. At the 


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planned safety review meeting, Novartis and the investigators must reach a consensus based on 
the available safety and clinical pharmacology data, to decide whether to continue with 
enrolment on the study. In addition, the Novartis study team will perform regular data review 
on safety and efficacy data reported in the CRFs. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
In addition to data entered into the eCRF, requisition forms may also need to be completed for 
(e.g. PK, Biomarker etc.) sample collection. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, enrolments, randomizations (if applicable), screen failures and study 
completion, as well as randomization codes (if applicable) and kit numbers and data about 
sabatolimab and azacitidine dispensed to the participant and all dose changes will be tracked 
using an Interactive Response Technology (IRT). The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis at specific 
timelines. 


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Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked.  Any changes to the database after that time can only 
be made after written agreement by Novartis development management. 
Samples collected for all third-party data such as biological samples (including PK, 
 
biomarkers) will be processed centrally and the results will be sent electronically to 
Novartis. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated Contract Research Organization (CRO) representative will review the 
protocol and data capture requirements (i.e., eSource DDE or eCRFs) with the investigators and 
their staff. During the study, Novartis employs several methods of ensuring protocol and Good 
Clinical Practice (GCP) compliance and the quality/integrity of the sites’ data. The field monitor 
will visit the site to check the completeness of participant records, the accuracy of data capture 
/ data entry, the adherence to the protocol and to Good Clinical Practice, the progress of 
enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis/delegated CRO/CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters and 
provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file.  The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
The first safety analysis (including adults from the first cohort) will be conducted when at least 
6 evaluable participants have received sabatolimab in monotherapy at 400 mg dose level for at 
least 2 cycles of treatment. The second safety analysis (including adults from the second 
cohort) will be conducted when at least 9 evaluable participants have received sabatolimab in 
monotherapy at 800 mg dose level for at least 2 cycles of treatment. 


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The primary efficacy analysis will be conducted on all adult participants data (from both safety 
run-in, expansion monotherapy and combination cohorts) at the time all adult participants who 
are still receiving study treatment will have completed at least 6 cycles of treatment or will be 
followed for at least 6 months after the first dose of study treatment or will have discontinued 
from the study earlier. 
The final analysis will occur at the end of the study. All available data from all participants up 
to this cut-off date will be analyzed and summarized in a final CSR. 
All data will be summarized by dose cohort: 
 Adults with sabatolimab 400 mg 
 Adults with sabatolimab 800 mg 
 Adults with azacitidine & sabatolimab combination 
 Adolescents with sabatolimab monotherapy 
For the combination cohort and the adolescent cohort, sabatolimab will be given at the 
recommended dose for expansion (see Section 6.5.2 for guidelines on determination of the 
recommended dose for expansion). 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all participants that received any study treatment. 
Participants will be analyzed according to the treatment(s) received. A participant randomized 
in the combination cohort who receives only sabatolimab and no dose of azacitidine will be 
analyzed with participants randomized in the expansion monotherapy cohort (the treatment 
received). 
The Safety Set includes all participants from the FAS. 
The Dose-Determining Set (DDS) includes all participants from the FAS enrolled in the safety 
run-in part who met the minimum exposure criterion and had sufficient safety evaluations or 
experienced a dose-limiting toxicity (DLT) between Cycle 1 Day 1 (first dose of sabatolimab) 
and the end of Cycle 2. 
A participant has met the minimum exposure criterion if the participant takes 2 infusions of 
sabatolimab at full dose (400 mg or 800 mg) during the first 2 cycles of treatment. 
Participants who do not experience a dose-limiting toxicity (DLT) during the first two cycles 
are considered to have sufficient safety evaluations if they have been observed for at least 28 
days following the second dose of sabatolimab. Participants will be analyzed according to the 
study treatment received as defined for FAS. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for the FAS. 


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Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term. 
12.3 
Treatments 
The duration of exposure to sabatolimab and azacitidine for the combination cohort only as well 
as the dose intensity (computed as the ratio of actual cumulative dose received and actual 
duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity 
and planned dose intensity) will be summarized by descriptive statistics using the safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system. 
The number of participants with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed. 
12.4 
Analysis supporting primary objectives 
For adults, the primary safety objective is to determine whether sabatolimab given in 
monotherapy at the tested dose level (400 mg and 800 mg) leads to an unacceptable level of 
toxicity including treatment emergent aGvHD and cGvHD and to determine the dose 
recommended for expansion (RDE). For adolescents, the primary objective is to determine 
whether sabatolimab given in monotherapy at the recommended dose for adults does not lead 
to an unacceptable level of toxicity in adolescents. 
The primary efficacy objective is to assess the proportion of adult participants with AML and 
MRD+ post-aHSCT in FAS who remain with no evidence of hematologic relapse after 6 cycles 
of study treatment for each cohort (sabatolimab at the RDE in monotherapy and sabatolimab at 
the RDE in combination with azacitidine). 
12.4.1 
Definition of primary endpoint(s) 
For the primary safety objectives (for adults and adolescents separately), the primary variable 
is the proportion of participants from the DDS who reported a dose-limiting toxicity (DLT) (see 
Section 6.5.3 for details) during the first two cycles. 
For the primary efficacy objective, the primary variable is the proportion of adults from the 
FAS treated at the recommended dose for expansion (RDE) who report no evidence of 
hematologic relapse (no evidence of bone marrow blasts ≥5%; no evidence of reappearance of 
blasts in the blood; no evidence of development of extramedullary disease) as per investigator 
assessment (Table 8-3) after 6 cycles of study treatment. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
Primary safety analysis in adults (incidence of treatment-emergent dose-limiting toxicities 
including but not limited to GvHD)  
Assessing whether sabatolimab at the tested dose levels does not lead to an unacceptable level 
of toxicity (DLTs) in adults will be guided by a Bayesian Logistic Regression Model (BLRM). 
This single-agent model will assess the relationship between the log-dose of sabatolimab and 


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the incidence of dose-limiting toxicities (DLTs). Details about this model is provided in 
Section 16.6. 
The posterior probability that the true incidence of dose-limiting toxicity (DLT) including 
aGvHD and cGvHD is lower than 50% will be summarized after each cohort in the safety run-
in part. If this posterior probability is less than 25%, it would be recommended to start the next 
cohort. 
Primary safety analysis in adolescents (incidence of treatment-emergent dose-limiting 
toxicities including but not limited to GvHD) 
Assessing whether sabatolimab at the recommended dose for adults does not lead to an 
unacceptable level of toxicity (DLTs) in adolescents will be guided by the same Bayesian 
Logistic Regression Model (BLRM) than used for the adult cohorts of the safety run-in part. 
Details about this model is provided in Section 16.6. 
The posterior probability that the true incidence of dose-limiting toxicity (DLT) is lower than 
50% will be summarized for the adolescent cohort. 
Primary efficacy analysis (proportion of adult participants with no evidence of 
hematologic relapse) 
A Bayesian design will be used to estimate the true rate of participants with no evidence of 
hematologic relapse after 6 cycles of study treatment for adults treated with sabatolimab at the 
recommended dose for expansion (RDE) in monotherapy and separately for adults treated with 
sabatolimab in combination with azacitidine. This Bayesian dual-criterion design will allow to 
base the trial success not only on the statistical significance for superiority against a certain 
threshold but also by considering a minimum clinically estimated effect size. The 
statistical significance threshold considered for trial success is a proportion of adult participants 
who remain with no evidence of hematologic relapse ≥ 15% and 30% for sabatolimab in 
monotherapy and sabatolimab in combination with azacitidine, respectively. The clinically 
meaningful threshold considered for trial success is a proportion of adult participants who 
remain with no evidence of hematologic relapse ≥ 30% and 50% for sabatolimab in 
monotherapy and sabatolimab in combination with azacitidine, respectively. 
Trial success will be declared if at least one of the two study treatment (sabatolimab in 
monotherapy or sabatolimab in combination with azacitidine) is meeting both statistical and 
clinical criteria. 
The decision criteria for adult participants treated with sabatolimab in monotherapy are the 
following: 
 Statistical decision rule: the posterior probability that the proportion of adult participants 
who remain with no evidence of hematologic relapse after 6 cycles of study treatment is ≥ 
15% is at least 97.5% (statistical significance at 2.5% level, 1-sided) 
 Clinical decision rule: the posterior median for the proportion of adult participants who 
remain with no evidence of hematologic relapse after 6 cycles of study treatment is ≥ 30% 
The decision criteria for adult participants treated with sabatolimab in combination with 
azacitidine are the following: 


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 Statistical decision rule: the posterior probability that the proportion of adult participants 
who remain with no evidence of hematologic relapse after 6 cycles of study treatment is ≥ 
30% is at least 97.5% (statistical significance at 2.5% level, 1-sided) 
 Clinical decision rule: the posterior median for the proportion of adult participants who 
remain with no evidence of hematologic relapse after 6 cycles of study treatment is ≥ 50% 
Inferential summaries (e.g., mean, median, standard deviation, 95% credible intervals, and 
interval probabilities) based on the Bayesian posterior distribution of the proportion of 
participants without a documented hematologic relapse will be presented by treatment arm 
(sabatolimab monotherapy and sabatolimab in combination with azacitidine). The results will 
be also presented with a frequentist formulation: the proportion of adult participants who remain 
with no evidence of hematologic relapse after 6 cycles of study treatment and the exact 95% 
confidence interval, as well as the 1-sided p-value will be provided by treatment arm 
(sabatolimab monotherapy and sabatolimab in combination with azacitidine). No adjustment of 
the type I error for multiplicity is planned for this study. 
12.4.3 
Handling of intercurrent events of primary estimand 
Handling of remaining intercurrent events of the primary efficacy and safety estimands are 
described in Section 2.1.   
12.4.4 
Handling of missing values not related to intercurrent event 
For the determination of the absence of evidence of hematologic relapse (ie, no evidence of 
bone marrow blasts ≥5%; no evidence of reappearance of blasts in the blood; no evidence of 
development of extramedullary disease) after 6 cycles of treatment, only the response 
assessment performed at Cycle 7 Day 1 or the response assessment performed 6 months after 
starting the study treatment is considered. 
An adequate response assessment is considered any disease assessment indicating response 
status apart from “unknown” or “not done”. Evaluation of response relies on bone marrow, 
peripheral blood, and extramedullary disease assessment. In case of missing data for the full 
assessment required to qualify for a given response or in case of a more than 7 days difference 
between bone marrow aspirate/biopsy assessments and hematology assessments of the same 
visit, the overall assessment “unknown” was assigned unless relapse was seen in at least one 
compartment (i.e. bone marrow or blood). 
A participant will be considered with no evidence of hematologic relapse if an adequate 
response assessment indicates a complete remission (CR) or a complete remission with 
incomplete hematologic recovery (CRi) response; and even if one or several inadequate 
response assessments ("unknown" or "not done") have been documented prior to the current 
adequate response assessment. 
12.4.5 
Sensitivity analyses  
No sensitivity analyses are planned. 


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12.4.6 
Supplementary analysis 
A supplementary clinical question of interest is: how similar is the effect of sabatolimab, as 
monotherapy and in combination with azacitidine, on prevention of hematologic relapse (i.e., 
maintenance of CR or CRi) when the AML high risk population is defined based on the 
biomarker central review? In this supplementary estimand, all except the definition of the 
population will be the same as the primary estimand (Section 2.1). 
The population considered for this supplementary estimand is all adult participants with 
AML who are in complete remission after having received an aHSCT and at high risk of relapse 
defined as positive MRD at baseline (determined by central assessment) any time at ≥ Day 60 
after aHSCT and who have been tapered off immunosuppressive therapy. 
12.4.7 
Supportive analyses 
A supportive clinical question of interest is: how similar is the effect of sabatolimab between 
the two doses tested (400 mg and 800 mg Q4W) on prevention of hematologic relapse (i.e., 
maintenance of CR or CRi) in participants with AML at high risk of relapse (MRD positivity)? 
In this supportive analysis, the proportion of participants with no evidence of hematologic 
relapse after 6 cycles of treatment with the exact 95% confidence interval will be presented for 
participants assigned to the sabatolimab dose level tested during the safety run-in part but not 
selected for the expansion part. 
12.5 
Analysis supporting secondary objectives 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Relapse-Free Survival (RFS) 
RFS is defined as the time from start of treatment to the date of first documented hematologic 
relapse or death due to any cause, whichever occurs first. RFS will be censored if no RFS event 
is observed before the first to occur between: (i) the analysis cut-off date, and (ii) the date when 
a new anti-neoplastic therapy or a donor leucocytes infusion (DLI) is started. The censoring 
date will be the date of the last adequate response assessment prior to cut-off/start of new anti-
neoplastic therapy or DLI. The handling of intercurrent events will be the same as the primary 
estimand (Section 2.1). 
RFS will be analyzed in the FAS population and the RFS distribution will be estimated using 
the Kaplan-Meier method. Kaplan-Meier curves, medians and 95% confidence intervals of the 
medians will be presented for each dose cohort. 
MRD conversion rate based on central MRD assessment 
MRD conversion rate is defined as the proportion of participants with centrally confirmed 
MRD+ status at baseline converting to MRD- as per central review within the first 6 cycles of 
study treatment. MRD-negativity will be defined as frequency of LAIP below 0.1%, as 
determined by a MFC-AML MRD assay by central review. A total of 4 post-baseline bone 
marrow aspirate or biopsy assessments is planned to be performed during the first 6 cycles of 
treatment (on Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 and Cycle 7 Day 1). A participant 
with at least one post-baseline MRD-negative sample as per central review will be considered 


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as having reached MRD-negativity regardless of the subsequent MRD assessments and 
regardless of treatment interruption or discontinuation. Only MRD samples collected before 
start of new anti-neoplastic therapy or DLI will be considered for this analysis. 
MRD conversion rate will be analyzed in the FAS population and will be provided with exact 
95% confidence interval for each dose cohort. 
GvHD-free/relapse-free survival (GRFS) 
GRFS is defined as the time from start of treatment to the date of first documented occurrence 
or worsening of treatment emergent grade III or IV aGvHD or moderate to severe cGvHD 
requiring initiation of systemic treatment, hematologic relapse, or death due to any cause, 
whichever occurs first. GRFS will be censored if no GRFS event is observed before the first to 
occur between: (i) the analysis cut-off date, and (ii) the date when a new anti-neoplastic therapy 
or a donor leucocytes infusion (DLI) is started. The censoring date will be the date of the last 
adequate response assessment prior to cut-off/start of new anti-neoplastic therapy or DLI. 
GRFS will be analyzed in the FAS population and the GRFS distribution will be estimated 
using the Kaplan-Meier method. Kaplan-Meier curves, medians and 95% confidence intervals 
of the medians will be presented for each dose cohort. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
dose cohort. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of participant’s informed consent to the day before first 
dose of study treatment 
2. On-treatment period: from day of first dose of study treatment to 30 days after last dose of 
study treatment 
3. Post-treatment period: starting at day 31 after last dose of study treatment. 
An overall safety period will be defined from date of first administration of study treatment to 
150 days after the last dose of sabatolimab. 
Adverse events 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period. The number (and percentage) of participants with treatment emergent 
adverse events will be summarized by primary system organ class, preferred term and maximum 
severity. 


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Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. 
Separate summaries will be provided for: 
 treatment emergent grade III or grade IV acute GvHD 
 treatment emergent moderate to severe chronic GvHD 
 treatment-emergent ≥ grade 3 immune-related adverse events not attributed to GvHD 
Serious adverse events and non-serious adverse events will be tabulated. All deaths (on-
treatment and post-treatment) will be summarized. 
In addition, all AEs and SAEs which started during the overall safety period will be 
summarized. All reported AEs will be listed and those that started during the pre-treatment, 
overall safety period and post-treatment period will be flagged. 
Vital signs 
All vital signs abnormalities will be summarized by visit. 
Clinical laboratory evaluations 
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE v5.0: 
 Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value 
For laboratory tests where grades are not defined by CTCAE v5.0: 
 Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value 
12.5.3 
Pharmacokinetics 
Sabatolimab plasma concentration data will be listed by participant and visit/sampling time 
point. Descriptive summary statistics will be provided by visit/sampling time point, including 
mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum, and 
maximum, as well as the frequency (n, %) of concentrations below the lower limit of 
quantification (LLOQ) and reported as zero. Values below the LLOQ will be treated as missing 
for the calculation of the geometric means and geometric CV%. The minimum observed plasma 
or serum drug concentration (Cmin or Ctrough) at steady-state will be estimated and reported. 
Missing values for any PK parameters or concentrations will not be imputed and will be treated 


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as missing. The concentrations collected on Cycle 3 and later cycles are considered steady-state 
concentrations for sabatolimab. 
All concentration data for sabatolimab versus time profiles will be displayed graphically. 


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12.7 
Interim analyses 
Interim analyses are planned for the monitoring of safety data and will be conducted after each 
dose level cohort of the safety run-in part to determine the recommended dose for expansion 
(RDE). Decisions will be guided by a Bayesian analysis and the review of all relevant data 
available from all dose levels evaluated in the ongoing study including safety information, 
incidence and severity of aGvHD and cGvHD, incidence of DLTs, all CTCAE Grade ≥ 2 
toxicity data, PK, and PD data from evaluable participants (Section 6.5.2). Such safety analyses 


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do not inflate the type I error for the primary efficacy hypothesis testing and thus no adjustment 
for multiplicity is required. 
The primary analysis will be performed after all participants have completed at least 6 cycles 
of treatment or will be followed for at least 6 months after the first dose of study treatment or 
will have discontinued from the study earlier. A final analysis will be performed after all 
participants have completed the study (or discontinued earlier). Formal testing of the primary 
endpoint with full level alpha will be performed at the primary analysis time point. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
Primary safety analysis (incidence of dose-limiting toxicity) 
No formal statistical power calculations to determine sample size were performed for the safety 
run-in part. 
A cohort of 6 to 8 participants will be enrolled in the first cohort treated with sabatolimab at 
400 mg Q4W dose level and a cohort of 9 to 12 participants will be enrolled in the second cohort 
treated with sabatolimab at 800 mg Q4W dose level. 
Table 12-1 presents different scenarios for the incidence of DLTs in the two cohorts of the 
safety run-in part and the decision made based on the Bayesian logistic regression model using 
weakly informative priors (with means corresponding to a risk of DLT at the reference dose of 
15%, and a doubling in dose leading to a doubling in the odds of the risk of a DLT). 
The 15% DLT rate corresponds to the anticipated intrinsic risk of GvHD in this post-transplant 
setting. Of note, no historical data has been considered in the Bayesian model as no participant 
was already treated with sabatolimab in this post-transplant setting. 
In the context of this intrinsic risk of GvHD, the definition of an acceptable level of toxicity 
does not follow the EWOC criterion (i.e. probability to observe a DLT rate exceeding 33% is 
below 25%) as defined in a standard oncology phase I study. Thus, instead of considering a 
33% threshold for the probability to observe a DLT rate, we will select 50% as the threshold to 
qualify for an acceptable toxicity (i.e. probability to observe a DLT rate exceeding 50% is below 
25%). 
Table 12-1 
Probability of unacceptable toxicity for different hypothetical 
scenarios 
Number of 
participants with at 
least one DLT 
(including GvHD) 
among evaluable 
participants 
Probability to observe a DLT rate with three different definition of over-
toxicity (>40%, >45% or >50%) 
 
DLT rate >40% 
DLT rate >45% 
DLT rate >50% 
1st 
cohort 
400 mg 
2nd 
cohort 
800 mg 
Next 
dose* 
P(excessive 
toxicity) 
Next 
dose* 
P(excessive 
toxicity) 
Next 
dose* 
P(excessive 
toxicity) 


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Number of 
participants with at 
least one DLT 
(including GvHD) 
among evaluable 
participants 
Probability to observe a DLT rate with three different definition of over-
toxicity (>40%, >45% or >50%) 
1/6 
-- 
800 
0.219 
800 
0.166 
800 
0.125 
2/6 
-- 
400 
0.211 
400 
0.145 
400 
0.094 
3/6 
-- 
Stop 
  
stop 
  
stop 
  
2/8 
-- 
400 
0.094 
400 
0.055 
800 
0.216 
3/8 
-- 
stop 
  
400 
0.199 
400 
0.129 
0/6 
2/9 
800 
0.038 
800 
0.016 
800 
0.007 
0/6 
3/9 
800 
0.136 
800 
0.076 
800 
0.040 
0/6 
4/9 
400 
0.012 
800 
0.214 
800 
0.134 
0/6 
5/9 
400 
0.025 
400 
0.012 
400 
0.005 
1/6 
3/9 
800 
0.212 
800 
0.125 
800 
0.068 
1/6 
4/9 
400 
0.068 
400 
0.033 
800 
0.184 
1/6 
5/9 
400 
0.130 
400 
0.072 
400 
0.036 
2/8 
3/9 
400 
0.052 
800 
0.179 
800 
0.097 
2/8 
4/9 
400 
0.106 
400 
0.053 
800 
0.224 
* Next dose is the dose recommended by the BLRM for the next cohort or the expansion part of the 
study that satisfies the definition of an acceptable level of toxicity (probability of excessive toxicity 
(i.e. DLT rate ≥ 40, 45 or 50%) is less than 0.25. 
Primary efficacy analysis (proportion of participants with no hematologic relapse) 
The sample size calculation is based on the proportion of participants reported with no evidence 
of hematologic relapse (ie, maintenance of CR or CRi), defined as absence of bone marrow 
blasts ≥5%; absence of reappearance of blasts in the blood; and absence of development of 
extramedullary disease after 6 cycles of treatment. The hypotheses to be tested and details of 
the testing strategy for each of the study treatment (sabatolimab in monotherapy and 
sabatolimab in combination with azacitidine) are described in Section 12.4.2. 
A sample size of 25 adults from both the safety-run and expansion monotherapy cohorts treated 
with sabatolimab in monotherapy at the recommended dose for expansion (RDE) is required to 
meet both statistical significance (posterior probability that proportion of adult participants who 
remain with no evidence of hematologic relapse ≥ 15% is greater or equal to 97.5%) and clinical 
relevance (posterior probability that proportion of adult participants who remain with no 
evidence of hematologic relapse ≥ 30% is greater or equal to 50%). At least 8 participants who 
remain with no evidence of hematologic relapse after 6 cycles of treatment out of 25 participants 
treated with sabatolimab in monotherapy are required for success (both statistical significance 
and clinical relevance met) (Table 12-2). In the absence of historical data in participants treated 
with sabatolimab in this post-transplant setting, a uniform Beta (1,1) prior has been used for 
these sample size calculations. 
Operating characteristics for various true proportion of participants with no evidence of 
hematologic relapse in participants treated with sabatolimab in monotherapy are presented in 


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Figure 12-1. The type-I error under the null value (proportion of participants who remain with 
no evidence of hematologic relapse = 15%) is 2.5% and power is 69.4% and 84.6% assuming a 
true proportion of participants with no evidence of hematologic relapse of 35% and 40%, 
respectively. 
Table 12-2 
Data scenarios, inferential results and decisions for different values of 
the proportion of participants with no hematologic relapse in the 
sabatolimab monotherapy arm (n=25) 
True proportion 
of participants with 
no hematologic 
relapse 
Posterior median  
Posterior probability 
for a positive effect 
(proportion of 
participants with no 
hematologic relapse 
≥15%) 
Decision for trial 
success 
5/25 (20%) 
21.5% 
0.815 
Failed 
6/25 (24%) 
25.3% 
0.917 
Failed 
7/25 (28%) 
29.1% 
0.968 
Failed 
8/25 (32%) 
32.9% 
0.989 
Successful 
9/25 (36%) 
36.7% 
0.997 
Successful 
10/25 (40%) 
40.5% 
0.999 
Successful 


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Figure 12-1 
Operating characteristics for the proportion of participants with no 
hematologic relapse in the sabatolimab monotherapy arm 
 
A sample size of 20 adult participants treated with sabatolimab in combination with azacitidine 
(combination cohort) is required to meet both statistical significance (posterior probability that 
the proportion of participants with no evidence of hematologic relapse ≥ 30% is greater or equal 
to 97.5%) and clinical relevance (posterior probability that the proportion of participants with 
no evidence of hematologic relapse ≥ 50% is greater or equal to 50%). At least 11 participants 
who remain with no evidence of hematologic relapse after 6 cycles of treatment out of 20 
participants treated with sabatolimab in combination with azacitidine are required for success 
(both statistical significance and clinical relevance met) (Table 12-3). In the absence of 
historical data in participants treated with sabatolimab in this post-transplant setting, a uniform 
Beta (1,1) prior has been used for these sample size calculations. 
Operating characteristic for various true proportion of participants with no evidence of 
hematologic relapse after being treated with sabatolimab in combination with azacitidine are 
presented in Figure 12-2. The type-I error under the null value (proportion of participants with 


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no evidence of hematologic relapse = 30%) is 1.7% and power is 75.5% assuming a true 
proportion of participants with no evidence of hematologic relapse of 60%. 
Table 12-3 
Data scenarios, inferential results, and decisions for different values 
of the proportion of participants with no hematologic relapse in the 
combination arm (sabatolimab + azacitidine) (n=20) 
True the proportion 
of participants with 
no hematologic 
relapse  
Posterior median  
Posterior probability 
for a positive effect 
(proportion of 
participants with no 
hematologic relapse 
≥30%) 
Decision for trial 
success 
8/20 (40%) 
40.6% 
0.852 
Failed 
9/20 (45%) 
45.3% 
0.932 
Failed 
10/20 (50%) 
50.0% 
0.974 
Failed 
11/20 (55%) 
54.7% 
0.991 
Successful 
12/20 (60%) 
59.4% 
0.998 
Successful 
13/20 (65%) 
64.1% 
0.999 
Successful 


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Figure 12-2 
Operating characteristics for the proportion of participants with no 
hematologic relapse in the combination arm (sabatolimab + 
azacitidine) 
 
These calculations were made using the software R (version 3.6.1) using the RBesT package.  
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 


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13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) . 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk-based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 


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Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
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Nakamura S, Yokoyama K, Shimizu E, et al (2019) Prognostic impact of circulating tumor 
DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS. Blood 
p. 2682-695. 
National Comprehensive Cancer Network (2020) Acute Myeloid Leukemia (Version 3.2020). 
nccn.org/professionals/physician_gls/pdf/aml.pdf Accessed on 21 Apr 2020. 
Ndhlovu LC, Lopez-Vergès S, Barbour JD, et al (2012) Tim-3 marks human natural killer cell 
maturation and suppresses cell-mediated cytotoxicity. Blood p. 3734-43. 
Ngiow SF, Teng MW, Smyth MJ (2011) Prospects for TIM3-Targeted Antitumor 
Immunotherapy. Cancer Res. p. 6567-71. 
Platzbecker U, Middeke JM, Sockel K, et al (2018) Measurable residual disease-guided 
treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic 
syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. 
Lancet Oncol. p. 1668-79. 
Platzbecker U, Wermke M, Radke J, et al (2012) Azacitidine for treatment of imminent relapse 
in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia p. 
381-9. 
 
 
Sakuishi K, Apetoh L, Sullivan JM, et al (2010) Targeting Tim-3 and PD-1 pathways to reverse 
T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. p. 2187-94. 
Sakuishi K, Jayaraman P, Behar SM, et al (2011) Emerging Tim-3 functions in antimicrobial 
and tumor immunity. Trends Immunol. p. 345-9. 


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Schuurhuis GJ, Heuser M, Freeman S, et al (2018a) Minimal/measurable residual disease in 
AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood p. 
1275-91. 
Schuurhuis GJ, Ossenkoppele GJ, Kelder A (2018b) Measurable residual disease in acute 
myeloid leukemia using flowcytometry: approaches for harmonization/standardization. Expert 
Rev Hematol. p. 921-35. 
Shah MV, Jorgensen JL, Saliba RM, et al (2018) Early Post-Transplant Minimal Residual 
Disease Assessment Improves Risk Stratification in Acute Myeloid Leukemia. Biol. Blood 
Marrow Transplant. p. 1514-20. 
Sánchez-Fueyo A, Tian J, Picarella D, et al (2003) Tim-3 inhibits T helper type 1-mediated 
auto- and alloimmune responses and promotes immunological tolerance. Nat. Immunol. p. 
1093-101. 
 
 
Terwijn M, van Putten WL, Kelder A, et al (2013) High prognostic impact of flow cytometric 
minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK 
AML 42A study. J. Clin. Oncol. p. 3889-97. 
Thekkudan SF, de Lima M, Metheny L (2020) Prevention of relapse after allogeneic stem cell 
transplantation in acute myeloid leukemia: Updates and challenges p. 3:e77. 
Thol F, Gabdoulline R, Liebich A, et al (2018) Measurable residual disease monitoring by NGS 
before allogeneic hematopoietic cell transplantation in AML. Blood p. 1703-13. 
Thol F, Heida B, Buettner K et al (2019) Post Transplantation Measurable Residual Disease 
(MRD) Monitoring Using Next-Generation Sequencing Is Highly Predictive for Relapse after 
Allogeneic Stem Cell Transplantation. Blood p. 184 
Vaughn JE, Gooley T, Maziarz RT, et al (2015) Pre-transplant comorbidity burden and post-
transplant chronic graft-versus-host disease. Br. J. Haematol. p. 411-6. 
Vidaza 
(Azacitadine) 
USPI 
2008. 
accessdata.fda.gov/drugsatfda_docs/label/2008/050794s011lbl.pdf Accessed on 8-Apr-2019. 
Walter RB, Gooley TA, Wood BL, et al (2011) Impact of pretransplantation minimal residual 
disease, as detected by multiparametric flow cytometry, on outcome of myeloablative 
hematopoietic cell transplantation for acute myeloid leukemia. J. Clin. Oncol. p. 1190-7. 
Zhou Y, Othus M, Araki D, et al (2016) Pre- and post-transplant quantification of measurable 
('minimal') residual disease via multiparameter flow cytometry in adult acute myeloid leukemia. 
Leukemia p. 1456-64. 


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16 
Appendices 
16.1 
Appendix 1: Acute GvHD Staging Criteria (Harris et al 2016) 
Organ staging will be performed according to updated NIH criteria as described by Harris et al 
(Harris et al 2016) in Table 16-1. 
Table 16-1 
Acute GvHD Staging Criteria (Harris et al 2016) 
Stage 
Skin 
(Active 
Erythema Only) 
Liver  
(Bilirubin) 
Upper GI 
Lower GI 
(stool 
output/day) 
Stage 0 
No active 
(erythematous) 
GvHD rash 
< 2 mg/dL 
No or intermittent 
nausea, vomiting, 
or anorexia 
Adult: 
<500mL/day or 
<3 episodes/day 
Child: 
<10mL/kg/day or 
<4 episodes/day 
Stage 1 
Maculopapular 
rash < 25% BSA 
2-3 mg/dL 
Persistent 
nausea, vomiting, 
or anorexia 
Adult: 500-
999mL/day or 3-4 
episodes/day 
Child: 10-
19.9mL/kg/day or 
4-6 episodes/day 
Stage 2 
Maculopapular 
rash < 25% - 50% 
BSA 
3.1-6 mg/dL 
  
Adult: 1000-
1500mL/day or 5-
7 episodes/day 
Child: 20-
30mL/kg/day or 
7-10 
episodes/day 
Stage 3 
Maculopapular 
rash > 50% BSA 
6.1-15 mg/dL 
  
Adult: 
>1500mL/day or 
> 7 episodes/day 
Child: 
>30mL/kg/day or 
> 10 
episodes/day 
Stage 4 
Generalized 
erythrodema 
(>50% BSA) plus 
bullous formation 
and 
desquamation 
>5% BSA 
> 15 mg/dL 
  
Severe 
abdominal pain 
with or without 
ileus or grossly 
bloody stool 
(regardless of 
stool volume) 
Overall clinical grade (based on most severe target organ involvement): 
Grade 0: No stage 1-4 of any organ. 
Grade I: Stage 1-2 skin without liver, upper GI or lower GI involvement. 
Grade II: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI. 
Grade III: Stage 2-3 liver and/or stage 2-3 lower GI with stage 0-3 skin and/or stage 0-1 upper GI. 


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Stage 
Skin 
(Active 
Erythema Only) 
Liver  
(Bilirubin) 
Upper GI 
Lower GI 
(stool 
output/day) 
Grade IV: Stage 4 skin, liver or lower GI involvement, with stage 0-1 upper GI. 


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16.2 
Appendix 2: Grading of Chronic GvHD (NIH Consensus Criteria) 
Grading of chronic GvHD as described by Jagasia et al (Jagasia et al 2015) should be performed 
as described below. 
 
Organ scoring of chronic GvHD. ECOG indicates Eastern Cooperative Oncology Group; KPS, 
Karnofsky Performance Status; LPS, Lansky Performance Status; BSA, body surface area; 
ADL, activities of daily living; LFTs, liver function tests; AP, alkaline phosphatase; ALT, 
alanine aminotransferase; ULN, normal upper limit. *Weight loss within 3 months. Skin scoring 
should use both percentage of BSA involved by disease signs and the cutaneous features scales. 
When a discrepancy exists between the percentage of total body surface (BSA) score and the 
skin feature score, OR if superficial sclerotic features are present (Score 2), but there is impaired 


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mobility or ulceration (Score 3), the higher level should be used for the final skin scoring.  To 
be completed by specialist or trained medical providers. **Lung scoring should be performed 
using both the symptoms and FEV1 scores whenever possible. FEV1 should be used in the final 
lung scoring where there is discrepancy between symptoms and FEV1 scores. 
 


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Table 16-2 
NIH global severity of chronic GvHD 
Mild 
1 or 2 organs involved with no more than score 
1 plus Lung score 0 
 
Mild oral symptoms, no decrease in oral 
intake 
 
Mild dry eyes, lubricant eyedrops ≤3x/day 
Moderate 
3 or more organs involved with no more than 
score 1 
OR 
Lung score 1 (FEV1 60-79% or dyspnea with 
stairs) 
OR 


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At least 1 organ (not lung) or site with score 2 
 
19-50% body surface area involved or 
superficial sclerosis 
 
Moderate dry eyes, eyedrops≥3x/days or 
punctal plugs 
Severe 
At least 1 organ or site with score 3 
 
≥ 50% body surface area involved 
 
Deep sclerosis, impaired mobility or 
ulceration 
 
Severe oral symptoms with major limitation 
in oral intake 
 
Severe dry eyes affecting ADL 
 OR 
Lung score 2 or 3(FEV1 40-59% or dyspnea 
walking on flat ground) 
(Jagasia et al 2015, Lee 2017) 
Key points: In skin: higher of the 2 scores to be used for calculating global severity. If the entire 
abnormality in an organ is noted to be unequivocally explained by a non-GvHD documented 
cause, that organ is not included for calculation of the global severity. If the abnormality in an 
organ is attributed to multifactorial causes (GvHD plus other causes) the scored organ will be 
used for calculation of the global severity regardless of the contributing causes (no downgrading 
of organ severity score). 


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16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Table 16-3 
Specific Renal Alert Criteria and Actions 
Renal Event 
Actions 
Confirmed serum creatinine increase 25 – 49% 
 
Consider causes and possible interventions 
 
Follow up within 2-5 days 
Serum creatinine increase 50 % +OR if <18 
years old, eGFR 35 mL/min/1.73 m2 
 
Consider causes and possible interventions 
 
Repeat assessment within 24-48h if possible 
 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
 
Consider patient hospitalization and 
specialized treatment 
New onset dipstick proteinuria ≥ 3+ 
OR Protein-creatinine ratio ≥ 1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory) 
 
Consider causes and possible interventions 
 
Assess serum albumin & serum total protein 
 
Repeat assessment to confirm 
 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
New onset hematuria ≥ 3+ on urine dipstick 
 
Assess & document 
 
Repeat assessment to confirm 
 
Distinguish hemoglobinuria from hematuria 
 
Urine sediment microscopy 
 
Assess sCr 
 
Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation 
 
Consider bleeding disorder 
+ Corresponds to Kidney Disease Improving Global Outcomes (KDIGO) criteria for Acute Kidney Injury 
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project-wide 
patterns of nephrotoxicity.) 
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event: 
 Blood pressure assessment (after 5-minute rest, with an appropriate cuff size) 
 Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema 
 Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output 


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 Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis 
Table 16-4 
Renal Event Follow Up 
FOLLOW-UP OF RENAL EVENTS 
Assess, document and record in CRF: 
 
Urine dipstick and sediment microscopy evidence of DIN:  crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial 
cells 
 
Blood pressure and body weight 
 
Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and 
uric acid 
 
Urine output 
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the CRF 
Monitor patient regularly (frequency at investigator’s discretion) until: 
 
Event resolution: (sCr within 10% of baseline or protein-creatinine ratio< 1 g/g Cr, or ACR <300 
mg/g Cr) or 
 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months. 
 
Analysis of urine markers in samples collected over the course of the DIN event 


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16.4 
Appendix 4: Infection Severity Grading 
Infections will be categorized according to type (i.e. bacterial, viral and fungal) and Blood and 
Marrow Transplant Clinical Trials Network (BMT CTN) severity (i.e. grade III infection, yes 
vs. no) (BMT CTN 2013). 
Table 16-5 
Severity grading table and recurrence interval definitions 
Type of 
Infection/Severity 
Grade 
Grade 1 
Grade 2 
Grade 3 
Bacterial infections 
Bacterial focus NOS 
requiring no more than 
14 days of therapy for 
treatment (e.g. urinary 
tract infection) 
Bacteremia (except 
CoNS) without severe 
sepsis*** 
Bacteremia with deep 
organ involvement 
(e.g. with new or 
worsening pulmonary 
infiltrates; 
endocarditis) 
Coag Neg Staph (S. 
epi), Corynebacterium, 
or Proprioniobacterium 
bacteremia 
Bacterial focus with 
persistent signs, 
symptoms or 
persistent positive 
cultures requiring 
greater than 14 days 
of therapy 
Severe sepsis with 
bacteremia 
Cellulitis responding to 
initial therapy within 14 
days 
Cellulitis requiring a 
change in therapy d/t 
progression 
Fasciitis requiring 
debridement 
  
Localized or diffuse 
infections requiring 
incision with or without 
drain placement 
  
  
Any pneumonia 
documented or 
presumed to be 
bacterial 
Pneumonia requiring 
intubation 
  
  
Brain abscess or 
meningitis without 
bacteremia 
C. Difficile toxin 
positive stool with 
diarrhea < 1L without 
abdominal pain (child 
< 20 mL/kg) 
C. Difficile toxin 
positive stool with 
diarrhea > 1L (child > 
20 mL/kg) or with 
abdominal pain 
C. Difficile toxin 
positive stool with toxic 
dilatation or renal 
insufficiency 
with/without diarrhea 
Fungal infections 
Superficial candida 
infection (e.g. oral 
thrush, vaginal 
candidiasis) 
Candida esophagitis 
(biopsy proven) 
Fungemia including 
Candidemia 


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Type of 
Infection/Severity 
Grade 
Grade 1 
Grade 2 
Grade 3 
  
Proven or probable 
fungal sinusitis 
confirmed 
radiologically without 
orbital, brain, or bone 
involvement 
Proven or probable 
invasive fungal 
infections (e.g. 
Aspergillus, Mucor, 
Fusarium, 
Scedosporium) 
  
  
Disseminated 
infections (defined as 
multifocal pneumonia, 
presence of urinary or 
blood antigen, and/or 
CNS involvement) with 
Histoplasmosis, 
Blastomycosis, 
Coccidiomycosis, or 
Cryptococcus 
  
  
Pneumocystis jiroveci 
pneumonia (regardless 
of PaO2 level) 
Viral infections 
Mucous HSV infection 
  
  
Dermatomal Zoster 
VZV infection with 3 or 
more dermatomes 
Severe ZVZ infection 
(coagulopathy or 
organ involvement) 
Asymptomatic CMV 
viremia untreated or a 
CMV viremia with viral 
load decline by at least 
2/3 of the baseline 
value after 2 weeks of 
therapy 
Clinically active CMV 
infection (e.g. 
symptoms, cytopenias) 
or CMV viremia not 
decreasing by at least 
2/3 of the baseline 
value after 2 weeks of 
therapy 
CMV end-organ 
involvement 
(pneumonitis, enteritis, 
retinitis) 
EBV reactivation not 
treated with rituximab 
EBV reactivation 
requiring institution of 
therapy with rituximab 
EBV PTLD 
Adenoviral 
conjunctivitis 
asymptomatic viruria, 
asymptomatic stool 
shedding and viremia 
not requiring treatment 
Adenoviral upper 
respiratory infection, 
viremia, or 
symptomatic viruria 
requiring treatment 
Adenovirus with end-
organ involvement 
(except conjunctivitis 
and upper respiratory 
tract) 
Asymptomatic HHV-6 
viremia untreated or 
an HHV-6 viremia with 
a viral load decline by 
at least 0.5 log after 2 
weeks of therapy 
Clinically active HHV-6 
infection (e.g. 
symptoms, cytopenias) 
or HHV-6 viremia 
without viral load 
decline 0.5 log after 2 
weeks of therapy 
  


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Type of 
Infection/Severity 
Grade 
Grade 1 
Grade 2 
Grade 3 
BK viremia or viruria 
with cystitis not 
requiring intervention 
BK viremia or viruria 
with clinical 
consequence requiring 
prolonged therapy 
and/or surgical 
intervention 
  
  
Enterocolitis with 
enteric viruses 
  
  
Symptomatic upper 
tract respiratory virus 
Lower tract respiratory 
viruses 
Viremia (virus not 
otherwise specified) 
not requiring therapy 
Any viremia (virus not 
otherwise specified) 
requiring therapy 
  
  
  
Any viral encephalitis 
or meningitis 
Parasitic infections 
  
  
CNS or other organ 
toxoplasmosis 
  
  
Strongyloides 
hyperinfection 
Non-microbiologically 
defined infections 
Uncomplicated fever 
with negative cultures 
responding within 14 
days 
  
  
Clinically documented 
infection not requiring 
inpatient management 
Pneumonia or 
bronchopneumonia not 
requiring mechanical 
ventilation 
Any acute pneumonia 
requiring mechanical 
ventilation 
  
Typhlitis 
  
  
  
Severe sepsis*** 
without an identified 
organism 
*Concomitant or multi-microbial infections are graded according to the grade of the infection with the 
higher grade of severity 
**Therapy includes both PO and IV formulations 
***Severe sepsis: 
Adults: 
Hypotension 
 A systolic blood pressure of <90 mm hg or a reduction of >40 mm hg from baseline in the 
absence of other causes for hypotension 
Multiple Organ Dysfunction Syndrome 
 2 or more of the following: Renal failure requiring dialysis, respiratory failure requiring 
bipap or intubation, heart failure requiring pressors, liver failure 
Pediatrics: 


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 Pediatric SIRS definition and suspected or proven infection and cardiovascular 
dysfunction or ARDS or TWO or MORE other organ dysfunctions 
Pediatric SIRS definition: 
Two or more of the following, one of which must be abnormal temperature or leukocyte count 
1. Core temperature >38.5C or < 36C 
2. Tachycardia, otherwise unexplained persistent in absence of external stimulus, chronic 
drugs or painful stimuli. or bradycardia, in < 1 year old, otherwise unexplained persistent. 
3. Tachypnea or mechanical ventilation for an acute process not related to underlying 
neuromuscular disease or general anesthesia 
4. Leukocytosis or leukopenia for age (not secondary to chemotherapy) or >10% bands 
Pediatric organ dysfunction criteria: 
Cardiovascular: despite administration of fluid bolus >40 ml/kg in 1 hour: 
 Hypotension <5th percentile for age (or per Table 16-3) 
 Pressors at any dose 
 Two of the following:  
 Capillary refill > 5 secs 
 Core to peripheral temperature gap > 3oC 
 Urine output < 0.5 mL/kg/hr 
 Unexplained metabolic acidosis (Base deficit > 5.0 mEq/L) 
 Blood lactate > 2 x ULN 
Respiratory: 
 ARDS or 
 Intubated or 
 >50% FiO2 to maintain SaO2 > 92% 
Neurological: 
 Glasgow Coma Score ≤ 11 or 
 Acute change in mental status with a decrease in GSC ≥3 pts from abnormal baseline 
Renal: 
 Serum creatinine ≥ 2 x ULN for age or 2-fold increase in baseline creatinine 
Hepatic: 
 Total bilirubin ≥ 4 mg/dL or 
 ALT ≥2 x ULN for age 
Table 16-6 
Four age groups relevant to HCT 
Age 
Tachycardia 
(bpm) 
Bradycardia 
(bpm) 
Tachypnea 
(breaths/min) 
Leukocytosis 
/ Leukopenia 
(WBC) 
Hypotension 
Systolic BP 
(mmHg) 
1 mo to 1 yr 
>180 
<90 
>34 
>17.5 to <5.0 
<100 


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Age 
Tachycardia 
(bpm) 
Bradycardia 
(bpm) 
Tachypnea 
(breaths/min) 
Leukocytosis 
/ Leukopenia 
(WBC) 
Hypotension 
Systolic BP 
(mmHg) 
2 yr to 5 yr 
>140 
NA 
>22 
>15.5 to <6.0 
<94 
6 yr to 12 yr 
>130 
NA 
>18 
>13.5 to <4.5 
<105 
13 yr to < 18 
yr 
>110 
NA 
>14 
>11 to <4.5 
<117 
Disseminated Infections: 
1. Two or more non-contiguous sites with the SAME organism 
2. A disseminated infection can occur at any level of severity, but most will be grade 2 or 3. 
Recurrence Intervals to Determine Whether an Infection is the Same or New: 
1. CMV, HSV, EBV, HHV6: 2 months (< 60 days) 
2. VZV, HZV: 2 weeks (< 14 days) 
3. Bacterial, non-C. difficile: 1 week (< 7 days) 
4. Bacterial, C. difficile: 1 month (< 30 days) 
5. Yeast: 2 weeks (< 14 days) 
6. Molds: 3 months (< 90 days) 
7. Helicobacter: 1 year (< 365 days) 
8. Adenovirus, Enterovirus, Influenza, RSV, Parainfluenza, Rhinovirus: 2 weeks (< 14 days) 
9. Polyomavirus (BK virus): 2 months (< 60 days) 
For infections coded as “Disseminated” per the Infection Form, any previous infection with the 
same organism but different site within the recurrence interval for that organism will be counted 
as part of the disseminated infection. 


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16.5 
Appendix 5: Patient Past History and Disease Characteristics 
AML diagnosis: diagnosis of AML will be reported as defined by the 2016 World Health 
Organization (WHO) AML classification (Arber et al 2016). 
Table 16-7 
2016 WHO AML classification 
1 
AML with recurrent 
genetic 
abnormalities 
 
AML with t(8;21)(q22;q22), RUNX1-RUNX1T1. 
 
AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), CBFB-MYH11. 
 
Acute promyelocytic leukemia (APL) with PML-RARA. 
 
AML with t(9;11)(p21.3;q23.3), MLLT3-KMT2A. 
 
AML with t(6;9)(p23;q34.1), DEK-NUP214. 
 
AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2), GATA2, 
MECOM. 
 
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3), RBM15-MKL1. 
 
AML with BCR-ABL1 (provisional entity). 
 
AML with mutated NPM1. 
 
AML with biallelic mutations of CEBPA. 
 
AML with mutated RUNX1 (provisional entity). 
2 
AML with 
myelodysplasia-
related features 
  
3 
Therapy-related 
myeloid neoplasms 
  
4 
AML, Not 
Otherwise 
Specified (NOS) 
 
AML with minimal differentiation (FAB classification M0). 
 
AML without maturation (FAB classification M1). 
 
AML with maturation (FAB classification M2). 
 
Acute myelomonocytic leukemia (FAB classification M4). 
 
Acute monoblastic/monocytic leukemia (FAB classification M5a 
and M5b). 
 
Pure erythroid leukemia (FAB classification M6a and M6b). 
 
Acute megakaryoblastic leukemia (FAB classification M7). 
 
Acute basophilic leukemia. 
 
Acute panmyelosis with myelofibrosis. 
5 
Myeloid sarcoma 
  
6 
Myeloid 
proliferations 
related to Down 
syndrome: 
 
Transient abnormal myelopoiesis (TAM). 
 
Myeloid leukemia associated with Down syndrome. 
7 
Acute Leukemias of 
Ambiguous 
Lineage 
 
Acute undifferentiated leukemia. 
 
Mixed phenotype acute leukemia (MPAL) with 
t(9;22)(q34.1;q11.2); BCR-ABL1. 
 
MPAL with t(v;11q23.3); KMT2A rearranged. 
 
MPAL, B/myeloid, NOS. 


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 
MPAL, T/myeloid, NOS. 
Cytogenetics and risk stratification: cytogenetic risk category will be reported according to 
the 2017 European LeukemiaNet (ELN) recommendations (Döhner et al 2017). 
Table 16-8 
2017 ELN risk stratification by genetics 
Risk 
category* 
Genetic abnormality 
Favorable 
t(8;21)(q22;q22.1); RUNX1-RUNX1T1 
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow† 
Biallelic mutated CEBPA 
Intermediate 
Mutated NPM1 and FLT3-ITDhigh† 
Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow† (without adverse-risk 
genetic lesions) 
t(9;11)(p21.3;q23.3); MLLT3-KMT2A‡ 
Cytogenetic abnormalities not classified as favorable or adverse 
Adverse 
t(6;9)(p23;q34.1); DEK-NUP214 
t(v;11q23.3); KMT2A rearranged 
t(9;22)(q34.1;q11.2); BCR-ABL1 
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) -5 or del(5q); -7; -
17/abn(17p) 
Complex karyotype,§ monosomal karyotype|| 
Wild-type NPM1 and FLT3-ITDhigh† 
Mutated RUNX1{ 
Mutated ASXL1{ 
Mutated TP53# 
Frequencies, response rates, and outcome measures should be reported by risk category, and, if 
sufficient numbers are available, by specific genetic lesions indicated. 
*Prognostic impact of a marker is treatment-dependent and may change with new therapies. 
†Low, low allelic ratio (,0.5); high, high allelic ratio ($0.5); semiquantitative assessment of FLT3-ITD 
allelic ratio (using DNA fragment analysis) is determined as ratio of the area under the curve “FLT3-ITD” 
divided by area under the curve “FLT3-wild type”; recent studies indicate that AML with NPM1 mutation 
and FLT3-ITD low allelic ratio may also have a more favorable prognosis and participants should not 
routinely be assigned to allogeneic HCT. 
‡The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene 
mutations. 
§Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated 
recurring translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), 
inv(3) or t(3;3); AML with BCR-ABL1. 
||Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 
additional monosomy or structural chromosome abnormality (excluding core-binding factor AML). 
{ These markers should not be used as an adverse prognostic marker if they co-occur with favorable-
risk AML subtypes. 
#TP53 mutations are significantly associated with AML with complex and monosomal karyotype.  
Molecular markers and risk stratification:   


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Protocol No. CMBG453F12201 
 
 
 
In addition to basic cytogenetic analysis, molecular markers that can help refining prognostics 
groups, particularly in participants with a normal karyotype, include: NPM1, FLT3 (FLT3-ITD 
and FLT3-TKD), CEBPA, isocitrate dehydrogenase 1 and 2 (IDH1/2), DNA methyltransferase 
3A 
(DNMT3A), 
c-KIT, 
MLL, 
TP53, 
RUNX1, 
and 
ASXL1 
gene 
mutations 
(National Comprehensive Cancer 2020). 


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16.6 
Appendix 6: Statistical details on the Bayesian Logistic 
Regression Model (BLRM) 
Statistical Models 
The safety run-in part of this study to confirm that the sabatolimab is safe will be guided by a 
Bayesian analysis of dose limiting toxicity (DLT) data. The statistical model will be a Bayesian 
Logistic Regression Model (BLRM) consisting of a single agent dose-DLT component. 
Let π (d) be the risk of DLT for sabatolimab given as a single agent Q4W at dose d. The single 
agent dose-DLT model is as follow: 
logit(π(d))=log(α)+β log(d/d*) 
where d*= 800 mg Q4W (reference dose of sabatolimab) is used to scale the doses of 
sabatolimab. Hence, α (>0) is the single-agent odd of a DLT at 800 mg Q4W; β (>0) is the 
increase in the log-odds of a DLT by a unit increase in log-dose. 
Taking into account the intrinsic risk of GvHD (which is part of the DLT definition) in the post-
transplant setting, we selected a weakly informative prior with means corresponding to a risk 
of DLT at the reference dose of 15%, and a doubling in dose leading to a doubling in the odds 
of the risk of a DLT. 
No meta-analytic-predictive (MAP) approach was used to derive the prior distribution as 
historical data are not available in this post-transplant setting. 
The prior distribution is specified in Table 16-9. 
Table 16-9 
Prior distribution 
Parameter 
Prior distribution 
μ1 
N(mean = logit(0.15), sd = 2) 
μ2 
N(mean = 0, sd=1) 
The recommended dose for expansion will be the highest dose between 400 mg and 800 mg 
Q4W for which the probability of excessive toxicity (i.e. DLT rate ≥ 50%) is less than 0.25. 
The summary of prior distribution of DLT rates is specified in Table 16-10. 
Table 16-10 
Summary of prior distribution of DLT rates 
Dose of 
sabatoli
mab 
Prior probabilities 
that P(DLT) is in the 
interval: 
Mean 
SD 
Quantiles 
  
[0, 0.50) 
[0.50,1] 
  
  
2.5% 
50% 
97.5% 
400 mg 
Q4W 
0.897 
0.103 
0.163 
0.220 
0.000 
0.061 
0.813 
800 mg 
Q4W 
0.806 
0.194 
0.257 
0.264 
0.003 
0.151 
0.900 
Hypothetical on-study scenarios 


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To illustrate the performance of the BLRM used to guide the tolerability assessment in the 
safety run-in part for sabatolimab in monotherapy, hypothetical data scenarios are displayed in 
Table 16-11. Decision will be based on additional safety, PK or PD information. 
Table 16-11 
Probability of unacceptable toxicity for different hypothetical 
scenarios 
Number of participants 
with at least one DLT 
(including GvHD) 
among evaluable 
participants 
Probability to observe a DLT rate with three different definition of 
over-toxicity (>40%, >45% or >50%) 
 
DLT rate >40% 
DLT rate >45% 
DLT rate >50% 
1st cohort 
400 mg 
2nd cohort 
800 mg 
Next 
dose* 
P(excessive 
toxicity) 
Next 
dose* 
P(excessive 
toxicity) 
Next 
dose* 
P(excessive 
toxicity) 
1/6 
-- 
800 
0.219 
800 
0.166 
800 
0.125 
2/6 
-- 
400 
0.211 
400 
0.145 
400 
0.094 
3/6 
-- 
stop 
  
Stop 
  
stop 
  
2/8 
-- 
400 
0.094 
400 
0.055 
800 
0.216 
3/8 
-- 
stop 
  
400 
0.199 
400 
0.129 
0/6 
2/9 
800 
0.038 
800 
0.016 
800 
0.007 
0/6 
3/9 
800 
0.136 
800 
0.076 
800 
0.040 
0/6 
4/9 
400 
0.012 
800 
0.214 
800 
0.134 
0/6 
5/9 
400 
0.025 
400 
0.012 
400 
0.005 
1/6 
3/9 
800 
0.212 
800 
0.125 
800 
0.068 
1/6 
4/9 
400 
0.068 
400 
0.033 
800 
0.184 
1/6 
5/9 
400 
0.130 
400 
0.072 
400 
0.036 
2/8 
3/9 
400 
0.052 
800 
0.179 
800 
0.097 
2/8 
4/9 
400 
0.106 
400 
0.053 
800 
0.224 
* Next dose is the dose recommended by the BLRM for the next cohort or the expansion part of the 
study that satisfies the definition of an acceptable level of toxicity (probability of excessive toxicity 
(i.e. DLT rate ≥ 40, 45 or 50%) is less than 0.25. 
Operating characteristics 
The following exact operating characteristics were performed for different true values of DLT 
rate observed in the safety run-in part (participants treated with sabatolimab in monotherapy at 
400 or 800 mg Q4W). Based on simulations with a 50% threshold to qualify for an excessive 
toxicity: when the true DLT rate observed in participants treated with sabatolimab 400 mg and 
800 mg is equal to 40% and 50% respectively, the probability to stop the trial is 0.38 and the 
probability to start the expansion part of the trial with sabatolimab at 400 mg and 800 mg is 
0.50 and 0.13 respectively (Table 16-12). 
Table 16-12 
Operating characteristics for different true values of DLT rate 
True DLT rates 
Probability to declare an excessive toxicity for three 
different thresholds to qualify for an excessive toxicity 


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1st 
cohort 
2nd 
cohort 
DLT rate >40% 
DLT rate >45% 
DLT rate >50% 
400 
mg 
800 
mg 
400 
mg 
800 
mg 
both 
doses 
400 
mg 
800 
mg 
both 
doses 
400 
mg 
800 
mg 
both 
doses 
15% 
20% 
0.248 
0.683 
0.049 
0.244 
0.709 
0.047 
0.170 
0.806 
0.024 
20% 
30% 
0.413 
0.427 
0.160 
0.386 
0.502 
0.112 
0.306 
0.615 
0.079 
30% 
40% 
0.472 
0.163 
0.365 
0.504 
0.213 
0.283 
0.477 
0.318 
0.205 
40% 
50% 
0.372 
0.053 
0.575 
0.448 
0.079 
0.473 
0.496 
0.127 
0.377 
Operating characteristics are performed with R3.6.1 with 1000 simulations and by considering a 
sample size of 6 to 8 participants for the first cohort and a sample size of 9 to 12 participants for the 
second cohort. 
 
 

SAP_001.pdf: 
Clinical Development 
MBG453 (sabatolimab) 
CMBG453F12201 /NCT04623216
A phase Ib/II, open label study of sabatolimab as a 
treatment for patients with acute myeloid leukemia and 
presence of measurable residual disease after allogeneic 
stem cell transplantation 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final version 2.0 – Amendment 1 
Release date: 
03-Jul-2024
Number of pages: 
35 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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SAP – Amendment 1 
 
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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 3 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design ............................................................................................................ 8 
1.2 
Study objectives, endpoints and estimands ............................................................. 9 
1.2.1 
Primary estimands ................................................................................. 12 
2 
Statistical methods ............................................................................................................. 15 
2.1 
Data analysis general information ......................................................................... 15 
2.2 
Analysis sets .......................................................................................................... 16 
2.2.1 
Subgroup of interest .............................................................................. 18 
2.3 
Participant disposition, demographics and other baseline characteristics ............. 18 
2.3.1 
Participant disposition ........................................................................... 18 
2.3.2 
Demographic and other baseline/disease characteristics ...................... 18 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 19 
2.4.1 
Study treatment / compliance ................................................................ 19 
2.4.2 
Prior, concomitant and post therapies ................................................... 20 
2.5 
Analysis of the primary objective .......................................................................... 20 
2.5.1 
Primary endpoints ................................................................................. 21 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.5.3 
Handling of intercurrent events ............................................................. 23 
2.5.4 
Handling of missing values not related to intercurrent event ............... 23 
2.5.5 
Sensitivity analyses ............................................................................... 23 
2.5.6 
Supportive analyses ............................................................................... 23 
2.6 
Analysis of secondary objective(s) ........................................................................ 23 
2.6.1 
Secondary endpoints ............................................................................. 24 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 26 
2.6.3 
Handling of missing values ................................................................... 26 
2.7 
Safety analyses....................................................................................................... 26 
2.7.1 
Adverse events (AEs) ............................................................................ 27 
2.7.2 
Deaths .................................................................................................... 28 
2.7.3 
Laboratory data ..................................................................................... 28 
2.7.4 
Other safety data ................................................................................... 28 
2.8 
Pharmacokinetic endpoints .................................................................................... 29 
2.8.1 
Sabatolimab drug concentrations .......................................................... 29 


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 29 
 
 29 
 
 30 
2.10 
Interim analysis ...................................................................................................... 30 
3 
Sample size calculation ..................................................................................................... 31 
4 
Change to protocol specified analyses .............................................................................. 32 
5 
Appendix ........................................................................................................................... 32 
5.1 
General definitions ................................................................................................ 32 
6 
Reference ........................................................................................................................... 35 
 
List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 10 
Table 2-1 
Participant classification based on protocol deviations and non 
protocol deviations criteria .................................................................... 17 
 


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Document History – Changes compared to previous final version of SAP 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and title impacted (Current) 
10-
June-
2021 
FPFV 
Creation of 
version 1.0 
N/A - First version 
(based on protocol 
from 30-Sep-2020) 
N/A 
03-Jul-
2024 
Before 
primay 
CSR DBL 
Creation of 
version 2.0 
Amendment 2 (based 
on protocol from 24-
March-2022) and 
MBG453 program 
termination 
Sections updated based on the protocol 
amendment 2 dated from 24 March 2022: 
 
Section 1.2.1: primary safety and 
efficacy estimand definitions 
 
Section 2.1: clarification of general 
definition 
Sections updated due to MBG453  program 
termination and thus, simplification of the 
analyses: 
 
Section 1: general statement 
added. Addition of a column in the 
objectives tables to summarize the 
analyses performed for this final 
analysis. 
 
Section 2.1: general statement 
added. 
 
Section 2.3.1: simplification of 
protocol deviations summaries and 
deletion of pre-screened and 
screened failures analyses 
 
Section 2.4.1: cycle delays analysis 
deleted 
 
Section 2.4.2: Clarifications. Donor 
Lymphocyte Infusions will be only 
listed. 
 
Section 2.5 and 2.6: general 
statement added. Following 
endpoints were flagged as not 
assessable: 
 
Primary safety analysis in 
adolescents 
 
p-value deleted for the primary 
efficacy analysis in adults 
 
GvHD-free/relapse-free survival 
 
 
 
Section 2.7: AEs, SAEs, COVID-19 
related events, GvHD, severe 
immune-related adverse events not 
attributed to GvHD, AESI and vital 
signs  analyses simplified. Figures 
and corresponding tables for 
hematology parameters deleted 
 
Section 2.8: PK analyses simplified 
 
 
Section 2.6:  Listings of all responses 
assessments 
 
 added. 


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Date 
Time point 
Reason for 
update 
Outcome for update 
Section and title impacted (Current) 
Section 5: updated date of last exposure to 
study treatment and duration of exposure to 
study treatment derivation 
Typos corrected 
Clerical updates 
Updating of list of Abbreviatons 


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List of abbreviations 
 
 
AE 
Adverse event 
AESI 
Adverse events of special interest 
aGvHD 
Acute Graft-versus-Host disease 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic classification 
BLQ 
Below the limit of quantitation 
BMI 
Body mass index 
BP 
Blood pressure 
BSA 
Body surface area 
cGvHD 
Chronic Graft-versus-Host disease 
CI 
Confidence interval 
CR 
Complete remission 
CRi 
Complete remission with incomplete hematologic recovery 
CSR 
Clinical study report 
CTC 
Common toxicity criteria 
CTCAE 
Common terminology criteria for adverse events 
CV 
Coefficient of variation 
DDS 
Dose-determining set 
DLI 
Donor lymphocyte infusion 
DLT 
Dose limiting toxicity 
DMS 
Document Management System 
eCRF 
Electronic case report form 
eCRS 
Electronic case retrieval strategy 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
EFS 
Event free survival 
ELN 
European Leukemia Net 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer - Quality of Life 
Questionnaire 
EOT 
End of treatment  
EQ-5D-5L 
EuroQol Group - standardized measure of health status questionnaire  
FAS 
Full analysis set 
GRFS 
GvHD-free/relapse-free survival 
GvHD 
Graft versus host disease 
HSCT 
Hematopoietic stem cell transplantation 
 
IST 
Immunosuppressive treatment 
LAIP 
Leukemia associated immunophenotype 
MedDRA 
Medical Dictionary for Regulatory Activities 
MLFS 
Morphologic leukemia free state 
MRD 
Measurable residual disease 


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OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PGI 
Patient global impression 
PK 
Pharmacokinetics 
PR 
Partial remission 
PT 
Preferred term 
QoL 
Quality of life 
Q4W 
Every 4 weeks 
RAP 
Report and analysis process 
RBC 
Red blood cells 
RDE 
Recommended dose for expansion 
RFS 
Relapse free survival  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SMQ 
Standardized MedDRA Query 
SOC 
System organ class 
SoC 
Standard of Care  
TFLs 
Tables, figures, listings 
WHO 
World Health Organization 


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1 
Introduction 
This statistical analysis plan (SAP) describes the planned analyses for the final Clinical Study 
Report (CSR) of the sabatolimab Study CMBG453F12201, A phase Ib/II, open label study of 
sabatolimab as a treatment for patients with acute myeloid leukemia and presence of measurable 
residual disease after allogeneic stem cell transplantation (aHSCT). 
As specified in Section 12.7 of the study protocol, interim analyses are planned for the 
monitoring of safety data, and will be conducted after each dose level cohort of the safety run-
in part to determine the recommended dose for expansion (RDE) (primary safety objective). 
This SAP will serve as the basis for those analyses as well; however, a separate selection of 
tables, figures and listings (TFL) will be done. 
The content of this SAP is based on the CMBG453F12201 protocol amendment 2 (24-Mar-
2022). All decisions regarding the analysis, as defined in the SAP document, have been made 
prior to database lock. 
Due to the study recruitment halt and the termination of the MBG453 program for non-safety-
related  reasons, this study will be terminated early.  Thus, not all protocol planned derivations 
and analyses will be performed. Although described in this document, please refer to table of 
endpoints for the selected planned analyses of this final CSR. Any secondary endpoint analyses 
not conducted due to limited number of patients available, will be documented as such in the 
final CSR and indicated as zero patients with an explanation for mandatory results posting, if 
required. 
1.1 
Study design 
CMBG453F12201 is a phase Ib/II, open label study of sabatolimab as monotherapy and in 
combination with azacitidine, in participants with AML/secondary AML who have received 
one aHSCT and who are in complete remission (CR) as described in the study protocol Table 
8-3 but measurable residual disease positive (MRD+). 
The study consists of 2 parts. Part 1 is a Safety Run-in including two cohorts tested sequentially 
to assess whether sabatolimab as a single agent is safe in this post-aHSCT setting: 
 Cohort 1: adults treated with sabatolimab as a single agent at 400 mg Q4W dose level 
(n~8), 
 Cohort 2: adults treated with sabatolimab as a single agent at 800 mg Q4W dose level) 
(n~12). 
Part 2 is the expansion phase to assess the efficacy, safety, pharmacokinetics (PK) and MRD 
status of sabatolimab in 3 different cohorts: 
 Cohort 3 (combination cohort): adults treated with sabatolimab at the RDE in combination 
with azacitidine (n~20), 
 Cohort 4 (monotherapy expansion cohort): adults treated with sabatolimab at the RDE 
(n~13 if the RDE is 800 mg Q4W and ~12 participants were already included in the safety 
run-in part at this dose level; n~17 if the RDE is 400 mg Q4W and ~8 participants were 
already included in the safety run-in part at this dose level), 


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 Cohort 5 (adolescent cohort): adolescents treated with sabatolimab as a single agent at the 
RDE (n ~6). 
During the expansion part, adults are randomized to be enrolled either in the combination cohort 
(Cohort 3) or in the monotherapy expansion cohort (Cohort 4) to minimize selection bias. 
A total of approximately 59 participants were planned to be enrolled in this study including 
approximately 25 adults treated with sabatolimab at the RDE as a single agent (Cohort 2 + 
Cohort 4 or Cohort 1 + Cohort 4) and approximately 20 adults treated with sabatolimab at the 
RDE in combination with azacitidine. The number of participants included in each study 
part/cohort was presented in Figure 3-1 of the protocol. 
Study treatment consists of cycles of sabatolimab (400 mg or 800 mg) administered intravenous 
on Day 1 of each 28-day cycle for the monotherapy cohorts (Cohorts 1, 2, 4 and 5). Study 
treatment consists of cycles of sabatolimab (400 mg or 800 mg) administered on Day 5 of each 
28-day cycle in combination with azacitidine administered intravenous or subcutaneous at 50 
mg/m2 daily during the first 5 days of each cycle (Cohort 3). Crossover between the different 
sabatolimab doses (400 mg and 800 mg Q4W) is not permitted at any time during the study. 
Study treatment may continue for up to a maximum of 24 cycles or until the participant 
experiences a documented hematologic relapse from CR/CRi (as defined by ELN 2017 Döhner 
et al 2017) or unacceptable toxicity, whichever is earlier. 
Interim analyses are planned for the monitoring of safety data, and will be conducted after each 
dose level cohort of the safety run-in part to determine the RDE. The first safety review meeting 
to assess whether sabatolimab 400 mg Q4W is not meeting overdose criteria (i.e. an excessive 
incidence of Dose Limiting Toxicities (DLT)) will take place after at least 6 evaluable 
participants treated with sabatolimab 400 mg Q4W have completed 2 cycles of treatment 
(Cohort 1). If no safety concerned are observed at this dose level, a second safety review 
meeting to assess whether sabatolimab 800 mg Q4W is not meeting overdose criteria will take 
place after at least 9 evaluable participants treated with sabatolimab 800 mg Q4W have 
completed 2 cycles of treatment (Cohort 2). Details on the definition of dose limiting toxicities 
(DLT) are presented in study protocol Table 6-2. 
The efficacy of sabatolimab when given as a single agent or in combination with azacitidine 
will be assessed after all adults from Cohorts 3 and 4 have completed 6 cycles of treatment 
(primary efficacy objective). The end of study is defined as all participants having completed 
the safety and post-treatment follow up (if applicable), or having died, been lost to follow-up 
or having withdrawn consent to further participation in the study.  
Due to the study recruitment halt and the termination of the sabatolimab program for non-safety-
related reasons, the study will be terminated early. Based on the limited numbers of participants, 
the final CSR will be written with a limited number of analyses. 
1.2 
Study objectives, endpoints and estimands 
Table 1-1 (which is a copy of the Table 2-1 from the study protocol) outlines the primary, 
secondary 
 objectives and belonging endpoints. Further details are given in the 
statistical methods section of this SAP. Due to the study recruitment halt and the termination of 
the sabatolimab program for non-safety-related reasons, not all protocol planned derivations 


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and analyses will be performed. Although described in this document, please refer to table of 
endpoints for the selected planned analyses of this final CSR. Any secondary endpoint analyses 
not conducted due to limited number of patients available, will be documented as such in the 
final CSR and indicated as zero patients with an explanation for mandatory results posting, if 
required. 
 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Final CSR  
Primary objective(s) 
Endpoint(s) for primary objective(s) 
Endpoint(s) selected 
 
For adults only (from the safety 
run-in part): To determine 
whether sabatolimab as 
monotherapy at the two tested 
dose levels (400 mg and 800 
mg Q4W) leads to an 
unacceptable level of toxicity 
when administered to adult 
participants with AML who are 
in complete remission but are 
MRD+ post-aHSCT. 
 
Incidence of treatment-emergent 
dose limiting toxicities (DLTs), 
including aGvHD and cGvHD 
during the first 2 cycles of study 
treatment. 
 
Yes 
 
For adults only (from both 
safety run-in and expansion 
parts): To evaluate preliminary 
efficacy of sabatolimab (at the 
recommended dose level for 
expansion) as monotherapy 
and in combination with 
azacitidine on prevention of 
hematologic relapse by 
assessing the proportion of 
adult participants with AML 
and  MRD+ post-aHSCT 
(according to local assessment) 
who remain with no evidence of 
hematologic relapse after 6 
cycles of study treatment. 
 
The proportion of adult participants 
for whom no evidence of 
hematologic relapse (no evidence 
of bone marrow blasts ≥5%; no 
evidence of reappearance of blasts 
in the blood; no evidence of 
development of extramedullary 
disease) have been documented 
after 6 cycles of study treatment 
(per investigator assessment).   
 
Yes 
 
For adolescents only: To 
determine whether sabatolimab 
as monotherapy at the 
recommended dose level for 
adults leads to an unacceptable 
level of toxicity when 
administered to 
adolescent participants with 
AML who are in complete 
remission but are MRD+ post-
aHSCT. 
 
Incidence of treatment-emergent 
dose limiting toxicities (DLTs), 
including aGvHD and 
cGvHD during the first 2 cycles of 
study treatment. 
 
No 
Secondary objective(s) 
Endpoint(s) for secondary 
objective(s) 
 
 
To assess the incidence of 
grade III or IV aGvHD and 
moderate to severe cGvHD. 
 
Incidence of treatment 
emergent grade III or grade IV 
aGvHD. 
 
Incidence of treatment emergent 
moderate to severe cGvHD. 
 
No 


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Objective(s) 
Endpoint(s) 
Final CSR  
 
To characterize the 
pharmacokinetics (PK) of 
sabatolimab. 
 
Summary of serum concentrations 
(pre-dose samples) and 
pharmacokinetic parameters (the 
minimum observed plasma or 
serum drug concentration: Cmin) 
for sabatolimab. 
 
Yes 
 
To assess GvHD-free/relapse-
free survival (GRFS). 
 
Time from start of treatment to the 
date of first documented 
occurrence or worsening of 
treatment emergent grade III or IV 
aGvHD or moderate to severe 
cGvHD requiring initiation of 
systemic treatment, hematologic 
relapse, or death due to any 
cause, whichever occurs first. 
 
No 
 
To assess Relapse-Free 
Survival (RFS). 
 
Time from start of treatment to the 
date of first documented 
hematologic relapse or death due 
to any cause, whichever occurs 
first. 
 
Yes 
 
To determine the safety and 
tolerability of sabatolimab in 
monotherapy and in 
combination with azacitidine. 
 
Incidence and severity of AEs and 
SAEs, changes in laboratory 
values and vital signs. 
 
Yes 
 
To assess severe immune-
related adverse events not 
attributed to GvHD. 
 
Incidence of treatment-emergent ≥ 
grade 3 immune-related adverse 
events not attributed to GvHD. 
 
Yes 
 
To assess the proportion of 
participants with centrally 
confirmed MRD+ at screening 
who become MRD- during the 
first 6 cycles of study treatment. 
 
Proportion of participants with 
centrally confirmed MRD+ status 
at baseline converting to MRD- 
within the first 6 cycles of study 
treatment. 
 
Yes 


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Objective(s) 
Endpoint(s) 
Final CSR  
1.2.1 
Primary estimands 
For adults participants included in this study, there are two primary clinical questions: 
 Safety: Does sabatolimab, administered as monotherapy at 400 mg and 800 mg Q4W dose 
levels, lead to an unacceptable level of toxicity [dose-limiting toxicity (DLT)], when given 
to treat participants with acute myeloid leukemia (AML) who have received an allogeneic 
hematopoietic stem cell transplantation (aHSCT), and are in complete remission but are 
MRD+ (per local assessment)?  
 Efficacy: What is the effect of sabatolimab at the RDE, as monotherapy and in 
combination with azacitidine, on prevention of hematologic relapse (i.e., no evidence of 
bone marrow blasts ≥ 5%, no evidence of reappearance of blasts in the blood, no evidence 
of development of extramedullary disease) [i.e., maintenance of complete remission 
(CR) or CR with incomplete hematologic recovery (CRi)] in participants with AML at 
high risk of relapse (MRD positivity as per local assessment) after aHSCT regardless of 
treatment interruption or discontinuation during study and until use of donor lymphocyte 
transfusions (DLIs) or other new antineoplastic therapies? 
For adolescent participants included in this study, there is one primary clinical question: 
 Safety: Does sabatolimab administered as monotherapy at the recommended dose level for 
adults, lead to an unacceptable level of toxicity (DLT), when given to 
treat adolescents with AML who have received an aHSCT, have been tapered off 
of systemic immunosuppressive therapy at enrollment, and are in complete remission but 
are MRD+ (per local assessment)? 
Justification: In this proof-of-concept study, the primary purpose is to determine whether or not 
the risk of developing GvHD, immune-related toxicities and other unacceptable toxicities is not 
exacerbated when sabatolimab is administered in the post-transplant setting. The activity of 
sabatolimab is assessed based on the absence of hematologic relapse (no evidence of any of the 
following: bone marrow blasts ≥5%; reappearance of blasts in the blood; or development of 


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extramedullary disease), which is the most clinically meaningful endpoint in this post-transplant 
setting where complete hematologic recovery may be delayed early post-transplant. 
The primary safety estimand for adult participants included in this study is described by the 
following attributes: 
1. Population: Adult participants with AML who are in CR after aHSCT and are at high risk 
of relapse defined as positive MRD (by local assessment) any time at Day ≥ Day 60 after 
aHSCT (with a confirmed MRD positivity at least 2 weeks after systemic 
immunosuppression has been tapered off) and who are exposed to study treatment for at 
least 2 cycles (minimum exposure criterion defined in the protocol Section 12.1) or who 
experienced a DLT within the DLT observation period. 
2. Primary variable: Proportion of adult participants who experience at least one DLT  
including but not limited to aGvHD and cGvHD as per investigator assessment between 
Cycle 1 Day 1 (first administration of sabatolimab) and end of Cycle 2 (Day 28). 
3. Treatment of interest: Treatment with sabatolimab as monotherapy at 400 mg and 800 mg 
Q4W dose levels taken for the entire study duration post aHSCT. 
4. Handling of remaining intercurrent events:  
 Delay to start Cycle 3 due to any reason: a DLT that will occur after Day 28 of Cycle 
2 and before starting Cycle 3 will be considered in the analysis (treatment policy 
strategy).  
 Failure to start Cycle 3 due to any reason: a DLT that will occur up to the theoretical 
last day of Cycle 2 (Cycle 2 Day 28) will be considered in the analysis regardless of 
permanent discontinuation after the dose of sabatolimab in Cycle 2 (treatment policy 
strategy). 
5. Summary measure for the primary safety estimand is the proportion of participants with 
treatment-emergent dose limiting toxicity as per investigator assessment reported during 
the first 2 cycles. 
The primary efficacy estimand for adult participants included in this study are described by 
the following attributes: 
1. Population: Adult participants with AML who are in CR after aHSCT and are at high risk 
of relapse defined as positive MRD at baseline any time at ≥ Day 60 after aHSCT (with a 
confirmed MRD positivity at least 2 weeks after systemic immunosuppression has been 
tapered off). 
2. Primary variable: Proportion of adult participants who remain with no evidence of 
hematologic relapse (no evidence of any of the following: bone marrow blasts ≥5%; 
reappearance of leukemic blasts in the blood; or development of extramedullary disease) 
as per investigator assessment 6 cycles after starting study treatment. 
3. Treatment of interest: Treatment with sabatolimab or sabatolimab in combination with 
azacitidine taken for the entire study duration post aHSCT. One estimand for each of the 
two treatments of interest (sabatolimab in monotherapy and sabatolimab in combination 
with azacitidine) will be considered. 
4. Handling of intercurrent events: 


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 Failure to complete 6 cycles of treatment due to death for any reason or relapse: a 
participant who dies or has a relapse before completing 6 cycles of treatment will be 
considered as a non-responder (composite variable strategy). 
 Start of donor lymphocyte infusions (DLI) or a new anti-neoplastic therapy before 
completing 6 cycles of study treatment: a participant who starts a DLI or a new 
antineoplastic therapy before completing 6 cycles of treatment will be considered as a 
non-responder (composite variable strategy). 
 Failure to complete 6 cycles of treatment due to reasons other than relapse and death 
for any reason (including due to adverse events, graft vs. host disease for example): 
all participants with an adequate response assessment (other than "unknown" 
response) will be taken into account regardless of any study treatment interruption or 
permanent discontinuation; for a participant who stops the study due to reasons other 
than relapse or death,  we will ask the participant to perform a response assessment 6 
months after starting study treatment; a participant with no evidence of hematologic 
relapse 6 months after starting treatment will be considered  a responder (treatment 
policy strategy). 
5. Summary measure for the primary efficacy estimand is the proportion of participants with 
no evidence of hematologic relapse with its exact 95% confidence interval for each of the 
two study treatment of interest: sabatolimab in monotherapy and sabatolimab in 
combination with azacitidine. The trial will be successful if at least one of the treatments 
of interest (sabatolimab monotherapy or sabatolimab in combination with azacitidine) 
meets both statistical and clinical significance.  
The primary safety estimand for adolescent participants included in this study is described 
by the following attributes: 
1. Population: Adolescent participants with AML who are in CR after aHSCT and at high 
risk of relapse defined as positive MRD any time at ≥ Day 60 after aHSCT (with a 
confirmed MRD positivity at least 2 weeks after systemic immunosuppression has been 
tapered off)  and who are exposed to study treatment for at least 2 cycles or who 
experienced a DLT within the DLT observation period. 
2. Primary variable: Proportion of adolescent participants who experience at least one DLT 
including but not limited to aGvHD and cGvHD as per investigator assessment between 
Cycle 1 Day 1 (first administration of MBG453) and end of Cycle 2 (Day 28). 
3. Treatment of interest: Treatment with sabatolimab as monotherapy at the recommended 
dose for adults taken for the entire study duration post aHSCT. 
4. Handling of remaining intercurrent events:  
 Delay to start Cycle 3 due to any reason: a DLT that will occur after Day 28 of Cycle 
2 and before starting Cycle 3 will be considered in the analysis (treatment policy 
strategy).  
 Failure to start Cycle 3 due to any reason: a DLT that will occur up to the theoretical 
last day of Cycle 2 (Cycle 2 Day 28) will be considered in the analysis regardless of 
permanent discontinuation after the dose of sabatolimab in Cycle 2 (treatment policy 
strategy). 


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5. Summary measure for the primary safety estimand is the proportion of participants with 
treatment-emergent dose limiting toxicity as per investigator assessment reported in the 
first 2 cycles. 
As Novartis decided to permanently hold recruitment on December 20th 2023 for non-safety-
related reasons, the study enrolled only one adolescent in part 2. Thus, all analyses on the 
adolescent cohort could not be performed and only listings will be provided. Therefore this 
objective could not be evaluated.  
2 
Statistical methods 
2.1 
Data analysis general information 
As Novartis decided to halt enrollment of the study in December 2023 for non-safety related 
reasons, the study data will be analyzed and reported based on all data up to last patient last 
visit in an abbreviated final Clinical Study Report (CSR).The final analysis, as well as the 
analyses that will be used for the safety review meetings of the safety run-in part of the study 
will be performed by Novartis. 
SAS or R will be used to perform all data analyses and to generate tables, figures and listings. 
Data included in the analysis / data cut-off handling  
For each of the safety review meetings a data cut-off date will be determined after the targeted 
number of participants has completed 2 cycles of treatment. All safety data (including duration 
of exposure to study drugs, dose interruptions/reductions, study drug discontinuation, etc.), 
demographics, disease history, hematology data, extramedullary disease assessment, MRD 
assessment with an assessment date or event start date (e.g. laboratory assessment date or start 
date of an adverse event) prior to or on the cut-off date will be included in the analysis. The 
list of analyses to be presented at the time of the safety review meetings are provided in Section 
2.10. 
For the primary analysis, a data cut-off date will be established after all adults have completed 
6 cycles of treatment (and completed the bone marrow aspirate or biopsy at Cycle 7 Day 1) or 
discontinued earlier. All data with an assessment date or event start date (e.g. laboratory 
assessment date or start date of an adverse event) prior to or on the cut-off date will be included 
in the analysis. Due to the study recruitment halt and the termination of the sabatolimab program 
for non-safety related reasons, the primary analysis will be the final analysis performed with 
the last patient last visit date, as the cut-off date. 
Whatever the planned analysis, any data collected beyond the cut-off date will not be included 
in the analysis and will not be used for any derivations regardless of when data were collected 
after the cut-off date. 
General analysis conventions 
Qualitative data (e.g., gender, race) will be summarized by means of contingency tables; a 
missing category will be included as applicable. Percentages will be calculated using the 
number of participants in the relevant population or subgroup as the denominator. 


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Quantitative data (e.g., age, body weight) will be summarized by appropriate descriptive 
statistics (e.g. mean, standard deviation, median, 25th and 75th percentiles, minimum, and 
maximum). 
General definitions 
“Investigational drug” refers to sabatolimab. 
“Study treatment” refers to the combination of sabatolimab plus azacitidine or sabatolimab 
alone in the monotherapy cohorts. 
“Study treatment component” or “study drug”  refers to sabatolimab or azacitidine. 
Other general definitions are detailed in Appendix Section 5.1. 
2.2 
Analysis sets 
For the safety review meetings, the analysis sets defined below will be restricted to the 
population enrolled in the safety run-in part and participants will be analyzed according to the 
dose regimen they have been assigned to: sabatolimab 400 mg Q4W for the first cohort and 
sabatolimab 800 mg Q4W for the second cohort. At the time of the second Safety Review 
meeting to assess the overtoxicity risk for the second cohort (800 mg Q4W dose level), the 
available data from the first cohort (400 mg Q4W dose level) will also be displayed. 
For the final analysis, the analysis sets defined below will include participants from both the 
safety run-in and the expansion parts. Participants will be analyzed according to the study 
treatment and the sabatolimab dose regimen they have been assigned to, as well as by the age 
group (adults versus adolescent). Thus, results will be presented by considering 4 dose cohorts: 
 Adults with sabatolimab 400 mg (Cohort 1 + Cohort 4 if the RDE is 400 mg Q4W) 
 Adults with sabatolimab 800 mg (Cohort 2 + Cohort 4 if the RDE is 800 mg Q4W) 
 Adults with azacitidine & sabatolimab combination (Cohort 3) 
 Adolescents with sabatolimab monotherapy (Cohort 5) 
Full Analysis Set  
The Full Analysis Set (FAS) comprises all participants who received at least one dose of any 
component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of 
azacitidine). 
Safety Set 
The Safety Set includes all participants from the FAS. 
Dose-Determining Set 
The Dose-Determining Set (DDS) includes all participants from the FAS enrolled in the safety 
run-in part and in the adolescent cohort (Cohort 5) who met the minimum exposure criterion 
described in the protocol Section 12.1 and had sufficient safety evaluations, or experienced a 
dose limiting toxicity (DLT) between Cycle 1 Day 1 (first dose of sabatolimab) and the end of 


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Cycle 2 (both inclusive). Details on the definition of dose limiting toxicities (DLT) are 
presented in study protocol Table 6-2. A participant will be considered evaluable for DLT if: 
 Participant has received 2 infusions of sabatolimab at the assigned dose level in Q4W 
dosing regimen, and participant has had safety assessments for a minimum period of 2 
cycles (from Cycle 1 Day 1 to the end of Cycle 2), or 
 Participant has experienced a DLT within the DLT observation period from first dose of 
sabatolimab to the end of Cycle 2. 
Note: For a participant with a grade 4 neutropenia, thrombocytopenia and pancytopenia 
(hematological toxicity that could be qualified as a DLT) occurred during the DLT evaluation 
period (from Cycle 1 Day 1 to the end of Cycle 2), a sufficient follow-up time will be considered 
to determine if the adverse event has to be qualified as a DLT.  
Note: The period from Cycle 1 Day 1 to the day before Cycle 3 Day 1 corresponds to the period 
from the first dose of sabatolimab in Cycle 1 to the day before the first dose of sabatolimab in 
Cycle 3. In case of Cycle 3 is not initiated, the period to consider for the DLT evaluation will 
be the period from the first dose of sabatolimab in Cycle 1 to the theoretical last day of Cycle 2 
(Cycle 2 Day 28). 
Pharmacokinetic Analysis Sets 
The sabatolimab pharmacokinetic analysis sets include all participants from the Safety Set who 
provide at least one evaluable sabatolimab PK concentration. 
For a concentration to be evaluable: 
 Dosing information must be properly documented (data and time of administration) 
 For post-dose samples: planned dose of sabatolimab must be taken prior to sampling 
 For pre-dose samples: the sample is collected before the next dose administration 
Participant Classification  
Participants may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific participant classification rules defined in 
Table 2-1. 
Table 2-1 
Participant classification based on protocol deviations and non protocol 
deviations criteria 
Analysis set 
Protocol deviations leading to 
exclusion 
Non protocol deviation leading to exclusion 
FAS 
No written informed consent for 
participation in the study 
No dose of any component of study treatment 
Safety Set 
No written informed consent for 
participation in the study 
No dose of any component of study treatment 
DDS 
No written informed consent for 
participation in the study 
Did not met the minimum exposure criterion or no 
sufficient safety evaluations in the absence of DLT 
during the DLT evaluation period 
Sabatolimab-PK 
analysis set 
No written informed consent for 
participation in the study 
See definition of PK analysis sets 


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Withdrawal of Informed Consent 
Any data collected in the clinical database after a participant withdraws the informed consent 
from all further participation in the study will not be included in the analyses. The date on which 
a participant withdraws the consent is recorded in the eCRF. 
Additional data for which there is a separate informed consent, e.g. biological sample etc., 
collected in the clinical database without having obtained an informed consent or after 
withdrawal of consent will not be included in the analyses.  
2.2.1 
Subgroup of interest 
Not applicable. 
2.3 
Participant disposition, demographics and other baseline 
characteristics 
The FAS will be used for the analyses below. Participant disposition, demographics and other 
baseline characteristics will be summarized by dose cohort (Adults with sabatolimab 400 mg, 
Adults with sabatolimab 800 mg, Adults with azacitidine and  sabatolimab combination, 
Adolescents with sabatolimab monotherapy). 
2.3.1 
Participant disposition 
Number (%) of participants  screened and enrolled will be summarized by country and center.  
The number (%) of participants in the FAS who started treatment, are still on treatment, who 
entered and discontinued post-treatment follow-up will be summarized together with the 
respective reasons for treatment/post-treatment follow-up discontinuation. All disposition 
information will be listed. 
The number (%) of participants in the FAS with any protocol deviation will be tabulated by 
deviation category and will be listed.  
2.3.2 
Demographic and other baseline/disease characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for all participants from the FAS. 
BMI (kg/m2) at baseline will be calculated as weight[kg] / (height[m]²) using weight at baseline 
and height at screening. Body Surface Area (BSA) is based on the Mosteller formula described 
in Section 2.4.1. 
Details on AML diagnosis (initial diagnosis, ELN classification, current disease status (de novo 
or secondary) and cytogenetic abnormalities will be tabulated and time since diagnosis 
summarized. 
Details on allogeneic transplant history (disease remission status at time of transplant, 
transplantation timing, etc. as well as history of acute Graft-versus-Host Disease (GvHD) and 
chronic GvHD) will be tabulated and time since transplant summarized. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term. Medical history and current medical conditions will be 


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coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The 
MedDRA version used for reporting will be specified in the CSR and as a footnote in the 
applicable outputs. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The Safety set will be used for the analyses below and summary tables will be presented by 
dose cohort (Adults with sabatolimab 400 mg, Adults with sabatolimab 800 mg, Adults with 
azacitidine & sabatolimab combination, Adolescents with sabatolimab monotherapy). 
2.4.1 
Study treatment / compliance 
The duration of exposure to sabatolimab, azacitidine, and to the combination 
sabatolimab+azacitidine for the combination cohort only, as well as the actual dose intensity, 
relative dose intensity, dose changes, will be summarized by descriptive statistics. 
Duration of exposure 
The duration of exposure (in months) will be summarized for study treatment (combination) 
and for each study drug individually (sabatolimab and azacitidine) based on summary statistics 
and categorical analyses (e.g. exposure < 1 month, at least 1 month, at least 2 months etc.). 
Details on start and end dates used for derivations are outlined in Appendix Section 5.1. 
Cumulative dose 
For sabatolimab the actual cumulative dose in mg is the sum of “dose administered” from the 
eCRF of all cycles during the exposure to sabatolimab. 
For azacitidine, the actual dose in mg/m2 in each cycle is the “dose administered” in mg during 
that cycle divided by the body surface area (BSA) at the beginning of the cycle using the weight 
measured before the infusion at that cycle. If the weight is not collected at the beginning of the 
cycle, the weight from the previous visit will be considered. The actual cumulative dose in 
mg/m2 is then the sum of all cycles. The following formula is used for BSA: 
BSA (m2) = ඥWeight ሺkgሻ∗Height at screening ሺcmሻ/3600 (Mosteller formula) 
Dose intensity and relative dose intensity 
Dose intensity is defined for participants with non-zero duration of exposure. For participants 
who did not take the drug, the dose intensity is by definition equal to zero. The actual dose 
intensity (computed as the ratio of actual cumulative dose received and duration in days from 
first to last cycle initiated) and the relative dose intensity (computed as the ratio of actual dose 
intensity and planned dose intensity) will be summarized for each study treatment component 
by descriptive statistics. The planned dose intensity for each of the study drugs is the ratio of 
planned cumulative dose and duration in days from first to last cycle initiated: 
 For sabatolimab the planned dose intensity is 400 mg/28 days or 800 mg/28 days, 
 For azacitidine, the planned dose intensity is 50 mg/m²/day which is equivalent to 250 
mg/m²/28 days, 


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The relative dose intensity is then computed as the ratio of actual dose intensity and planned 
dose intensity. As example, if a participant received sabatolimab at 600 mg Q4W on average 
throughout the study (instead of the 800 mg Q4W as planned per protocol), the relative dose 
intensity for this participant is 0.75. 
Details on the duration in days from the first to last cycle initiated for the derivation of the dose 
intensity and the relative dose intensity are provided in Appendix Section 5.1. 
Dose reduction, dose interruption and permanent discontinuations 
The number (%) of participants with any dose changes (incl. reductions, interruptions, or 
permanent discontinuations) and the reasons (e.g. AE, dosing error, dispensing error) will be 
taken from the ‘Study Treatment eCRF’ and summarized by study drug.  The total duration of 
interruptions by participant will be summarized for the study population by time intervals, e.g. 
< 1week, ≥ 1-< 2 weeks, ≥ 2-< 3 week etc. (these time intervals may be adjusted depending on 
the observed data). 
2.4.2 
Prior, concomitant and post therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system. 
Prior anti-neoplastic medications will be summarized using the FAS. Medications will be 
summarized by ATC class and preferred term. Prior surgical and medical procedures will be 
summarized by SOC and PT. 
Anti-neoplastic medications and cellular therapies after discontinuation of study treatment 
during follow-up within the study will be summarized by ATC class and preferred term. Donor 
lymphocyte infusions (DLI)  will be listed. 
2.5 
Analysis of the primary objective 
For adults, the primary safety objective is to determine whether sabatolimab given in 
monotherapy at the tested dose level (400 mg and 800 mg) leads to an unacceptable level of 
toxicity including treatment emergent aGvHD and cGvHD and to determine the dose 
recommended for expansion (RDE).  
For adolescents, the primary objective is to determine whether sabatolimab given in 
monotherapy at the recommended dose for adults does not lead to an unacceptable level of 
toxicity in adolescents. Following Novartis decision to permanently hold recruitment for non-
safety related reasons, only one adolescent was enrolled in part 2. Thus, all analyses on the 
adolescent cohort could not be perform and only listings will be provided. 
The primary efficacy objective is to assess the proportion of adult participants with AML and 
MRD+ post-aHSCT (according to local assessment) who remain with no evidence of 
hematologic relapse after 6 cycles of study treatment for each cohort (sabatolimab at the RDE 
in monotherapy and sabatolimab at the RDE in combination with azacitidine). 


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2.5.1 
Primary endpoints 
Primary safety analysis in adults (safety run-in part only) 
The primary endpoint is the incidence of DLTs between Cycle 1 Day 1 and the end of Cycle 2 
of treatment in participants enrolled in the safety run-in part and included in the DDS. 
Details on the definition of DLT which are to be captured in the Adverse Event eCRF are  
defined in Table 6-2 in the protocol.  
Primary safety analysis in adolescent (Cohort 5 only) – Not assessable 
The primary endpoint is the incidence of DLTs between Cycle 1 Day 1 and the end of Cycle 2 
of treatment in participants enrolled in the adolescent cohort (Cohort 5) and included in the 
DDS. 
The same definition of DLT is applied for adolescents and adults. 
Primary efficacy analysis in adults (safety run-in and expansion parts) 
The primary endpoint is the proportion of participants included in the FAS with no evidence of 
hematologic relapse after 6 cycles of study treatment or discontinue earlier for adults treated 
with sabatolimab at the recommended dose for expansion (RDE) in monotherapy and separately 
for adults treated with sabatolimab in combination with azacitidine. 
Details on the definition of response categories which are to be captured in the eCRF by the 
investigator are defined in Table 8-3 of the protocol. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
Primary safety analysis in adults (safety run-in part only) 
A Bayesian model will be used to assess whether sabatolimab at the two tested dose levels is 
not meeting an unacceptable level of toxicity in adults from the DDS. The threshold to qualify 
for an acceptable level of toxicity was higher (50%) than the standard threshold used in phase I 
study (33%) because: 
 aGvHD and cGvHD are included in the DLT definition, 
 Yet, the curative efficacy of aHSCT is attributable to GvL, which inherently maybe 
associated with risk of GvHD, 
 Therefore, post-aHSCT immunomodulatory interventions, including sabatolimab, that 
promote GvL could potentially induce GvHD and other immune-related adverse events. 
The relationship between the dose of sabatolimab and the probability of DLT is modeled using 
a logistic regression detailed in Appendix Section 16.6 of the protocol. A summary of the 
characteristics of this Bayesian model is presented below: 
 A single agent dose-DLT logistic model will assess the toxicity risk of sabatolimab. 
 Taking into account the lack of historical data and the intrinsic risk of GvHD (which is 
part of the DLT definition) in the post-aHSCT setting, a weakly informative priors with 
means corresponding to a risk of DLT at the reference dose of 15%, and a doubling in 
dose leading to a doubling in the odds of the risk of a DLT were selected. 


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 The prior risk of excessive toxicity (i.e. risk of DLT within [50%-100%]) is 10.3% for the 
sabatolimab 400 mg Q4W and 19.4% for the sabatolimab 800 mg Q4W. 
After each cohort in the safety run-in part, the posterior distribution for the risk of DLT for new 
participants at the dose level of interest will be evaluated. The posterior distributions will be 
summarized to provide the posterior probability that the risk of DLT for each dose level of 
sabatolimab lies within the interval [50%, 100%] (i.e. excessive toxicity). After the first cohort, 
if this posterior probability is less than 25% for the two dose levels (400 mg and 800 mg), it 
would be recommended to start enrolling participants in Cohort 2 with sabatolimab 800 mg 
Q4W dose level. 
Primary safety analysis in adolescent (Cohort 5 only) - Not assessable 
The same Bayesian dose-DLT model will be used for the adolescent cohort (Cohort 5) if we 
have at least 3 participants evaluable in the DDS. The posterior probability that the risk of DLT 
for adolescents treated with sabatolimab at the dose recommended for adults lies within the 
interval [50%, 100%] (i.e. excessive toxicity) will be presented. 
Primary efficacy analysis in adults (safety run-in and expansion parts) 
A Bayesian design will be used to estimate the proportion of participants with no evidence of 
hematologic relapse after 6 cycles of study treatment in adults from the FAS treated with 
sabatolimab at the RDE in monotherapy and separately for adults treated with sabatolimab in 
combination with azacitidine, and to provide inferential summaries (e.g. mean,  standard 
deviation, 95% credible intervals, and interval probabilities). This dual-criterion design will 
allow for  base trial success not only on the statistical significance for superiority against the 
effect size expected with the Standard of Care (SoC) (the “null-value”), but also by considering 
a minimum clinically estimated effect size (the “decision value”). 
The decision criteria for trial success for adult participants treated with sabatolimab in 
monotherapy (participants enrolled in Cohorts 1, 2, 4 and treated at the RDE) are the following: 
1. Statistical decision rule: the posterior probability that the proportion of adult participants 
who remain with no evidence of hematologic relapse after 6 cycles of study treatment is  ≥ 
15% is at least 97.5% (statistical significance at 2.5% level, 1-sided). 
2. Clinical decision rule: the posterior median for the proportion of adult participants who 
remain with no evidence of hematologic relapse after 6 cycles of study treatment is ≥ 30%. 
The decision criteria for trial success for adults participants treated with sabatolimab in 
combination with azacitidine (participants enrolled in Cohort 3, “combination cohort”) are the 
following: 
3. Statistical decision rule: the posterior probability that the proportion of adult participants 
who remain with no evidence of hematologic relapse after 6 cycles of study treatment is ≥ 
30% is at least 97.5% (statistical significance at 2.5% level, 1-sided). 
4. Clinical decision rule: the posterior median for the proportion of adult participants who 
remain with no evidence of hematologic relapse after 6 cycles of study treatment is ≥ 50%. 
Inferential summaries (e.g. mean, median, standard deviation and 95% credible intervals) based 
on the Bayesian posterior distribution of the proportion of participants without a documented 
hematologic relapse will be presented by treatment arm (sabatolimab monotherapy and 


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sabatolimab in combination with azacitidine). The results will  also be presented with a 
frequentist formulation: the proportion of adult participants who remain with no evidence of 
hematologic relapse after 6 cycles of study treatment and the exact 95% confidence interval 
(Clopper and Pearson 1934), as well as the 1-sided p-value will be provided by treatment arm 
respectively (sabatolimab monotherapy and sabatolimab in combination with azacitidine). No 
adjustment of the type I error for multiplicity is planned for this study. The p-value will not be 
assessed due to the limited number of participants. 
2.5.3 
Handling of intercurrent events 
Handling of intercurrent events of the primary efficacy and safety estimands is described in 
Section 1.2.1. 
2.5.4 
Handling of missing values not related to intercurrent event 
Primary efficacy analysis in adults (safety run-in and expansion parts) 
For a participant who completed at least 6 cycles of treatment or who discontinued treatment 
earlier before completion of 6 cycles (for reasons other than death, relapse or start of new anti-
neoplastic therapy) and the response assessment on Cycle 7 Day 1 (after completing 6 cycles) 
or 6 months after start of study treatment (if 6 cycles were not completed) is missing or the 
response is “unknown”: 
 If no relapse (maintenance of CR or CRi) is documented at the subsequent response 
assessment (any time after Cycle 7 Day 1 or 6 months after study entry if 6 cycles are not 
completed), the participant will be considered  a responder. 
 If a relapse (no maintenance of CR or CRi) is documented in the subsequent response 
assessment (any time after Cycle 7 Day 1 or 6 months after study entry if 6 cycles are not 
completed), the participant will be considered  a non-responder. 
 If the subsequent response assessment (any time after Cycle 7 Day 1 or 6 months after 
study entry if 6 cycles are not completed) is also missing or the response is “unknown”, 
the participant will be considered as a non- responder. 
2.5.5 
Sensitivity analyses 
Not applicable. 
2.5.6 
Supportive analyses 
Not applicable. 
2.6 
Analysis of secondary objective(s) 
Secondary efficacy endpoints will be analyzed and summarized for the FAS and by dose cohort 
(Adults with sabatolimab 400 mg, Adults with sabatolimab 800 mg, Adults with azacitidine and  
sabatolimab combination, Adolescents with sabatolimab monotherapy). 
A listing of all responses assessments by participant will be provided. 


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2.6.1 
Secondary endpoints 
Relapse-Free Survival (RFS) 
RFS is defined as the time from start of treatment to the date of first documented hematologic 
relapse or death due to any cause, whichever occurs first. RFS will be censored if no RFS event 
is observed before the first to occur between: (i) the analysis cut-off date, (ii) the date when a 
new anti-neoplastic therapy or a donor lymphocyte infusion (DLI) is started, and (iii) lost to 
follow-up or withdrawal of consent. The censoring date will be the date of the last adequate 
response assessment prior to cut-off/start of new anti-neoplastic therapy or DLI. The handling 
of intercurrent events will be the same as the primary estimand. 
RFS will be analyzed in the FAS population and the RFS distribution will be estimated using 
the Kaplan-Meier method. Kaplan-Meier curves, medians and 95% confidence intervals of the 
medians will be presented for each dose cohort. 
The following events could occur during the study and may affect the interpretation of the 
results: 
 Start of donor lymphocyte infusions (DLI) or a new anti-neoplastic therapy: For a 
participant without an event before the time he/she receives any DLI or further anti-cancer 
therapy, RFS would be censored at the date of the last adequate assessment prior to start of 
DLI or further anti-neoplastic therapy. 
 Stopping study treatment (including due to toxicities): All events will be taken into 
account when they occur, regardless of any study treatment interruption or permanent 
discontinuation. 
 Discontinuation from study due to lost to follow-up or withdrawal of consent: For a 
participant without an event prior to discontinuation due to lost to follow-up or withdrawal 
of consent, RFS will be censored at the last adequate assessment date. 
In case of two or more missing assessments prior to documented relapse or death, RFS will be 
censored at the last adequate response assessment prior to the documentation of relapse or death. 
The rule to determine whether there are two missing assessments is described in Section 2.6.3. 
The RFS censoring reason will be summarized as:  
1. Ongoing without event 
2. New anti-neoplastic therapy 
3. Donor lymphocyte infusions 
4. Withdrew consent 
5. Lost to follow-up 
6. Event documented after two or more missing response assessments 
GvHD-free/relapse-free survival (GRFS) – Not assessable 
GRFS is defined as the time from start of treatment to the date of first documented occurrence 
or worsening of treatment emergent grade III or IV aGvHD or moderate to severe cGvHD 
requiring initiation of systemic treatment, hematologic relapse, or death due to any cause, 
whichever occurs first. GRFS will be censored if no GRFS event is observed before the first to 
occur between: (i) the analysis cut-off date, (ii) the date when a new anti-neoplastic therapy, or 
a donor lymphocyte infusion (DLI) is started, and (iii) lost to follow-up or withdrawal of consent. 


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The censoring date will be the date of the last adequate response assessment prior to cut-off/start 
of new anti-neoplastic therapy or DLI. 
GRFS will be analyzed in the FAS population and the GRFS distribution will be estimated 
using the Kaplan-Meier method. Kaplan-Meier curves, medians and 95% confidence intervals 
of the medians will be presented for each dose cohort. 
The following events could occur during the study and may affect the interpretation of the 
results: 
 Start of donor lymphocyte infusions (DLI) or a new anti-neoplastic therapy: For 
participant without an event before the time he/she receives any DLI or further anti-cancer 
therapy, GRFS will be censored at the date of the last adequate assessment prior to start of 
DLI or further anti-neoplastic therapy. 
 Stopping study treatment (including due to toxicities): All events will be taken into 
account when they occur, regardless of any study treatment interruption or permanent 
discontinuation. 
 Discontinuation from the study due to lost to follow-up or withdrawal of consent: For 
participants without an event prior to discontinuation due to lost to follow-up or 
withdrawal of consent, GRFS will be censored at the last adequate assessment date. 
In case of two or more missing assessments prior to documented relapse or death or treatment 
emergent grade III or IV aGvHD, or moderate to severe cGvHD requiring initiation of systemic 
treatment, GRFS will be censored at the last adequate response assessment prior to the 
documentation of the event. The rule to determine whether there are two missing assessments 
is described in Section 2.6.3. 
The GRFS censoring reason will be summarized as:  
1. Ongoing without event 
2. New anti-neoplastic therapy 
3. Donor lymphocyte infusions 
4. Withdrew consent 
5. Lost to follow-up 
6. Event documented after two or more missing response assessments 
MRD conversion rate based on central MFC-MRD assessment from BMA 
MRD conversion rate is defined as the proportion of participants with centrally confirmed 
MRD+ status at baseline converting to MRD- as per central review within the first 6 cycles of 
study treatment. MRD-negativity will be defined as frequency of LAIP below 0.1%, as 
determined by a MFC-AML MRD assay by central review. A total of 4 post-baseline bone 
marrow aspirate or biopsy assessments is planned to be performed during the first 6 cycles of 
treatment (on Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 and Cycle 7 Day 1). A participant 
with at least one post-baseline MRD-negative sample as per central review will be considered 
as having reached MRD-negativity regardless of the subsequent MRD assessments and 
regardless of treatment interruption or discontinuation. Only MRD samples collected before 
start of new anti-neoplastic therapy or DLI will be considered for this analysis. 


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MRD conversion rate will be analyzed in the FAS population and will be provided with exact 
95% confidence interval for each dose cohort. 
Local MRD assessment will be listed including chimerism data used for inclusion criteria. 
2.6.2 
Statistical hypothesis, model, and method of analysis 
No formal statistical tests will be performed for any of the secondary efficacy endpoints and 
hence no multiplicity adjustment will be applied. 
2.6.3 
Handling of missing values 
For RFS analysis, the rule to determine whether there are two missing assessments will be based 
on the distance between the last adequate response assessment date and the event date. If the 
distance is larger than threshold D2 then the analysis will assume that there are two missing 
assessments. This threshold D2 is defined as two times the protocol specified interval between 
the response assessments plus the allowed window around the assessments.  The protocol 
defines that response assessment has to be done at least at the time of bone marrow assessments 
that are to be done on Day 1 at Cycles 2, 3 and 4 (4 weeks +/- 1 week), then every 3 cycles (12 
weeks +/- 2 weeks) until Cycle 13 and every 6 months (24 weeks +/- 4 weeks) thereafter. 
Therefore, for the cycles until Cycle 4, any distance larger than D2 = 2*5 weeks = 10 weeks 
(2.5 months) between last adequate assessment and the event means that there are two missing 
assessments. For the period between Cycle 4 and Cycle 13, any distance larger than D2 = 2*14 
weeks = 28 weeks (7 months) means that there are two missing assessments. And finally, for 
the period beyond Cycle 13, any distance larger than D2 = 2*28 weeks = 56 weeks (1 year) 
means that there are two missing assessments. 
2.7 
 Safety analyses 
Safety analyses will be summarized for the safety set and by dose cohort (adults with 
sabatolimab 400 mg, adults with sabatolimab 800 mg, adults with azacitidine & sabatolimab 
combination, adolescents with sabatolimab monotherapy). 
Safety summaries (tables) include only data from the on-treatment period with the exception of 
baseline data which will also be summarized where appropriate (e.g. change from baseline 
summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). Listings will be also provided. 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of participant’s informed consent to the day before the first 
administration of study treatment 
2. On-treatment period: from the date of the first administration of study treatment to 30 days 
after the  date of the last administration of study treatment 
3. Post-treatment period: any observation starting at day 31 after the last administration of 
study treatment 
An overall safety period will be defined from date of the first administration of study treatment 
to 150 days after the last dose of sabatolimab. 


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2.7.1 
Adverse events (AEs) 
Summary tables for adverse events (AEs) will include all AEs that started or worsened during 
the on-treatment period, including acute Graft-versus-Host Disease (GvHD) and chronic GvHD. 
When specified, some AEs summaries will include all AEs occurring during the overall safety 
period. 
The number (and percentage) of participants with treatment emergent adverse events will be 
summarized by primary system organ class (SOC), preferred term (PT) and maximum CTCAE 
grade. A participant with multiple occurrences of an AE will be counted only once in the 
respective AE category. A participant with multiple CTCAE grades for the same PT will be 
summarized under the maximum CTCAE grade recorded for the event. AEs will be assessed 
according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
In the AE summaries, the primary SOC will be presented alphabetically, and the PT will be 
sorted within primary SOC in descending frequency. The sort order for the PT will be based on 
their frequency in the highest dose level of sabatolimab. The summaries will show ‘All grades’ 
(including AEs with missing grade) and ‘Grades ≥ 3’. 
The following adverse event summaries will be produced selecting all or a subset of AEs 
depending on seriousness, relationship to study drugs, and outcome or action taken:  
 AEs (by SOC and by PT) and separately those considered related to study drugs 
 SAEs  
 SAEs with the number of occurrences (an occurrence is defined as > 1 day between start 
and prior end date of record of same PT) 
 Non-SAEs 
 SAEs with fatal outcome  
 AEs leading to sabatolimab permanent discontinuation 
In addition, all AEs and SAE by SOC and PT will be  provided on the overall safety period. All 
reported AEs will be listed and those that started during the pre-treatment, on-treatment and 
post-treatment period will be flagged. 
2.7.1.1 
Grade III or IV aGvHD and moderate to severe cGvHD 
Separate listings including information on the maximum GvHD stage by organ will be provided 
for: 
 treatment emergent grade III or grade IV acute GvHD 
 treatment emergent moderate to severe chronic GvHD 
2.7.1.2 
Severe immune-related adverse events not attributed to GvHD 
Treatment-emergent ≥ grade 3 immune-related adverse events not attributed to GvHD will be 
described in the AE listing. 
2.7.1.3 
Adverse events of special interest / grouping of AEs 
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to the compound sabatolimab. These groupings are defined using 


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MedDRA terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), 
HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA 
queries, NMQ; and Customized MedDRA queries, CMQ) may also be used. NMQ and CMQ 
are a customized group of search terms which defines a medical concept for which there is no 
official SMQ available or the available SMQ does not completely fit the need. Unlike a NMQ, 
the CMQ is more specific for a particular compound. Both may include a combination of single 
terms and/or an existing SMQ, narrow or broad. These searches will be defined in the eCRS 
(electronic Case Retrieval Strategy) in the DMS (Document Management System) and a listing 
of search terms will be provided in the CSR.  
For each specified AESI, the number (%) of participants with at least one event of the AESI 
occurring during the on-treatment period will be summarized together with the individual 
preferred terms in that grouping.  
2.7.2 
Deaths 
Separate summaries for on-treatment and all deaths (including post-treatment deaths not in the 
AE CRF but in the survival CRF) will be produced showing deaths reasons by SOC and PT. 
All deaths will be listed; post treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened participants. 
2.7.3 
Laboratory data 
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by CTCAE  v5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE v5.0: 
 Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value 
Liver function parameters of interest are total bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST) and alkaline phosphatase. The number (%) of participants 
with worst post-baseline values as per Novartis Liver Toxicity guidelines will be summarized. 
All CTCAE grade 3 or 4 laboratory toxicities will be listed. 
2.7.4 
Other safety data 
Safety data listed in this section will be listed for the safety set and presented by dose cohort 
(Adults with sabatolimab 400 mg, Adults with sabatolimab 800 mg, Adults with azacitidine and  
sabatolimab combination, Adolescents with sabatolimab monotherapy) and by visit/sampling 
timepoint. 


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2.7.4.1 
ECG 
Local ECGs are performed at screening, end of treatment and as clinically indicated. If 
abnormalities are observed based on these local ECGs, these abnormalities are to be reported 
and thus summarized as AEs. 
2.7.4.2 
Vital signs 
Vital sign values during the on-treatment period will be listed. 
2.8 
Pharmacokinetic endpoints 
2.8.1 
Sabatolimab drug concentrations 
Pharmacokinetic analyses will be summarized for the sabatolimab pharmacokinetic analysis set. 
Sabatolimab concentration data will be listed by participant, and visit/sampling time point. 
Descriptive statistics (n, m (number of non-zero concentrations), mean, coefficient of variation 
(CV%), standard deviation, median, geometric mean, geometric CV%, minimum and 
maximum) for sabatolimab will be presented at each scheduled timepoint. Below the limit of 
quantitation (BLQ) values will be set to zero by the Bioanalyst and will be displayed in the 
listing of all PK concentrations as zero and flagged. However, BLQ values will be treated as 
missing for the calculation of the geometric means and geometric CV% but included as zero in 
the other summary statistics. Missing values for PK concentrations will not be imputed and will 
be treated as missing. 


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2.10 
Interim analysis 
Interim analyses are planned for the monitoring of safety data, and will be conducted after each 
dose level cohort of the safety run-in part to determine the recommended dose for expansion 
(RDE): 
 One meeting after participants included in the first cohort (treated with sabatolimab at the 
400 mg Q4W) have completed 2 cycles of treatment, 
 A second meeting after participants included in the second cohort (treated with 
sabatolimab at 800 mg Q4W) have completed 2 cycles of treatment. 
The decision to start enrollment in the second cohort and to continue with the sabatolimab dose 
of 800 mg Q4W in the expansion phase will be guided by a Bayesian analysis based on the 
incidence of dose limiting toxicity (DLT) data. 
For each cohort (sabatolimab 400 mg and 800 mg Q4W) of the safety run-in part, the following 
information (summaries and/or listings) will be provided: 
 Number (%) of participants treated and included in the analysis sets 
 Basic demographic and background data 
 Disease characteristics (including ELN risk category) 
 Medical history 
 Prior and concomitant medications (including immunosuppressive treatments) 
 Participant disposition 


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 Protocol deviations 
 Duration of exposure to study treatment 
 Dose intensity and relative dose intensity 
 Number (%) of participants with any dose changes (including reductions, interruptions, or 
permanent discontinuations) and the reasons 
 DLTs, AEs, treatment related AEs, SAEs, on-treatment deaths reported during the DLT 
evaluation period, as well as DLTs, AEs, treatment related AEs, SAEs, on-treatment 
deaths reported up to the data cut-off date 
 AESI overview (if AESI definition is available at the time of the safety review meetings) 
 Posterior distribution for the risk of DLT for new participants at the dose level tested (see 
Section 2.5) 
 Laboratory data and vital signs abnormalities 
 Investigator’s response assessment 
 Sabatolimab concentrations (if available) 
For the regular safety review meetings conducted after the safety run-in part, the same 
information as listed above will be provided except the investigator’s response assessment as 
this information is only used for decision making on the RDE. 
The exact list of tables, listings and figures prepared for those safety review meetings will be 
defined in a separate planning document (e.g. TFL). 
3 
Sample size calculation 
Primary safety analysis (incidence of dose-limiting toxicity) 
No formal statistical power calculations to determine sample size were performed for the safety 
run-in part. 
A cohort of 6 to 8 participants will be enrolled in the first cohort treated with sabatolimab at 
400 mg Q4W dose level and a cohort of 9 to 12 participants will be enrolled in the second cohort 
treated with sabatolimab at 800 mg Q4W dose level. 
In the context of this intrinsic risk of GvHD, the definition of an acceptable level of toxicity 
does not follow the EWOC criterion (i.e. probability to observe a DLT rate exceeding 33% is 
below 25%) as defined in a standard oncology Phase I study. Thus, instead of considering a 33% 
threshold for the probability to observe a DLT rate, 50% will be selected as the threshold to 
qualify for an acceptable toxicity (i.e. probability to observe a DLT rate exceeding 50% is below 
25%). 
Data scenarios for the incidence of DLTs in the two cohorts of the safety run-in part, including 
the decision made based on the dose-DLT Bayesian logistic regression model, as well as 
operating characteristics, are presented in Appendix 16.6 of the protocol. 
Primary efficacy analysis (proportion of participants with no hematologic relapse) 
The sample size calculation is based on the proportion of participants reported with no evidence 
of hematologic relapse (i.e. maintenance of CR or CRi), defined as absence of bone marrow 
blasts ≥ 5%; absence of reappearance of blasts in the blood; and absence of the development of 


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extramedullary disease after 6 cycles of treatment. The hypotheses to be tested and details of 
the testing strategy for each of the study treatment (sabatolimab in monotherapy and 
sabatolimab in combination with azacitidine) are described in Section 2.5.2. 
A sample size of 25 adults, from both the safety-run and expansion monotherapy cohorts treated 
with sabatolimab in monotherapy at the recommended dose for expansion (RDE), is required 
to meet both statistical significance (posterior probability that the proportion of adult 
participants who remain with no evidence of hematologic relapse ≥ 15% is greater or equal to 
97.5%) and clinical relevance (posterior probability that the proportion of adult participants 
who remain with no evidence of hematologic relapse ≥ 30% is greater or equal to 50%). At least 
8 participants who remain with no evidence of hematologic relapse after 6 cycles of treatment 
out of 25 participants treated with sabatolimab in monotherapy are required for success (both 
statistical significance and clinical relevance met). 
A sample size of 20 adult participants treated with sabatolimab in combination with azacitidine 
(combination cohort) is required to meet both statistical significance (posterior probability that 
the proportion of participants with no evidence of hematologic relapse ≥ 30% is greater or equal 
to 97.5%) and clinical relevance (posterior probability that the proportion of participants with 
no evidence of hematologic relapse ≥ 50% is greater or equal to 50%). At least 11 participants, 
who remain with no evidence of hematologic relapse after 6 cycles of treatment out of 20 
participants treated with sabatolimab in combination with azacitidine, are required for success 
(both statistical significance and clinical relevance met). 
Data scenarios including the decisions for different values of the proportion of participants with 
no hematologic relapse, as well as operating characteristics, are presented in Section 12.8 of the 
protocol. 
4 
Change to protocol specified analyses 
Not applicable. 
5 
Appendix 
5.1 
General definitions 
Date of first administration of study drug (sabatolimab) or azacitidine 
The date of first administration of study drug (sabatolimab) or azacitidine is defined as the first 
date when a non-zero dose of the respective study drug or azacitidine is administered and 
recorded on the study treatment eCRF page.  
Date of last administration of study drug (sabatolimab) or azacitidine 
The date of the last administration of the study drug (sabatolimab) or azacitidine is defined as 
the last date when a non-zero dose of the respective study drug or azacitidine is administered 
and recorded on the study treatment eCRF page. So both, first and last date of study drug, are 
derived separately for each drug which is part of the study treatment. 


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Date of first administration of study treatment (combination cohort) 
The date of the first administration of study treatment (or the start date of study treatment) is 
defined as the first date when a non-zero dose of any component of the study treatment 
(sabatolimab or azacitidine) is administered. 
Date of last administration of study treatment (combination cohort) 
The date of the last administration of study treatment (or the end date of study treatment) is 
defined as the last date when the last non-zero dose of any last component of the study treatment 
(sabatolimab or azacitidine) is administered. 
Date of last exposure to study drug (sabatolimab) or azacitidine 
One planned cycle length is 28 days and the start date of a cycle is defined as the first 
administration of sabatolimab within a cycle in cohorts when administered in monotherapy 
(Cohorts 1, 2, 4, and 5) and as the first administration of azacitidine within a cycle in the 
combination cohort (Cohort 3). Sabatolimab, when administered in monotherapy, is 
administered every 4 weeks (Q4W), on Day 1 of each cycle, unless there was a toxicity leading 
to a dosing interval increase. Sabatolimab, when administered in combination with azacitidine, 
is administered every 4 weeks (Q4W), on Day 5 of each cycle, unless there was a toxicity 
leading to a dosing interval increase. Azacitidine is planned to be administered daily every cycle 
during the first 5 days of each cycle (Day 1 to Day 5).  
As treatment is given in cycles, the date of the last administration of study treatment is not 
considered the date of the last exposure but instead the planned end date of the last cycle in 
which the last non-zero dose was given. 
The date of last exposure to sabatolimab is therefore calculated as: 
 If sabatolimab is given Q4W: Minimum (last date of administration of sabatolimab + 27 
days, date of death, last contact date in case participant is lost to follow-up, data cut-off 
date).  
The date of last exposure to azacitidine is calculated as: 
 Minimum (the last date of administration of azacitidine + 23 days, date of death, the last 
contact date in case participant is lost to follow-up, data cut-off date) as azacitidine doses 
are given daily every cycle during 5 days at the beginning of each cycle (between Day1 to 
Day 5). 
The date of last exposure to study treatment (sabatolimab and azacitidine) is defined as: 
 The latest date among the last date of exposure to sabatolimab and azacitidine treatment. 
This date will be taken to derive duration of exposure to study treatment (sabatolimab and 
azacitidine). 
End date of the last cycle initiated 
The end date of the last cycle initiated is the planned end date (Day 28) of the last cycle initiated 
when the last non-zero dose of any last component of the study treatment (sabatolimab or 
azacitidine) is administered. 


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The end date of the last cycle initiated (Day 28 or beyond) will be applicable even if this date 
goes beyond the data cut-off date (i.e. it should not be truncated to the date of data cut-off). 
Date of last exposure and duration of exposure to study treatment (combination cohort) 
For the calculation of the duration of exposure to study treatment (combination), the date of the 
last exposure to study treatment (combination) will be derived as the minimum date between: 
 The date of last exposure to study treatment,  
 Date of death, 
 Last contact date in case the participant is lost to follow-up. 
The duration of exposure to study treatment (combination) will be calculated as follows: date 
of last exposure to study treatment (combination) - date of first administration of study treatment 
(combination) + 1.  
Duration from first to last cycle initiated to calculate dose intensity and the relative dose 
intensity 
For the calculation of the dose intensity and relative dose intensity, the duration in days from 
first to last cycle initiated will be calculated as follow: date of last exposure - date of first 
administration of study treatment (combination) + 1. 
Thus, this derivation will be irrespective of date of death or last contact date (i.e. it should not 
be truncated to the date of death or date of last contact date). 
Study day 
The study day, describes the day of the event or assessment date, relative to the reference start 
date (start date of study treatment).  
The study day is calculated as follows: 
 The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date + 1 if event is on or after the reference start date; 
 The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if event precedes the reference start date. 
The reference start date for safety assessments (e.g. adverse event onset, laboratory or ECG 
assessment, vital sign measurement etc.) is the start of study treatment. The same reference 
start date will be used for efficacy (e.g. response assessment, time-to-event endpoints). 
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 
Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375. If duration is reported in 
years, duration in days will be divided by 365.25. 


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Baseline 
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of start of study treatment is taken as “baseline” value or “baseline” 
assessment.   
For safety evaluations, the last available assessment including unscheduled assessments on or 
before the date of start of study treatment is taken as “baseline” assessment.  
If participants have no value as defined above, the baseline result will be missing.  
Laboratory parameter derivations 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100) 
The following rules will be applied to derive the WBC differential percentages when only 
absolute differential counts are available for a xxx differential 
xxx %value = (xxx count * 100) / WBC count 
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
if only serum calcium is collected, the corrected calcium can be derived using the total serum 
calcium value and serum albumin at the same assessment using the following formula (after 
values had been converted to SI units): 
Corrected Calcium (mmol/L) = Calcium (mmol/L) + 0.02 (40 – [Albumin (g/L)] 
For laboratory CTC grade derivations, the normal range for derived corrected calcium is set to 
the same limits (in mmol/L) as for serum calcium. 
6 
Reference 
Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation with 
overdose control. Stat Med p. 1103-20.  
Cheson BD, Bennett JM, Kopecky KJ, et al (2003) Revised recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J. Clin. 
Oncol. p. 4642-9. 
Clopper CJ and Pearson ES (1934) The use of confidence or fiducial limites illustrated in the 
case of the binomial. p. 404-413. 
Döhner H, Estey E, Grimwade D, et al (2017) Diagnosis and management of AML in adults: 
2017 ELN recommendations from an international expert panel. Blood p. 424-447.