Conditions: Myelodysplastic Syndrome (MDS)
Keywords: MGM453 Phase II sabatolimab TIM-3 venetoclax azacitidine Myelodysplastic syndrome MDS
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 20
Healthy volunteers: no

Brief summary:
The purpose of the study was to find out if the new drug sabatolimab when given in combination with azacitidine and venetoclax, was safe and had beneficial effects in participants with high or very high risk myelodysplastic syndrome (MDS) who were not suitable for treatment with intensive chemotherapy or a stem-cell transplant (HSCT).

Detailed description:
Approximately 76 people with high or very high risk myelodysplastic syndrome (MDS) and age ≥ 18 years were to be asked to join this study but due to the decision by Novartis to halt recruitment the study did not enroll the approximately 76 participants.

The primary purpose of Part 1 (Safety run-in) was to rule out excessive toxicity of sabatolimab, when administered in combination with azacitidine and venetoclax. The primary purpose of the combined cohort 2 of the Safety run-in (Part 1) and Expansion (Part 2) was to have evaluated efficacy of sabatolimab, when administered in combination with azacitidine and venetoclax in adult participants with high or very high risk MDS. But due to the decision by Novartis to halt recruitment at the end of the Safety run-in, the study enrolled participants in Part 1 only.

This study was to have consisted of two parts:

Safety Run-in Part:

The first approximately 18 participants to have joined the study would have been part of the safety run-in. The first approximately 6 participants would have been enrolled to the lower dose given every four weeks sabatolimab safety run-in cohort.

After these participants would have completed 2 cycles of treatment a decision would have been made to confirm whether the chosen combination of sabatolimab with azacitidine and venetoclax was considered safe to continue with approximately 12 participants, to have been enrolled to the higher dose given every four weeks safety run-in cohort. After these participants would have completed 2 cycles of treatment a decision would have been made to confirm whether the chosen combination of sabatolimab with azacitidine and venetoclax was considered safe to continue with expansion part of the study.

Expansion Part (which did not occur):

After the safety run-in part would have confirmed that the study treatment (higher dose of sabatolimab given every four weeks with azacitidine and venetoclax) was safe, about 58 more participants would have been enrolled in the expansion part to better investigate the efficacy of the study treatment.

Arms:
arm 1: Part 1: Safety run-in consisted of 2 subsequent cohorts of a lower dose (cohort 1) and a higher dose (cohort 2) of sabatolimab in combination with fixed dose of venetoclax and azacitidine.

Part 2 (did not start as recruitment was stopped in Part 1) Expansion was to enroll additional participants to further investigate the regimen including sabatolimab at the higher dose, azacitidine and venetoclax. Participants data from Part 1 and Part 2 treated with the higher dose was to have been combined to determine the complete remission rate.

Interventions: intervention 1: sabatolimab intervention 2: azacitidine intervention 3: venetoclax
Intervention descriptions: intervention 1: Sabatolimab was administered at a low dose (Safety run-in (Part 1) cohort 1) or a high dose (Safety run-in (Part 1) cohort 2) via i.v. infusion over 30 minutes on Day 8 of every treatment cycle. Cycle = 28 days intervention 2: A standard dose of azacitidine was given subcutaneously or intravenously every day for seven consecutive days on days 1-7 of a confirmed treatment cycle. In keeping with standard clinical practice, the alternative schedules for five consecutive days on days 1-5, followed by a two day break, then two consecutive days on days 8-9 was permitted (alternative schedule). intervention 3: Venetoclax film-coated tablets was administered at a dose of 400 mg orally or corresponding reduced dose for concomitant use with P-gp inhibitors or moderate or strong CYP3A4 inhibitors, once a day, from C1D1 to C1D14 during the treatment cycle. No ramp-up for venetoclax was necessary.

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
MBG453/Sabatolimab
Clinical Trial Protocol CMBG453B122031&7
A single-arm, open-label, Phase II study of sabatolimab in 
combination with azacitidine and venetoclax in adult 
participants with high or very high risk myelodysplastic 
syndrome (MDS) as per IPSS-R criteria
Document type:
Clinical Trial Protocol Amendment
EUDRACT number:
2020-003669-21
Version number:
02 (Clean)
Clinical Trial Phase:
II
Release date:
06-Oct-2021
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 (06-Oct-2021) ............................................................................................13
Amendment 1 (17-May-2021)...........................................................................................15
Protocol summary..............................................................................................................16
1
Introduction .......................................................................................................................22
1.1
Background............................................................................................................22
1.2
Purpose ..................................................................................................................25
2
Objectives and endpoints...................................................................................................26
3
Study design ......................................................................................................................29
4
Rationale............................................................................................................................33
4.1
Rationale for study design .....................................................................................33
4.2
Rationale for dose/regimen and duration of treatment ..........................................33
4.3
Rationale for choice of combination drugs............................................................35
4.4
Rationale for MRD assessment and exploratory biomarkers ................................37
4.4.1
Rationale for MRD assessments ...........................................................37
37
4.5
Purpose and timing of interim analyses/design adaptations..................................38
4.6
Risks and benefits..................................................................................................38
5
Study Population ...............................................................................................................40
5.1
Inclusion criteria ....................................................................................................40
5.2
Exclusion criteria...................................................................................................41
6
Treatment...........................................................................................................................43
6.1
Study treatment......................................................................................................43
6.1.1
Investigational and control drugs..........................................................44
6.1.2
Additional study treatments ..................................................................45
6.1.3
Treatment arms/group ...........................................................................45
6.1.4
Guidelines for continuation of treatment ..............................................46
6.1.5
Treatment duration................................................................................46
6.2
Other treatment(s)..................................................................................................46
6.2.1
Concomitant therapy.............................................................................46
6.2.2
Prohibited medication ...........................................................................48
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6.3
Participant numbering, treatment assignment, randomization ..............................49
6.3.1
Participant numbering...........................................................................49
6.3.2
Treatment assignment, randomization ..................................................49
6.4
Treatment blinding.................................................................................................50
6.5
Dose escalation and dose modification..................................................................50
6.5.1
Dose escalation guidelines....................................................................50
6.5.2
Definitions of dose limiting toxicities (DLTs)......................................51
6.5.3
Dose modifications................................................................................54
6.5.4
Follow-up for toxicities.........................................................................59
6.6
Additional treatment guidance...............................................................................63
6.6.1
Treatment compliance...........................................................................63
6.6.2
Emergency breaking of assigned treatment code..................................64
6.7
Preparation and dispensation.................................................................................64
6.7.1
Handling of study treatment and additional treatment..........................65
6.7.2
Instruction for prescribing and taking study treatment .........................65
7
Informed consent procedures ............................................................................................65
8
Visit schedule and assessments .........................................................................................67
8.1
Screening ...............................................................................................................79
8.1.1
Eligibility screening ..............................................................................79
8.1.2
Information to be collected on screening failures.................................79
8.2
Participant demographics / other baseline characteristics .....................................79
8.3
Efficacy..................................................................................................................81
8.3.1
Efficacy assessments.............................................................................81
8.3.2
Appropriateness of efficacy assessments..............................................85
8.4
Safety.....................................................................................................................86
8.4.1
Laboratory evaluations..........................................................................87
8.4.2
Electrocardiogram (ECG) .....................................................................89
8.4.3
Pregnancy and assessments of fertility .................................................90
8.4.4
Appropriateness of safety measurements..............................................91
8.5
Additional assessments..........................................................................................91
8.5.1
Clinical Outcome Assessments (COAs) ...............................................91
8.5.2
Pharmacokinetics ..................................................................................92
95
9
Study discontinuation and completion ..............................................................................98
9.1
Discontinuation and completion............................................................................98
9.1.1
Study treatment discontinuation and study discontinuation..................98
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9.1.2
Withdrawal of informed consent.........................................................100
9.1.3
Lost to follow-up.................................................................................100
9.1.4
Early study termination by the sponsor...............................................100
9.2
Study completion and post-study treatment ........................................................101
10 Safety monitoring and reporting......................................................................................102
10.1
Definition of adverse events and reporting requirements....................................102
10.1.1
Adverse events ....................................................................................102
10.1.2
Serious adverse events ........................................................................104
10.1.3
SAE reporting......................................................................................105
10.1.4
Pregnancy reporting ............................................................................105
10.1.5
Reporting of study treatment errors including misuse/abuse..............106
10.2
Additional Safety Monitoring..............................................................................107
10.2.1
Data Monitoring Committee ...............................................................107
10.2.2
Steering Committee.............................................................................107
11 Data Collection and Database management....................................................................107
11.1
Data collection.....................................................................................................107
11.2
Database management and quality control..........................................................108
11.3
Site monitoring ....................................................................................................108
12 Data analysis and statistical methods ..............................................................................109
12.1
Analysis sets ........................................................................................................109
12.2
Participant demographics and other baseline characteristics...............................110
12.3
Treatments ...........................................................................................................110
12.4
Analysis of the primary endpoint(s) ....................................................................111
12.4.1
Definition of primary endpoints and estimands..................................111
12.4.2
Statistical model, hypothesis, and method of analysis........................112
12.4.3
Handling of remaining intercurrent events of primary endpoint ........113
12.5
Analysis of secondary endpoints .........................................................................113
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)..................................114
12.5.2
Safety endpoints..................................................................................118
12.5.3
Pharmacokinetics ................................................................................120
121
121
121
12.7
Interim analyses...................................................................................................122
12.8
Sample size calculation........................................................................................122
12.8.1
Primary endpoint(s).............................................................................122
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13 Ethical considerations and administrative procedures ....................................................124
13.1
Regulatory and ethical compliance......................................................................124
13.2
Responsibilities of the investigator and IRB/IEC................................................124
13.3
Publication of study protocol and results.............................................................125
13.4
Quality Control and Quality Assurance...............................................................125
14 Protocol adherence ..........................................................................................................125
14.1
Protocol amendments...........................................................................................126
15 References .......................................................................................................................127
16 Appendices ......................................................................................................................132
16.1
Appendix 1: Statistical considerations for Safety run-in Part .............................132
16.1.1
Statistical model for triple combination..............................................132
16.1.2
Prior specifications..............................................................................133
16.1.3
Hypothetical on-study scenarios .........................................................136
16.1.4
Operating characteristics.....................................................................138
16.1.5
References...........................................................................................140
16.2
Appendix 2: Concomitant medications to be used with caution and/or 
requiring action....................................................................................................141
List of tables
Table 2-1
Objectives and related endpoints ..........................................................26
Table 6-1
Study Treatment....................................................................................44
Table 6-2
Management of potential interactions of CYP3A and P-gp 
inhibitors with venetoclax.....................................................................47
Table 6-3
Provisional dose levels of sabatolimab during Safety run-in (Part 1)...50
Table 6-4
Criteria for defining dose-limiting toxicities during the Safety run-
in (Part 1)...............................................................................................52
Table 6-5
Criteria for dose interruption and re-initiation or discontinuations 
of sabatolimab for adverse drug reactions ............................................55
Table 6-6
Dose modifications for venetoclax........................................................57
Table 6-7
Follow-up of abnormal liver chemistry results .....................................61
Table 6-8
Action required for isolated total bilirubin elevation............................62
Table 8-1
Assessment Schedule ............................................................................68
Table 8-2
Modified response classification per IWG-MDS criteria 
(Platzbecker et al 2019, Cheson et al 2006, Cheson et al 2000) ...........81
Table 8-3
Assessments and specifications.............................................................86
Table 8-4
ECOG performance status.....................................................................87
Table 8-5
Local clinical laboratory parameters collection plan ............................87
Table 8-6
Central clinical laboratory parameters collection plan..........................89
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Table 8-7
Central ECG collection plan .................................................................89
Table 8-8
Local ECG collection plan....................................................................89
Table 8-9
Sabatolimab PK, IG 
 blood collection log .........................93
Table 8-10
Venetoclax PK blood collection log .....................................................94
97
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................106
Table 12-1
Data scenarios, inferential results and decisions (n=70).....................123
Table 12-2
Operating characteristics for true CR rate (n=70)...............................124
Table 16-1
Prior distributions for single-agent and interactionparameters ...........134
Table 16-2
Historical data from [PDR001X2105 (arm 6b)] for sabatolimab in 
combination with azacitidine ..............................................................134
Table 16-3
Historical data from [Wei et al (2019)] for venetoclax and 
azacitidine ].........................................................................................135
Table 16-4
Prior distribution (BVN Mixture (log(α, β)).......................................135
Table 16-5
Summary of posterior distributions.....................................................135
Table 16-6
Probability of excessive toxicity estimated by the Bayesian model 
after each cohort..................................................................................136
Table 16-7
Operating characteristics for different true values of DLT rate..........139
Table 16-8
List of medications to be used with caution and/or requiring action 
during study drug treatment ................................................................141
List of figures
Figure 3-1
Study design..........................................................................................31
Figure 3-2
Study flow.............................................................................................32
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List of abbreviations
ADA
Anti-drug antibody
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AML
Acute Myeloid Leukemia
APTT
Activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area under the curve
BCL-2
B-cell lymphoma 2
BCRP
Breast cancer resistance protein
BMA
Bone marrow aspirate
BMI
Body Mass Index
BSA
Body surface area
BUN
Blood Urea Nitrogen
CABG
Coronary artery bypass graft
CDP
Clinical Development Plan
CK
Creatinine Kinase
CMML
Chronic myelomonocytic leukemia
CO
Country Organization
COA
Clinical Outcome Assessment
COVID-19
Coronavirus disease 2019
CR
Complete remission
CRF
Case Report/Record Form (paper or electronic)
CRi
Complete Remission with incomplete hematologic recovery
CRO
Contract Research Organization
CSR
Clinical study report
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
CYP
Cytochrome P450
DBP
Diastolic Blood Pressure
DDI
Drug-drug interaction
DDS
Dose Determining Set
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCOA
Electronic Clinical Outcome Assessment
ECOG
Eastern Cooperative Oncology Group
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EDC
Electronic Data Capture
EFS
Event-free survival
eGFR
Estimated glomerular filtration rate
ELISA
Enzyme-linked immunosorbent assay
ELN
European Leukemia Network
EMA
European Medicines Agency
EOT
End of treatment
ePRO
Electronic Patient Reported Outcome
ESA
Erythropoiesis Stimulating Agent
eSAE
Electronic Serious Adverse Event
ESMO
European Society for Medical Oncology
eSource
Electronic Source
EWOC
Escalation with overdose control
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy- Fatigue
FAS
Full Analysis Set
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
G-CSF
Granulocyte-colony stimulating factor
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
GLDH
Glutamate dehydrogenase
h
Hour
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCG
Human chorionic gonadotropin
HCV
Hepatitis C Virus
HEOR
Health Economics & Outcomes Research 
HI
Hematological improvement
HIV
Human immunodeficiency virus
HMA
Hypomethylating agents
HSCT
Hematopoietic Stem Cell Transplant
i.v.
intravenous
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
ICU
Intensive care unit
IEC
Independent Ethics Committee
IG
Immunogenicity
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INR
International Normalized Ratio
IPSS-R
Revised International Prognostic Scoring System
irAE
Immune related adverse event
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine device
IWG
International Working Group
LC-MS
Liquid chromatography-mass spectrometry
LDH
lactate dehydrogenase
LFS
Leukemia-free survival
LFT
Liver function test 
LUC
Large unstained cells
mCR
Marrow complete remission
MDRD
Modification of Diet in Renal Disease
MDS
Myelodysplastic syndromes
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)
MPN
Myeloproliferative neoplasm
MRD
Measurable residual disease
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NK
Natural killer
NTproBNP
N-terminal prohormone of brain natriuretic peptide
ORR
Overall response rate
OS
Overall survival
PAS
Pharmacokinetic Analysis Set
PBMC
Peripheral blood mononuclear cell
PCR
Polymerase chain reaction
PD
Progressive Disease
PD-1
Programmed cell death protein 1
PFS
Progression-free survival
Pgp
P-glycoprotein
PK
Pharmacokinetic(s)
PR
Partial Remission
PRO
Patient Reported Outcomes
Q4W
every 4 weeks
QTcF
QT interval corrected by Fridericia’s formula
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RBC
red blood cell(s)
RNA
Ribonucleic acid
RoW 
Rest of World
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome Coronavirus 2
SBP
Systolic Blood Pressure
SCT
Stem cell transplant
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SJS
Steven-Johnson syndrome
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total bilirubin
TEN
Toxic epidermal necrolysis
TIM-3
T-cell immunoglobulin domain and mucin domain-3
TLS
Tumor lysis syndrome
TSH
Thyroid-Stimulating Hormone
ULN
upper limit of normal
ULQ
upper limit of quantification
USPI
United States Prescribing Information
WBC
white blood cell(s)
WHO
World Health Organization 
WoC
Withdrawal of study Consent
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Glossary of terms
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 
Cohort
A specific group of participants fulfilling certain criteria and generally treated at 
the same 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 paper source forms used at the point of care
Enrollment
Point/time of participant entry into the study at which informed consent must 
be obtained 
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)
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
An individual who has consented to participate in this study. The term 
participant may be used to describe either 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
Screen Failure
A participant who did not meet one or more criteria that were required for 
participation in the study
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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
Stage
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
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 completion
Point/time at which the subject came in for a final evaluation visit or when 
study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal.
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 number
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm
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.
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)
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data 
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Amendment 2 (06-Oct-2021)
Amendment rationale 
As of the release of this amendment, 9 sites have been initiated, 9 participants have been 
screened and 5 participants have received study treatment in this trial.
The purpose of the amendment is to clarify DLT criteria (Table 6-4) to specify that prolonged 
cytopenias beyond Day 42 from the start of a study treatment cycle should be considered DLTs
and to clarify language around intercurrent events in the estimand section as well as analysis of 
duration of response.
Additionally, language around COVID-19 vaccines and time frame for SAE follow-up 
reporting was added.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using the strike through red font for deletions and red underline for insertions.
!
Section 6.2.2: wording around COVID-19 vaccination added
!
Section 6.5.1.3 and section 12.1: Number of venetoclax doses for a participant to be 
evaluable for DLT updated to match the venetoclax regimen
!
Section 6.5.2: Update definition of hematological toxicity DLT criteria to clarify 
persistent grade 4 cytopenias beyond Day 42 from the start of a study treatment cycle
should be considered DLTs
!
Section 6.5.2: Update to DLT criteria with respect to blood bilirubin increased
!
Section 6.5.2: Adding a formal DLT criteria for grade 4 non-hematologic toxicity
!
Section 6.5.2: Clarify that Grade 3 nausea, vomiting or diarrhea not requiring tube 
feeding, total parenteral nutrition, or prolonged hospitalization are exceptions to DLT 
criteria
!
Section 9.1.1.2: remove start of a new antineoplastic treatment (including HSCT) as a 
reason for discontinuing post-treatment follow-up
!
Section 10.1.3: Clarify that 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 immediately, without undue delay, and under no 
circumstances later than within 24 hours of the investigator receiving the follow-up 
information
!
Section 12.4.1.2: Clarify that CR achieved after initiation of a new antineoplastic
therapy will not be considered for the primary endpoint
!
Section 12.5.1.1: Clarify that Transfusion dependence is defined as a minimum 3 units 
of transfusion received within the 8 consecutive weeks prior to start of treatment
!
Section 12.5.1.2: Clarify that duration of CR, duration of CR/mCR, duration of response
will be derived regardless of HSCT and to perform two supplementary analyses
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!
Section 12.5.1.2: Clarify that PFS, EFS, LFS events will be counted regardless of HSCT 
but censored in case of events after initiation of a new antineoplastic therapy
!
Section 2 (Table 2-1); Section 4.4.1; Section 8.3.1 (Table 8-2) Definition of CR/mCR 
was updated to match the definition of CR in table 8-2
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. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
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Amendment 1 (17-May-2021)
Amendment rationale 
As of the release of this amendment, no site has been initiated, no participant has been screened 
and no participant has received study treatment in this trial.
The purpose of the amendment is to address Health Authorities’ requests (from Belgium and 
France) to specify that women of childbearing potential using a hormonal contraception should 
add a barrier method, as stated in the venetoclax SmPC, and to add a cross-reference to 
venetoclax local label in the prohibited medication section (Section 6.2.2).
Additionally, preliminary results of the first cohort of the safety run-in of CMBG453C12201 
study are included. The pharmaceutical dose form and route of administration terms for 
azacitidine have been updated to be in alignment with other sabatolimab protocols. Lastly, one 
clarification to the analysis of primary endpoints is added.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using the strike through red font for deletions and red underline for insertions.
!
Section 4.2: Update the clinical safety data with the preliminary results from the first 
five patients treated with the triplet sabatolimab-venetoclax-azacitidine combination on 
the CMBG453C12201 study.
!
Section 5.2: Amend exclusion criterion 17 to specify that women of childbearing 
potential using a hormonal contraception should add a barrier method as stated in the 
venetoclax SmPC.
!
Section 6.1.1: Update the dosage form and route of administration of azacitidine to align 
with other sabatolimab study protocols.
!
Section 6.2.2: Clarify that prohibited medication related to both azacitidine and 
venetoclax will apply according to local label.
!
Section 12.4.1: Clarify further the efficacy analysis: to count CR after progression and 
to censor time to event endpoints in case of a new antineoplastic therapy.
In addition, format and grammatical updates are made throughout the protocol to improve flow 
and consistency.
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. 
The changes herein affect the Informed Consent Form. Sites are required to update and submit 
for approval a revised Informed Consent Form taking into account the changes described in this 
protocol amendment.
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Protocol summary
Protocol number
CMBG453B12203
Full Title
A single-arm, open-label, phase II study of sabatolimab in 
combination with azacitidine and venetoclax in adult participants 
with high or very high risk myelodysplastic syndromes (MDS) as per 
IPSS-R criteria
Brief title
A study of sabatolimab in combination with azacitidine and 
venetoclax in high or very high risk MDS participants
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Biological
Study type
Interventional
Purpose and 
rationale
Sabatolimab, a novel monoclonal antibody inhibitor of TIM-3, has 
shown preliminary evidence of clinical activity as a single-agent in 
participants with MDS. The study will be conducted in two parts. The 
primary purpose of Part 1 (Safety run-in) is to rule out excessive 
toxicity of sabatolimab, when administered in combination with 
azacitidine and venetoclax. The primary purpose of the combined 
cohort 2 of the Safety run-in (Part 1) and Expansion (Part 2) is to 
evaluate efficacy of sabatolimab, when administered in combination 
with azacitidine and venetoclax in adult participants with high or 
very high risk MDS.
The current trial will seek to extend the preliminary findings of 
efficacy of sabatolimab in combination with hypomethylating agents 
(HMA) by evaluating sabatolimab in combination with the HMA 
azacitidine and the Bcl-2 inhibitor venetoclax in adult participants with 
higher-risk MDS (per IPSS-R). The doublet of venetoclax and 
azacitidine has demonstrated improved efficacy relative to azacitidine 
alone in early phase Ib trials (DiNardo et al 2019), and recently has 
received regular approval by the FDA (on 16-Oct-2020) for treatment 
of newly diagnosed AML, or who have comorbidities precluding 
intensive induction chemotherapy. More recently, a Phase Ib trial 
conducted in higher-risk MDS participants indicated that the 
combination of venetoclax and azacitidine is feasible and reported also 
promising preliminary results in this patient population. The 
recommended schedule for further development of venetoclax in 
combination with azacitidine in MDS will be used in this trial 
(Wei et al 2019).
Primary 
Objective(s) 
Safety run-in (Part 1):
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To determine whether sabatolimab is safe when added to azacitidine + 
venetoclax in participants with high or very high risk MDS as per 
IPSS-R criteria
Cohort 2 of the Safety run-in (Part 1) and Expansion (Part 2):
To determine the complete remission (CR) rate of sabatolimab (800 
mg Q4W) in combination with azacitidine and venetoclax.
Secondary 
Objectives
Safety run-in (Part 1) and Expansion (Part 2): 
!
To assess Complete Remission (CR) + marrow complete 
remission (mCR) rate
!
To assess Overall Response Rate (ORR) defined as [CR + mCR + 
partial remission (PR) + HI]
!
To assess the improvement of RBC/platelets transfusion 
independence
!
To assess the safety and tolerability of sabatolimab in 
combination with azacitidine and venetoclax
!
To further characterize the pharmacokinetics of sabatolimab
!
To characterize the immunogenicity of sabatolimab in 
combination with azacitidine and venetoclax
Cohort 2 of the Safety run-in (Part 1) and Expansion (Part 2):
!
To assess Duration of CR
!
To assess Duration of CR/mCR
!
To assess Duration of response
!
To assess Time to CR/mCR
!
To assess Progression Free Survival (PFS)
!
To assess Leukemia-Free survival (LFS)
!
To assess Event-Free Survival (EFS)
!
To assess Overall Survival
Expansion (Part 2):
!
To evaluate changes from baseline in fatigue
Study design
This phase II, open-label, single-arm, multi-center study of 
sabatolimab in combination with azacitidine and venetoclax in adult 
participants with high or very high risk MDS as per IPSS-R criteria 
will be conducted in two parts.
Part 1 is a Safety run-in part of approximately 18 participants, to assess 
whether sabatolimab at the two dose levels tested consecutively (400 
mg Q4W: cohort 1 of Safety run-in and then 800 mg Q4W: cohort 2 
of Safety run-in) is safe when given in combination with fixed dose of 
azacitidine 
and 
venetoclax 
in 
MDS patients. Following 
the 
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observation period, a Safety Review Meeting will be conducted for 
each dose level. If no safety concerns are identified with the 
tested combination of sabatolimab at 400 mg Q4W, azacitidine and 
venetoclax, then the second dose level (800 mg Q4W) will open to 
enrollment. Thereafter, if no safety concerns are identified with the 
tested combination of sabatolimab at 800 mg Q4W, azacitidine and 
venetoclax, Novartis will provide notification to the investigational 
sites that Part 2 of study testing this dose level in a larger group of 
participants (Expansion) is open to enrollment. Otherwise the study 
will be stopped.
Part 2 is an Expansion part to further assess efficacy and safety of 
sabatolimab at 800 mg Q4W in combination with venetoclax and 
azacitidine. Enrollment to Expansion (Part 2) will continue until 
enrollment of approximately 58 additional participants has been 
achieved.
The total sample size (Part 1 and Part 2) of the study is approximately 
76 participants i.e. approximately 6 participants in cohort 1 of Part 1 
testing sabatolimab at 400 mg Q4W, 12 participants in cohort 2 of Part 
1 testing sabatolimab at 800 mg Q4W and 58 participants in Expansion 
(Part 2) further testing sabatolimab at 800 mg Q4W.
Study population
The study population will include approximately 76 adult participants 
with high or very high risk MDS, as per the revised International 
Prognostic Scoring System (IPSS-R).
Key Inclusion 
criteria
1. Signed informed consent must be obtained prior to participation in 
the study
2. Age ≥ 18 years at the date of signing the informed consent form 
(ICF)
3. Morphologically confirmed diagnosis of myelodysplastic syndrome 
(MDS) based on 2016 WHO classification (Arber et al, 2016) by local 
investigator assessment with one of the following Prognostic Risk 
Categories, based on the revised International Prognostic Scoring 
System (IPSS-R) (Greenberg et al 2012):
!
Very high (> 6 points)
!
High (> 4.5-6 points)
4. 
Not immediately eligible 
for 
hematopoietic 
stem-cell 
transplantation (HSCT) or intensive chemotherapy at the time of 
screening due to individual clinical factors such as age, comorbidities 
and performance status, donor availability (de Witte et al 2017)
5. Eastern Cooperative Oncology Group (ECOG) performance status 
of 0, 1 or 2
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Key Exclusion 
criteria
1. Prior exposure to TIM-3 directed therapy or any BCL-2 inhibitor 
(including venetoclax) at any time
2. Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, 
anti-PD-1, anti-PD-L1, or anti-PD-L2) or cancer vaccines is not 
allowed if the last dose of the drug was administered within 4 months 
prior to start of treatment
3. Previous first-line treatment for very high risk or high 
risk myelodysplastic syndromes 
(based 
on IPSS-R,
Greenberg et al 2012 and Arber et al, 2016) with any antineoplastic 
agents, 
approved 
or 
investigational, including for 
example chemotherapy, lenalidomide and hypomethylating agents 
(HMAs) such as decitabine or azacitidine
However, a one single cycle of HMAs treatment only started prior to 
enrollment is allowed.
4. Live vaccine administered within 30 days prior to start of treatment
5. Current use or use within 14 days prior to start of treatment of 
systemic steroid therapy (> 10 mg/day prednisone or equivalent) or 
any immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic 
steroids are allowed. Replacement therapy, steroids given in the 
context of a transfusion, are allowed and not considered a form of 
systemic treatment
6. History of severe hypersensitivity reactions to any ingredient of 
study drug(s) (azacitidine, venetoclax or sabatolimab) or monoclonal 
antibodies (mAbs) and/or their excipients
7. Participants with Myelodysplastic syndrome (MDS) based on 2016 
WHO classification (Arber et al, 2016) with revised International 
Prognostic Scoring System (IPSS-R) ≤ 4.5
Study treatment
Sabatolimab + azacitidine + venetoclax
Efficacy 
assessments
Disease response will be assessed locally by the investigator in all 
participants (MDS) according to modified IWG criteria for MDS and 
WHO criteria (Cheson et al 2000, Cheson et al 2006, 
Arber et al, 2016, Platzbecker 2019). Bone marrow aspirate 
(BMA)/biopsy and peripheral blood will be collected at screening 
and at regular intervals during treatment and efficacy follow-up phase 
for assessment of disease.
Participants can be assessed for disease response at any time if 
clinically indicated, for example in case of suspicion of 
progression/relapse.
Pharmacokinetic 
assessments
Pharmacokinetic (PK) samples will be obtained and evaluated in all 
participants.
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Key safety 
assessments
· Adverse event monitoring,
· Physical examination,
· Vital signs,
· ECOG PS,
· Monitoring of laboratory evaluations in blood and urine,
· 12-lead electrocardiograms (ECGs).
Other 
assessments
Clinical Outcomes Assessment:
 
 
 
 
 
 
In addition, 
, 
the Functional Assessment of Chronic Illness Therapy Fatigue scale 
(FACIT-Fatigue) 
 
 
 
Immunogenicity:
Immunogenicity samples will be obtained and evaluated in all 
participants.
Data analysis
For participants included in the Safety run-in (Part 1), the tolerability 
of the two tested dose levels of sabatolimab (two consecutive cohorts 
at 400 mg Q4W (with approximately 6 participants) and then 800 mg 
Q4W (with approximately 12 participants) administered in 
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combination with venetoclax and azacitidine will be guided by a 
Bayesian analysis based on the DLT incidence reported during the two 
first cycles as well as an overall safety overview. The probability that 
the true DLT rate is ≥ 33% (i.e. overdose criteria) will be modeled 
using a Bayesian Model. If the dose of 400 mg Q4W (cohort 1) meets 
overdose criteria with at least 3 evaluable participants, the study will 
be stopped. If the dose of 400 mg Q4W does not meet overdose 
criteria, cohort 2 with sabatolimab 800 mg Q4W will be opened with 
approximately 12 participants. If the dose of 800 mg Q4W meets 
overdose criteria with at least 9 evaluable participants, Part 2 
(Expansion) will not be opened and the study will be 
stopped. Otherwise, Part 2 (Expansion) will be opened at 800 mg Q4W 
of sabatolimab (see Figure 3-1).
For all participants treated with sabatolimab at 800 mg Q4W, the 
efficacy of sabatolimab in combination with venetoclax and 
azacitidine will be based on the proportion of participants achieving a 
complete remission (CR) as per investigator assessment. Trial success 
will be assessed based on dual decision criterion with a null value (no 
effect) of 39% (statistical criteria) and a minimum estimated effect size 
(clinical relevance) of 50% (clinical criteria) for the CR rate. If the 
statistical and clinical criteria are both met, the trial will be declared 
successful.
With two criteria stated above, approximately 70 participants 
(including participants from cohort 2 of the Safety run-in (Part 1) and 
Expansion part) are required. Therefore, the total sample size is 76 
participants (including the 6 participants treated at 400 mg Q4W in the 
Cohort 1 of the Safety run-in (Part 1)).
AL least thirty six participants with CR out of 70 are needed to declare 
the trial successful.
For a true CR rate of 55.7% (i.e. 39 participants with CR), 
the probability for the trial success is 80% (power).
Key words
Phase 
II, 
sabatolimab, 
TIM-3, 
venetoclax, 
azacitidine, 
Myelodysplastic syndromes (MDS).
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1
Introduction
1.1
Background
It is estimated that 15,000 to 20,000 new cases of Myelodysplastic Syndromes (MDS) are 
diagnosed annually in the USA (Klepin 2016). In Europe, the incidence rate of MDS is about 2 
new cases per 100,000 each year (Visser et al 2012). The incidence of MDS is more frequent 
in male patients and increases with age, with a median age at diagnosis of about 70 years.
MDS correspond to a heterogeneous group of hematological malignancies that are associated 
with impaired bone marrow function, ineffective hematopoiesis, elevated bone marrow blasts 
and persistent peripheral blood cytopenias. Cytogenetics abnormalities are frequently present 
at time of diagnosis. Patients with MDS have a predisposition to developing acute myeloid 
leukemia (AML) (Heaney and Golde 1999). Although progression to AML can frequently lead 
to death in patients with MDS, many deaths are consequences of cytopenias and marrow failure 
in the absence of leukemic transformation. To account for disease heterogeneity, assess the risk 
of progression to AML and estimate survival, MDS prognostication systems have been 
proposed. In the context of a clinical trial, prognosis is usually determined using the revised 
International Prognostic Scoring System (IPSS-R), which considers the percentage of bone 
marrow blasts, the number of cytopenias, and bone marrow cytogenetics. Patients with 
untreated MDS are stratified into five IPSS-R prognostic risk categories: very low, low, 
intermediate, high and very high. In a large database of MDS patients (n = 7,012), distribution 
of patients across the 5 IPSS-R risk categories were as follows: very low (19%), low (38%), 
intermediate (20%), high (13%) and very high (10%) (Greenberg et al 2012). For high and very 
high risk MDS patients, the prognosis is dismal: median survival times are limited (1.6 years 
and 0.8 years, respectively) and risk of leukemic transformation is high (time to observe 25% 
AML transformation rate in this group of patients is 1.4 and 0.73 years, respectively). Current 
treatment guidelines for patients with high and very high risk MDS recommend hematopoietic 
stem cell transplantation (HSCT) in rare patients who are eligible for this procedure , intensive 
chemotherapy 
or 
hypomethylating 
agents 
(HMAs; 
azacitidine 
and 
decitabine) 
(Fenaux et al 2014; Platzbecker 2019). Choice of therapy is mainly driven by the IPSS-R score, 
the overall general health status and clinical assessment of comorbidities, and donor availability 
for a transplant. For patients eligible for HSCT or for whom the marrow blast count requires 
reduction, intensive chemotherapy may be considered and may precede HSCT (Steensma 2018). 
HSCT remains the only curative option for MDS patients; however, many MDS patients are 
not candidates for HSCT (Passweg et al 2011; de Witte et al 2017). In MDS patients who are 
classified as high, very high risk by IPSS-R, and who do not qualify for HSCT or intensive 
chemotherapy, HMAs are the first-line reference treatment. Azacitidine is the sole HMA which 
demonstrated a prolongation of overall survival (OS) compared to conventional care regimens 
among patients with higher-risk MDS [median OS, 24.5 versus 15 months, respectively, hazard 
ratio (HR) = 0.58; P < 0.0001] in the pivotal AZA-001 randomized phase III trial 
(Fenaux et al 2009). Other controlled clinical trials reported lower median OS between 19 to 20 
months in patients receiving azacitidine (Silverman et al 2002). Azacitidine is generally 
administered for a minimum of 6 cycles (repeat cycle after 4 weeks), and continued for as long 
as the patient benefits.
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In clinical practice, azacitidine safety profile is mainly characterized by bone marrow 
suppression leading to dose-reduction or temporary or permanent discontinuations of 
azacitidine. Supportive care, including blood transfusions, is frequently required during the 
course of the disease. HMAs have improved outcomes for patients with high risk/very high risk 
MDS; especially for patients who are not candidates for intensive chemotherapy regiments or 
HSCT. However, despite these improvements, prognosis for patients treated with HMAs 
remains poor. Median survival in high and very high MDS patients are only 1.6 years and < 1 
year respectively (Greenberg et al 2012). Treatment failure, relapse and transformation to acute 
myeloid leukemia (AML) are frequent events. Once a patient with higher risk MDS has failed 
treatment with HMAs or transformation to AML has occurred, survival generally will not 
exceed 6 months. Thus, improved treatments in addition to HMAs and/or as an alternative to 
HMAs are urgently warranted in this MDS patient population.
Novel targeted therapies and immune checkpoint inhibitors are being clinically studied in MDS 
such as venetoclax and immunotherapeutic agents.
In 2018, venetoclax, a small molecule inhibitor of BCL-2, the over-expression of which has 
been implicated in the maintenance and survival of AML cells and has been associated with 
resistance to chemotherapeutics (Kojima et al 2006), has received full approval by the FDA (on 
16-Oct-2020) in combination with azacitidine or decitabine or low-dose cytarabine for the 
treatment of newly-diagnosed AML in adults who are age 75 years or older, or who are unfit 
for intensive induction chemotherapy. Approval was based on two open-label, non-randomized 
trials, and efficacy was established based on the rate of complete remission (CR) and CR 
duration. In a most recent data update (DiNardo et al 2019), it is reported that the CR and CRi 
rates were 37% and 30% respectively, for patients treated with venetoclax in combination with 
azacitidine or decitabine, with a median observed time in remission (CR or CRi) of 11.3 months 
(95% CI, 8.9 months-not reached). Furthermore, only 29% of patients in remission achieved 
levels of MRD below 0.1%, suggesting that deep leukemic clearance (< 0.1%) remains a 
challenge for a majority of the patients. Thus, although these results represent an advance in 
treatment of the unfit AML population, remission duration and leukemic clearance to MRD 
levels below 0.1% is still modest, and an unmet need remains for new therapy options for this 
patient population.
More recently, a Phase Ib trial conducted in higher-risk MDS participants indicated that the 
combination of venetoclax and azacitidine is feasible and reported promising preliminary 
results (Wei et al 2019). In this trial, the Complete Remission (CR) rate per IWG - MDS criteria 
was approximately 38%, median time to CR about 2 months and the 12-month estimate duration 
of CR was about 83%.
The safety profile of the combination is reported to be manageable and mainly consists of 
myelosuppression including neutropenia, febrile neutropenia, thrombopenia and anemia. The 
recommended dose for Phase II trial of venetoclax is 400 mg for days 1-14 of a 28-day cycle 
when combined with azacitidine (75mg/m2, days 1-7). Recent retrospective studies of real 
world experience (Ball et al 2020, Azizi et al 2020) evaluating venetoclax in association with 
HMA to treat higher-risk MDS participants confirmed the feasibility of this regimen, overall 
good tolerability and reported promising signs of efficacy with overall hematological response 
rates reaching approximately 75% in HMA-naive participants. Consistent with the findings of 
aforementioned Phase Ib trial (Wei et al 2019), these studies recommended the use of an 
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abbreviated dosing schedule for venetoclax (i.e. 400 mg for days 1 to 14 of a 28-day cycle) in 
order to manage optimally the myelosuppression.
Blocking Programmed cell death protein 1/ligand (PD-1/PD-L1) or Cytotoxic T Lymphocyte 
Associated Protein 4 (CTLA4) pathways enhances anti-leukemia responses by unleashing T-
cells in murine models of AML/MDS. In addition, there is evidence of pharmacodynamic 
activity and promise for checkpoint inhibition in MDS (Chen et al 2008, Zhang et al 2009, 
Yang et al 2014, Kong et al 2015, Ørskov et al 2015); however, it will be important to 
determine the ideal checkpoint inhibitor strategy and to consider combination therapies in order 
to optimize anti-tumor immunity. A few clinical trials have investigated immune checkpoint 
inhibitors in MDS and AML participants. An ongoing Phase II study investigates the clinical 
effects of the checkpoint inhibitors nivolumab (PD1) and ipilimumab (CTLA4) with or without 
the hypomethylating agent azacitidine in front-line and relapsed MDS participants. Front-line
MDS participants were treated with the combination azacitidine+nivolumab or ipilimumab, 
whereas relapsed MDS participants received single-agent nivolumab or ipilimumab. Twenty 
participants were treated with azacitidine+nivolumab, 21 with azacitidine+ipilimumab, 15 with 
nivolumab, and 20 with ipilimumab. The observed overall response rate was 75%(15/20), 71% 
(15/21), 13% (2/15), and 35% (7/20) of participants treated with azacitidine combined with 
nivolumab, 
azacitidine 
combined 
with 
ipilimumab, 
nivolumab, 
and 
ipilimumab, 
respectively; Complete 
Remission 
or 
Complete 
Remission 
with 
residual 
thrombocytopenia was observed in 10/20 (50%), 8/21 (38%), 0 (0%), and 3 (15%) in 
participants treated with azacitidine combined with nivolumab, azacitidine combined with 
ipilimumab, nivolumab, and ipilimumab, respectively. Main toxicities reported were as follows: 
skin rash (11%); fatigue (9%); pain (7%); infection (6%); febrile neutropenia (5%); pruritus 
(6%); diarrhea (5%); constipation, nausea (4% each), alanine aminotransferase (ALT) 
elevations, anorexia, cough (3% each). This provides preliminary evidence that checkpoint 
inhibition combined with hypomethylating agents is feasible in front-line MDS and may have 
clinical activity (Daver et al 2019). A Phase Ib/II study involving azacitidine and nivolumab 
has been conducted in 70 relapsed/refractory AML participants. The overall response rate 
(ORR) in this study was 33%: 23 clinical responses were reported including 4 complete 
remission, 11 complete remission with insufficient recovery of counts (CRi), 1 partial remission 
(PR), and 7 participants with hematologic improvement (HI) maintained > 6 months. The ORR 
was 58% and 22% in HMA-naive (n = 25) and HMA pre-treated (n = 45) participants, 
respectively. Duration of response among responders was 5.2 months. Three participants in 
CR/CRi underwent HSCT. Additionally, 6 participants had stable disease lasting for more than 
6 months.
Overall the combination azacitidine plus nivolumab was well tolerated. Grade 3 or 4 immune 
related adverse events (irAE) occurred in 8 (11%) participants (Daver et al 2019). A Phase Ib 
study reported that ipilimumab in participants with MDS after HMA failure is safe but has 
limited efficacy as monotherapy. However, prolonged stable disease was reported and some 
participants received allo HSCT. Prolonged stable disease for ≥ 46 weeks occurred in 7 
participants (24% of the participants), including 3 participants with more than a year of stable 
disease. 5 participants underwent allografting without excessive toxicity (Zeidan et al 2018).
T-cell immunoglobulin domain and mucin domain- 3 (TIM-3; also known as hepatitis A virus 
cellular receptor 2) is a negative regulator of T-cells (immune checkpoint). TIM-3+ 
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hematopoietic stem cells from participants with MDS display aberrant differentiation, increased 
proliferation and decreased apoptosis (Sakuishi et al 2011). TIM-3 is overexpressed in bone 
marrow mononuclear cells and detection on blasts increases as MDS progresses. Therefore the 
blockade of this immune checkpoint constitutes a potential target for novel therapies in MDS, 
and 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 (MBG453) is a high-affinity, ligand-
blocking, humanized anti TIM-3 IgG4 antibody which blocks the binding of TIM-3 to 
phosphatidylserine (PtdSer). First in human trials have shown that sabatolimab can be safely 
administered including with decitabine or azacitidine in MDS/AML participants. Preliminary 
clinical activity has been observed particularly in high and very high risk MDS participants (see 
clinical responses in Section 4.3). 
There are ongoing Phase II trial [CMBG453B12201] and Phase III trial [CMBG453B12301]
which are investigating sabatolimab in higher risk MDS participants. These trials are double-
blind placebo-controlled studies comparing sabatolimab plus HMA versus placebo plus HMA. 
Another ongoing single-arm, open label, Phase II trial [CMBG453C12201] is investigating 
sabatolimab in combination with venetoclax and azacitidine in AML participants. 
For further details about sabatolimab, refer to the IB [MBG453 Investigator's Brochure].
1.2
Purpose
The current study will enroll untreated adult participants with high or very-high risk MDS (per 
IPSS-R criteria) and it will be conducted in two sequential parts (see Figure 3-1).
The primary purpose of the Safety run-in (Part 1) is to rule out excessive toxicity and investigate 
safety of 400 mg (Cohort 1 of Part 1) first and then 800 mg (Cohort 2 of Part 1) sabatolimab 
when administered every 4 weeks in combination with azacitidine and venetoclax. Cohort 2 
will be opened only if data from Cohort 1 does not indicate excessive toxicity of the sabatolimab 
400 mg Q4W dose level. Thereafter, Expansion (Part 2) will be opened only if data from Cohort 
2 does not indicate excessive toxicity of the sabatolimab 800 mg Q4W dose level. If overdose 
criteria are met in Cohort 2, then the study will be stopped (See Figure 3-1).
The primary purpose of the Expansion (Part 2) is to enroll additional participants in order to 
evaluate further efficacy, safety, tolerability and characterize the pharmacokinetics of 
sabatolimab at 800 mg Q4W when administered in combination with azacitidine and venetoclax. 
The complete remission rate will be determined in all participants (i.e. enrolled in Cohort 2 of 
Part 1 and Expansion) treated with sabatolimab at 800 mg Q4W with azacitidine and venetoclax.
Sabatolimab 
is 
a 
novel 
monoclonal 
antibody 
inhibitor 
of 
TIM-3. 
In 
study 
[CPDR001X2105], sabatolimab was safe and well tolerated and has shown promising evidence 
of efficacy, including durable CRs, when administered in combination with HMA (decitabine 
or azacitidine) in newly diagnosed higher-risk MDS participants. The current trial will seek to 
extend these preliminary findings of efficacy by evaluating sabatolimab in combination with 
azacitidine and venetoclax. The doublet of venetoclax and azacitidine has demonstrated 
improved efficacy relative to azacitidine alone in AML patients (DiNardo et al 2019). Recently, 
venetoclax has received approval by FDA for treatment of unfit AML patients on 16-Oct-2020. 
Several prospective and retrospective trials (Ball et al 2020, Wei et al 2019, Azizi et al 2020, 
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reported also promising efficacy and acceptable safety profile of the doublet of venetoclax and 
azacitidine in participants with higher-risk MDS. Despite the improved efficacy suggested by 
the addition of venetoclax to azacitidine in higher-risk MDS, a significant unmet medical need 
remains as a substantial number of participants still do not achieve durable CR (complete 
response).
2
Objectives and endpoints
The objectives and associated endpoints are presented in Table 2-1 below:
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
!
Safety run-in (Cohort 1 and 
Cohort 2 of Part 1) 
To determine whether sabatolimab 
is safe when added to azacitidine + 
venetoclax in participants with high
or very high risk MDS per IPSS-R 
criteria
!
Incidence of DLTs between Cycle 1 Day 8 and end of 
Cycle 2
!
Cohort 2 of Safety run-in (Part 1) 
and Expansion (Part 2)
To 
determine 
the 
complete 
remission (CR) rate of sabatolimab 
in combination with azacitidine and 
venetoclax in participants with high 
or very high risk MDS as per IPSS-
R criteria treated with sabatolimab at 
800 mg Q4W.
!
Proportion of participants from cohort 2 of Part 1 and 
Part 2 achieving CR according to investigator 
assessment (per modified IWG-MDS - Cheson 2006 
criteria). CR is defined as follow: bone marrow blasts 
<=5%, hemoglobin level ≥ 10 g/dL, platelets count ≥ 
100*10^9/L, neutrophils count ≥ 1.0*10^9/L, absence 
of blasts in peripheral blood (Please see Section 12.4
for estimand definition).
Secondary objective(s)
Endpoint(s) for secondary objective(s)
!
Safety run-in (Part 1) and 
Expansion (Part 2) 
!
To assess the [CR + marrow 
complete remission (mCR)] rate
!
Proportion of participants with [CR + marrow complete 
remission 
(mCR)] 
according 
to 
investigator 
assessment by dose level for the safety run-in part 
(cohort 1 (400 mg Q4W) and cohort 2 (800 mg Q4W)) 
and for participants treated with sabatolimab 800 mg 
(Q4W) (cohort 2 of safety run-in and expansion parts).
!
To assess Overall Response Rate 
(ORR), per modified IWG-MDS 
Cheson 2006 criteria, defined as the 
proportion of participants achieving 
[CR + mCR + partial remission (PR) 
+ hematologic improvement (HI)]
!
Overall Response Rate (ORR) is the proportion of
participants who achieved HI or better as best 
response as per investigator assessment (per 
modified IWG-MDS Cheson 2006 criteria). ORR will 
be summarized by dose level for the safety run-in part 
(cohort 1 (400 mg Q4W) and cohort 2 (800 mg Q4W)) 
and for participants treated with sabatolimab 800 mg 
(Q4W) (cohort 2 of safety run-in and expansion parts).
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Objective(s)
Endpoint(s)
!
To assess the improvement in 
RBC/platelets 
transfusion 
independence
!
Proportion of participants who are RBC/platelets 
transfusion independent and duration of transfusion 
independence (Section 8.3) as per IWG-MDS by dose 
level for the safety run-in part (cohort 1 (400 mg Q4W) 
and cohort 2 (800 mg Q4W)) and for participants 
treated with sabatolimab 800 mg (Q4W) (cohort 2 of 
safety run-in and expansion parts).
!
To characterize the safety profile of 
sabatolimab when administered in 
combination with azacitidine and 
venetoclax
!
Incidence and severity of AEs and SAEs, changes in 
laboratory values and vital signs, and incidence of 
notable ECG abnormalities by dose level for the safety 
run-in part (cohort 1 (400 mg Q4W) and cohort 2 (800 
mg 
Q4W)) 
and 
for 
participants 
treated 
with 
sabatolimab 800 mg (Q4W) (cohort 2 of safety run-in 
and expansion parts).
!
To 
further 
characterize 
the 
pharmacokinetics of sabatolimab 
when administered in combination 
with azacitidine and venetoclax
!
Serum 
concentrations 
and 
pharmacokinetic 
parameters (see Section 8.5.2) for sabatolimab by 
dose level for the safety run-in part (cohort 1 (400 mg 
Q4W) and cohort 2 (800 mg Q4W)) and for participants 
treated with sabatolimab 800 mg (Q4W) (cohort 2 of 
safety run-in and expansion parts).
!
To characterize the immunogenicity 
of sabatolimab when given in 
combination with venetoclax and 
azacitidine
!
Anti-drug Antibody (ADA) prevalence at baseline and 
ADA incidence on-treatment by dose level for the 
safety run-in part (cohort 1 (400 mg Q4W) and cohort 
2 (800 mg Q4W)) and for participants treated with 
sabatolimab 800 mg (Q4W) (cohort 2 of safety run-in 
and expansion parts).
!
Cohort 2 of Safety run-in (Part 1) 
and Expansion (Part 2) 
!
To assess duration of CR
!
Duration of CR is defined as time from first 
occurrence of CR to relapse from CR, progression or 
death due to any cause whichever occurs first for 
participants treated with sabatolimab at 800 mg 
Q4W.
!
To assess time to CR/mCR
!
Time to CR/mCR is defined as time from start of 
treatment to first occurrence of CR or mCR as per 
investigator assessment for participants treated with 
sabatolimab at 800 mg Q4W.
!
To assess duration of CR/mCR
!
Duration of CR/mCR is defined as time from first 
occurrence
of CR/mCR to relapse from CR, 
progression or death due to any cause whichever 
occurs first for participants treated with sabatolimab at 
800 mg Q4W.
!
To assess duration of response 
(responding participants defined as 
hematological improvement (HI) or 
better, per modified IWG-MDS 
!
Duration of response for participants who achieved 
HI or better per modified IWG-MDS Cheson 2006 
criteria) as per investigator assessment until relapse 
or death. Participants who did not relapse or die are 
censored to last adequate response assessment 
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Objective(s)
Endpoint(s)
Cheson 2006 criteria) as per 
investigator assessment.
for participants treated with sabatolimab at 800 mg 
Q4W.
!
To assess Progression-Free 
Survival (PFS)
!
Time from start of treatment to disease progression 
(including transformation to acute leukemia per WHO 
2016 classification), relapse from CR or death due to 
any cause, whichever occurs first for participants 
treated with sabatolimab at 800 mg Q4W.
!
To assess Leukemia-Free Survival 
(LFS)
!
Time from start of treatment to transformation to acute 
leukemia [as defined as ≥ 20% blasts in bone marrow/ 
peripheral blood (per WHO 2016 classification) or 
diagnosis of extramedullary acute leukemia or death 
due 
to 
any 
cause, 
whichever 
occurs 
first] 
for participants treated with sabatolimab at 800 mg 
Q4W.
!
To assess Event-free Survival 
(EFS)
!
Time from start of treatment to lack of reaching CR 
within the first 6 cycles, relapse from CR or death due 
to any cause, whichever occurs first for participants 
treated with sabatolimab at 800 mg Q4W.
!
To assess Overall Survival (OS)
!
Time from start of treatment to death due to any cause 
for participants treated with sabatolimab at 800 mg 
Q4W.
!
Expansion (Part 2)
!
To evaluate the changes from 
baseline in fatigue
!
Changes in fatigue as measured by the FACIT-Fatigue 
for participants treated with sabatolimab at 800 mg 
Q4W of the expansion part only.
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Objective(s)
Endpoint(s)
3
Study design
This Phase II, open-label, single-arm, multi-center study of sabatolimab in combination with 
azacitidine and venetoclax in adult participants with high or very high risk MDS as per IPSS-R 
criteria is described in Figure 3-1 below. The study will enroll a total of approximately 76 
participants and will be conducted in two sequential parts:
!
Part 1: Safety run-in consists of 2 subsequent cohorts of 400 mg Q4W (cohort 1) and 800 
mg Q4W (cohort 2) of sabatolimab in combination with fixed dose of venetoclax and 
azacitidine. Cohort 2 will be open only after the review of safety data from cohort 1 indicates 
the regimen is safe. If the regimen using sabatolimab at 400 mg Q4W is not safe, the study 
will be stopped. Subsequently, if the review of safety data from participants enrolled in 
cohort 2 indicates that the regimen is safe, then Part 2 will be opened. Otherwise, if the 
regimen at 800 mg Q4W is not safe, the study will be also stopped.
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!
Part 2: Expansion will enroll additional participants to further investigate the regimen 
including sabatolimab at 800 mg Q4W, azacitidine and venetoclax. Participants data from 
Part 1 and Part 2 treated with 800 mg Q4W will be combined to determine the complete 
remission rate.
Part 1 is a Safety run-in to assess whether sabatolimab (400 mg Q4W and subsequently 800 mg 
Q4W) is safe when given in combination with fixed dose of azacitidine and venetoclax. A total 
of approximately 18 participants will be enrolled to Part 1 across the two dose levels. 
Approximately 6 participants will be initially enrolled at the starting dose level, 400 mg Q4W 
(cohort 1), in order to obtain at least 3 evaluable participants (see Section 6.5.1.3 for evaluability 
criteria). If the dose level of sabatolimab 400 mg Q4W in combination with azacitidine and 
venetoclax is assessed to be safe, then a second cohort of participants investigating sabatolimab 
at 800 mg Q4W combined to azacitidine and venetoclax (cohort 2) will be opened. Otherwise, 
the study will be stopped. Approximately 12 participants will be enrolled in cohort 2, in order 
to obtain at least 9 evaluable participants (see Section 6.5 for evaluability criteria). If the 
combination regimen used in cohort 2 is safe then the Expansion part will be opened (Part 2). 
Otherwise the study will be stopped. 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 (see Section 6.5), and a Safety Review Meeting has been conducted 
(see Section 6.5.1). If no safety concerns are identified at either dose level (see Section 12.4.2
for statistical model, hypothesis, and method of analysis as well as Section 6.5.1.3 for guidelines 
to assess tolerability), Novartis will provide notification to the investigational sites that 
Expansion (Part 2) of the study is open to enrollment. Enrollment to Part 2 will continue until 
a total enrollment of approximately 70 participants treated at the sabatolimab dose of 800 mg 
Q4W (including the participants treated in cohort 2 in the Safety run-in (Part 1) and participants 
treated in the Expansion (Part 2)) has been achieved.
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Figure 3-1
Study design
* The Safety run-in cohort 1 investigating sabatolimab 400 mg Q4W requires at least 3 evaluable 
participants (6 enrolled participants) to have been observed for at least 2 cycles.
** The Safety run-in cohort 2 investigating sabatolimab 800 mg Q4W requires at least 9 evaluable 
participants (12 enrolled participants) to have been observed for at least 2 cycles.
*** To achieve 70 participants at the dose level 800 mg Q4W
Hospitalization is required at Cycle 1 from Day 1 to Day 3 for participants participating to 
Safety run-in (cohorts 1 and 2) in order to monitor closely the chemistry parameters, in 
particular to detect occurrence of TLS, (see Section 6.5.4.2), and thereafter at the discretion of 
the investigator. Study treatment will be administered in cycles with a planned duration of 28 
days, and study treatment may continue until the participant experiences disease progression 
(Fenaux et al 2014) or unacceptable toxicity.
In each 28 day-cycle:
!
azacitidine will be administered intravenously or subcutaneously at 75 mg/m2 on Days 1 to 
7 (or, at discretion of the investigator on Days 1-5 and Day 8-9), during Safety run-in (Part 
1) and Expansion (Part 2).
!
venetoclax will be administered orally at 400 mg daily for 14 consecutive days, during 
Safety run-in (Part 1) and Expansion (Part 2). No ramp-up of venetoclax is necessary in this 
trial (see Section 4.3).
!
sabatolimab will be administered intravenously at 400 mg (during Safety run-in cohort 1) 
or 800 mg (during Safety run-in cohort 2 and Expansion) on Day 8 (Q4W).
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At any time during the study, participants unable to tolerate one or two of the study treatment 
drugs, may continue study treatment with only the tolerated drug(s). Use of prophylactic 
antibiotics as per institutional guidelines is mandatory at Cycle 1; and thereafter prophylactic 
antibiotics may be used at the physician's discretion. Prophylactic antifungals as per institutional 
guidelines may be used at the physician's discretion at anytime. See Section 6.2.1.1, regarding 
the adjustment of dose for venetoclax in case of concomitant use of antibiotics and/or 
antifungals.
After the end of study treatment, all participants must be followed for adverse events (AEs) for 
30 days; in addition, follow-up for AEs will be conducted for 150 days following the last dose 
of sabatolimab. All participants who discontinue study treatment will enter a long-term follow-
up (for efficacy and/or survival status) as described in the study flow diagram below 
(Figure 3-2) and outlined in Section 9.1.
Figure 3-2
Study flow
The study flow is comprised of 3 study periods see (Figure 3-2): Pre-treatment (Screening), 
treatment and follow-up.
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Participants will undergo safety and efficacy assessments during screening and periodically 
during treatment and follow-up as outlined in Section 8.1.
An end of treatment (EOT) visit will be performed when participants permanently discontinue 
study treatment. Participants will then enter safety/efficacy follow-up as shown in Figure 3-2
(see also Section 9.1.1).
All participants will be followed for survival as per Section 9.1.1.3.
4
Rationale
4.1
Rationale for study design
The overall study design, Phase II, single-arm, open-label, multi-center, is a design to evaluate 
safety, tolerability and efficacy of a novel combination. To avoid overdosing of sabatolimab in 
combination with azacitidine and venetoclax, the study does employ a two part design with a 
halt to enrolment between Part 1 (Safety run-in) and Part 2 (Expansion part). This design 
element allows, in Part 1, a Safety Review Meeting at each dose level, with evaluation of DLTs, 
and review of all available safety data to confirm that sabatolimab (400 mg and subsequently 
800 mg Q4W) in combination with azacitidine and venetoclax, is safe, prior to opening 
enrollment to a larger participant population, in Expansion (Part 2). If the combination regimen 
with sabatolimab at 400 mg Q4W or 800 mg Q4W is not safe, the study will be stopped. A 
Steering Committee (Section 10.2.2) will be convened to review the safety during the entire 
course of study (Safety run-in (Part 1) and Expansion (Part 2)). The Expansion part and Cohort 
2 (800 mg) will contribute to assess efficacy of the triple regimen (sabatolimab, venetoclax and 
azacitidine).
4.2
Rationale for dose/regimen and duration of treatment
Rationale for dose/regimen of sabatolimab
The study will start with cohort 1 (Part 1) of at least 3 evaluable participants treated with 
sabatolimab at a dose level of 400 mg Q4W in order to minimize the risk for unexpected 
toxicities of this novel combination of sabatolimab in combination with venetoclax and 
azacitidine. The proposed sabatolimab dose level for evaluation of efficacy in the study is 800 
mg Q4W based on data accumulated from 2 phase I studies [CMBG453X2101], 
[CPDR001X2105], [CMBG453X2101] in solid tumor participants has a wide sabatolimab dose 
range. In sabatolimab single agent arms, sabatolimab doses ranged from 80 to 1200 mg every 
2 weeks (Q2W) or every 4 weeks (Q4W), with a lower 20 mg Q2W sabatolimab dose 
additionally tested in combination with PDR001. Because of the data obtained in 
[CMBG453X2101], [CPDR001X2105] study started evaluating sabatolimab at 240 mg Q2W, 
400 mg Q2W and 800 mg Q4W in combination with decitabine.
Clinical Pharmacology:
The pharmacokinetics (PK) of sabatolimab were similar between studies [CMBG453X2101] in 
solid tumor participants and [CPDR001X2105] in AML and high risk MDS participants. At 
lower doses (at 80 mg and below for Q2W dosing or at 240 mg and below for Q4W dosing), 
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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 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. As the dose of 800 mg Q4W is 
more convenient for the patients, it is the recommended dose for further development in MDS 
including the ongoing phase 3 trial [CMBG453B12301] and the present study.
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 that 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/mCR/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 09-Mar-2020, 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 nausea (5%) and 
decreased appetite (4%). There were no DLTs during the first cycle. No participants 
discontinued study treatment due to treatment-related AEs.
In study [CPDR001X2105], as of 10-Apr-2020, a total of 156 participants with hematological 
malignancies have been treated with sabatolimab as a single agent (n=26) or in combination 
with decitabine (n=82) or azacitidine (n=48). 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 events attributed to study treatment were diarrhea and 
rash in two participants (8%), each. 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 82 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 AE of possible hemophagocytic lymphohistiocytosis. In the 48 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 neutropenia), platelet count decrease (and 
thrombocytopenia), and fatigue. There were no DLTs during the first 2 cycles. No participants 
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discontinued study treatment due to treatment-related AEs. No study treatment-related deaths 
were observed in any of the studies mentioned above.
In study [CMBG453C12201], results from the first cohort of the safety run-in indicate 
sabatolimab 400 mg Q4W to be safe when administered in combination with azacitidine and 
venetoclax. A total of five adult participants with AML unfit for intensive chemotherapy were 
enrolled in that cohort, and a safety review meeting was conducted per the study protocol. No 
DLTs, deaths, or discontinuations due to AEs were reported. The overall safety profile of these 
5 participants on triplet combination was generally consistent with that of venetoclax+ 
azacitidine. At the time of a data cut-off for the safety review meeting, two participants had 
discontinued study treatment; one participant achieved CR and discontinued after treatment 
cycle 2 to receive HSCT, and one participant discontinued due to disease progression. The 
remaining 3 participants were observed for at least 2 treatment cycles and study treatment was 
ongoing. The safety review concluded it was permissible to start enrollment in cohort 2 and to 
treat participants with sabatolimab at the dose level of 800 mg Q4W in combination with 
azacitidine and venetoclax.
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 potentially 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 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 both 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 Q4W dose 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.
4.3
Rationale for choice of combination drugs
Rationale for combining sabatolimab with azacitidine and venetoclax
Venetoclax in combination with azacitidine or decitabine or low dose cytarabine has recently 
received approval from FDA (on 16-Oct-2020) in AML based on efficacy and safety, 
demonstrated in two open-label trials (see Section 1.1). Based on these trial results, venetoclax 
in combination with HMA is emerging as a potential new standard of care in this indication. 
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Furthermore, preliminary data indicate that venetoclax in combination with azacitidine is 
feasible, safe in MDS participants and associated with encouraging signs of efficacy. Ramp-up 
of venetoclax in AML and CLL is necessary; as in these indications are associated with high 
tumor burden, rapid death leukemic cells at the initiation of therapy and occurrence of TLS is 
frequent (Cairo and Bishop 2004). In contrast, ramp-up of venetoclax in MDS is not necessary 
based on the fact that risk of TLS in MDS is extremely low (Cairo and Bishop 2004) and also 
based on Phase Ib and retrospective studies findings, where ramp-up was not required, 
indicating absence of clinical TLS (Wei et al 2019, Ball et al 2020, Azizi et al 2020). 
Nevertheless, the participants enrolled in the Safety run-in part, will be hospitalized at Cycle 1 
for 3 days to monitor the risk of TLS, See Section 3.
The rationale for combining sabatolimab with azacitidine and venetoclax is based on the 
following:
Emerging data suggest that immunotherapy may be a novel and promising therapeutic approach 
in higher-risk MDS, a disease with an important unmet medical need. However, the optimal 
immunotherapy has yet to be defined, and to date PD-1 inhibitors have demonstrated minimal 
single-agent activity, suggesting exploration of alternative approaches.
TIM-3 is a checkpoint inhibitor that plays a complex role in the negative regulation of innate 
and adaptive immune responses. Further, TIM-3 is expressed on leukemic stem cells and 
leukemic progenitor cells but not on normal hematopoietic stem cells. This suggests that TIM-
3 inhibition by sabatolimab (MBG453) may have immunomodulatory as well as direct anti-
leukemic effects.
Hypomethylating agents induce broad epigenetic effects including downregulating genes 
involved in cell cycle, cell division and mitosis, and upregulating genes involved in cell 
differentiation. However, these potentially anti-leukemic effects are accompanied by increased 
expression of TIM-3 as well as PD-1, PD-L1, PD-L2 and CTLA4, potentially downregulating 
immune-mediated anti-leukemic effects. These later effects justify the exploration of novel 
checkpoint inhibitors to decrease an immunosuppressive tumor microenvironment 
(Yang et al 2014, Ørskov et al 2015).
Venetoclax is an inhibitor of BCL-2. BCL-2 inhibits apoptosis of factor-deprived cells, but does 
not prevent apoptosis of immune cell mediated killing, indicating different mechanisms of 
apoptosis induction (Vaux et al 1992). Therefore, blockage of both BCL2, which promotes 
direct leukemic cell apoptosis, and TIM-3, which may promote both immune cell mediated 
killing and direct leukemia-stem cell targeting, may induce cancer cell elimination via different 
pathways and possibly create a synergistic effect.
Study [CPDR001X2105] has demonstrated that sabatolimab can be administered safely in 
combination with an HMA, decitabine, and that this combination demonstrates preliminary 
efficacy including durable responses in participants with AML and high-risk MDS (see 
Section 4.2).
Further, as a mAb, sabatolimab is not metabolized by cytochrome P450 (CYP450) enzymes, or 
transported by P-glycoprotein (Pgp) or related ABC membrane transporters, therefore an impact 
of DDIs on the PK of sabatolimab by azacitidine, or venetoclax is not anticipated. Cytokines 
produced by activated lymphocytes may impact the levels of Pgp and the activity of CYP450 
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enzymes (Renton 2005, Dumais et al 2008, Harvey and Morgan 2014); the clinical relevance to 
sabatolimab is unknown. However, preliminary data from the clinical study [CPDR001X2105], 
which has shown that the co-administration of sabatolimab with decitabine did not result in 
changes in their PK parameters. Therefore, a clinically relevant DDI effect is considered 
unlikely.
Taken together, these data suggest that the combination of sabatolimab, venetoclax and 
azacitidine, can be administered safely with little overlapping toxicity contributed by 
sabatolimab, and that sabatolimab may improve the efficacy of azacitidine and venetoclax.
4.4
Rationale for MRD assessment 
4.4.1
Rationale for MRD assessments
Minimal residual disease (MRD) in AML/higher risk MDS refers to the presence of leukemic 
cells at a sensitivity of detection below the threshold of conventional morphologic methods. 
Participants who experience a CR according to morphologic assessments (<=5% blast in the 
bone marrow), can potentially still harbor a large number of leukemic cells in the bone marrow 
which can confer a 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, 
Jongen-Lavrencic et al 2018, Freeman et al 2018), indicating that depth of leukemic clearance 
should be considered as a relevant prognostic endpoint in this setting. While the majority of 
MRD studies to date have focused on AML participants, higher risk MDS participants have 
been included in some of the participants cohorts (Freeman et al 2013, Freeman et al 2018), 
since detection of MRD in this setting is likely to yield similar prognostic value. Consistently, 
post-transplant MRD positivity predicted relapse in higher risk MDS participants 
(Mo et al 2016).
 
 
 
 
 
 
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4.5
Purpose and timing of interim analyses/design adaptations
No formal interim analyses are planned (see Section 12.7).
However, the study design foresees that during and at the conclusion of Part 1 (Safety run-in), 
decisions based on emerging data are taken at safety review meetings following completion of 
enrollment at each dose level (or earlier if required) and prior to starting the Expansion (Part 2). 
At the Safety Review Meetings, the decision to escalate to the 800 mg Q4W dose level or to 
open the Expansion part at the sabatolimab dose level of 800 mg Q4W will be guided by a 
Bayesian analysis based on the incidence of dose limiting toxicity (DLT) data, and supported 
by all available data, including safety data, clinical pharmacology data, tolerability data, and 
recommendations from participating investigators. The decision to enroll further participants at 
the sabatolimab 800 mg Q4W in the Safety run-in part and to open Part 2 (Expansion Part) to 
enrollment, will be communicated to investigators.
Details of this procedure and the process for communication with investigators are provided in 
Section 6.5.1.
The primary analysis on CR rate (Expansion (Part 2)) will be performed after all participants 
have completed at least 6 cycles of treatment with sabatolimab + azacitidine + venetoclax 
(see Section 12.7).
4.6
Risks and benefits
Venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine has been 
approved by the FDA in 16-Oct-2020 to treat newly-diagnosed AML in adults 75 years or older, 
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or who have comorbidities precluding intensive induction chemotherapy. Venetoclax was 
initially granted accelerated approval for AML in Nov-2018.
Findings from a Phase Ib (Wei et al 2019) and retrospective clinical evaluation of venetoclax 
in combination with azacitidine suggested promising efficacy results in higher-risk MDS 
participants (Ball et al 2020, Azizi et al 2020).
The potential benefit of sabatolimab combined with HMA in MDS is suggested by early 
efficacy results from the study [CPDR001X2105], which showed achievement of durable 
complete remission or bone marrow CR in high risk MDS participants receiving sabatolimab 
in combination with HMA. The proportion of higher-risk MDS participants achieving CR/mCR 
and durable CR/mCR under treatment with sabatolimab combined with HMA appears to be 
larger as compared to historic and published data on similar MDS participants treated with 
HMA alone. As of 25-Jun-2020, among 35 evaluable participants with HR-MDS who were 
treated with sabatolimab in combination with HMA, the overall response rate (ORR) was 
62.9%: 8 complete remissions (CR), 8 marrow CR (5 with hematologic improvement [HI]), 6 
stable diseases with HI. Median time to response was 2.0 months and estimated 6-months 
duration of response rate for CR/mCR/PR was 90% (95% CI: 73.2-100%).
The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring. Further, dose modifications are 
provided and must be applied per protocol based on clinical or laboratory findings (see 
Section 6.5.3).
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 will adhere to recent American Society of 
Clinical Oncology (ASCO) practices guidelines for management of immune-related adverse 
events in participants treated with checkpoint inhibitors (Brahmer et al 2018) (see Section 6.5.3
and Section 6.5.4.1).
Based on currently available data, there are no known significant overlapping toxicities between 
the combination of venetoclax and azacitidine and sabatolimab. However, this novel 
combination treatment may have unforeseen risks, which could be serious. In particular, there 
is the potential for 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 administered in combination with azacitidine + 
venetoclax has not been assessed previously, the protocol stipulates that consecutive Safety run-
in cohorts at 400 mg Q4W and 800 mg Q4W (Part 1) 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 (Expansion). A Steering Committee (see Section 10.2.2) will review the 
safety data during the course of the study including at the time of the two safety reviews planned 
during the Safety run-in.
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Women of childbearing potential and sexually active males 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 outlined in the exclusion criteria until at least 30 days after the last dose of 
venetoclax, 90 days after the last dose of azacitidine, and 150 days after the last dose of 
sabatolimab, whichever is later. If there is any question that the participant will not reliably 
comply, they should not be entered or continue in the study.
No substantial additional risk for participants' safety due to the SARS-CoV-2 virus and the 
COVID-19 pandemic has been identified at this time and therefore the benefit risk remains 
unchanged. 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 approximately 76 adult participants (i.e. approximately 18 
participants in Safety run-in (Part 1) [including 6 participants in cohort 1, 12 participants in 
cohort 2] and approximately 58 participants in Expansion (Part 2) with high or very high risk 
(per IPSS-R prognostic risk categories) myelodysplastic syndromes. These participants have an 
indication for treatment with azacitidine in first-line setting and are not immediately eligible at 
the time of screening for intensive chemotherapy or HSCT according to medical judgment and 
local standard medical practice/institutional guidelines for treatment decisions.
The investigator or designee must ensure that only participants who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in 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. Age ≥ 18 years at the date of signing the informed consent form (ICF)
3. Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on 2016 
WHO classification (Arber et al, 2016) by local investigator assessment with one of the 
following Prognostic Risk Categories, based on the revised International Prognostic Scoring 
System (IPSS-R) (Greenberg et al 2012):
!
Very high (> 6 points)
!
High (> 4.5-6 points)
4. Not immediately eligible for hematopoietic stem-cell transplantation (HSCT) or intensive 
chemotherapy at the time of screening due to individual clinical factors such as age, 
comorbidities and performance status, donor availability (de Witte et al 2017)
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
6. Indication for azacitidine treatment according to the investigator, based on local standard 
medical practice and institutional guidelines for treatment decisions
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7. AST and ALT ≤ 3 × upper limit of normal (ULN)
8. Total bilirubin ≤ 1.5 × ULN (except in the setting of isolated Gilbert syndrome, where 
participants may only be included with total bilirubin ≤ 3.0 x ULN)
9. Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73 m2 (estimation based on 
Modification of Diet in Renal Disease) (MDRD) formula, by local laboratory)
10. Participant is able to communicate with the investigator, and has the ability to comply with 
the requirements of the study procedures
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 or any BCL-2 inhibitor (including venetoclax) at 
any time.
2. Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1,
or anti-PD-L2) or cancer vaccines is not allowed if the last dose of the drug was 
administered within 4 months prior to start of treatment.
3. Previous first-line treatment for very high risk or high risk myelodysplastic syndromes 
(based on IPSS-R, Greenberg et al 2012 and Arber et al, 2016) with any antineoplastic 
agents, approved or investigational, including chemotherapy, lenalidomide and 
hypomethylating agents (HMAs) such as decitabine or azacitidine.
However, a single cycle of HMAs treatment only started prior to enrollment is allowed.
4. Live vaccine administered within 30 days prior to start of treatment
5. Current use or use within 14 days prior to start of treatment of systemic steroid therapy (> 
10mg/day prednisone or equivalent) or any immunosuppressive therapy. Topical, inhaled, 
nasal, ophthalmic steroids are allowed. Replacement therapy, steroids given in the context 
of a transfusion are allowed and not considered a form of systemic treatment
6. History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, 
venetoclax or sabatolimab) or monoclonal antibodies (mAbs) and/or their excipients
7. Participants with myelodysplastic syndrome (MDS) based on 2016 WHO classification 
(Arber et al, 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 4.5
8. Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and 
extra-medullary acute myeloid leukemia based on WHO 2016 classification 
(Arber et al, 2016)
9. Diagnosis of therapy-related MDS based on WHO 2016 classification (Arber et al, 2016)
10. Diagnosis of chronic myelomonocytic leukemia (CMML), MDS/MPN or primary or 
secondary myelofibrosis based on 2016 WHO classification (Arber et al, 2016)
11. History of organ transplant or allogenic hematopoietic stem cell transplant
12. Any concurrent severe and/or uncontrolled medical condition e.g., any active systemic 
infection, or any severe and/or uncontrolled infection requiring parenteral anti-infectives 
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including antibacterial, antiviral or antifungal therapy (such as severe pneumonia, 
meningitis, or septicemia)
13. Participants with prior malignancy, except:
a) Participants with history of intermediate risk MDS or lower risk MDS treated by any 
supportive care (e.g. growth factors, TGF'beta agents) or untreated are eligible
b) Participants with history of intermediate or lower risk MDS who were treated adequately 
with lenalidomide and then failed are eligible
c) Participants with history of adequately treated malignancy for whom no systemic anti
cancer therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or 
required during the course of the study. Subjects who are receiving adjuvant therapy such 
as hormone therapy are eligible. However, subjects who developed therapy-related 
MDS are not eligible (see exclusion criterion 9).
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) QTcF > 470 ms at screening, long QT syndrome or family history of unexplained cardiac 
death
c) 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. Sexually active males unless they use a condom during intercourse while taking azacitidine 
and for 3 months after stopping the 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.
16. Participant is pregnant or breastfeeding
17. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
study treatment and for at least one month after the last dose of venetoclax, 3 months after 
the last dose of azacitidine (or as per their respective local labels, 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 
participant). 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
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!
Male sterilization (at least 6 months prior to screening/baseline). For female participant 
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. It is currently unknown whether venetoclax may reduce the effectiveness 
of hormonal contraceptives, and therefore women using hormonal contraceptives 
should add a barrier method.
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.
Women are considered post-menopausal and not of childbearing potential if they have had 
over 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate , history of vasomotor symptoms) in the absence of other medical 
justification or have had surgical bilateral oophorectomy (with or without hysterectomy) or 
bilateral tubal ligation at least 6 weeks ago. 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.
18. 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: 
testing positive for HIV during screening using a local test
19. Active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Participants whose 
disease is controlled under antiviral therapy may be eligible 
20. Other co-morbidity that, in the opinion of the investigator, predisposes the participant to 
high risk of noncompliance with the protocol
21. Participant has consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of 
study treatment (C1D1) 
6
Treatment
6.1
Study treatment
In this study, the term “investigational drug” refers to the Novartis study drug, sabatolimab. The 
term "study treatment” refers to the combination of study drugs: sabatolimab plus venetoclax 
plus azacitidine.
All dosages prescribed, dispensed to the participant and all dose changes during the study 
including the reason for any component of the study treatment must be recorded on the 
appropriate eCRF page.
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6.1.1
Investigational and control drugs
Table 6-1
Study Treatment
Investigational/ 
Combination 
Drug
(Name 
and 
Strength)
Strength 
Pharmaceutical 
dosage form 
and route of 
administration
Supply Type
Sponsor 
(global or 
local)
Sabatolimab
400 mg/4 ml
solution in vial 
for i.v. infusion
Open Label
Sponsor 
(global)
Venetoclax
100 mg and/or 
50
mg and/or 10 
mg
tablet for oral use
Open Label
Sponsor 
(global/local)
Azacitidine*
100 mg / vial
powder for 
suspension for 
injection or 
powder for 
solution for 
infusion for 
subcutaneous use 
or intravenous 
use
Open Label
Sponsor 
(global/local)
*formulation for generic azacitidine as approved by local regulations
Sabatolimab
Sabatolimab will be administered at a dose of 400 mg Q4W (Safety run-in (Part 1) cohort 1) or 
800 mg Q4W (Safety run-in (Part 1) cohort 2 and Expansion (Part 2)) via i.v. infusion over 30 
minutes on Day 8 of every 28-day cycle. 
If the alternative schedule is selected for azacitidine by the investigator, azacitidine and 
sabatolimab will be given on the same day (Day 8 of the 28-day cycle). Azacitidine should be 
administered first, followed by sabatolimab. 
Further instructions for the preparation, dispensation and administration of sabatolimab are 
described in the Pharmacy Manual.
Venetoclax
Venetoclax film-coated tablets should be administered at a dose of 400 mg orally or 
corresponding reduced dose for concomitant use with P-gp inhibitors or moderate or strong 
CYP3A4 inhibitors (see Table 6-2 and Venclexta® (Venclexta® (Venetoclax) USPI (2020)), 
once a day, from C1D1 to C1D14 during the 28-day cycle. Participants should be instructed to 
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swallow the tablets whole (tablets should not be crushed or broken), with water, at 
approximately the same time each day. The tablets should be taken with a meal (ideally at 
breakfast). No ramp-up for venetoclax is necessary, See Section 3, Section 4.3 and 
Section 6.5.4.2.
A reduced dose of venetoclax per day for concomitant use with P-gp inhibitors or moderate or 
strong 
CYP3A4 
inhibitors 
(see 
Table 6-2
and 
Venclexta® (Venclexta® (Venetoclax) USPI (2020)) is necessary. In particular, many 
antifungals (e.g. posaconazole) and antibiotics, frequently used for prophylaxis or treatment of 
infection, are strong or moderate CYP3A4 inhibitors and their use should lead to dose 
adjustment of venetoclax as indicated in Table 6-2.
If a participant misses doses of venetoclax within 8 hours of the time it is usually taken, the 
participant should take the missed dose as soon as possible on the same day. If the participant 
misses a dose by more than 8 hours, the participant should not take the missed dose and should 
resume the usual dosing schedule at the usual time the following day. If a participant vomits 
after taking venetoclax, the dose should not be re-administered and the participant should take 
their next dose at the usual time the following day.
On the days of PK sampling, the participant will be instructed to bring his/her drug supply to 
the site, and take the dose in the clinic, under supervision of the site personnel. The exact time 
for dose administration and breakfast (if applicable) intake must be recorded in the source 
documents and electronic Case Report Form (CRF).
Azacitidine
Azacitidine is considered as a Standard of Care in the population enrolled in this study and it 
should be administered according to standard local clinical practice. A standard dose of 
azacitidine (75 mg/m2) will be given subcutaneously or intravenously every day for seven 
consecutive days on days 1-7 out of a 28 days cycle (see local azacitidine package insert). In 
keeping with standard clinical practice, the alternative schedules of 75 mg/m2 for five 
consecutive days on days 1-5, followed by a two day break, then two consecutive days on days 
8-9 will be permitted (alternative schedule).
Azacitidine regimen used in this protocol were selected because they are the most studied 
regimens and recommended by international treatment guidelines (NCCN, ESMO) 
(Fey and Buske 2013, O'Donnell et al 2017).
NOTE: On days of co-administration of venetoclax, azacitidine and sabatolimab, please refer 
to the Pharmacy Manual for instructions.
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
Not applicable.
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6.1.4
Guidelines for continuation of treatment
Per protocol, dose modifications, including dose interruptions, for toxicities are permitted and 
are outlined in Section 6.5.
6.1.5
Treatment duration
A participant may be discontinued from study treatment for reasons of unacceptable toxicity, 
progressive disease (including transformation to leukemia per WHO 2016 classification) or 
relapse, HSCT, intensive chemotherapy, withdrawal of consent by the participant, pregnancy, 
failure to adhere the protocol or at the discretion of the investigator or if the study is terminated 
by the Sponsor.
Patients who complete participation in this trial and continue to derive clinical benefit from the 
treatment based on the investigator’s evaluation may receive post-trial access. Post Trial Access 
(PTA) means the provision of investigational treatment to trial participants following their 
completion of trial participation. PTA will be provided until one of the following is met: 
participant no longer derives clinical benefit, investigator discontinues treatment, launch or 
reimbursement (where applicable), treatment fails to achieve registration in the trial 
participant’s country, or the clinical program is discontinued for any other reason.
Mechanisms for provision of PTA may include an extension phase to this study, a separate 
extension protocol, a rollover protocol, provision of the Novartis investigational product in a 
non-trial setting (known as post-study drug supply [PSDS]) when no further safety or efficacy 
data are required, or any other mechanism appropriate for the country.
The PTA mechanism must comply with local laws and regulations in the participating trial 
countries. If Novartis discontinues the PTA for this trial, Novartis will work with investigators 
to transition patients onto locally available alternative treatment, or standard of care.
6.1.5.1
Treatment beyond disease progression
Treatment beyond disease progression is not permitted.
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 antibiotics, antifungals, anti-emetics, anti-diarrheal) is permitted (see 
Section 6.2.1.1), except when specifically prohibited (see Section 6.2.2). Prophylaxis with 
antibiotics as per local institutional guidelines is mandatory at Cycle 1 and thereafter this type 
of prophylaxis may be used per investigator's discretion. Prophylaxis antifungals, as per 
institutional guidelines, is allowed at anytime. In case of concomitant medications (e.g 
antibiotics, antifungals), dose adjustment of venetoclax may be necessary, as indicated below. 
The participant must be told to notify the investigational site about any new medications he/she 
takes after the start of the study treatment.
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 
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pre-medication on subsequent dosing days. The pre-medication should be chosen per 
institutional standard of care, at the discretion of the treating physician.
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 (see Section 6.5.3 for guidance).
Sabatolimab should be administered in a facility equipped for cardiopulmonary resuscitation. 
Appropriate resuscitation equipment should be available, and a physician readily available.
Participants should receive appropriate prophylaxis (e.g. antiemetics) for azacitidine as per local 
practice.
All medications, procedures, and significant non-drug therapies including physical therapy and 
blood transfusions received within 16 weeks before the first dose of study treatment is 
administered, during the course of the study and until the end of efficacy follow-up, should be 
recorded in the appropriate Case Report Forms (see Table 8-1).
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medications 
and 
local 
prescribing 
information 
of 
azacitidine 
(Vidaza® (Azacitidine) USPI (2008)) and venetoclax (Venclexta® (Venetoclax) USPI (2020)). 
If in doubt, the investigator should contact the Novartis medical monitor before a participant 
starts treatment or allowing a new medication to be started. If the participant has already started 
treatment, contact Novartis medical monitor to determine if the participant should continue 
study treatment. Supportive therapy including prophylactic antibiotic and antifungal treatments, 
transfusions, growth factors (e.g. GCSF, ESA) etc. will be administered at the discretion of the 
investigators according to their local standard of care.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Medications to be used with caution during study treatment in this study are listed below. Please 
also refer to Appendix 2 (see Section 16.2) for detailed guidance.
Strong or moderate CYP3A4 inhibitors and P-gp inhibitors: If, such therapy is necessary, 
it can be introduced, under the provision that the dose of venetoclax is reduced. 
Recommendation for venetoclax dose, when given in combination with strong CYP3A 
inhibitors (e.g., posaconazole, ketoconazole, conivaptan, clarithromycin, indinavir, 
itraconazole, lopinavir, ritonavir, telaprevir, and voriconazole), moderate CYP3A inhibitors 
(e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, and verapamil) or P-gp 
inhibitors (e.g., amiodarone, azithromycin, captopril, carvedilol, felodipine, quercetin, 
quinidine, ranolazine, and ticagrelor) are provided in Table 6-2 below.
Table 6-2
Management of potential interactions of CYP3A and P-gp inhibitors 
with venetoclax
Concomitant drug
Dose Reduction
Posaconazole
Reduce venetoclax dose to 70 mg
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Other strong CYP3A inhibitor
Reduce venetoclax dose to 100 mg
Moderate CYP3A inhibitor or P-gp inhibitor
Reduce venetoclax dose to 200 mg
The venetoclax dosage that was used prior to concomitant use with a strong or moderate CYP3A 
inhibitor or a P-gp inhibitor should be resumed 2 to 3 days after discontinuation of the inhibitor. 
Participants should be instructed to avoid grapefruit products, Seville oranges, and starfruit 
during treatment with venetoclax as they contain inhibitors of CYP3A4.
Strong or Moderate CYP3A4 inducers: Concomitant use of venetoclax with strong CYP3A 
inducers (e.g., carbamazepine, phenytoin, rifampin, St.John's wort) or moderate CYP3A 
inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided. 
Alternative treatments with less CYP3A induction should be considered.
P-gp or BCRP substrates: Co-administration of narrow therapeutic index P-gp, or BCRP 
substrates (e.g., digoxin, sirolimus) with venetoclax should be avoided.
If a narrow therapeutic index P-gp or BCRP substrate must be used, it should be used with 
caution. For an orally administered P-gp or BCRP substrate sensitive to inhibition in the 
gastrointestinal tract (e.g., dabigatran etexilate), its administration should be separated from 
venetoclax administration as much as possible to minimize a potential interaction.
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 closely. Participants who develop a 
new requirement for anticoagulant 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 the study, participants must not receive additional investigational drugs, 
devices, chemotherapy, or any other therapies that may be active against cancer or modulate 
the immune response.
The use of systemic steroid therapy at immunosuppressive dose (> 10 mg/day of prednisone or 
equivalent) and other immunosuppressive drugs are not allowed except for the treatment of 
infusion reaction, immune related adverse events (irAEs), for prophylaxis against imaging 
contrast dye allergy or in the context of transfusion, for replacement-dose steroids in the setting 
of adrenal insufficiency or for treatment of transient exacerbation of other underlying diseases 
such as chronic obstructive pulmonary disease requiring treatment for ≤ 3 weeks.
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Systemic corticosteroids required for control of infusion reactions or irAEs must be tapered and 
be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) before the next 
sabatolimab administration. 
If more than 10 mg/day prednisone is used, sabatolimab should be temporarily interrupted until 
the participant receives 10 mg/day or less of prednisone. 
Topical, inhaled, nasal and ophthalmic steroids are allowed.
The use of live vaccines are not allowed through the duration of the study treatment and 150 
days after the last dose of sabatolimab. Inactivated vaccines, subunits recombinant, 
polysaccharide and conjugate vaccines and toxoid vaccines are allowed.
Vaccination against COVID-19, unless these are live vaccines, is allowed during screening and 
during the treatment phase but should not be administered on the same day of study treatment 
administration to avoid potential overlapping adverse events.
In addition, prohibited medication related to azacitidine and venetoclax will apply according to 
local 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 first enrolled for screening and is retained as the primary 
identifier for the participant, unless 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 participant is numbered uniquely across 
the entire database. Upon signing the informed consent form, the site will use the electronic 
data capture system to assign the participant the next sequential participant No.
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 
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.
6.3.2
Treatment assignment, randomization
This study is open label and non-randomized.
Prior to dosing at Cycle 1 Day 1, participants who fulfill all the inclusion/exclusion criteria will 
be enrolled via IRT and a treatment number will be provided for the study treatments 
sabatolimab, venetoclax, and azacitidine.
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The Investigator (or delegate) will call or log on to the IRT and confirm that the participant 
fulfills all the inclusion/exclusion criteria by completing the eligibility criteria checklist 
embedded in the system. The IRT will assign a unique medication number for the first package 
of study treatments to be dispensed to the participant.
6.4
Treatment blinding
The study is open-label with no blinding.
6.5
Dose escalation and dose modification
Two dose levels of sabatolimab, 400 mg Q4W (Safety run-in (Part 1) cohort 1) and 800 mg 
Q4W (Safety run-in (Part 1) cohort 2) will be evaluated. Intra-participant dose escalation is not 
permitted. Guidance for dose modifications is provided in Section 6.5.1.
6.5.1
Dose escalation guidelines
6.5.1.1
Sabatolimab dose level and regimen
Sabatolimab will be given at 400 mg every 4 weeks in the first approximately 6 enrolled 
participants (at least 3 evaluable participants) (cohort 1 of the Safety run-in (Part 1)). If this 
dose level is considered safe, sabatolimab will be given at 800 mg every 4 weeks in the next 
approximately 12 participants (at least 9 evaluable participants) (cohort 2 of the Safety run-in 
(Part 1)).
In case the combination does not meet overdose criteria at the cohort 1 of Safety the run-in (Part 
1) (participants treated with sabatolimab at 400 mg Q4W); but meets the overdose criteria at 
cohort 2 of the Safety run-in (Part 1) (participants treated with sabatolimab at 800 mg Q4W), 
the Expansion (Part 2) will not be opened. The Expansion (Part 2) will be opened only if the 
two cohorts does not meet the overdose criteria consecutively.
6.5.1.2
Provisional dose levels
Table 6-3 below describes the starting dose and the dose levels that may be evaluated during 
the Safety run-in (Part 1) of this trial.
Table 6-3
Provisional dose levels of sabatolimab during Safety run-in (Part 1)
Dose level
Proposed dose* (Q4W) 
Increment from previous 
dose
1
400 mg
(starting dose)
2
800 mg
100%
* In combination with azacitidine (75 mg/m2 Day 1-7) + venetoclax (400 mg Day 1-14)
6.5.1.3
Guidelines for assessing tolerability
For the purpose of assessing the risk of overdosing (as defined by EWOC criterion, see details 
below) of sabatolimab in combination with azacitidine and venetoclax, at each sabatolimab dose 
level, after the required number of evaluable participants, at least 3 participants for cohort 1 
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(Part 1) and at least 9 participants for cohort 2 (Part 1), have been included, and observed for at 
least 2 cycles, a safety review meeting will be conducted.
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 has taken at least 75 % of the planned dose of azacitidine and venetoclax (i.e. for 
2 cycles: 11 doses of azacitidine out of the 14 doses planned and 21 doses of venetoclax out of 
the 28 doses planned), and participant has had safety assessments for a minimum period of 2 
cycles (from Cycle 1 Day 1 to the end of Cycle 2). Participants receiving a reduced dose of 
venetoclax due to co-administration of strong or moderate CYP3A4 inhibitors or P-gp inhibitors 
as described in Table 6-2, will be considered to have received the planned dose.
or
· Participant has experienced a DLT within the DLT observation period from first dose of
sabatolimab to the end of Cycle 2. Note that participants who experience toxicity that meets the 
criteria for DLT but occurs prior to the first dose of sabatolimab will be considered not 
evaluable.
At the Safety Review Meetings, Investigators and Novartis study personnel will review all 
relevant data available from the ongoing study including safety information, DLTs, time of 
occurrence of DLT, supported by all CTCAE v5.0 ≥ Grade 2 toxicity data during the first 2 
cycles of the study treatment, and pharmacokinetic data from evaluable participants.
The decision will be guided by a Bayesian model with EWOC principle evaluating the 
probability of DLT. For each cohort of the Safety run-in, the probability of excessive toxicity 
(i.e. DLT rate ≥ 33%) will be assessed after the required number of evaluable participants have 
been treated and observed for up to end of Cycle 2. If the EWOC criteria is satisfied (probability 
of excessive toxicity is lower than 25%), the Bayesian model will recommend to start 
enrollment to either cohort 2 (Part 1) or the Expansion Part (Part 2).
At the safety review meetings, the available toxicity information (including adverse events and 
laboratory abnormalities that are not DLTs), the time (days from start of therapy) of occurrence 
of DLT, the recommendations from the Bayesian analysis, and the available PK and 
pharmacodynamic information will all be evaluated by the Investigators and Novartis study 
personnel. Once the results of the safety review meeting are available, the investigator will 
receive written confirmation from Novartis indicating that the results of the Safety run-in part 
(Part 1) were evaluated and that it is permissible to start enrollment to either cohort 2 (Part 1) 
or the Expansion Part (Part 2).
6.5.2
Definitions of dose limiting toxicities (DLTs)
Dose-limiting toxicities will be collected and evaluated in participants enrolled to the Safety 
run-in part. 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 or in combination with other component(s) of study treatment that occurs 
during the DLT observation period and meets any of the criteria included in Table 6-4. The 
DLT observation period is Cycle 1 Day 8 (starting from the first infusion of sabatolimab) to the 
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end of Cycle 2. The National Cancer Institute Common Terminology Criteria for Adverse 
events (NCI CTCAE) version 5.0 will be used for all grading.
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 resolves to CTCAE Grade 1 or baseline value, the participant may continue to 
receive study treatment following consultation with the Novartis medical monitor.
The investigator must notify the sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. 
Table 6-4
Criteria for defining dose-limiting toxicities during the Safety run-in 
(Part 1)
Toxicity
DLT Criteria
Hematology 
Because marrow suppression is an expected 
consequence of MDS and its therapy, 
for participants participating in this study, 
only persistent grade 4 neutropenia, 
thrombocytopenia and pancytopenia 
beyond Day 42 from the start of a study 
treatment cycle and is not related to the 
underlying disease will be considered to be a 
DLT (bone marrow evaluation may be 
required to determine if the bone marrow 
suppression is due to the underlying 
disease).
OR
Febrile neutropenia CTCAE Grade 4
OR
Sepsis CTCAE Grade 4
Vascular disorders
Hypertension CTCAE Grade 3 persisting for 
> 7 days after treatment is administered, 
despite adequate antihypertensive therapy
General disorders and administration site 
conditions
Infusion reaction CTCAE Grade 3 that does 
not resolve to Grade 1 within 72 hours or 
CTCAE Grade 4 of any duration
Immune
Immune-related adverse events ≥ CTCAE 
Grade 3 persisting > 7 days after starting 
appropriate treatment* (e.g. with 
corticosteroids)
Occular
Eye pain or vision decreased:
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Toxicity
DLT Criteria
≥ CTCAE Grade 2 that does not improve to 
Grade 1 severity within 2 weeks after the 
initiation of topical therapy
OR
Eye pain or vision decreased that requires 
systemic treatment
Pulmonary
Pneumonitis of non infectious etiology 
≥CTCAE Grade 2 persisting > 7 days 
despite treatment with corticosteroids
Pneumonitis of non infectious etiology 
≥CTCAE Grade 3
Skin and subcutaneous tissue disorders
Photosensitivity ≥ CTCAE Grade 3 for > 
7 days after treatment
Rash ≥ CTCAE Grade 3 for > 7 days after 
treatment
Rash CTCAE Grade 4
Any severe skin reactions (such as Toxic 
Epidermal 
Necrolysis, 
Steven 
Jones 
Syndrome)
Gastrointestinal disorders
Diarrhea CTCAE Grade ≥ 3 ≥ 48 hrs., 
despite the use of anti-diarrhea therapy
Nausea/ vomiting CTCAE Grade ≥ 3 ≥ 48 
hrs., despite the use of anti-emetic therapy
Pancreatitis CTCAE Grade ≥ 3
Investigations
Blood bilirubin increase ≥ CTCAE 
Grade 2 (caused by increased direct 
bilirubin) with ALT and/or AST ≥ 
CTCAE Grade 2, without evidence of 
cholestasis and with absence of any 
alternative cause likely explaining the 
combination of increased ALT or AST 
and blood bilirubin
Other
Other clinically significant toxicities, 
including a single event or multiple 
occurrences of the same event that lead to a 
dosing delay of > 7 days in cycle 1, or result 
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Toxicity
DLT Criteria
in an inability to deliver ≥ 75% of the 
planned dose intensity for any of the study 
drugs in a cycle of treatment because of 
treatment-related toxicity.
Any other unacceptable toxicity encountered 
by a participant as determined by the 
Investigators and Novartis.
Any grade 4 non-hematologic toxicity that is 
not clearly related to a cause other than the 
study treatment under study.
Exceptions to DLT Criteria
· Grade 3 fatigue, asthenia, fever, anorexia, or constipation
· Grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total parenteral nutrition, 
or prolonged hospitalization
· Infection, bleeding, or other expected direct complication of cytopenias due to active 
underlying disease
· Grade 3 or 4 tumor lysis syndrome if it is successfully managed clinically and resolves 
within 7 days without end-organ damage
· Grade 3 or 4 isolated laboratory abnormalities that last ≤3 days
*Unless 
otherwise 
specified 
for 
organ-specific 
immune-related 
DLTs
· CTCAE 
version 
5.0 
will 
be 
used 
for 
all 
grading
6.5.3
Dose modifications
For participants who do not tolerate the protocol-specified dosing schedule: dose interruptions 
(for sabatolimab, azacitidine and venetoclax), and/or dose reductions (azacitidine and 
venetoclax only) are either recommended or mandated in order to allow participants to continue 
the study treatment. Dose reductions for sabatolimab are not allowed.
Guidelines for permanent treatment discontinuation is mandatory for specific events indicated 
as such in Table 6-5  and Table 6-6.
Dose interruption at the start of a new treatment cycle
In participants who have achieved CR or mCR and have Grade 4 neutropenia and/or Grade 4 
thrombocytopenia dosing of both venetoclax and azacitidine should be interrupted until 
resolution to ≤ Grade 2. Sabatolimab should not be administered during the dose interruption. 
After resolution, dosing of both azacitidine and venetoclax should be resumed on the same day 
with dose modification for venetoclax as specified in Table 6-6. The first day dosing is resumed 
will be considered as D1 of the new treatment cycle and sabatolimab will be administered on 
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Day 8 of the new cycle. In cases in which venetoclax and azacitidine have been permanently 
discontinued and the participant remains on sabatolimab, then, in participants who have 
achieved CR or mCR and 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 D8 of the new cycle.
Dose modifications for sabatolimab
Dose modifications for sabatolimab will be done according to ASCO guidelines about 
management of immune-related AEs (Brahmer et al 2018).
Additionally, the guidance indicated in Table 6-5 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, venetoclax and MDS and its complications.
Deviations to dose interruptions and/or permanent discontinuations outlined in Table 6-5 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 (irAE) that do not recover to 
≤ Grade 1 or baseline at a dose of immunosuppression of ≤ 10 mg/day prednisone or equivalent 
(or as indicated in Table 6-5) within 12 weeks after initiation of immunosuppressive therapy, 
sabatolimab must be permanently discontinued.
Table 6-5
Criteria for dose interruption and re-initiation or discontinuations of 
sabatolimab for adverse drug 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 sabatolimab
Grade 3
Stop infusion
If the AE resolves to ≤ Grade 1 within 72hrs:
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Worst Toxicity Grade (CTCAE v5.0)
Recommended Dose Modifications
· At next scheduled treatment visit, 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.
· 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:
· Discontinue sabatolimab
Grade 4
Discontinue sabatolimab
For adverse events thought to be immune-related AEs 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.
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 toxicities clinically significant** and at least 
possible attributable to sabatolimab (NCI CTCAE v5.0) 
(The guideline does not apply to for toxicities attributable to azacitidine or venetoclax or the 
underlying MDS including its complications)
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Worst Toxicity Grade (CTCAE v5.0)
Recommended Dose Modifications
Grade 1 and Grade 2 tolerable
Continue treatment with sabatolimab
Grade 2 intolerable (includes all Grade 2 events 
defined as DLT in Table 64) and Grade 3
1st or 2nd occurrence:
· Interrupt sabatolimab until toxicity recovers to ≤ 
Grade 1 or baseline
· 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:
· 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
If azacitidine treatment is deemed by the investigator to possibly have contributed to an 
observed adverse event, the dose or schedule of azacitidine treatment may be modified within 
a cycle and/or for subsequent cycles or temporary/permanent interruptions of azacitidine 
treatment may be decided by the investigator according to local practice and/or the country-
specific label guiding azacitidine use.
Dose modifications for venetoclax
If venetoclax treatment is deemed by the investigator to possibly have contributed to an 
observed adverse event, the dose or duration of venetoclax treatment may be modified 
according to the following guidelines:
Table 6-6
Dose modifications for venetoclax
Event
Occurrence
Action
Grade 4 neutropenia with or 
without fever or infection; or 
Grade 4 thrombocytopenia
Occurrence prior to achieving 
remission
Transfuse blood products, 
administer prophylactic and 
treatment anti-infectives as 
clinically indicated.
First occurrence after achieving 
remission and lasting at least 7 
days
Delay subsequent treatment 
and monitor blood counts.
Administer granulocyte-colony 
stimulating factor (G-CSF) if 
clinically indicated for 
neutropenia.
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Event
Occurrence
Action
Once the toxicity has resolved 
to Grade 1 or 2, resume 
venetoclax therapy at the same 
dose.
Subsequent occurrences in 
cycles after achieving 
remission and lasting at least 7 
days
Delay subsequent treatment 
and monitor blood counts.
Administer G-CSF if clinically 
indicated for neutropenia.
Once the toxicity has resolved 
to Grade 1 or 2, resume 
venetoclax therapy at the same 
dose and the duration reduced 
by 7 days for each subsequent 
cycle.
Blood chemistry changes 
suggestive of TLS
-
Withhold treatment.
If the event is resolved within 
48 hours of last dose, 
treatment with venetoclax can 
be resumed at the same dose.
Events of clinical TLS or blood 
chemistry changes requiring 
more than 48 hours to resolve
-
Withhold treatment.
Treatment should be resumed 
at a reduced dose (per the 
investigator discretion). When 
resuming treatment after 
interruption due to TLS, the 
instructions for prevention of 
TLS should be followed.
Grade 3 or 4 non-hematologic 
toxicities
First occurrence
Withhold treatment.
Once the toxicity has resolved 
to Grade 1 or baseline level, 
venetoclax therapy may be 
resumed at the same dose.
Subsequent occurrences
Withhold treatment.
Treatment should be resumed 
at a reduced dose (per the 
investigator discretion).
Permanent discontinuation of study treatment
If the study treatment (i.e. sabatolimab + azacitidine + venetoclax) is interrupted for toxicities 
and the start of the subsequent study treatment cycle is delayed for more than 28 consecutive 
days (measured from the intended start date of the new cycle (Day 29 of the previous cycle), 
the participant should be discontinued from study treatment.
At any time during the study, participants unable to tolerate one or two of the study treatment 
drugs may continue study treatment with only the tolerated drug(s) provided the participant 
benefits per investigator's judgement.
These dose changes must be recorded on the appropriate CRF.
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6.5.4
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 must be followed up for AEs (including irAEs and SAEs) for 30 days following 
the last dose of venetoclax or azacitidine (whichever was later) and 150 days following the last 
dose of sabatolimab, whichever is later.
6.5.4.1
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. All participants with signs 
or symptoms of irAEs 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). See guidance in Table 6-5 for immune-
related AEs not covered by ASCO guidelines.
In case of a suspected irAE, 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 8-1 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.
6.5.4.2
Follow-up for Tumor Lysis Syndrome (TLS)
Tumor lysis syndrome (TLS) is a clinical entity observed in some hematological malignancies 
resulting from massive tumor cells lysis. It is characterized by a constellation of metabolic 
abnormalities caused by the massive and abrupt release of cellular components (including 
nucleic acids, proteins, and electrolytes) into the systemic circulation after the rapid lysis of 
malignant cells (Cairo and Bishop 2004, Coiffier et al 2008).
TLS is not frequent in MDS and no cases of TLS have been reported in the ongoing 
[CPDR001X2105] for participants receiving sabatolimab in combination with hypomethylating 
agents.
Futhermore no cases of clinical TLS have been reported when MDS participants were treated 
with venetoclax in combination with azacitidine (Wei et al 2019, Ball et al 2020, 
Azizi et al 2020).
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Nevertheless, during this study, participants should be closely monitored (including relevant 
laboratory tests) for signs and symptoms of TLS before initiation and during a treatment cycle. 
At Cycle 1, all participants involved in the Safety run-in (Part 1) must be hospitalized from Day 
1 to Day 3 [clinical signs and chemistry will be monitored daily] and thereafter at the 
investigator's discretion.
To minimize risk of TLS, all participants should receive allopurinol, or an alternative 
prophylaxis with anti-hyperuricemic agents, as well as adequate hydration (including 
instructing participants to drink 1.5 to 2.0 L of water daily, among other measures as 
clinically indicated), prior to study treatment. Events should be managed according to local 
guidelines.
Before initiation of a treatment cycle and during a treatment cycle, the following measures 
should be followed:
Before initiation of a treatment cycle
· Prophylactic allopurinol, or a non-allopurinol alternative (eg, febuxostat), and increased oral/ 
i.v. hydration prior to treatment should be given in participants with elevated uric acid or high 
tumor burden
· Prompt supportive care in case of acute TLS (i.v. fluids and treatment with rasburicase as 
clinically indicated, when uric acid continues to rise despite allopurinol/febuxostat and fluids)
During a treatment cycle
· Frequent monitoring of the following laboratory tests (per assessment cycle and as clinically 
indicated): potassium, phosphorus, calcium, creatinine, and uric acid
· Encourage oral hydration
Based on laboratory and clinical TLS criteria (modified from Cairo and Bishop 2004), the 
following measures for TLS should be also followed:
Laboratory tumor lysis syndrome
· Defined as two or more of the following values within three days before or in the days 
following initiation of a treatment cycle:
· Uric acid ≥ 8 mg/dL or 25% increase from baseline
· Potassium ≥ 6 mEq/L or 25% increase from baseline
· Phosphorus ≥ 6.5 mg/dL (children) or ≥ 4.5 mg/dL (adults) or 25% increase from baseline
· Calcium ≤ 7 mg/dL or 25% decrease from baseline
· Regimen:
· If none or one of the laboratory values above is abnormal, continue to manage with allopurinol 
or a non-allopurinol alternative (e.g., febuxostat) and oral fluids. If uric acid remains elevated, 
consider i.v. fluids, treatment with rasburicase, and hospital monitoring.
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· Laboratory TLS should be managed with i.v. fluids, laboratory blood tests every 6 to 8 hours 
and inparticipant care. Cardiac monitoring and treatment with rasburicase should be considered 
if uric acid remains elevated.
Clinical tumor lysis syndrome
· Defined as the presence of laboratory TLS and ≥ 1 of the following criteria that cannot be 
explained by other causes:
· Serum creatinine ≥ 1.5 times the upper limit of the age-adjusted normal range
· Symptomatic hypocalcemia
· Cardiac arrhythmia
· Regimen:
· Clinical TLS should be managed with i.v. fluids, laboratory blood tests every 6 to 8 hours, 
cardiac monitoring, treatment with rasburicase/allopurinol/febuxostat and inparticipant care 
(consider intensive care unit (ICU)).
Participants who have been treated for TLS with favorable outcome (defined as return to within 
10% of baseline value or within limit of normal of relevant laboratory parameters) may re-start 
study treatment upon investigator's discretion.
6.5.4.3
Follow up on potential drug-induced liver injury (DILI) cases
Guidelines for follow-up on potential DILI cases are described in Table 6-7 and Table 6-8.
Table 6-7
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 
ALT, 
AST, ALP, GGT, 
TBL, INR, albumin, 
CK, and 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, 
TBL, INR, albumin, 
If elevated at 
baseline:
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ALT
TBL
Liver Symptoms
Action
ALT > 3 x baseline 
or 
> 
300 
U/L 
(whichever 
occurs 
first) for more than 
two weeks
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 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)
Table 6-8
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
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Abnormality
Action required
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 history, including relevant information, such as cardiac disease, history of any pre-
existing liver conditions or risk factors, blood transfusions, i.v. 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.
2. 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.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted.
4. Obtain an unscheduled PK sample, as close as possible to last dose of study treatment.
Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist.
6.5.4.4
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 and 
submit the triplicate for central review.
· Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). 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 study treatment sabatolimab is to be administered, IRT must be contacted to assign 
a medication (kit) number and (where applicable) for registration of the other study drugs 
dispensed to the participants.
For study treatment taken at home (e.g. for tablets of venetoclax), the investigator must promote 
compliance by instructing the participant to take the study treatment exactly as prescribed and 
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by stating that compliance is necessary for the participant’s safety and the validity of the study. 
The participant must also be instructed to contact the investigator if he/she is unable for any 
reason to take the study treatment as prescribed. Compliance will be assessed by the investigator 
and/or study personnel at each visit using pill counts and information provided by the participant. 
This information should be captured in the source document at each visit.
The date and time of all study treatment administrations (sabatolimab, venetoclax, and 
azacitidine) during the study and any deviations from the protocol treatment schedule will be 
captured by the investigator staff on the appropriate study treatment dispensing form. 
Compliance with the study treatment and any protocol deviations will be assessed by the field 
monitor on an ongoing basis. All study treatment dispensed and returned (if applicable) must 
be recorded in the Drug Accountability Log.
Pharmacokinetic parameters (measures of sabatolimab and venetoclax) will be determined in 
all participants treated with sabatolimab, as detailed in the pharmacokinetic section 
(Section 8.5.2). 
6.6.2
Emergency breaking of assigned treatment code
Not applicable.
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.
All dosages for study treatment (sabatolimab, azacitidine and venetoclax) prescribed to the 
participant and all dose changes during the study must be recorded on the Dosage 
Administration Record eCRF.
Sabatolimab
Each study site will be supplied by Novartis with the investigational drug sabatolimab as global 
clinical open supply and will be packed and labeled 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), 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 i.v. Further instructions for the preparation and dispensation 
of sabatolimab are described in the Pharmacy Manual.
Azacitidine
Azacitidine may be administered i.v or subcutaneously. Use of oral azacitidine is not allowed.
For details on preparation refer to the country-specific label instructions and/or azacitidine 
package insert.
Venetoclax
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Participants will be provided with adequate supply of venetoclax (tablets for oral 
administration) for on-site administration, if applicable, or for self-administration at home, 
including instructions for administration, until at least their next scheduled study visit. 
Venetoclax will be supplied globally or locally.
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.
The study drug supply can be destroyed at the local Novartis facility or third party, as 
appropriate, or locally at site only if permitted by local regulations and authorized by Novartis.
6.7.1.2
Handling of additional treatment
Not applicable.
6.7.2
Instruction for prescribing and taking study treatment
Please refer to Section 6.1.1.
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), 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 
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possible given his/her 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 
that complies with the ICH 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 included 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 subjects or the female 
partners of any male subjects who took study treatment
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 for the duration 
of the study. If there is any question that the participant will not reliably comply, they should 
not be entered in the study.
Male participants, including vasectomized men, in the study, must agree not to father a child 
and to use a condom during intercourse, to prevent delivery of the drug via seminal fluid during 
the study, and for the period of 3 months after the last dose of azacitidine.
Prior to starting treatment, male participants are advised to seek consultation on sperm storage 
and female participants of childbearing potential should seek consultation regarding oocyte 
cryopreservation.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
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8
Visit schedule and assessments
Assessment schedule (Table 8-1) 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).
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). If sabatolimab administration on Day 8 is delayed within a cycle due to 
toxicities, visit assessments for Day 8 should be shifted accordingly or occur on Day 22, in case of no administration. See Section 6.1 for 
details on study treatment.
A window of+/- 7 days from the planned visit date is allowed for BMA procedures. During the post-treatment and survival follow-up phases, 
a visit window of +/- 14 days is allowed.
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. When treatment 
is resumed, the first day of azacitidine and venetoclax administration will be considered as D1 of the new treatment cycle and visit schedule 
will be shifted accordingly.
On PK collection days the windows 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 efficacy follow-up and survival information, please refer to Section 8.3.1 and Section 9.1.
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Table 8-1
Assessment Schedule
Period
Screening
Treatment
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Visit Name Screening (-
28 to -1)
D1
D8
D22
D28
D1
D8
D22
D28
D1
D8
D28
D1
D8
D28
D1
D8
D28
D1
D8
Days
-28 to -1
D1
D8
D22
D28
D1
D8
D22
D28
D1
D8
D28
D1
D8
D28
D1
D8
D28
D1
D8
Informed consent
X
IRT Registration
X
X
Demography
X
Inclusion / Exclusion 
criteria
X
Medical 
history/current 
medical conditions
X
Disease History1
X
Prior antineoplastic 
therapies
X
Prior/concomitant 
medications, surgery 
and medical 
procedures (including 
blood transfusions 
requirement)2
X
Adverse Events
X
Continuous
Physical Examination
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
Body Height
X
BSA (use height from 
screening)
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Period
Screening
Treatment
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Visit Name Screening (-
28 to -1)
D1
D8
D22
D28
D1
D8
D22
D28
D1
D8
D28
D1
D8
D28
D1
D8
D28
D1
D8
Days
-28 to -1
D1
D8
D22
D28
D1
D8
D22
D28
D1
D8
D28
D1
D8
D28
D1
D8
D28
D1
D8
Chemistry
X3
Pre-dose and at 7 hrs (+_1hr) post dose during first cycle from Day 1 to Day 3, then at Predose on Day 1 of every subsequent 
Cycle, at EOT and unscheduled as clinically indicated
Coagulation
X
X
X
X
X
X
X
Cytogenetics 4
X
Ferritin, iron, 
erythrocyte and 
serum folates, 
vitamin B12
X
If clinically indicated
Cytokines for safety
X
Anytime for a suspected cytokine release syndrome, immediately after the AE, and one week after occurrence of AE
Urinalysis (dipstick)
S
If clinically indicated
Thyroid function5
X
X
X
Virology hepatitis B 
and C
S
If clinically indicated
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
Urine Pregnancy Test 
OR Serum 
Pregnancy Test8
S
S
S
S
S
12-Lead ECG 
(triplicates)10
X
X
X
S
S
X
S
S
S
IRT - Drug 
dispensation for 
sabatolimab
X
X
X
X
X
X
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Period
Screening
Treatment
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Visit Name Screening (-
28 to -1)
D1
D8
D22
D28
D1
D8
D22
D28
D1
D8
D28
D1
D8
D28
D1
D8
D28
D1
D8
Days
-28 to -1
D1
D8
D22
D28
D1
D8
D22
D28
D1
D8
D28
D1
D8
D28
D1
D8
D28
D1
D8
IRT - Drug 
dispensation for 
venetoclax and 
azacitidine11
X
X
X
X
X
X
Sabatolimab infusion
X
X
X
X
X
X
Venetoclax 
administration
400 mg daily po D1 to D14 of each cycle
Azacitidine infusion
on Days 1- 7 of each Cycle OR on Days 1-5 and then on Day 8 and Day 9 of each cycle
Efficacy - Bone 
marrow aspirate 
and/or biopsy AND 
peripheral blood 
smears
X
X
Efficacy - response 
assessment12
X
Efficacy - Peripheral 
blood collection
X
X
PK sampling for 
sabatolimab13
X
X
X
X
PK sampling for 
venetoclax14
X
X
Immunogenicity (IG) 
sampling for 
sabatolimab13
X
X
X
X
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Period
Screening
Treatment
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Visit Name Screening (-
28 to -1)
D1
D8
D22
D28
D1
D8
D22
D28
D1
D8
D28
D1
D8
D28
D1
D8
D28
D1
D8
Days
-28 to -1
D1
D8
D22
D28
D1
D8
D22
D28
D1
D8
D28
D1
D8
D28
D1
D8
D28
D1
D8
Concomitant 
medications and 
medical procedures 
(including blood 
transfusions 
requirement)
Continuous
FACIT-Fatigue17
X
X
X
X
X
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Period
Screening
Treatment
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Visit Name Screening (-
28 to -1)
D1
D8
D22
D28
D1
D8
D22
D28
D1
D8
D28
D1
D8
D28
D1
D8
D28
D1
D8
Days
-28 to -1
D1
D8
D22
D28
D1
D8
D22
D28
D1
D8
D28
D1
D8
D28
D1
D8
D28
D1
D8
Hospitalizations20
X
Antineoplastic 
therapies, HSCT and 
transfusions since 
discontinuation of 
study treatment
Disposition
X
Survival Follow-up
Period
Treatment
End of Treatment
Safety Follow-up
Efficacy Follow-up
Survival Follow-up
Cycle
Cycle 6
Cycle 7 (and subsequent cycles)
Visit Name
D28
D1
D8
D28
EOT
30, 90, 150 day
Every 12 weeks until 
Disease Progression
Every 3 months 
Days
D28
D1
D8
D28
EOT
30, 90, 150 days
Every 12 weeks 
Every 12 weeks
Informed consent
IRT Registration
X
Demography
Inclusion / Exclusion 
criteria
Medical 
history/current 
medical conditions
Disease History1
Prior antineoplastic 
therapies
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Period
Treatment
End of Treatment
Safety Follow-up
Efficacy Follow-up
Survival Follow-up
Cycle
Cycle 6
Cycle 7 (and subsequent cycles)
Visit Name
D28
D1
D8
D28
EOT
30, 90, 150 day
Every 12 weeks until 
Disease Progression
Every 3 months 
Days
D28
D1
D8
D28
EOT
30, 90, 150 days
Every 12 weeks 
Every 12 weeks
Prior/concomitant 
medications, 
surgery and medical 
procedures 
(including blood 
transfusions 
requirement)2
Adverse Events
Continuous
X21
Physical 
Examination
S
S
S
Vital Signs
X
X
X
Body Height
BSA (use height 
from screening)
X
Body Weight
X
X
ECOG PS
X
X
Hematology
X
X
X
every 12 weeks 
(aligned to time of 
response 
assessments) and if 
clinically indicated22
Chemistry
Pre-dose and at 7 hrs (+_1hr) post dose during first cycle from Day 1 to 
Day 3, then at Predose on Day 1 of every subsequent Cycle, at EOT and 
unscheduled as clinically indicated
Coagulation
X
X
Cytogenetics 4
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Period
Treatment
End of Treatment
Safety Follow-up
Efficacy Follow-up
Survival Follow-up
Cycle
Cycle 6
Cycle 7 (and subsequent cycles)
Visit Name
D28
D1
D8
D28
EOT
30, 90, 150 day
Every 12 weeks until 
Disease Progression
Every 3 months 
Days
D28
D1
D8
D28
EOT
30, 90, 150 days
Every 12 weeks 
Every 12 weeks
Ferritin, iron, 
erythrocyte and 
serum folates, 
vitamin B12
If clinically indicated
Cytokines for safety
Anytime for a suspected cytokine release syndrome, immediately after the 
AE, and one week after occurrence of AE
Urinalysis (dipstick)
If clinically indicated
Thyroid function5
at Cycle 8 Day 1 then every 
3 cycles (Day 1) thereafter 
and as clinically indicated
X
Virology hepatitis B 
and C
If clinically indicated
HIV serology (only if 
required per local 
regulation)
Additional hepatic 
tests in case of DILI6
If clinically indicated
Serum Pregnancy 
test 8
S
Urine Pregnancy 
Test OR Serum 
Pregnancy Test8
S
monthly23
12-Lead ECG 
(triplicates)10
S
X
IRT - Drug 
dispensation for 
sabatolimab
X
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Period
Treatment
End of Treatment
Safety Follow-up
Efficacy Follow-up
Survival Follow-up
Cycle
Cycle 6
Cycle 7 (and subsequent cycles)
Visit Name
D28
D1
D8
D28
EOT
30, 90, 150 day
Every 12 weeks until 
Disease Progression
Every 3 months 
Days
D28
D1
D8
D28
EOT
30, 90, 150 days
Every 12 weeks 
Every 12 weeks
IRT - Drug 
dispensation for 
venetoclax and 
azacitidine11
X
Sabatolimab 
infusion
X
Venetoclax 
administration
400 mg daily po D1 to D14 of each 
cycle
Azacitidine infusion
on Days 1- 7 of each Cycle OR on 
Days 1-5 and then on Day 8 and Day 
9 of each cycle
Efficacy - Bone 
marrow aspirate 
and/or biopsy AND 
peripheral blood 
smears
At Cycle 7 Day 1, Cycle 10 Day 1, Cycle 13 Day 1, then every 6 cycles (C19D1 and C25D1), then every 12 
cycles (C37 Day 1, C49D1, etc.) and when clinically indicated at any time during the treatment period. At EOT 
and thereafter at least every 12 months and anytime if clinically indicated during the efficacy follow-up period
Efficacy - response 
assessment12
At Cycle 7 Day 1, Cycle 10 Day 1, Cycle 13 Day 1, then every 6 cycles (C19D1 and C25D1), then every 12 
cycles (C37 Day 1, C49D1, etc.) and when clinically indicated at any time during the treatment period. At EOT 
and thereafter at least every 12 months and anytime if clinically indicated during the efficacy follow-up period
Efficacy - Peripheral 
blood collection
At Cycle 7 Day 1, Cycle 10 Day 1, Cycle 13 Day 1, then every 6 cycles (C19D1 and C25D1), then every 12 
cycles (C37 Day 1, C49D1, etc.) and when clinically indicated at any time during the treatment period. At EOT 
and thereafter at least every 12 months and anytime if clinically indicated during the efficacy follow-up period
PK sampling for 
sabatolimab13
At Day 8 of 
cycles 9, 12, 18 
and 24
X
at 30 and 150 days 
(if visit is conducted 
at site)
PK sampling for 
venetoclax14
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Period
Treatment
End of Treatment
Safety Follow-up
Efficacy Follow-up
Survival Follow-up
Cycle
Cycle 6
Cycle 7 (and subsequent cycles)
Visit Name
D28
D1
D8
D28
EOT
30, 90, 150 day
Every 12 weeks until 
Disease Progression
Every 3 months 
Days
D28
D1
D8
D28
EOT
30, 90, 150 days
Every 12 weeks 
Every 12 weeks
Immunogenicity (IG) 
sampling for 
sabatolimab13
At Day 8 of 
cycles 9, 12, 18 
and 24
X
at 30 and 150 days 
(if visit is conducted 
at site)
Concomitant 
medications and 
medical procedures 
(including blood 
transfusions 
requirement)
Continuous
X24
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Period
Treatment
End of Treatment
Safety Follow-up
Efficacy Follow-up
Survival Follow-up
Cycle
Cycle 6
Cycle 7 (and subsequent cycles)
Visit Name
D28
D1
D8
D28
EOT
30, 90, 150 day
Every 12 weeks until 
Disease Progression
Every 3 months 
Days
D28
D1
D8
D28
EOT
30, 90, 150 days
Every 12 weeks 
Every 12 weeks
FACIT-Fatigue17
X
X
Every 24 weeks 
(aligned with response 
assessment)22
Hospitalizations20
Antineoplastic 
therapies, HSCT 
and transfusions 
since 
discontinuation of 
study treatment
Continuous
Disposition
X
X
Survival Follow-up
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 The last assessment of bone marrow and/or peripheral blood counts should be used within 28 days prior to enrollment.
2 Blood transfusions administered within 16 weeks prior to the first dose will be collected and recorded in the eCRF. 
3 Blood chemistry should be confirmed within 72 hours prior to planned first dose.
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Period
Treatment
End of Treatment
Safety Follow-up
Efficacy Follow-up
Survival Follow-up
Cycle
Cycle 6
Cycle 7 (and subsequent cycles)
Visit Name
D28
D1
D8
D28
EOT
30, 90, 150 day
Every 12 weeks until 
Disease Progression
Every 3 months 
Days
D28
D1
D8
D28
EOT
30, 90, 150 days
Every 12 weeks 
Every 12 weeks
4 Cytogenetics to be performed locally. Assessment to be recorded in the clinical database (eCRF)
5 Any deficiency should be corrected before the start of Study Treatment.  Refer to Table 8-3 for details on analytes to be tested.
6 Refer to Section 6.5.4.3 for DILI follow-up
7 Only GLDH to be tested at baseline - see Table 8-7
8 This test will be performed only for women of child bearing potential
9 Does not need to be performed if it was done in screening within 72 hours before first dose
10 Refer to Section 8.4.2 for detailed guidance on timepoints
11 Venetoclax will be dispensed via IRT on Day 1 of each Cycle.  Azacitidine will be dispensed via IRT daily as per standard clinical practices.
12 See Section 8.3.1 for details on response assessments
13 See Table 8-9 for detailed PK/IG sampling timepoints and schedule
14 See Table 8-10 for detailed timepoints and collection schedule for venetoclax PK sampling. Venetoclax PK sampling will be collected during Phase 1 (safety run-in) 
only.
17 PROs will be collected during Phase 2 (expansion) only
20 Hospitalization is required at Cycle 1 from Day 1 to Day 3 for subjects participating to the Safety run-in Part. Chemistry will be collected on pre-dose Day 1, Day 2 and 
Day 3 for TLS monitoring. 
21 If the patient begins new antineoplastic medication before the end of the safety follow-up period, then only suspected AEs and suspected SAEs will continue to be 
collected. See Section 10.1
22 Starting from last on treatment efficacy assessment
23 Pregnancy testing for women of child bearing potential should be performed monthly during the safety follow-up period (urine or serum test may be performed, 
depending on local regulations).
24 Transfusions administered during efficacy follow-up will be recorded in the CRF every 12 weeks (aligned with efficacy assessment visits).
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8.1
Screening
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. 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 childbearing potential) which must be conducted and confirmed as negative within 
72 hrs prior to the start of study treatment. Laboratory parameters may be retested within the 
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 as soon as possible 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, confirmation of MDS diagnosis, IPSS-R risk 
classification for MDS participants at time of screening, prior antineoplastic therapies. 
Calculation of IPSS-R risk score for MDS participants and should be done based on the 
hematology values obtained at screening.
!
Relevant prior antineoplastic therapies and all concomitant medications and medical 
procedures
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!
Blood transfusions (RBC/platelets) administered within 16 weeks before the first dose is 
administered
Other assessments will be completed for the purpose of determining eligibility for inclusion in 
the study as reported in Table 8-1.
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, coagulation, urinalysis (dipstick and sediment), 
serum pregnancy test for women of child-bearing potential, thyroid function, cytogenetics, 
virology hepatitis B and C, HIV serology (only if required per local regulation)
!
Triplicate 12-lead central ECG
!
Bone marrow aspirate (BMA) or biopsy will be performed locally to establish the diagnosis. 
Cytogenetics will be performed locally as per local standard. If a bone marrow aspirate or 
biopsy was conducted during the regular work-up of the participant and fall within the 28 
days prior to start of treatment (although prior to signing main study ICF), it may be 
considered as the baseline assessment for the study.
Bone marrow and peripheral blood pathology specimens (i.e. bone marrow slides, bone 
marrow biopsy block if applicable, peripheral blood smears) prepared locally for establishing 
the MDS diagnosis at the time of screening, should be sent to the Novartis designated central 
laboratory for storage. A copy of the corresponding pathology reports should be collected and 
sent to the Novartis designated central laboratory for storage. Central morphology review of the 
pathology specimens may be performed, if deemed necessary.
 
!
Blood sample for Cytokines
!
Adverse events
 
 
 
 
 
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Authorities. Investigators will have the discretion to record abnormal test findings on the 
medical history CRF whenever in their judgment, the test abnormality occurred prior to the 
informed consent signature. Significant new findings that begin or worsen after informed 
consent must be recorded on the AE page of the participant’s eCRF.
After all applicable study ICFs are signed, the participant will be registered in the IRT system.
8.3
Efficacy
8.3.1
Efficacy assessments
Disease response will be assessed locally by the investigator in all participants (MDS) according 
to modified IWG for MDS and WHO criteria (Cheson et al 2000, Cheson et al 2006, 
Arber et al, 2016, Platzbecker 2019). Response criteria are described in Table 8-2.
Investigators will assess and document response/progression at each time point as per the visit 
schedule. For efficacy analyses, baseline assessment is defined as the last non-
missing assessment on or before the date of sabatolimab.
In 
addition, 
the 
hematological 
improvement 
per 
modified 
IWG-MDS 
criteria 
(Cheson et al 2006) will be assessed in all enrolled participants to report specific hematologic 
improvement (HI) of cytopenias in the three hematopoietic lineages: erythroid (HI-E), platelet 
(HI-P), and neutrophil (HI-N).
Table 8-2
Modified response classification per IWG-MDS criteria (Platzbecker et 
al 2019, Cheson et al 2006, Cheson et al 2000)
Response category
Definition#
Complete remission (CR)
Bone marrow:
<= 5% blasts with normal maturation of all 
cell lineages. (Note: Persistence of dysplasia 
will be noted but does not preclude 
achievement of complete remission [CR])
Peripheral blood:
1. Hgb ≥ 10 g/dl AND
2. Platelets ≥ 100*109/L AND
3. Neutrophils ≥ 1.0*109/L AND
4. Blasts 0%
(Note: the participant must not receive RBC 
or platelet transfusions, myeloid growth 
factor within 2 weeks before this disease 
assessment)
marrow Complete remission (mCR)
Bone marrow:
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Response category
Definition#
<= 5% blasts and blast count decrease by ≥ 
50% compared to baseline
Peripheral blood/transfusion: Marrow CR 
may be achieved with or without improved 
blood counts or with or without transfusions
Partial remission (PR)
All CR criteria except
Bone marrow: ≥ 50% decrease from 
baseline in blasts in bone marrow AND blast 
count in bone marrow > 5%
Stable Disease (SD)
Failure to achieve at least PR, but no 
evidence of progression for >8 weeks
Relapse from CR
Only in participants with a CR
At least 1 of the following criteria is met: 
[in absence of another explanation not due to 
MDS, such as acute infection, bleeding, 
hemolysis, etc. Note that observation of 
peripheral blasts is not a sufficient criterion 
for relapse. However in that case, a bone 
marrow examination should be made to 
determine whether relapse has occurred]
1. Return to baseline bone marrow blast 
percentage
2. Decrease of ≥ 50% from maximum 
remission/response*** levels in neutrophils 
AND 
neutrophils 
<1.0*109/L. 
Note: 
neutrophils counts during periods of active 
infection 
will 
not 
be 
considered 
in 
determining the maximum
3. Decrease of ≥ 50% from maximum 
remission/response*** levels in platelets 
AND platelets < 100*109/L
4. 
Decrease 
from 
maximum 
remission/response*** 
levels
in 
Hgb 
concentration by ≥ 1.5g/dL AND Hgb < 10 
g/dL
5. Becoming transfusion dependent**
Disease progression
At least 1 of the following criteria is met:
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Response category
Definition#
[in absence of another explanation not due to 
MDS, such as acute infection, bleeding, 
hemolysis, etc. Note that observation of 
peripheral blasts is not a sufficient criterion 
for progression. However in that case, a bone 
marrow examination should be made to 
determine whether relapse has occurred]
Bone marrow according to the number of 
blasts of the participant at baseline:
1. Less than 5% blasts at baseline: ≥ 50% 
increase in blasts over baseline to > 5% blasts
2. 5% - < 10% blasts at baseline: ≥ 50% 
increase over baseline to > 10% blasts
3. 10% - < 20% blasts at baseline: ≥ 50% 
increase over baseline to > 20% blasts.
Participants with more than 20% of blasts 
will be considered to have transformation to 
acute leukemia per 2016 WHO classification 
(Arber et al, 2016)
Peripheral blood:
1. Decrease of ≥ 50% from maximum 
remission/response*** levels in neutrophils 
AND 
neutrophils 
< 
1.0*109/L. 
Note: 
neutrophils counts during periods of active 
infection 
will 
not 
be 
considered 
in 
determining the maximum
2. Decrease of ≥ 50% from maximum 
remission/response*** levels in platelets 
AND platelets < 100*109/L
3. 
Reduction 
from 
maximum 
remission/response*** levels in Hgb by ≥ 
2g/dL AND Hgb < 10g/dL
Becoming transfusion dependent**
Occurrence 
of 
acute 
leukemia, 
or 
extramedullary leukemia per investigator's 
judgement
Modified Hematologic Improvement per IWG-MDS criteria (Cheson et al 2006)
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Response category
Definition#
HI category
Definition# (HI must last at least 8 weeks)
Erythroid response (HI-E) 
(pretreatment*, <11 g/dL)
1. Hgb increase from baseline by ≥ 1.5 g/dL, 
in at least 2 consecutive Hgb measurements 
and maintained over at least 8 weeks
2. Relevant reduction from baseline of units 
of RBC transfusions by an absolute number 
of at least 4 RBC transfusions/8 weeks 
compared with the pre-treatment transfusion 
number in the previous 8 weeks. Only RBC 
transfusions given for a Hgb of < 9 g/dL pre-
treatment will count in the RBC transfusion 
response evaluation.
Platelet response (HI-P) (pretreatment*, 
<100 x 109/L)
1. Absolute increase from baseline of ≥ 30 x 
109/L for participants starting with > 20 x 
109/L platelets
2. Increase from baseline from < 20 x109/L to 
> 20 x109/L and by at least 100% for 
participants starting with < 20 x 109/L 
platelets
Neutrophil response (HI-N)
(pretreatment*, <1.0 x 109/L)
At least 100% increase and an absolute 
increase from baseline of > 0.5 x 109/L
#If not defined otherwise, all of the criteria apply. Words that are written in italics highlights the 
modifications from the IWG criteria described in the reference publications.
*Pretreatment counts correspond to the baseline (not influenced by transfusions)
**Definition of transfusion dependence and independence for red blood cells (RBC) and/or platelets are 
described below.
***maximum remission/response levels correspond to the best values reported in post baseline.
Transfusions Status Definitions for RBC/platelets
Transfusions for intercurrent diseases not due to study indication (e.g. bleeding, surgical 
procedure, hemolysis, infections) should not be taken into account for the following:
Transfusion dependence:
1. At baseline: participants having received ≥ 3 units of transfusion within the 8 consecutive 
weeks 
prior 
to 
baseline.
2. Post-baseline: participants having received ≥ 3 units of transfusion within any 8 consecutive 
weeks during the course of the study
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Transfusion independence:
1. At baseline: participants having received 0 units of transfusion within the 8 consecutive 
weeks prior to baseline.
2. Post-baseline: participants having received 0 units of transfusion within any 8 consecutive 
weeks during the course of the study.
Response assessment will be performed by investigator according to the assessment schedule 
depicted in Table 8-1. Moreover, participants can be assessed for disease response (bone 
marrow assessment, hematology, transfusion) at any time if clinically indicated as an example 
if there is a clinical suspicion of progression/relapse, in particular after a participant has 
achieved a CR.
Bone marrow assessments will be performed at screening and pre-dose on C3D1. From C7D1, 
bone marrow assessments will be performed every 3 cycles until C13D1 (C7D1, C10D1, 
C13D1), then every 6 cycles until C25D1 (C19D1 and C25D1) and thereafter every 12 cycles
(C37D1, C49D1 etc.) and as clinically indicated during the treatment period.
Hematology assessments will be performed at screening, pre-dose on D1, D8 and D22 of Cycles 
1 and 2, and thereafter pre-dose on D1 and D8 of each cycle until end of treatment.
Bone marrow and peripheral blood pathology specimens (i.e. bone marrow aspirate slides, bone 
marrow biopsy block if applicable, peripheral blood smears) prepared locally for the disease 
response assessment, should be sent to the Novartis designated central laboratory for storage. 
This includes specimens taken during the regular work-up of the participant and used as baseline 
assessment for the study as mentioned in Section 8.2 . A copy of the corresponding pathology 
reports should be collected and sent to the Novartis designated central laboratory for storage. 
Central morphology review of the pathology specimens may be performed, if deemed necessary. 
For China only: Storage of the above pathology specimens and reports in a Novartis designated 
laboratory will be performed, if adequate approval has been obtained from all relevant Chinese 
authorities.
Participants who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent, will enter the efficacy follow-up phase.
In the efficacy follow-up phase, hematology assessments must continue to be performed every 
3 months, response should be assessed at least every 12 months, and bone marrow assessment 
should be done at least every 12 months thereafter per Table 8-1, or as clinically indicated any 
time in case disease progression is suspected. Further information about blood transfusions will 
be continuously collected throughout the efficacy follow-up period.
The efficacy follow-up period will last until participant's documented disease progression (per 
IWG criteria Table 8-2), death, lost to follow-up, or withdrawal of consent, or the end of the 
study whichever comes first. Post-treatment antineoplastic therapies, including HSCT, will 
continue to be captured during survival follow-up (see Section 9.1.1.3 and Table 8-1).
8.3.2
Appropriateness of efficacy assessments
The assessment of response to study treatment is based on standardized criteria as proposed 
by modified IWG-MDS criteria (Cheson et al 2006) in Table 8-2.
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8.4
Safety
Safety assessments are specified in Table 8-3 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 8-3
Assessments and 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 D1 of each cycle. At D8 of each cycle and 
D22 of Cycles 1 and 2, an abbreviated 
examination can be done at investigator's 
discretion.
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.
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 timepoints as 
specified in Table 8-1
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Performance status:
ECOG Performance status scale will be used as described in Table 8-4.
Table 8-4
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 house work, 
office work)
2
Ambulatory and capable of all self-care but 
unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair
5
Death
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 8-5) 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 8-6 and as per the schedule 
in Table 8-1.
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 in the trial.
Table 8-5
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
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Test Category
Test Name
(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, Uric 
Acid, Amylase, Lipase, Glucose (fasting), 
Troponin-T or Troponin-I, NTproBNP**
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)
Thyroid
At baseline: TSH, Free-T3 and Free-T4.
During 
treatment: 
TSH 
at 
timepoints 
indicated in Table 8-1 and as clinically 
indicated. If TSH is abnormal, then test free-
T3 and free-T4.
Urinalysis***
(dipstick)
Dipstick examination includes specific 
gravity, pH, glucose, protein, blood, 
bilirubin, ketones and WBC as clinically 
indicated. If urinalysis dipstick shows 
abnormalities, the site should perform a 
more detailed urinalysis follow-up as 
clinically indicated and per local practice.
Pregnancy Test***
Serum / Urine pregnancy test (refer to 
Section 8.4.3 'Pregnancy and assessments of 
fertility')
Additional Tests
Ferritin, iron, vitamin B12, erythrocyte 
and/or serum folates ****
* 
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
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*** Virology, urinalysis, and pregnancy test will only be reported in the source documentation
**** Preferred method is erythrocyte folate but in case is not available then serum should be performed. 
However, every effort should be made to perform both test.
Table 8-6
Central clinical laboratory parameters collection plan
Test category
Test Name
Cytokines
IFN-γ, IL-6, IL-1b, TNF-α
Chemistry for DILI 1
Glutamate dehydrogenase (GLDH)
1 at baseline and as clinically indicated for follow-up of DILI per Section 6.5.4.3
8.4.2
Electrocardiogram (ECG)
The ECGs are to be collected with ECG machines supplied by the central laboratory during the 
following timepoints: Screening, C1D1 predose, C1D8 post dose, and C3D8 postdose, EOT 
and unscheduled if clinically indicated. At the remaining time-points ECG will be collected 
locally (please refer to Table 8-7 and Table 8-8). The QT interval corrected by Fridericia's 
formula (QTcF) should be used for clinical decisions.
When triplicate ECG is required, collect three serial ECGs approximately 3 minutes apart after 
the participant has been resting comfortably in a supine position for about 10 minutes (it should 
be obtained before blood collection if a blood sample is scheduled at the same time point). Pre-
dose ECG to be collected prior to any study drug dosing. Post-dose ECG to be collected at the 
end of study drug infusion.
Table 8-7
Central ECG collection plan
Cycle
Day
Time point *
Screening
Day -28 to Day -1
Anytime
Cycle 1
Day 1
Pre-dose1
Day 8
Post-dose2
Cycle 3
Day 8
Post-dose2
EOT
N/A
Anytime
Unscheduled
Any
As clinically indicated3
* all ECGs to be collected in 12-lead triplicate
1 ECG collection prior to any study drug dosing
2 ECG collection at end of sabatolimab infusion
3 Only required if clinically significant findings in local ECG
Table 8-8
Local ECG collection plan
Cycle
Day
Time point *
Cycle 2
1
Pre-dose
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Cycle
Day
Time point *
Cycle 3
1
Pre-dose
Cycle 4 and subsequent 
cycles
1
Pre-dose
* all ECGs to be collected in 12-lead triplicate
Clinically significant ECG abnormalities present at screening should be reported on the 
appropriate CRF. New or worsened clinically significant findings occurring after informed 
consent must be recorded as adverse events. All ECGs recorded using the machines supported 
by the central ECG vendor must be transmitted electronically to the central ECG vendor and 
should be centrally reviewed by an independent reviewer. Any original ECG not transmitted 
electronically to the central laboratory should be forwarded for central review.
Any identifier details must be redacted e.g. participant initials, date of birth, where local 
regulations require it.
In case of QTcF prolongation, please refer to Section 6.5.4.4.
8.4.3
Pregnancy and assessments of fertility
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.
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
At screening, a serum pregnancy test (serum ß-HCG) must be performed within 3 days (72 
hours) 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 for pregnancy testing 
schedule.
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.
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Women of childbearing potential should employ the use of highly effective contraception 
during study treatment, for 90 days after the last dose of azacitidine, 30 days after the last dose 
of venetoclax (or as per their respective local labels, whichever is longer) and 150 days after 
the last dose of sabatolimab. 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. In addition, male participants should not 
donate sperm for the time period specified above.
8.4.4
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 combination with azacitidine and venetoclax, the study employs a two part 
design with a halt to enrollment following the Safety run-in part of the study as explained in 
Section 4.1.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
The Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-Fatigue) is a 13-
item PRO measure designed to assess fatigue in people with cancer (Yellen et al 1997). It 
includes seven items that assess fatigue-related symptoms and six items that assess impacts of 
fatigue on daily activities and function over the past seven days. The higher the score, the better 
the quality of life. The score ranges from 0 to 52, and a score of less than 30 indicates severe 
fatigue.
 
 
 
 
 
 
 
 
 
 
 
 
 
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All global items will be used to assign clinical meaning to observed group differences e.g., to 
generate clinically important difference (CID estimates) and within person change (e.g., to
generate clinically important response estimates) in the on the FACIT Fatigue 
 
total score from the participant perspective.
Participants will be prompted to complete all PRO questionnaires 
 via a 
provisioned ePRO device at time-points indicated in Table 8-1. At baseline, the questionnaire(s) 
will be completed prior to any interaction with the study investigator including any tests, 
treatments or receipt of results from any tests to avoid biasing participant responses to study 
questionnaires. The participant will be provided an ePRO device to be able to complete the 
PROs at home the day prior to visits to the clinic site as indicated. Please refer to the study 
ePRO manual for detailed instructions for completion and handling of the ePROs.
The PRO measure(s) should be completed in the order they appear on ePRO device.
8.5.2
Pharmacokinetics
Pharmacokinetic (PK), Immunogenicity (IG) 
 samples will be 
obtained and evaluated in all participants. Please refer to Table 8-9 and Table 8-10 for details 
on PK, IG 
 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. If participants experience suspected 
immunologically related AE such as infusion-related reaction, hypersensitivity, cytokine 
release syndrome and anaphylaxis, an unscheduled IG 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
The sabatolimab PK, 
 and IG blood sampling schedule is outlined in Table 8-9. A single 
blood sample of approximately 5 mL will be collected at each time point.
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The venetoclax PK blood sampling schedule is outlined in Table 8-10. A single blood sample 
of approximately 3 mL will be collected at each time point.
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. When PK is collected at the same time 
point as ECG, the PK sample should be taken immediately after ECG.
The exact date and clock times of drug administration and blood draws for PK, IG 
 
assessment will be recorded on the appropriate eCRF.
After permanent discontinuation of sabatolimab, the samples scheduled for pre-sabatolimab 
infusion should no longer be collected.
Detailed instructions for the collection procedures, handling, and shipment of sabatolimab PK, 
IG 
, and venetoclax PK samples will be provided in the [CMBG453B12203 
Laboratory Manual].
Table 8-9
Sabatolimab PK, IG 
 blood collection log
Cycle
Day
Scheduled 
Time Point*
PK sample 
(sabatolima
b)
IG sample
1
1
Pre-
azacitidine/
venetoclax 
dose
8
Pre-
sabatolimab 
infusion
X
X
2
8
Pre-
sabatolimab 
infusion
X
X
3
8
Pre-
sabatolimab 
infusion
X
X
6
8
Pre-
sabatolimab 
infusion
X
X
9
8
Pre-
sabatolimab 
infusion
X
X
12
8
Pre-
sabatolimab 
infusion
X
X
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Cycle
Day
Scheduled 
Time Point*
PK sample 
(sabatolima
b)
IG sample
18
8
Pre-
sabatolimab 
infusion
X
X
24
8
Pre-
sabatolimab 
infusion
X
X
EOT1
Anytime
X
X
30-Day Safety Follow-up
Anytime
X
X
150-Day Safety Follow-up2
Anytime
X
X
Unscheduled3
Anytime
X
X
*All pre-dose samples should be collected within 2 hours before start of infusion
1 If EOT is due to reasons other than disease progression, an unscheduled PK and IG sample should also 
be 
collected 
at 
the 
time 
of 
confirmed 
disease 
progression.
2 Samples at the 150 day safety follow-up visit can be collected at the Investigator's discretion if the 
follow-up 
visits 
are 
conducted 
at 
the 
site.
3Unscheduled PK and IG samples may be collected at any time if clinically indicated or at the 
Investigator's discretion.
Table 8-10
Venetoclax PK blood collection log
Cycle 
Day
Scheduled 
timepoint*
PK sample 
(venetoclax)**
1
8
Pre-venetoclax dose
X
3
8
Pre-venetoclax dose
X
*All pre-dose samples must be collected within 30 min before dose administration
** Venetoclax PK samples will be collected only during Part 1 (Safety run-in) of the study
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.
· Plasma concentrations of venetoclax will be determined using a validated LC-MS assay.
· Immunogenicity testing will consist a multi-tiered ADA testing. A screening assay will be 
used to assess clinical samples. Samples testing positive in the screening assay will then be 
subjected to a confirmatory assay to demonstrate that ADAs are specific for the therapeutic 
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protein product. Samples identified as positive in the confirmatory assay will be further 
characterized in titration and neutralization assays.
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8.5.3.1
Use of residual biological samples
If participant agrees the biological samples from the bone marrow aspirate and blood collected 
may be used for additional studies related to sabatolimab or hematological disease/cancer, 
including research to help develop ways to detect, monitor or treat cancer. Those biological 
samples may be stored for up to 15 years after the end of the study and the decision to perform 
such 
 research studies would be based on outcome data from this study 
or from new scientific findings related to the drug class or disease, as well as assay availability.
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 meets 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
· Use of prohibited treatment as per recommendations in the prohibited treatment section 
(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 
participation in the study
· Progression of disease (including transformation to acute leukemia per WHO 2016
classification, as defined as ≥20% blasts in bone marrow and/or peripheral blood),
· Termination of the study by Novartis
· Subjects who are scheduled for hematopoietic stem cell transplant (HSCT) or intensive 
chemotherapy at any time during the course of the study
If discontinuation of study treatment occurs, 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) 
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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.
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, safety and survival as detailed in Section 9.1.1.1, Section 9.1.1.2
and Section 9.1.1.3.
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 or venetoclax whichever is longer.
After the 30-Day on-site safety follow-up visit, participants will be followed via telephone call 
(or on-site 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. However, if 
the participant begins new antineoplastic 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. For female participants of childbearing potential, a pregnancy 
test will be performed at the timepoints listed in Table 8-1.
9.1.1.2
Post-treatment follow-up
For participants who discontinue treatment for reasons other than disease progression, death, 
lost to follow-up, or withdrawal of consent; efficacy assessments, and other required 
assessments will continue to be performed as per the assessment schedule (see Table 8-1) until 
disease progression, death, lost to follow-up, or withdrawal of consent.
9.1.1.3
Survival follow-up
Participants will enter the survival follow-up period in parallel with the safety follow-up or 
efficacy follow-up periods. Participants will then be contacted by telephone every 12 weeks to 
follow-up on their survival status. Any new antineoplastic therapies that have been started since 
the previous contact will be collected. HSCT information will also be collected during these 
phone calls.
9.1.1.4
Replacement policy
Participants will not be replaced on study. However, if a participant is considered as non-
evaluable for the Safety run-in (Part 1) (see Section 6.5.1), enrollment of a new participant to 
the Safety run-in will be considered if there are less than the required number of evaluable 
participants.
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9.1.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:
!
Does not want to participate in the study anymore,
and
!
Does not want any further visits or assessments
and
!
Does not want any further study related contacts
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 and 
record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of 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. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
For United States (US): All biological samples not yet analyzed at the time of withdrawal may 
still be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For European Union (EU) and Rest of World (RoW): All biological samples not yet analyzed 
at the time of withdrawal will no longer be used, unless permitted by applicable law. They will 
be stored according to applicable legal requirements.
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 or withdraw, 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 
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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 Table 8-1 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. based on recommendation of the 
steering committee (see also Section 10.2.2), participants still receiving study treatment and 
who, according to investigator assessment, continue to benefit from the treatment, will be 
offered to complete study treatment as per protocol or through an alternate setting (see 
Section 9.2).
9.2
Study completion and post-study treatment
Following completion of the safety follow-up period and/or efficacy follow-up period, all 
participants will be followed for survival (see Section 9.1.1.3).
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 CR rate analysis will be conducted after the last participant enrolled has completed 6 cycles 
of treatment or discontinued earlier. 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 the earliest occurrence of one of the following:
· Last participant has been followed for at least 3 years or have discontinued treatment, have 
died, have been lost to follow-up or have withdrawn consent to further participation in the study.
· The last participant on treatment has been enrolled into a separate rollover study or another 
option of continued treatment with sabatolimab.
At the end of the study, in alignment with local regulations, Post Trial Access (PTA) will be 
set-up to provide 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 (see Section 6.1.5). 
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.
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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.
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. AEs 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):
Adverse events will be assessed and graded according to:
1. the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
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
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· its outcome (i.e. recovery status or whether it was fatal)
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, or 30 days after the last administration of venetoclax, whichever is later.
OR
· 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.
Adverse events separate from the progression of malignancy (i.e. deep vein thrombosis at the 
time of progression or hemoptysis concurrent with finding of disease 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.
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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
!
constitutes a congenital anomaly/birth defect
!
requires in participant 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 out participant 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 and the malignant neoplasm is not a disease progression of the 
study indication.
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 
event irrespective if a clinical event has occurred.
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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 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.
SAE reporting timeframes: 
1. Screen Failures (e.g. a participant who is screened but is not treated): 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.
2. Treated participants SAEs collected between time participant signs ICF until 30 days after 
the participant has discontinued or stopped azacitidine or venetoclax 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 must 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 
immediately, without undue delay, and under no circumstances later than within 24 hours of 
the investigator receiving the follow-up information. An 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 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 participant has completed the safety follow-up period should 
only be reported to Novartis Safety if the investigator suspects a causal relationship to study 
treatment.
10.1.4
Pregnancy reporting
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her 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 for 12 months after the estimated date of 
delivery to determine outcome, including spontaneous or voluntary termination, details of the 
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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 participant 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.
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.
Pregnancy outcomes will not be collected for the female partners of any males who took study 
treatment in this study.
10.1.5
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 (see Table 10-1). 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.
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10.2
Additional Safety Monitoring
10.2.1
Data Monitoring Committee
A Data Monitoring Committee (DMC) will not be required for this study considering that it is 
open-label single-arm study. However, close monitoring of safety is planned; 
specifically, Novartis and the study investigators involved in the Safety run-in (Part 1) will 
conduct at least one safety review meeting for each cohort: 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 each 
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 
enrollment on the study. 
10.2.2
Steering Committee
The steering committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being Novartis representatives from the Clinical Trial Team. The SC will ensure 
transparent management of the study according to the protocol through recommending and 
approving modifications as circumstances require. During the Safety run-in (Part 1) the SC will 
review the safety data during the planned safety reviews. Thereafter, during the Expansion (Part 
2), the SC will review periodically the safety data, at least approximately every 6 months. After 
each safety review, the SC will make recommendations on the study conduct (including study 
termination). The SC will review protocol amendments as appropriate. Together with the 
clinical trial team, the SC will also develop recommendations for publications of study results 
including authorship rules. The details of the role of the SC will be defined in a Steering 
Committee charter.
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.
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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, 
etc.) sample collection.
11.2
Database management and quality control
Novartis personnel 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.
Kit numbers and data about sabatolimab, venetoclax and azacitidine dispensed to the participant 
and all dose interruptions (for sabatolimab only) 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.
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, IG, 
) and ECGs 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 
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 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 or delegated CRO CRA organization. Additionally, a 
central analytics organization may analyze data, identify risks and 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 
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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
For each cohort of the safety run-in part, the primary safety analysis will be conducted when 
the evaluable participants would have been observed for 2 cycles of treatment. If the dose of 
400 mg of sabatolimab in combination with azacitidine and venetoclax with at least 3 evaluable 
participants is judged to be safe, then at least 9 new evaluable participants would be needed to 
evaluate the safety of the 800 mg of sabatolimab in combination with azacitidine and venetoclax. 
Otherwise, the study will be stopped. If the 800 mg of sabatolimab is not meeting overdose 
criteria, Expansion (Part 2) of the study will be opened. Otherwise study will be stopped.
The primary efficacy analysis (CR rate analysis) will be performed on all participant data treated 
at dose level of 800 mg of sabatolimab at the time last enrolled participant will have completed 
at least 6 cycles of treatment or discontinued earlier.
The final efficacy and safety analyses will be conducted when last enrolled participant have 
been followed up for at least 3 years (see Section 9.2 for details).
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
12.1
Analysis sets
The Full Analysis Set (FAS) comprises all participants who received at least one dose of study 
treatment.
The Safety Set includes all participants who received at least one dose of study treatment.  
The Dose Determining Set (DDS) includes all participants from the FAS enrolled the Safety 
run-in part who met the minimum exposure criterion and had sufficient safety evaluations, or 
experienced a dose limiting toxicity (DLT) during the first 8 weeks of dosing (two cycles).
A participant has met the minimum exposure criterion if the participant has received during the 
first 2 cycles 2 infusions of sabatolimab at the assigned dose level in Q4W dosing regimen, and 
has taken at least 75 % of the planned dose of azacitidine and venetoclax (i.e. for 2 cycles: 11 
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doses of azacitidine out of the 14 doses planned and 21 doses of venetoclax out of the 28 doses 
planned). 
Participants who do not experience a DLT during Cycles 1 and 2 are considered to have 
sufficient safety evaluations if they have been observed for at least 56 days following the first 
dose, and are considered by both the sponsor and investigators to have enough safety data to 
conclude that a DLT did not occur.
The sabatolimab and venetoclax pharmacokinetic analysis sets include all participants from 
the Safety Set who provide at least one evaluable sabatolimab/venetoclax PK concentration.
For a concentration to be evaluable:
!
Dosing information must be properly documented (data and time of administration).
!
For pre-dose samples: the sample is collected before the next dose administration.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for all participants from the FAS. These data will be summarized by 
dose level of sabatolimab for the safety run-in part and for participants entering the expansion 
part.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure to study treatment as well as each study treatment component 
(sabatolimab (mg), venetoclax (mg) and azacitidine (mg)) as well the dose intensity by cycle 
(mg/day) (derived as the ratio of actual cumulative dose and planned dose intensity per cycle) 
and the relative dose intensity (%) by cycle (derived as the ratio of dose intensity and planned 
dose intensity) will be summarized by descriptive statistics.
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, interruptions or permanent 
discontinuation) for each study treatment component and the reasons will be summarized. All 
exposure data will be listed.
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12.4
Analysis of the primary endpoint(s)
The primary objective of the Safety run-in (Part 1) of the study is to determine whether 
sabatolimab 400 mg and 800 mg are safe (i.e. not meeting overdose criteria) when added in 
combination with azacitidine and venetoclax.
The primary objective of the Expansion (Part 2) is to determine the complete remission rate 
(CR) of sabatolimab (800 mg Q4W) in combination with azacitidine and venetoclax. This 
analysis will include all participants’ data from cohort 2 of the Safety run-in (Part 1) and 
Expansion (Part 2).
12.4.1
Definition of primary endpoints and estimands
12.4.1.1 Safety run-in (Part 1)
For the Safety run-in part, the primary endpoint is the incidence of DLTs in the first 2 cycles of 
treatment for participants in the DDS.
12.4.1.2 Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2)
The primary clinical question of interest is the following:
Is Sabatolimab 800 mg Q4W in combination with fixed doses of azacitidine (75 mg/m2 Day 1-
7) and venetoclax (400 mg Day 1-14) associated with improved efficacy (i.e. CR rate >= 50%) 
for participants with high or very high risk MDS? 
The primary endpoint (combining data from cohort 2 of the Safety run-in (Part 1) and the 
Expansion (Part 2) (i.e. sabatolimab 800 mg (Q4W)) is the proportion of participants achieving 
a complete remission (CR) as per investigator assessment (Section 2 and Table 2-1).
The primary efficacy estimand is described by the following five attributes:
!
Population: Adult participants not eligible for intensive chemotherapy nor for HSCT with 
high or very high risk MDS (IPSS-R criteria (Greenberg et al 2012)) as assessed locally by 
the investigator.
!
Variable: Best overall response among all disease response assessments as assessed by 
investigator per modified IWG MDS criteria (Cheson et al 2006) up to new anti-cancer 
therapy (including HSCT).
!
Treatment: Study treatment is sabatolimab 800 mg Q4W + azacitidine (75 mg/m2 Day 1-
7) + venetoclax (400 mg Day 1-14). Participants will continue treatment until a reason of 
treatment discontinuation is met (e.g. progression, unacceptable toxicity, HSCT) 
(Section 6.1.5).
!
Intercurrent events:
!
Study treatment modification: all CR will be taken into account regardless of any 
study treatment component interruption, dose adjustment or permanent discontinuation 
(Section 6.1.5).
!
Concomitant medications and supportive care: A participant may receive blood 
transfusion as supportive care and prophylactic treatment as clinically indicated (e.g. 
antiemetics, antibiotics, antifungals, Section 6.2.1). All CR will be taken into account 
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regardless of any concomitant medication administration including prohibited 
medications.
!
New anti-cancer therapy/HSCT: CR achieved after initiation of a new anti-cancer 
therapy or HSCT will not be taken into account.
!
Summary measures: The CR rate and the 95% confidence interval (CI).
12.4.2
Statistical model, hypothesis, and method of analysis
12.4.2.1 Safety run-in (Part 1)
Dose Limiting Toxicities (DLT) analysis 
Assessment of sabatolimab 400 and 800 mg (4QW) not meeting overdose criteria when added 
to azacitidine and venetoclax will be based on the estimation of the probability of DLT in the 
first 2 cycles (starting from Cycle 1 Day 8) for participants in the DDS.
The assessment in Safety run-in (Part 1) will be guided by a Bayesian analysis of DLT data for 
sabatolimab, azacitidine and venetoclax in the first 2 cycles (starting from Cycle 1 Day 8) of 
treatment. The probability of DLT is modeled using a Bayesian approach detailed in 
Section 16.1.
After each cohort, the posterior distributions for the risk of DLT will be summarized to provide 
the posterior probability that the risk of excessive toxicity (DLT rate >=33%) is less than 25%.
The escalation with overdose control (EWOC) principle
Dosing decisions are guided by the escalation with overdose control principle 
(Rogatko et al 2007). A combination dose will be judged to be safe if the risk of excessive 
toxicity at that combination dose is less than 25%.
Prior information
A meta-analytic framework approach was used to derive the prior distribution for the single-
agent sabatolimab, azacitidine and venetoclax model parameters. The prior for the logistic 
model parameters for this study is the conditional distribution of the parameters given the 
historical data (see Spiegelhalter 2004, Neuenschwander 2010, Neuenschwander 2014). Priors 
are derived from hierarchical models, which take into account possible differences between the 
studies.
A full description of the application of the meta-analytic framework approach to derive the prior 
distributions of the single agent sabatolimab, azacitidine and venetoclax model parameters is 
given Section 16.
The prior distributions for the interaction parameters were based upon prior understanding of 
possible drug safety interactions. These priors are fully described in Appendix Section 16.
Listing of DLTs
DLTs will be listed, and their incidence summarized by primary system organ class and worst 
grade (CTCAE version 5.0) Listings and summaries will be based on the DDS.
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The Section 16.1 provides details of the statistical method and the probability of excessive 
toxicity for different scenarios in the Safety run-in (Part 1).
12.4.2.2 Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2)
CR primary analysis 
The CR primary analysis will be performed for participants from cohort 2 of Safety run-in (Part 
1) and Expansion (Part 2) treated with sabatolimab 800 mg Q4W.
A Bayesian design will be used in order to estimate the CR rate in the FAS (Full Analysis Set) 
and to provide inferential summaries (e.g., mean, median, standard deviation, 95% credible 
intervals, and interval probabilities) based on Bayesian posterior distribution of the CR rate. 
Assuming a non-informative prior distribution (Beta(1,1)), the distribution of the CR rate will 
be updated with all available data from the participants included in the FAS.
The decision criteria for trial success are the following:
!
Posterior median of CR rate is ≥ 50% and
!
Posterior probability that CR rate is > 39% is at least 97.5%.
The cumulative posterior distribution will be used to derive the probability that the true CR rate 
is superior to 50%. Based on preliminary efficacy data observed with the combination 
azacitidine + venetoclax (Wei et al 2019), a 50% CR rate is a reasonable threshold to be 
considered in this specific setting.
The results will be also presented with a frequentist formulation. The CR rate and the exact 
95% confidence interval (CI) (Clopper CJ and Pearson ES 1934), as well as the 1-sided p-value 
will be provided on the FAS. The test will be performed using an overall one-sided 2.5% level 
of significance. Thus, the null hypothesis (H0:CR ≤ 39%) will be rejected if the lower bound of 
the two-sided 95% exact CI is >39%.
The analysis will be performed using data up to the analysis data cut-off date, which will be 6 
cycles after the last participant is enrolled.
12.4.3
Handling of remaining intercurrent events of primary endpoint
For the primary analysis, only CR assessments after first dose of study treatment and prior start 
of any other anti-neoplastic therapy or HSCT are considered. An adequate response assessment 
is considered any disease assessment indicating response status apart from “unknown” or “not 
done”.
12.5
Analysis of secondary endpoints
The secondary objectives are to assess the overall response rate (ORR), CR/mCR rate, duration 
of CR, time to response, time to CR/mCR, duration of response, duration of CR/mCR, overall 
survival (OS), event free survival (EFS), progression free survival (PFS), leukemia free survival 
(LFS), RBC/platelets transfusion independence, changes from baseline in fatigue, 
pharmacokinetic and safety.
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12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
12.5.1.1 Safety run-in (Part 1)
CR+mCR rate 
CR+mCR rate is defined as the proportion of participants with best overall response of either 
complete remission (CR) or marrow complete remission as per investigator assessment 
(Table 8-3). CR/mCR rate will be provided with exact 95% confidence interval 
(Clopper CJ and Pearson ES 1934).
CR/mCR will be provided by dose level of sabatolimab.
Overall Response Rate (ORR) 
ORR rate is defined as the proportion of participants with best overall response of hematological 
improvement (HI) or better as per investigator assessment (Table 8-3). ORR rate will be 
provided with exact 95% confidence interval (Clopper CJ and Pearson ES 1934).
ORR will be provided by dose level of sabatolimab.
Improvement of RBC/platelets transfusion independence
Red blood cells (RBC)/Platelets transfusion independence rate is defined as the proportion of 
participants having received no RBC/Platelets transfusions during at least 8 consecutive weeks 
(see Section 8.3.1 for details).
The number and percentage of participants will be shown for the overall FAS and then also in 
only those with transfusion dependence at baseline (i.e ≥ 3 units of transfusion within 8 
consecutive weeks prior to start of treatment).
Percentages 
will 
be 
provided 
with 
exact 
95% 
confidence 
intervals 
(Clopper CJ and Pearson ES 1934). For participants with at least one period of transfusion 
independence, the total duration of all transfusion independence periods will be also 
summarized.
The duration of the transfusion independence is defined from the end date of the last transfusion 
received until the date transfusions are given again or last treatment in case transfusions had not 
(re-)started during treatment.
The data will be summarized by dose level of sabatolimab.
Immunogenicity analysis
Immunogenicity will be characterized descriptively by tabulating ADA prevalence at baseline 
and ADA incidence on-treatment. The data will be summarized by dose level of sabatolimab.
12.5.1.2 Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2)
CR+mCR rate 
CR+mCR rate is defined as the proportion of participants treated with sabatolimab at 800 mg 
Q4W with best overall response of either complete remission (CR) or marrow complete 
remission as per investigator assessment (Table 8-3). CR/mCR rate will be provided with exact 
95% confidence interval (Clopper CJ and Pearson ES 1934).
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Overall Response Rate (ORR) 
ORR rate is defined as the proportion of participants treated with sabatolimab at 800 mg Q4W 
with best overall response of hematological improvement (HI) or better as per investigator 
assessment (Table 8-3). ORR rate will be provided with exact 95% confidence interval 
(Clopper CJ and Pearson ES 1934).
Duration of CR
The duration of CR will be derived for participants treated with sabatolimab at 800 mg Q4W 
who achieve CR per modified IWG-MDS CHeson 2006 (prior to any new antineoplastic 
therapy, including HSCT) as per investigator assessment and is defined from the first 
occurrence of CR until relapse, progression or death due to any reason. Relapse, disease 
progression or death occurring after HSCT will be considered as event for the duration of CR. 
The date of the event will be the date of relapse, progression, death whichever occurs first. If 
participant did not relapse nor progressed/died, the duration of response will be censored at last 
adequate response assessment. If the participant has started a new antineoplastic therapy 
without prior documented relapse or progression, the duration of CR is censored at last adequate 
assessment prior to start of that therapy and thus any subsequent relapse/ progression /death not 
considered an event for duration of CR.
Two supplementary analyses will be performed in which (a) new antineoplastic therapy and 
HSCT will not be censored and not counted as an event, and (b) start of new antineoplastic 
therapy will be considered as an event and HSCT will not be censored and not be counted as an 
event.
Duration of CR will be estimated using the Kaplan-Meier Method. The median duration of CR 
along with 95% Confidence interval will be presented.
Duration of CR/mCR 
The duration of CR/mCR will be derived for participants treated with sabatolimab at 800 mg 
Q4W who achieve CR or mCR (prior to any new antineoplastic therapy, including HSCT) as 
per investigator assessment and is defined from the first occurrence of CR or mCR until relapse, 
progression or death due to any reason. Relapse, progression or death occurring after HSCT
will be considered as event for the duration of CR/mCR. The date of the event will be the date 
of relapse, progression, death whichever occurs first. If participant did not relapse nor 
progressed/died, the duration of CR/mCR will be censored at last adequate response assessment.
If the participant has started a new antineoplastic therapy without prior documented relapse or 
progression, the duration of CR/mCR is censored at last adequate assessment prior to start of 
that therapy and thus any subsequent relapse/ progression /death not considered an event for 
duration of CR/mCR.
Two supplementary analyses will be performed in which (a) new antineoplastic therapy and 
HSCT will not be censored and not counted as an event, and (b) start of new antineoplastic 
therapy will be considered as an event and HSCT will not be censored and not be counted as an 
event.
Duration of CR/mCR will be estimated using the Kaplan-Meier Method. The median duration 
of CR/mCR along with 95% Confidence interval will be presented.
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Duration of response 
The duration of response will be derived for participants treated with sabatolimab at 800 mg 
Q4W who achieve HI or better (prior to any new antineoplastic therapy, including HSCT) as 
per investigator assessment and is defined from the first occurrence of CR, mCR, PR or HI until 
relapse, progression or death due to any reason.
Relapse, progression or death occurring after HSCT will be considered as event for the duration 
of response. The date of the event will be the date of relapse, progression, death whichever 
occurs first. If participant did not relapse nor progressed/died, the duration of response will be 
censored at last adequate response assessment. If the participant has started a new antineoplastic 
therapy without prior documented relapse or progression, the duration of response is censored 
at last adequate assessment prior to start of that therapy and thus any subsequent relapse/ 
progression /death not considered an event for duration of response.
Two supplementary analyses will be performed in which (a) new antineoplastic therapy and 
HSCT will not be censored and not counted as an event, and (b) start of new antineoplastic 
therapy will be considered as an event and HSCT will not be censored and not be counted as an 
event.
Duration of response will be estimated using the Kaplan-Meier method. The median duration 
of response along with 95% confidence interval will be presented.
Time to CR/mCR 
The time to CR/mCR will be derived for all participants treated with sabatolimab at 800 mg 
Q4W and is defined from start of treatment to first occurrence of CR/mCR (prior to any new 
antineoplastic therapy, including HSCT). For participants who reached CR /mCR after HSCT 
or a new antineoplastic therapy, the time to CR/mCR will be censored at time of HSCT or 
initiation of new antineoplastic therapy.
Participants who did not reach CR/mCR will be censored at last adequate response assessment. 
For participants who progressed, died or the disease progressed to acute myeloid leukemia, the 
time to CR/mCR will be censored at maximum follow-up (last participant last visit).
Time to CR/mCR will be estimated using the Kaplan-Meier method. The median time to 
CR/mCR along with 95% confidence interval will be presented.
Event-free survival (EFS) 
Event-free survival (EFS) is defined from the date of start of treatment to:
!
Lack of complete remission within the first 6 cycles of start of treatment
!
Progression/Relapse
!
Death from any cause
whichever occurs first.
Participants treated with sabatolimab at 800 mg Q4W who failed to achieve CR within 6 cycles 
of treatment will have their EFS event documented at start of treatment. If participant 
discontinued treatment due to any reason (including death) prior to 6 cycles and without CR 
will be considered as EFS event documented at start of treatment date.
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Progression/Relapse, death events after HSCT and transfusion of blood products will be taken 
into account. However,
Progression/Relapse, death occurring after initiation of new 
antineoplastic therapy will not be considered as event and EFS will be censored at last adequate 
response assessment.
In case of two or more missing assessments prior to documented progression, relapse or death, 
EFS will be censored at the last adequate response assessment prior to the documentation of 
relapse or death.
EFS will be estimated using the Kaplan-Meier method. The median EFS along with 95% 
confidence interval will be presented.
Progression free survival (PFS) 
PFS is defined as the time from start date of treatment to date of relapse, progression (including 
transformation to acute leukemia per WHO 2016 classification) or death due to any cause. If a 
participant is not known to have relapsed progressed nor died, PFS will be censored at the last 
adequate response assessment (on or before the cut-off date). Progression/relapse or death after 
HSCT, interruptions, or discontinuation of study treatment due to any reason will be taken into 
account. However, Progression/Relapse, death occurring after initiation of new antineoplastic 
therapy will not be considered as event and PFS will be censored at last adequate response 
assessment.
In case of two or more missing assessments prior to documented progression, relapse or death, 
PFS will be censored at the last adequate response assessment prior to the documentation of 
progression, relapse or death.
PFS will be estimated using the Kaplan-Meier method. The median PFS along with 95% 
confidence interval will be presented.
Leukemia free survival (LFS) 
LFS is defined as the time from start of treatment to transformation to acute leukemia as per 
investigator assessment defined as the following:
!
≥ 20% blasts in bone marrow/ peripheral blood (per WHO 2016 classification)
!
Diagnosis of extramedullary acute leukemia
!
Death due to any cause
whichever occurs first.
If a participant is known to not have progressed to leukemia, then LFS will be censored at the 
last bone marrow/peripheral blood assessments (on or before the cut-off date). All of three 
events (≥ 20% blasts in bone marrow/peripheral blood, diagnosis of extramedullary acute 
leukemia or death) after HSCT, interruptions, or discontinuation of study treatment due to any 
reason will be taken into account. However, events occurring after initiation of new 
antineoplastic therapy will not be considered as event and LFS will be censored at last 
assessment of bone marrow/peripheral blood, diagnosis of extramedullary acute leukemia or 
survival follow-up prior to initiation of new antineoplastic therapy.
LFS will be estimated using the Kaplan-Meier method. The median LFS along with 95% 
confidence interval will be presented.
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Overall Survival (OS) 
OS is defined as the time from start date of treatment to date of death due to any cause. If a 
participant is not known to have died, then OS will be censored at the latest date the participant 
was known to be alive (on or before the cut-off date). All deaths will be taken into account 
whenever the death occurred, i.e. even after new anti-neoplastic therapy, HSCT, interruptions, 
or discontinuation of study treatment due to any reason.
OS will be estimated using the Kaplan-Meier method. The median OS along with 95% 
confidence interval will be presented.
Improvement of RBC/platelets transfusion independence 
Red blood cells (RBC)/Platelets transfusion independence rate is defined as the proportion of 
participants having received no RBC/Platelets transfusions during at least 8 consecutive weeks 
(see Section 8.3.1 for details).
The number and percentage of participants will be shown for the overall FAS and then also in 
only those with transfusion dependence at baseline (i.e ≥ 3 units of transfusion within 8 
consecutive weeks prior to start of treatment).
Percentages 
will 
be 
provided 
with 
exact 
95% 
confidence 
intervals 
(Clopper CJ and Pearson ES 1934). For participants with at least one period of transfusion 
independence, the total duration of all transfusion independence periods will be also 
summarized.
The duration of the transfusion independence is defined from the end date of the last transfusion 
received until the date transfusions are given again or last treatment in case transfusions had not 
(re-)started during treatment.
Immunogenicity analysis 
Immunogenicity will be characterized descriptively by tabulating ADA prevalence at baseline 
and ADA incidence on-treatment.
12.5.1.3 Expansion (Part 2)
MDS symptoms and fatigue
The following analyses will be performed:
!
Changes from baseline to post-baseline in fatigue using the FACIT-Fatigue 
.
12.5.2
Safety endpoints
Safety analyses will be summarized for the safety set of the Safety run-in (Part 1) and Expansion 
(Part 2). Safety data will be provided by dose level of sabatolimab in the Safety run-in part.
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).
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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 
administration of study treatment
2. On-treatment period: from date of first administration of study treatment to 30 days after date 
of last administration of study treatment
3. Post-treatment period: any observation starting at day 31 after last administration 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.
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.
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.
12-lead ECG
HR PR, and QTcF will be obtained from 12-lead ECGs for each participant at screening and 
during the study. ECG data will be read and interpreted centrally.
Categorical analysis of QTcF interval and HR data will be based on the summary of number of 
participants meeting or exceeding predefined limits.
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.
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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
Other safety evaluations
ECOG PS
ECOG PS will be summarized at each timepoint during the study.
12.5.3
Pharmacokinetics
The respective Pharmacokinetic Analysis Set (PAS) for sabatolimab and venetoclax from 
Safety run-in (Part 1) and Expansion (Part 2) will be used in all pharmacokinetic data analysis.
Sabatolimab and venetoclax drug concentrations
Sabatolimab and venetoclax concentration data will be listed by participant, and visit/sampling 
time point. Descriptive summary statistics for sabatolimab and venetoclax concentrations will 
be provided by visit/sampling time point. Summary statistics will include 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%. PK parameters (the minimum observed plasma or serum 
drug concentration (Cmin or Ctrough) will be estimated and reported. Missing values for any 
PK parameters or concentrations will not be imputed and will be treated as missing.
All concentration data for sabatolimab and venetoclax vs. time profiles will be displayed 
graphically. 
As the half-life of venetoclax is approximately 26 hours, the sample collected at Cycle 1 Day 8 
will be considered as the baseline venetoclax concentration at steady state before any dose 
administration of sabatolimab. The impact of sabatolimab on the venetoclax concentrations may 
be assessed by comparing concentrations before and after sabatolimab.
Population pharmacokinetic analysis
If data permit, a mixed-effects model may be applied to the serum sabatolimab concentration-
time data from this study along with other studies to generate post-hoc estimates of 
pharmacokinetic parameters using appropriate software to characterize sabatolimab exposure 
and to determine the effects of intrinsic (i.e. demographic factors) and extrinsic covariates (e.g. 
combination partners) on sabatolimab exposure. If there is sufficient data for analysis, the 
details of the population pharmacokinetic analyses may be provided in a separate reporting and 
analysis plan, and the results may be reported in a separate population pharmacokinetic report.
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12.7
Interim analyses
No formal interim analysis is planned for this trial. During the Expansion (Part 2), a periodic 
safety review by the Steering Committee will occur approximately every 6 months.
In the Safety run-in (Part 1), the first safety review meeting will be conducted after participants 
included in the first cohort (N=6 with at least 3 evaluable participants treated with sabatolimab 
at the 400 mg Q4W) have completed 2 cycles of treatment. If the 400 mg Q4W dose of 
sabatolimab is considered to be safe in combination with venetoclax and azacitidine guided by 
the Bayesian analysis based on the incidence of dose limiting toxicity (DLT) data as well as all 
available safety, clinical pharmacology and tolerability data a second cohort with 12 
participants will be opened (sabatolimab at 800 mg Q4W), otherwise the study will be stopped.
After completion of 2 cycles of treatment with at least 9 evaluable participants, the second safety 
review meeting will take place. The decision will be made based on DLT observation and the 
Bayesian model to open the Expansion (Part 2) (or not) at this dose level (sabatolimab at 800 
mg Q4W) in combination with venetoclax and azacitidine. If sabatolimab 800 mg Q4W is 
considered to be safe then Expansion (Part 2) will be opened at the same dose level (800 mg 
Q4W). Otherwise the study will be stopped.
The primary analysis on CR rate will be performed after last participant have completed 6 cycles 
of treatment with sabatolimab + azacitidine + venetoclax or discontinued earlier. A final 
analysis will be performed after last enrolled participant have been followed for 3 years or 
discontinued study earlier. Formal testing of the primary endpoint with full level alpha will be 
performed at the primary analysis. If required or requested by Health Authorities, updated 
analyses after the primary CR rate analysis may be conducted prior to the final analysis.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
12.8.1.1 Safety run-in (Part 1)
No formal statistical power calculations to determine sample size were performed for this part 
of the study. In case the starting dose (sabatolimab 400 mg Q4W (N=6)) with the fixed dose 
combination of azacitidine plus venetoclax is confirmed to be safe and tolerated for at least 3 
evaluable participants, another cohort will be opened at 800 mg of sabatolimab Q4W (N=12) 
with fixed dose of venetoclax plus azacitidine with at least 9 evaluable participants. Otherwise, 
the study will be stopped.
In total, the Safety run-in (Part 1) is expected to enroll approximately 18 participants (6 
participants for cohort 1 (Sabatolimab (400 mg Q4W) and 12 participants for cohort 2 (800 mg 
(Q4W)) in order to have at least 12 evaluable participants (3 evaluable participants in cohort 1 
and 9 evaluable participants in cohort 2).
12.8.1.2 Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2) (CR primary 
analysis)
The sample size calculation is based on the Complete Remission (CR) rate (primary efficacy 
endpoint) for participants treated with sabatolimab 800 mg Q4W from Safety run-in (Part 1) 
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and Expansion (Part 2). The hypotheses to be tested and details of the testing strategy are 
described in Section 12.4.2.
Based on available data (Wei et al 2019), the CR rate with the combination azacitidine and 
venetoclax is expected to be around 39%. The first criteria to declare the trial successful is to 
test if the CR rate with sabatolimab in combination with azacitidine and venetoclax is at least 
50% (statistical significance).
The Bayesian formulation of this dual criterion design can be expressed as below:
!
Bayesian statistical significance: probability for a positive treatment effect (i.e. CR rate > 
39% | data) ≥ 0.975.
!
Clinical relevance: posterior median of CR rate ≥ 50%.
With two criteria stated above the minimally required sample (nmin) size is 67 and the sample 
size was set to 70 including participants from cohort 2 of the Safety run-in (Part 1) and the 
Expansion (Part 2) and thus 76 for the total sample size (including the 6 participants treated at 
400 mg Q4W in the cohort 1 of the Safety run-in (Part 1). For 70 participants (included for the 
primary efficacy analysis), the table below shows data scenarios (number of participant 
achieving complete remission) with respective inferential results and decisions.
The minimum number of participants with CR to declare this trial successful (both statistical 
significance and clinical relevance met) is 36 out of 70 participants (51.4%).
Based on simulations (Table 12-1), a total of 36 responders out of 70 participants is required 
for trial success, with estimates of 51.4% for the posterior median CR rate and 98.3% for the 
posterior probability for a positive effect (CR>39%). If the number of participants with CR is 
less than 36, both criteria are not met (NO-GO).
Table 12-1
Data scenarios, inferential results and decisions (n=70)
True CR rate
Posterior median CR
Posterior probability 
for a positive effect 
(CR>39%)
Decision for trial 
success
30/70 (42.9%)
43.0%
0.754
Failed
31/70 (44.3%)
44.4%
0.823
Failed
32/70 (45.7%)
45.8%
0.879
Failed
33/70 (47.1%)
47.2%
0.920
Failed
34/70 (48.6%)
48.6%
0.950
Failed
35/70 (50.0%)
50.0%
0.970
Failed
36/70 (51.4%)
51.4%
0.983
Successful
A non-informative Beta (1,1) prior with mean 50% has been used in these calculations.
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Operating characteristics for various true CR rates are presented in the table below. The type-I 
error under the null value (CR rate = 38.6%) is 2.0% and power is 80% assuming a true CR of 
55.7 %.
Table 12-2
Operating characteristics for true CR rate (n=70)
True CR rate
Probability of success (Go)
Probability of futility (No 
Go)
27/70 (38.6%)*
0.020
0.980
28/70 (40.0%)
0.035
0.965
29/70 (41.4%)
0.056
0.944
30/70(42.9%)
0.094
0.906
31/70 (44.3%)
0.140
0.860
32/70 (45.7%)
0.204
0.796
33/70 (47.1%)
0.272
0.728
34/70 (48.6%)
0.355
0.645
35/70 (50%)
0.452
0.548
36/70 (51.4%)
0.546
0.454
37/70 (52.9%)
0.644
0.356
38/70 (54.3%)
0.721
0.279
39/70 (55.7%)**
0.800
0.200
*For a true CR rate of 38.6% (null value), the probability for a trial success is 2.0% (type-I error). **For 
a 
true 
CR 
rate 
of 55.7%, 
the probability 
for 
a 
trial 
success 
is 
80% 
(power).
These calculation were made using the software R (version 3.6.1) using the RBestT 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.
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 
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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 participant 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 
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 
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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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Venclexta® (Venetoclax) USPI (2020)
Vidaza® (Azacitidine) USPI (2008)
Visser O, Trama A, Maynadié M, et al (2012) Incidence, survival and prevalence of myeloid 
malignancies in Europe. Eur. J. Cancer p. 3257-66.
Wei et al (2019) A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax in 
Combination with Azacitidine in Treatment-Naïve Patients with Higher-Risk Myelodysplastic 
Syndrome [abstract] p. Blood.2019 ;134(suppl 1). Abstract 568.
Yang H, Bueso-Ramos C, DiNardo C, et al (2014) Expression of PD-L1, PD-L2, PD-1 and 
CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. 
Leukemia p. 1280-8.
Yellen SB, Cella DF, Webster K, et al (1997) Measuring fatigue and other anemia-related 
symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J 
Pain Symptom Manage p. 63-74.
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Zeidan AM, Knaus HA, Robinson TM, et al (2018) A Multi-center Phase I Trial of Ipilimumab 
in Patients with Myelodysplastic Syndromes following Hypomethylating Agent Failure. Clin. 
Cancer Res. p. 3519-3527.
Zhang L, Gajewski TF, Kline J (2009) PD-1/PD-L1 interactions inhibit antitumor immune 
responses in a murine acute myeloid leukemia model. Blood p. 1545-52.
de Witte T, Bowen D, Robin M, et al (2017) Allogeneic hematopoietic stem cell transplantation 
for MDS and CMML: recommendations from an international expert panel. Blood p. 1753-
1762.
Ørskov AD, Treppendahl MB, Skovbo A, et al (2015) Hypomethylation and up-regulation of 
PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of 
PD-1 and DNA methylation. Oncotarget p. 9612-26.
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16
Appendices
16.1
Appendix 1: Statistical considerations for Safety run-in Part
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical data, the results of the Bayesian analyses and respective dosing decisions for some 
hypothetical data scenarios. A simulation study of the operating characteristics of the model is 
also presented in this appendix.
16.1.1
Statistical model for triple combination
The statistical model comprises single-agent toxicity parts, which allow the incorporation of 
single-agent goxicity information, and interaction parts to describe two-way drug safety 
interactions. The proposed statistical model uses a meta-analytic framework (Spiegelhalter 
2004, Neuenschwander 2016) to combine all historical and concurrent data.
16.1.1.1 Single agent parts
Let πi (di) be the risk of DLT for a compound i given as a single agent dose at dose 
di (i=1,2,3) The single agent dose-DLT models are logistic:
logit(πi (di))=log(αi)+βi log(di/di*) i=1,2,3 (1)
where di*, the reference dose, is used to scale the doses of each compound. The reference doses 
are defined in the appropriate model specifications sections.
Hence, αi (>0) is the single-agent odds of a DLT at di* and βi (>0) are the increase in the log-
odds of a DLT by a unit increase in log-dose.
16.1.1.2 Interaction
Under no interaction, the risk of a DLT for combination dose (d1, d2, d3) is:
π1230(d1, d2, d3) = 1 - (1-π1(d1))(1-π2(d2))(1-π3(d3))
To allow for interaction between each pair of compounds, odds mutlipliers, η12, η13, η23, are 
introduced.
The risk of DLT for combination dose (d1, d2, d3) is then given by:
odds (π123(d1, d2, d3))=exp [η12 (d1d2/ d1* d2*) + η13 (d1d3/ d1* d3*) + η23 (d2d3/ d2* d3*)]*odds 
(π1230(d1,d2,d3))
where,
odds (π) = π/ (1-π);
ηij is the log of the odds ratio between the interaction and no interaction model at dose di* and 
dj* for treatment i and j and a zero dose of the third treatment;
η = η12 + η13 + η23 is the log of the odds ratio between the interaction and no interaction model 
at dose d1* d2* and d3* for all three treatments. Here η=0 corresponds to no overall interaction 
with η>0 and η<0 representing overall synergetic and antagonistic toxicity respecvtively.
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16.1.2
Prior specifications
The Bayesian approach requires the specification of prior distributions for the model parameters 
log(α) and log(β).A meta-analytic framework approach was used to derive the prior distribution 
for these model parameters.
16.1.2.1 Prior distributions for the logistic parameters
16.1.2.1.1
Description of the meta-analytic framework approach
The aim of this approach is to derive prior distribution for the logistic parameters (log (α*), log 
(β*)) of the new trial using DLT data from historical studies.
Let rds and nds be the number of participants with a DLT, and the total number of participants at 
dose d in historical trial s (s=1,…,S). The corresponding probability of a DLT is πds. The model 
specifications for the derivation of the prior are as follows:
rds | πds ~ Bin (πds,nds )
logit (πds )=log(αs ) + βs log(d/d*)
(log(αs ),log(βs ))| μ,ψ ~ BVN(μ,ψ), s=1,…,S
(log(α* ),log(β* )) | μ,ψ ~ BVN(μ,ψ)
The parameters μ =(μ1,μ2) and ψ are the mean and between-trial covariance matrix for the 
logistic parameters, the latter with standard deviations τ1, τ2, and correlation ρ. The parameters 
τ1 and τ2 quantify the degree of between trial heterogeneity. The following priors will be used 
for these parameters:
!
normal priors for μ1 and μ2,
!
log-normal priors for τ1 and τ2, and
!
a uniform prior for ρ
The prior for model parameters in the new trial, (log(α* ),log(β* )), is the predictive distribution:
(log(α* ), log(β* )) | (rds, nds  s=1,…,S)
Since the predictive distribution is not available analytically, Markov chain Monte Carlo 
(MCMC) is used to simulate values from this distribution. This is implemented using JAGS 
version 3.12. The sample from this distribution is then approximated by a mixture of bivariate 
normal (BVN) distributions. BVN mixtures with increasing numbers of mixture components 
are fitted to the sample using the expectation-maximization (EM) algorithm (Dempster 1977). 
The optimal number of components of the mixture is then identified using the Akaike 
information criterion (AIC) (Akaike 1974).
16.1.2.1.2
Prior specification
Single agent components
Weakly informative priors are assumed for log(α) and log(β), with mean (μ1) equal to logit 
(0.10) corresponding to the anticipated DLT rate at the reference dose (d1*=sabatolimab 800 
mg, d2*=azacitidine 75 mg/m2, d3*=venetoclax 400 mg)) and with mean (μ2) equal to 0 
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corresponding to a dose leading to a doubling in the odds of the risk of a DLT. Priors for τ1 and 
τ2 are assigned such that (1) their medians correspond to substantial between trial heterogeneity, 
and (2) their uncertainty (95% prior interval) cover plausible between trial standard deviations 
(Neueuschwander 2014).
Interaction components
Because of no-drug interactions observed so far in clinical studies in patients treated with 
sabatolimab and azacitidine or treated with venetoclax and azacitidine and no drug-drug 
interactions expected between sabatolimab and venetoclax, a prior centered on an assumption 
of no interaction but with appropriate uncertainty that allows for both synergistic and 
antagonistic toxicity was considered for each 2-by-2 drug interactions.
The prior distributions for the model used for deriving the meta-analytic priors are specified 
in Table 16-1 below.
Table 16-1
Prior distributions for single-agent and interactionparameters
Parameter
Prior distribution
Intercept and slope for each single-agent 
component
!
μ1
N(mean = logit(0.10), sd = 2)
!
μ2
N(mean = 0, sd=1)
!
τ1
log-normal(mean = 0.5, sd = log(4)/1.96)
!
τ2
log-normal(mean = 0.25, sd = log(4)/1.96)
!
ρ
uniform (-1,1)
!
Probabilities of exchangeability
1
Slope for each 2-by-2 interaction term
!
μ
N(mean = 0, sd=0.5)
!
τ
log-normal(mean - log(0.125), sd= log(4)/1.96)
!
Probability of exchangeability
0.9
16.1.2.1.3
Historical data
The prior described above was then updated by using the dose-DLT data from a Novartis 
study [PDR001X2105] in participants treated with sabatolimab in combination with azacitidine 
(arm 6b) as well an external study (Wei et al (2019)). Historical data are presented 
in Table 16-2 and Table 16-3.
Table 16-2
Historical data from [PDR001X2105 (arm 6b)] for sabatolimab in 
combination with azacitidine
Sabatolimab dose 
level (mg)
Number of enrolled 
participants
Number of participants 
for DDS
Number of participants 
with a DLT
400 mg Q2W
6
6
0
400 mg Q2W
9
9
0
240 mg Q2W
6
4
0
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Sabatolimab dose 
level (mg)
Number of enrolled 
participants
Number of participants 
for DDS
Number of participants 
with a DLT
800 mg Q4W
5
5
0
Table 16-3
Historical data from [Wei et al (2019)] for venetoclax and azacitidine ]
Azacitidine or 
Venetoclax dose level
Number of participants 
enrolled
participants evaluable 
for DDS
Number of participants 
with a DLT
Azacitidine (75 mg/m2 
Day 1- 7)
2
2
0
Azacitidine (75 mg/m2 
Day 1- 7) + Venetoclax 
(400 mg D1 -28)
5
5
1
16.1.2.2 Summary of prior distributions
The prior distributions of the model parameters are summarized in Table 16-4.
The prior summaries for DLT rates are summarized in Table 16-5.
Table 16-4
Prior distribution (BVN Mixture (log(α, β))
Parameter
Mean
Standard deviations
Single agent sabatolimab (μ1, 
μ2)
(-4.059 ; 0.03786)
(1.402 ; 0.9895)
Single agent 
azacitidine (μ1, μ2)
(-4.085 ; 0.00547
(1.356 ; 1.018)
Single agent venetoclax 
(μ1, μ2)
(-2.287 ; 0.00427)
(1.494 ; 0.9826)
Interaction sabtolimab-
azacitidine (μ)
-0.199353
0.4931
Interaction azacitidine-
venetoclax (μ)
-0.003551
0.5091
Interaction azacitidine-
venetoclax (μ)
0.014003
0.4839
Table 16-5
Summary of posterior distributions
Sabatoli
mab 
Q4W 
dose 
(mg)*
Prior probabilities that 
p(DLT) is in the interval:
Quantiles
[0,16)
[0,16,0.3
3)
[0.33,1]
Mean
SD
2.5%
50%
97.5%
400
0.506
0.277
0.217
0.218
0.192
0.017
0.158
0.752
800
0.492
0.262
0.246
0.232
0.210
0.014
0.164
0.805
* in combination with fixed dose of Venetoclax and Azacitidine.
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16.1.3
Hypothetical on-study scenarios
To illustrate the performance of the Bayesian model used to guide the tolerability assessment 
in the Safety run-in part for sabatolimab in combination with venetoclax plus azacitidine, 
hypothetical data scenarios are displayed in Table 16-6 below. Decision might be based on 
additional safety, pharmacokinetic and pharmacodynamic information.
The study will continue if probability of excessive toxicity (i.e. DLT rate ≥ 33% i.e. excessive 
toxicity) every dose level is less than 0.25, satisfying the EWOC criteria. In addition, the 
probability of excessive toxicity for newly participants is provided.
Table 16-6
Probability of excessive toxicity estimated by the Bayesian model 
after each cohort
Scenario
Cohort 
of 
safety 
run-in 
part
Sabatoli
mab 
Q4W 
dose 
(mg)**
Number of
Dose level 
Evaluab
le 
particip
ants
DLTs*
Sabatoli
mab 
dose
Median 
P(DLT)
P 
(excessi
ve 
toxicity)
1
Cohort
1
400
3
0
400
0.090
0.058
2
Cohort
1
400
3
1
400
0.193
0.262
3
Cohort
1
400
4
0
400
0.082
0.039
4
Cohort
1
400
4
1
400
0.167
0.182
5
Cohort
1
400
5
0
400
0.076
0.028
6
Cohort
1
400
5
1
400
0.150
0.128
7
Cohort
1
400
5
2
400
0.257
0.377
8
Cohort
1
400
6
0
400
0.071
0.016
9
Cohort
1
400
6
1
400
0.142
0.097
10
Cohort
1
400
6
2
400
0.233
0.298
11
Cohort
1
400
3
0
Cohort
2
800
9
0
800
0.049
0.002
12
Cohort
1
400
3
0
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Cohort
2
800
9
1
800
0.094
0.015
13
Cohort
1
400
3
0
Cohort
2
800
9
2
800
0.153
0.068
14
Cohort
1
400
3
0
Cohort
2
800
9
3
800
0.222
0.208
15
Cohort
1
400
3
1
Cohort
2
800
9
0
800
0.085
0.010
16
Cohort
1
400
3
1
Cohort
2
800
9
1
800
0.143
0.060
17
Cohort
1
400
3
1
Cohort
2
800
9
2
800
0.206
0.173
18
Cohort
1
400
3
1
Cohort
2
800
9
3
800
0.277
0.376
19
Cohort
1
400
4
1
Cohort
2
800
9
0
800
0.08
0.009
20
Cohort
1 
400
4
1
Cohort
2
800
9
1
800
0.136
0.050
21
Cohort
1 
400
4
1
Cohort
2 
800
9
2
800
0.196
0.154
22
Cohort
1 
400
4
1
Cohort
2 
800
9
3
800
0.264
0.331
* Number of participants with at least one DLT.
**In combination with fixed dose of Venetoclax and Azacitidine
Dose level Sabatolimab 400 mg Q4W:
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If one DLT with 3 evaluable participants, the probability of excessive toxicity (i.e. DLT rate of 
>= 33%) with dosing regimens of sabatolimab 400 mg is >= 25% not satisfying the EOWC 
criteria. In this case, it would be recommended to stop the trial.
If more than 1 DLT with 4,5,6 evaluable participants, the probability of excessive toxicity (i.e. 
DLT rate of >= 33%) with dosing regimens of sabatolimab 400 mg is >= 25% not satisfying 
the EOWC criteria. In this case, it would be recommended to stop the trial.
Dose level Sabatolimab 800 mg Q4W:
!
In case of no DLT in the first cohort (sabatolimab 400 mg Q4W:
!
If <=3 DLTs out of 9 evaluable participants are observed in the second cohort, the 
probability of excessive toxicity (i.e. DLT rate of >= 33%) with dosing regimens of 
sabatolimab 800 mg is < 25% satisfying the EOWC criteria. In this case, it would be 
recommended to start expansion part.
!
If 4 or more DLT out of 9 evaluable participants are observed in the second cohort, the 
probability of excessive toxicity (i.e. DLT rate of >= 33%) with dosing regimens of 
sabatolimab 800 mg does not satisfy the EOWC criteria. In this case, it would be 
recommended to stop the trial.
!
In case of 1 DLT out of 4 evaluable participants in the first cohort (sabatolimab 400 
mg Q4W)
!
If <= 2 DLTs out of 9 evaluable participants are observed in the second cohort, the 
probability of excessive toxicity (i.e. DLT rate of >= 33%) with dosing regimens of 
sabatolimab 800 mg is < 25% satisfying the EOWC criteria. In this case, it would be 
recommended to start expansion part
!
If >=3 DLTs out of 9 evaluable participants are observed in the second cohort, the 
probability of excessive toxicity (i.e. DLT rate of >= 33%) with dosing regimens of 
sabatolimab 800 mg does not satisfy the EOWC criteria. In this case, it would be 
recommended to stop the trial.
16.1.4
Operating characteristics
16.1.4.1 Scenarios
In order to show how the design performs, six hypothetical scenarios are investigated:
!
Scenario 1 (prior toxicity): the true DLT rate in both cohorts (Sabatolimab 400 and 800 mg 
Q4W) are similar to prior information; the combination of sabatolimab in combination with 
venetoclax and azacitidine is safe whatever the dose of sabatolimab tested.
!
Scenario 2 (low toxicity with dose-DLT slope): the true DLT rate in first cohort is equal to 
10% (defined as safe) and the true DLT rate in the second cohort is equal to 20% (defined 
as safe).
!
Scenario 3 (threshold toxicity): the true DLT rate in both cohorts are equal to 33% 
(threshold to declare an excessive toxicity) without a dose-DLT relationship.
!
Scenario 4 (high toxicity without dose-DLT slope): The true DLT rate in both cohorts are 
equal to 40% (defined as an excessive toxicity) without a dose-DLT relationship.
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!
Scenario 5 (high toxicity with dose-DLT slope): The true DLT rate in first cohort is equal 
to 20% (defined as safe) and the true DLT rate in the second cohort is equal to 40% (defined 
as an excessive toxicity).
!
Scenario 6 (very high toxicity with dose-DLT slope): The true DLT rate in first cohort is 
equal to 25% (defined as safe) and the true DLT rate in the second cohort is equal to 50% 
(defined as an excessive toxicity).
16.1.4.2 Simulation results
Metrics to assess the operating characteristics
Operating characteristics are reviewed based on the simulation results under the six scenarios. 
The metrics reviewed are:
!
True DLT rate in the first cohort
!
True DLT rate in the second cohort
!
Probability of excessive toxicity after the first cohort.
!
Probability of excessive toxicity after the second cohort.
!
Probability of excessive toxicity in at least one cohort.
!
Average sample size for the safety run-in part.
Operating characteristics
Table 16-7 presents the probability to declare an excessive toxicity (i.e. the number of 
simulations for which the probability that the true DLT rate is ≥ 33% is equal or higher than 
25% for the different scenarios mentioned above.
Table 16-7
Operating characteristics for different true values of DLT rate
Scenario
True DLT rate 
in the first 
cohort
True DLT rate 
in the second 
cohort
Patients 
receiving an 
overdose
probability to 
stop
average 
sample size of 
safety run-in 
part
1 (prior 
toxicity)
21.8%
23.2%
0
42%
12
2 (low toxicity 
with dose-DLT 
slope)
10%
20%
0
19%
14
3 (Threshold 
toxicity)
33%
33%
100%
70%
9
4 (high toxicity 
without dose-
DLT slope)
40%
40%
100%
84%
8
5 (high toxicity 
with dose-DLT 
slope)
20%
40%
51%
59%
12
6 (very high 
toxicity with 
dose-DLT 
slope)
25%
50%
43%
75%
10
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Simulation performed in R3.6.1 with number of simulation =1000 and randomization seed 453453
First cohort size of 3, 4, 5, 6 participants and second cohort size of 9, 10, 11 or 12 participants were 
considered for the simulation.
16.1.5
References
Akaike H (1974) A New Look at the Statistical Model Identification. IEEE Trans Automat 
Contr AC;19, p 716-723.
Dempster AP, Laird NM, Rubin DB (1977) Maximum likelihood from incomplete data via the 
EM algorithm. J Royal Stat Soc, p 1-38.
DiNardo CD, Pratz KW, Letai A (2018) Safety and preliminary efficacy of venetoclax with 
decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: 
a non-randomised, open-label, phase 1b study. Lancet Oncol, p 216-28.
Neuenschwander B, Matano A, Tang Z (2014) A Bayesian Industry Approach to Phase I 
Combination Trials in Oncology. In Zhao, W., & In Yang, H. (2015). Statistical methods in 
drug combination studies, p 95-136.
Wei et al (2019) A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax in 
Combination with Azacitidine in Treatment-Naïve patients with Higher-Risk Myelodysplastic 
Syndrome [abstract] p. Blood.2019 ;134(suppl 1). Abstract 568.
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16.2
Appendix 2: Concomitant medications to be used with caution 
and/or requiring action
The following lists are not comprehensive and are only meant to be used as a guide. The lists 
are based on the Novartis Internal Oncology Clinical Pharmacology Guidance, Drug-Drug 
Interaction and Co-Medication Considerations (v05, release date: 2015), which was compiled 
from the Indiana University School of Medicine’s P450 Drug Interaction Table 
(medicine.iupui.edu/clinpharm/ddis/main- table/) and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies –Study Design, Data Analysis, and 
Implications 
for 
Dosing 
and 
Labeling 
(February 
2012) 
(fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.p
df), and the University of Washington’s Drug Interaction Database (druginteractioninfo.org/).
Please refer to Section 6.2.1.1 for actions that need to be taken when using these concomitant 
medications. Please contact the Novartis medical monitor with any questions.
Table 16-8
List of medications to be used with caution and/or requiring action 
during study drug treatment
Strong inhibitors of CYP3A
ombitasvir/paritaprevir/dasabuvir/ritonavir 
(Viekira Pak), indinavir/ritonavir, 
tipranavir/ritonavir, ritonavir, cobicistat, 
indinavir, ketoconazole, troleandomycin, 
telaprevir, danoprevir/ritonavir, 
elvitegravir/ritonavir, saquinavir/ritonavir, 
lopinavir/ritonavir, itraconazole, 
voriconazole, mibefradil, clarithromycin, 
posaconazole, telithromycin, grapefruit 
juice1, conivaptan, nefazodone, nelfinavir, 
idelalisib, boceprevir, atazanavir/ritonavir, 
darunavir/ritonavir
Moderate inhibitors of CYP3A
aprepitant, amprenavir, atazanavir, 
cimetidine, ciprofloxacin, crizotinib, 
cyclosporine, darunavir, diltiazem, 
dronedarone, erythromycin, faldaprevir, 
fluconazole, grapefruit juice1, imatinib, 
isavuconazole, netupitant, nilotinib, 
tofisopam, Schisandra sphenanthera (nan 
wu wei zi), asafoetida resin (Ferula 
asafoetida), verapamil
Strong inducers of CYP3A
carbamazepine, enzalutamide, lumacaftor, 
phenobarbital, phenytoin, rifabutin, 
rifampicin, mitotane, St. John’s wort 
(Hypericum perforatum)
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Moderate inducers of CYP3A
bosentan, dabrafenib, efavirenz, etravirine, 
genistein, modafinil, nafcillin, 
tipranavir/ritonavir, lopinavir, telotristat, 
thioridazine
Inhibitors of P-gp
alogliptin, amiodarone, azithromycin, 
canaglifozin, captopril, carvedilol, 
clarithromycin, clopidrogel, conivaptan, 
cremophor EL and RH40, curcumin, 
daclatasvir, diltiazem, dronedarone, 
eliglustat, erythromycin, felodipine, 
fluvoxamine, fostamatinib, ginkgo (Ginkgo 
biloba), green tea, indinavir, isavuconazole, 
itraconazole, ivacaftor, ketoconazole, 
lapatinib, lopinavir, mibefradil, milk thistle 
(silymarin, silibinin), mirabegron, nelfinavir, 
nifedipine, nitrendipine, 
ombitasvir/paritaprevir/dasabuvir/ritonavir 
(Viekira Pak), paroxetine, propafenone, 
quercetin, quinidine, quinine, ranolazine, 
rifampicin, ritonavir, rolapitant, saquinavir, 
Schisandra chinensis extract (wuweizi), 
simeprevir, St. John’s wort extract 
(Hypericum perforatum) , survorexant, 
talinolol, telaprevir, telmisartan, ticagrelor, 
tipranavir, tolvaptan, valspodar, vandetanib, 
velpatasvir, verapamil, voclosporin, 
vorapaxar
NTI substrates of P-gp
cyclosporine, digoxin, fentanyl, paclitaxel, 
phenytoin, quinidine, sirolimus, tacrolimus
Substrates of P-gp (≥2X AUC change)
aliskiren, ambrisentan, atorvastatin, 
azithromycin, colchicine, dabigatran, 
digoxin, docetaxel, domperidone, 
doxorubicin, fentanyl, fexofenadine, 
lapatinib, linezolid, loperamide, maraviroc, 
nadolol, nevirapine, paclitaxel, proguanil, 
quinidine, ranolazine, ritonavir, saquinavir, 
simvastatin, sirolimus, sofosbuvir, 
tacrolimus, ticagrelor, topotecan
Substrates of P-gp mentioned in USPI
afatinib, alfuzosin, aliskiren, alogliptin, 
ambrisentan, apixaban, apremilast, 
aprepitant, boceprevir, bosentan, carvedilol, 
carvedilol, caspofungin, ceritinib, 
citalopram, colchicine, cyclosporine, 
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Amended Protocol Version 02 (Clean)
Protocol No. CMBG453B12203
dabigatran, digoxin, doxepin, doxorubicin, 
eribulin, everolimus, fidaxomicin, 
fluvastatin, fosamprenavir, gatifloxacin, 
idelalisib, iloperidone, indacaterol, 
irbesartan, lacosamide, lapatinib, 
levetiracetam, levofloxacin, linagliptin, 
losartan, maraviroc, mirabegron, 
moxifloxacin, naloxegol, nateglinide, 
nintedanib, olodaterol, pantoprazole, 
paroxetine, pazopanib, posaconazole, 
pravastatin, quinine, ranolazine, riociguat, 
risperidone, rivaroxaban, saquinavir, 
silodosin, simeprevir, sirolimus, sitagliptin, 
sorafenib, telaprevir, tenofovir, ticagrelor, 
tipranavir, tolvaptan, topotecan, 
umeclidinium, valsartan, vardenafil, 
vincristine, voriconazole
Substrates of BCRP
Atorvastatin, daunorubicin, dolutegravir, 
doxorubicin, hematoporphyrin, imatinib, 
methotrexate, mitoxantrone, paritaprevir, 
pitavastatin, rosuvastatin, irinotecan, ethinyl 
estradiol, simvastatin, sofosbuvir, 
sulfasalazine, tenofovir, topotecan, 
venetoclax
1 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent.
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SAP_001.pdf: 
Clinical Development
MBG453/Sabatolimab
CMBG453B122031&7
A single-arm, open-label, Phase II study of sabatolimabin 
combination with azacitidine and venetoclax in adult participants 
with high or very high risk myelodysplastic syndrome (MDS) as per 
IPSS-R criteria
Statistical Analysis Plan (SAP)  
Author:
Statistician, 
; Statistician, 
Document type:
SAP Documentation
Document status:
Amendment 2
Release date:
06-June-2023
Number of pages:
46
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template Version 3.0, Effective from 01-Jul-2020
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Statistical Analysis Plan (SAP)
MBG453B12203
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for 
update
Section and title impacted 
(Current)
17-May-2021
FPFV
Creation of 
first version
NA First
version 
(based
on protocol 
v00 from 07-
Dec-20)
NA
17-Jan-2023
Prior to 
final CSR 
DBL
Update to 
align with 
protocol 
amendment 
1 and 2, 
and
lean the 
final CSR 
due to the
recruitment 
halt after 
the 
completion 
of safety 
run-in part. 
Amendment 
1 (based on 
protocol 
amendment 
2 from 06-
Oct-2021)
-Change the term “subject” to 
“participant” throughout the SAP.
- Change the term referring to 
sabatolimab from “study drug” to 
“investigational drug”.
-Section 2.2.5, subgroup analysis 
removed.
-Section 2.5.2.2, CR primary 
analysis removed.
-Section 2.6.1.2, - Update the 
definition of time-to-event endpoints; 
General sentence about the 
production of K-M outputs added
-Section 2.6.5, analysis of fatigue 
removed.
-
6-Jun-2023
Prior to 
final DBL
Update per 
program-
level 
standard
for safety, 
review of 
dry-run and 
PK dry-run
discussion
Amendment 
2 (updates 
on PK and
IG analyses,
definition of 
vital sign 
population 
and last 
exposure to 
study 
treatment)
Section 2.5.1.1, Summary table of 
DLTs added.
Section 2.6.3.1, Exclude the 
concentration at EOT, 30-day safety 
follow-up and 150-day safety follow-
up visit from the sabatolimab PK 
concentraction summary table and 
graph;
For the summary table of venetoclax 
PK concentraction, only display the 
patients whose prior dose was 400 
mg;
Drug-drug interactions analysis 
removed.
Section 2.6.4, Analysis for ADA 
status updated.
Section 2.6.2.7, Population for vital 
sign summary updated 
Section 4, Calculations of dates of 
last exposure to study treatment 
updated
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Statistical Analysis Plan (SAP)
MBG453B12203


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Statistical Analysis Plan (SAP)
MBG453B12203
Table of contents
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
1.2
Study objectives and endpoints .............................................................................11
2
Statistical methods.............................................................................................................14
2.1
Data analysis / general information.......................................................................14
2.1.1
General definitions................................................................................14
2.2
Analysis sets ..........................................................................................................15
2.2.1
Full Analysis Set ...................................................................................15
2.2.2
Safety Set ..............................................................................................15
2.2.3
Dose-Determining Set...........................................................................15
2.2.4
Pharmacokinetic Analysis Sets .............................................................15
2.2.5
Subgroup of interest ..............................................................................16
2.3
Patient disposition, demographics and other baseline characteristics ...................16
2.3.1
Patient disposition.................................................................................17
2.3.2
Demographics and other baseline characteristics .................................17
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................17
2.4.1
Study treatment / compliance................................................................18
2.4.2
Prior, concomitant and post therapies...................................................19
2.5
Analysis of the primary objectives ........................................................................19
2.5.1
Primary endpoints and estimand...........................................................20
2.5.2
Statistical hypothesis, model, and method of analysis..........................25
2.5.3
Handling of missing values/censoring/discontinuations.......................25
2.6
Analysis of secondary objective(s)........................................................................26
2.6.1
Efficacy .................................................................................................26
2.6.2
Safety.....................................................................................................31
2.6.3
Pharmacokinetic....................................................................................35
2.6.4
Immunogenicity ....................................................................................36
2.6.5
Patient-Reported outcome: MDS symptoms and fatigue (Part II 
only) ......................................................................................................38
38
38
 
38
38
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Statistical Analysis Plan (SAP)
MBG453B12203
39
2.8
Interim analysis......................................................................................................39
2.9
Sample size calculation..........................................................................................40
2.9.1
Safety run-in (Part 1).............................................................................40
2.9.2
Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2) (CR 
primary analysis)...................................................................................40
3
Change to protocol specified analyses ..............................................................................41
4
Appendix - General definitions .........................................................................................42
5
Reference...........................................................................................................................46
List of tables
Table 1-1
Objectives and related endpoints ..........................................................11
Table 2-1
Participant classification based on protocol deviations and non protocol 
deviations criteria
16
Table 2-2
Modified response classification per IWG-MDS criteria 
(Platzbecker et             al 2019, Cheson et al 2006, Cheson et al 2000) .....................21
Table 2-3
Notable ECG values..............................................................................34
Table 2-4
Notable vital sign values.......................................................................35
Table 2-5
Data scenarios, inferential results and decisions (n=70).......................41
Table 2-6
Operating characteristics for true CR rate (n=70).................................41
Table 4-1
Time windows for PRO and ECOG data ..............................................44
Table 4-2
Last contact date data sources...............................................................45
List of figures
Figure 1-1
Study design..........................................................................................10
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Statistical Analysis Plan (SAP)
MBG453B12203
List of abbreviations
ADA
Anti-drug antibody
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AML
Acute Myeloid Leukemia
APTT
Activated partial thromboplastin time
AST
Aspartate Aminotransferase
AUC
Area under the curve
BMA
Bone marrow aspirate
BMI
Body Mass Index
BSA
Body surface area
BUN
Blood Urea Nitrogen
CK
Creatinine Kinase
COVID-19
Coronavirus disease 2019
CR
Complete remission
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
CYP
Cytochrome P450
DBP
Diastolic Blood Pressure
DDS
Dose Determining Set
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EFS
Event-free survival
eGFR
Estimated glomerular filtration rate
EOT
End of treatment
ePRO
Electronic Patient Reported Outcome
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
EWOC
Escalation with overdose control
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy- Fatigue
FAS
Full Analysis Set
h
Hour
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen


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Statistical Analysis Plan (SAP)
MBG453B12203
HBV
Hepatitis B Virus
HCG
Human chorionic gonadotropin
HCV
Hepatitis C Virus
HEOR
Health Economics & Outcomes Research 
HI
Hematological improvement
HIV
Human immunodeficiency virus
HMA
Hypomethylating agents
HSCT
Hematopoietic Stem Cell Transplant
IG
Immunogenicity
INR
International Normalized Ratio
IPSS-R
Revised International Prognostic Scoring System
IRT
Interactive Response Technology
IWG
International Working Group
LDH
lactate dehydrogenase
LFS
Leukemia-free survival
mCR
Marrow complete remission
MDS
Myelodysplastic syndromes
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)
MPN
Myeloproliferative neoplasm
MRD
Measurable residual disease
NCI
National Cancer Institute
NGS
Next Generation Sequencing
ORR
Overall response rate
OS
Overall survival
PAS
Pharmacokinetic Analysis Set
PD
Progressive Disease
PFS
Progression-free survival
PK
Pharmacokinetic(s)
PR
Partial Remission
PRO
Patient Reported Outcomes
Q4W
every 4 weeks
QTcF
QT interval corrected by Fridericia’s formula
RBC
red blood cell(s)
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome Coronavirus 2
SBP
Systolic Blood Pressure
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Statistical Analysis Plan (SAP)
MBG453B12203
SCT
Stem cell transplant
SD
Stable Disease
TSH
Thyroid-Stimulating Hormone
WBC
white blood cell(s)
WoC
Withdrawal of study Consent
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Statistical Analysis Plan (SAP)
MBG453B12203
1
Introduction
This statistical analysis plan (SAP) describes the planned analyses for the Clinical Study Report 
(CSR) of the study MBG453B12203, a phase II, open-label, single-arm, multi-center study of 
sabatolimab in combination with azacitidine and venetoclax in adult participants with high or 
very high risk myelodysplastic syndrome (MDS) as per IPSS-R criteria.
The content of this SAP is based on the MBG453B12203 protocol including amendment 2 (06-
Oct-2021). All decisions regarding the analysis, as defined in the SAP document, have been 
made prior to database lock (DBL). 
As specified in the section 12.7 of the study protocol, safety meetings were conducted during 
the safety run-in part of the study to assess the tolerability of sabatolimab at two different doses 
(400 mg and 800 mg administered every 4 weeks) when given together with azacitidine and 
venetoclax before enrolling participants in the expansion part of the study. The second safety 
review meeting was held on 26-Sep-2022. The investigators and steering committee members 
agreed that there was no new safety concern identified with the combination of sabatolimab
800mg Q4W, azacitidine 75mg/m2 for 7days out of a 28-day cycle, venetoclax 400 mg QD for 
14 days and that the expansion phase (Part 2) could be opened for enrollment of participants.
However, Novartis decided to permanently halt the recruitment of new participants into study 
MBG453B12203 in September 2022 (recruitment halt letter sent to investigators on 27-Sep-
2022). As a result, the expansion part of the study will not be opened. This decision was not 
based on any safety findings or safety concerns with sabatolimab or the triplet combination but 
rather it was a Novartis strategic consideration. The decision about recruitment halt was not 
reflected in a protocol amendment but will be documented in the Early Termination Plan for 
the study. The study data will be analyzed and reported based on all available data up to DBL
in an abbreviated final Clinical Study Report (CSR).
1.1
Study design
This Phase II, open-label, single-arm, multi-center study of sabatolimab, in combination with 
azacitidine and venetoclax in adult participants with high or very high risk MDS as per IPSS-R 
criteria, is described in Figure 1-1 below. The study will enroll a total of approximately 76 
participants and will be conducted in two sequential parts:

Part 1: The safety run-in consists of two subsequent cohorts of 400 mg Q4W (cohort 1) 
and 800 mg Q4W (cohort 2) of sabatolimab in combination with a fixed dose of 
venetoclax and azacitidine. Cohort 2 will be open only after the review of safety data from 
cohort 1 indicates the regimen is safe. If the regimen using sabatolimab at 400 mg Q4W is 
not safe, the study will be stopped. 

Part 2: If the review of safety data from participants enrolled in cohort 2 of part I 
indicates that the regimen is safe, then Part 2 will be opened. Otherwise, if the regimen at 
800 mg Q4W is not safe, the study will be stopped. Expansion will enroll additional 
participants to further investigate the regimen including sabatolimab at 800 mg Q4W, 
azacitidine and venetoclax. Participants data from Part 1 and Part 2 treated with 800 mg 
Q4W will be combined to determine the complete remission rate.


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Statistical Analysis Plan (SAP)
MBG453B12203
Part 1 is a Safety run-in to assess whether sabatolimab (400 mg Q4W and subsequently 800 mg 
Q4W) is safe when given in combination with fixed dose of azacitidine and venetoclax. A total 
of approximately 18 participants will be enrolled to Part 1 across the two dose levels. 
Approximately 6 participants will be initially enrolled at the starting dose level, 400 mg Q4W 
(cohort 1), in order to obtain at least 3 evaluable participants. If the dose level of sabatolimab
400 mg Q4W in combination with azacitidine and venetoclax is assessed to be safe, then a 
second cohort of participants investigating sabatolimab at 800 mg Q4W combined to azacitidine 
and venetoclax (cohort 2) will be opened. Otherwise, the study will be stopped. Approximately 
12 participants will be enrolled in cohort 2, in order to obtain at least 9 evaluable participants. 
If the combination regimen used in cohort 2 is safe then the Expansion part will be opened (Part 
2). Otherwise, the study will be stopped. 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, and a Safety Review Meeting has been conducted. If 
no safety concerns are identified at either dose level, Novartis will provide notification to the 
investigational sites that Expansion (Part 2) of the study is open to enrollment. Enrollment to 
Part 2 will continue until a total enrollment of approximately 70 participants treated at the 
sabatolimab dose of 800 mg Q4W (including the participants treated in cohort 2 in the Safety 
run-in (Part 1) and participants treated in the Expansion (Part 2)) has been achieved.
Figure 1-1
Study design
* The Safety run-in cohort 1 investigating sabatolimab 400 mg Q4W requires at least 3 evaluable participants (6 
enrolled participants) to have been observed for at least 2 cycles.
** The Safety run-in cohort 2 investigating sabatolimab 800 mg Q4W requires at least 9 evaluable participants (12 
enrolled participants) to have been observed for at least 2 cycles.
*** To achieve 70 participants at the dose level 800 mg Q4W


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Statistical Analysis Plan (SAP)
MBG453B12203
1.2
Study objectives and endpoints
The objectives and associated endpoints are presented in Table 1-1 below. Due to the
recruitment halt for the expansion part after the safety run-in,the evaluation of the changes from 
baseline in fatigue (only for Part 2) 
 will not be analyzed for the 
abbreviated CSR. All other objectives and endpoints will be presented.
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
!
Safety run-in (Cohort 1 and Cohort 2 of Part 1) 
To determine whether sabatolimab is safe when 
added to azacitidine + venetoclax in participants 
with high or very high risk MDS per IPSS-R criteria
!
Incidence of dose limiting toxicities (DLTs)
between Cycle 1 Day 8 and end of Cycle 2
!
Cohort 2 of Safety run-in (Part 1) and 
Expansion (Part 2)
To determine the complete remission (CR) rate of 
sabatolimab in combination with azacitidine and 
venetoclax in participants with high or very high 
risk MDS as per IPSS-R criteria treated with 
sabatolimab at 800 mg Q4W.
!
Proportion of participants from cohort 2 of Part 1 
and Part 2 achieving CR according to investigator 
assessment (per modified IWG-MDS - Cheson 
2006 criteria). CR is defined as follows: bone 
marrow blasts <5%, hemoglobin level ≥ 10 g/dL, 
platelets count ≥100*10^9/L, neutrophils count ≥ 
1.0*10^9/L, absence of blasts in peripheral blood.
Secondary objective(s)
Endpoint(s) for secondary objective(s)
!
Safety run-in (Part 1) and Expansion (Part 2) 
!
To assess the [CR + marrow complete remission 
(mCR)] rate
!
Proportion of participants with [CR + marrow 
complete 
remission 
(mCR)] 
according 
to 
investigator assessment by dose level for the 
safety run-in part (cohort 1 (400 mg Q4W) and 
cohort 2 (800 mg Q4W)) and for participants 
treated with sabatolimab 800 mg (Q4W) (cohort 2 
of safety run-in and expansion parts).
!
To assess Overall Response Rate (ORR), per 
modified IWG-MDS Cheson 2006 criteria, defined 
as the proportion of participants achieving [CR + 
mCR + partial remission (PR) + hematologic 
improvement (HI)]
!
Overall Response Rate (ORR) is the proportion of 
participants who achieved HI or better as best 
response as per investigator assessment (per 
modified IWG-MDS Cheson 2006 criteria). ORR 
will be summarized by dose level for the safety run-
in part (cohort 1 (400 mg Q4W) and cohort 2 (800 
mg Q4W)) and for participants treated with 
sabatolimab 800 mg (Q4W) (cohort 2 of safety run-
in and expansion parts).
!
To assess the improvement in RBC/platelets 
transfusion independence
!
Proportion of participants who are RBC/platelets 
transfusion 
independent 
and 
duration 
of 
transfusion independence as per IWG-MDS by 
dose level for the safety run-in part (cohort 1 (400 
mg Q4W) and cohort 2 (800 mg Q4W)) and for 
participants treated with sabatolimab 800 mg 
(Q4W) (cohort 2 of safety run-in and expansion 
parts).
!
To characterize the safety profile of sabatolimab
when 
administered 
in 
combination 
with 
azacitidine and venetoclax
!
Incidence and severity of AEs and SAEs, changes 
in laboratory values and vital signs, and incidence 
of notable ECG abnormalities by dose level for the 
safety run-in part (cohort 1 (400 mg Q4W) and 
cohort 2 (800 mg Q4W)) and for participants 
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Statistical Analysis Plan (SAP)
MBG453B12203
Objective(s)
Endpoint(s)
treated with sabatolimab 800 mg (Q4W) (cohort 2 
of safety run-in and expansion parts).

To further characterize the pharmacokinetics of 
sabatolimab when administered in combination 
with azacitidine and venetoclax

Serum 
concentrations 
and 
pharmacokinetic 
parameters for sabatolimab by dose level for the 
safety run-in part (cohort 1 (400 mg Q4W) and 
cohort 2 (800 mg Q4W)) and for participants 
treated with sabatolimab 800 mg (Q4W) (cohort 2 
of safety run-in and expansion parts).

To 
characterize 
the 
immunogenicity 
of 
sabatolimab when given in combination with 
venetoclax and azacitidine

Anti-drug Antibody (ADA) prevalence at baseline 
and ADA incidence on-treatment by dose level for 
the safety run-in part (cohort 1 (400 mg Q4W) and 
cohort 2 (800 mg Q4W)) and for participants 
treated with sabatolimab 800 mg (Q4W) (cohort 2 
of safety run-in and expansion parts).

Cohort 2 of Safety run-in (Part 1) and 
Expansion (Part 2) 

To assess duration of CR

Duration of CR is defined as time from first 
occurrence of CR to relapse from CR, progression 
or death due to any cause whichever occurs first 
for participants treated with sabatolimab at 800 
mg Q4W.

To assess time to CR/mCR

Time to CR/mCR is defined as time from start of 
treatment to first occurrence of CR or mCR as per 
investigator assessment for participants treated 
with sabatolimab at 800 mg Q4W.

To assess duration of CR/mCR

Duration of CR/mCR is defined as time from first 
occurrence of CR/mCR to relapse from CR, 
progression or death due to any cause whichever 
occurs 
first 
for participants 
treated 
with 
sabatolimab at 800 mg Q4W.

To assess duration of response (responding 
participants defined as hematological 
improvement (HI) or better, per modified IWG-
MDS Cheson 2006 criteria) as per investigator 
assessment.

Duration of response for participants who achieved 
HI or better per modified IWG-MDS Cheson 2006 
criteria) as per investigator assessment until 
relapse or death. Participants who did not relapse 
or die are censored to last adequate response 
assessment 
for participants 
treated 
with 
sabatolimab at 800 mg Q4W.

To assess Progression-Free Survival (PFS)

Time from start of treatment to disease progression 
(including transformation to acute leukemia per 
WHO 2016 classification), relapse from CR or 
death due to any cause, whichever occurs first 
for participants treated with sabatolimab at 800 mg 
Q4W.

To assess Leukemia-Free Survival (LFS)

Time from start of treatment to transformation to 
acute leukemia [as defined as ≥ 20% blasts in bone 
marrow/ peripheral blood (per WHO 2016 
classification) or diagnosis of extramedullary acute 
leukemia or death due to any cause, whichever 
occurs 
first] 
for participants 
treated 
with 
sabatolimab at 800 mg Q4W.

To assess Event-free Survival (EFS)

Time from start of treatment to lack of reaching CR 
within the first 6 cycles, relapse from CR or death 
due to any cause, whichever occurs first 


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Statistical Analysis Plan (SAP)
MBG453B12203
Objective(s)
Endpoint(s)
for participants treated with sabatolimab at 800 mg 
Q4W.
!
To assess Overall Survival (OS)
!
Time from start of treatment to death due to any 
cause for participants treated with sabatolimab at 
800 mg Q4W.
!
Expansion (Part 2)
!
To evaluate the changes from baseline in fatigue
!
Changes in fatigue as measured by the FACIT-
Fatigue for participants treated with sabatolimab at 
800 mg Q4W of the expansion part only.
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Statistical Analysis Plan (SAP)
MBG453B12203
Objective(s)
Endpoint(s)
2
Statistical methods
2.1
Data analysis / general information
The primary 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.
As Novartis decided to halt enrollment of the expansion part of the study in September 2022, 
the study data will be analyzed and reported based on all data up to DBL in an abbreviated final 
Clinical Study Report (CSR).
Data included in the analysis / data cut-off handling 
For each of the safety review meetings a data cut-off date will be established after the targeted 
number of evaluable participants have 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, blast counts from bone 
marrow and PK 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. The list of analyses to be presented at the time of the safety review meetings are 
provided in Section 2.8.
For the abbreviated CSR, all data collected prior to DBL will be included in the analysis.
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.
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).
2.1.1
General definitions
“Investigational drug” refers to sabatolimab
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Statistical Analysis Plan (SAP)
MBG453B12203
“Study treatment component” refers to sabatolimab or azacitidine or venetoclax.
“Study treatment” will refer to the combination of sabatolimab with azacitidine and venetoclax.
Other general definitions are detailed in Appendix Section 4.
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 over toxicity 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 analysis in the abbreviated CSR, the analysis sets defined below will include all participants 
from the safety run-in part. Participants will be analyzed according to the dose regimen they 
have been assigned to (sabatolimab 400 mg or 800 mg Q4W columns) and overall (“All 
participants” column), unless otherwise specified.
2.2.1
Full Analysis Set 
The Full Analysis Set (FAS) comprises all participants who received at least one dose of study 
treatment. If a participant was assigned to a specific cohort without any administration of 
sabatolimab, but received venetoclax or azacitidine, the participant will be included in the 
analysis.
2.2.2
Safety Set
The Safety Set includes all participants who received at least one dose of study treatment.  
2.2.3
Dose-Determining Set
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) during the first two cycles.
A participant has met the minimum exposure criterion if the participant received, during the 
first 2 cycles 2 infusions of sabatolimab at the assigned dose level in Q4W dosing regimen, and 
has taken at least 75 % of the planned dose of azacitidine and venetoclax (i.e. for 2 cycles: 11 
doses of azacitidine out of the 14 doses planned and 21 doses of venetoclax out of the 28 doses 
planned). 
Participants who do not experience a DLT during Cycles 1 and 2 are considered to have 
sufficient safety evaluations if they have been observed for at least 2 cycles following the first 
dose and are considered by both, the sponsor and investigators, to have enough safety data to 
conclude that a DLT did not occur.
2.2.4
Pharmacokinetic Analysis Sets
The sabatolimab and venetoclax pharmacokinetic analysis sets include all participants from 
the Safety Set who provide at least one evaluable sabatolimab/venetoclax PK concentration.


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For a concentration to be evaluable:

Dosing information must be properly documented (data and time of administration).

For pre-dose samples: the sample is collected before the next dose administration.

For pre-dose samples of venetoclax: patient does not vomit within 4 hours of 
venetoclax administration of the previous dose.
2.2.4.1
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
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
Venetoclax-PK 
analysis set
No written informed consent for 
participation in the study
See definition of PK analysis sets
2.2.4.2
Withdrawal of Informed Consent
Any data collected in the clinical database after a participant withdraws informed consent from 
all further participation in the study will not be included in the analyses. The date on which a 
participant withdraws 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 that consent or after withdrawal of consent will not be included in the analyses. 
2.2.5
Subgroup of interest
No subgroup analysis will be conducted for the abbreviated CSR.
2.3
Patient disposition, demographics and other baseline 
characteristics
The FAS will be used for the analyses below. Patient disposition, demographics and other 
baseline characteristics will be summarized by dose level of sabatolimab (400 mg Q4W, 800 
mg Q4W) and for all participants (“All participants” column).


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2.3.1
Patient disposition
Number (%) of participants screened and enrolled will be summarized by country and center. 
For participants who did not complete screening, the reasons for not completing screening will 
be summarized based on “Screening Phase Disposition” eCRF.
The number (%) of participants in the FAS who started treatment, are still on treatment, who 
entered and discontinued post-treatment follow-up and who discontinued the study after 
survival follow-up will be summarized together with the respective reasons for treatment/post-
treatment follow-up/end of study discontinuation (which corresponds to end of survival follow-
up). All disposition information will be listed.
Protocol deviation
The number (%) of participants in the FAS with any protocol deviation will be tabulated by 
deviation category. All protocol deviations will be listed.
In addition to the pre-defined standard protocol deviation terms, Novartis has also defined new 
protocol deviations and the corresponding relationship to the COVID-19 pandemic. The 
protocol deviations related to the COVID-19 pandemic will be summarized by relationship 
category.
2.3.2
Demographics and other baseline characteristics
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 MDS diagnosis (initial diagnosis, IPSS-R risk category including the components 
(blasts in BM, number of cytopenias and cytogenetic abnormalities), WHO classification, 
current disease status (de novo or secondary) and cytogenetic abnormalities) will be tabulated 
and time since diagnosis summarized.
Medical history
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 
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 level of sabatolimab (400 mg Q4W, 800 mg Q4W) and for all participants (“All 
participants” column).


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2.4.1
Study treatment / compliance
The duration of exposure to study treatment and to each study drug (sabatolimab, azacitidine 
and venetoclax) as well as the actual dose intensity, relative dose intensity and doses changes 
will be summarized by descriptive statistics.
2.4.1.1
Duration of exposure
The duration of exposure (in months) will be summarized for study treatment (combination) 
and for each study drug individually (sabatolimab, azacitidine and venetoclax) 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 4.
2.4.1.2
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 (Mosteller) is used for BSA:
BSA (m2) = ℎ
 () ∗ℎ
 
  ()/3600
For venetoclax, the actual cumulative dose in mg is the sum of “dose administered” from the 
eCRF of all cycles during the exposure of venetoclax.
2.4.1.3
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 treatment components
is the ratio of planned cumulative dose and duration in days from first to last cycle initiated:

Sabatolimab: the planned dose intensity is 400 mg/28 days or 800 mg/28 days,

Azacitidine: the planned dose intensity is 75 mg/m²/day which is equivalent to 525 
mg/m²/28 days,

Venetoclax: the planned dose intensity is 400 mg/day which is equivalent to 5600 mg/28 
days when the recommended full daily dose of venetoclax is 400 mg.
The relative dose intensity is then computed as the ratio of actual dose intensity and planned 
dose intensity. For 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.


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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 4.
2.4.1.4
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 treatment component.  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).
2.4.1.5
Cycle initiated 
The number of cycles initiated by participant will be summarized. 
2.4.2
Prior, concomitant and post therapies / HSCT
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.
Anti-neoplastic medications after discontinuation of study treatment during follow-up within 
the study will be summarized using the FAS by ATC class and preferred term. All HSCTs will 
be listed.
Transfusions of blood products (including those not related to MDS) prior and after start of 
study treatment will be listed. Only MDS related transfusions (e.g. bleeding, surgical procedure, 
hemolysis, infections) of platelets and red blood cells will be summarized using the FAS. For 
that, the number of transfusion units will be normalized by time (i.e. fixed 8 week interval, 
mentioned below as episode) prior to and on-treatment.  The number of participants with at 
least one transfusion episode, the number of transfusion episode per participant and the number 
of units per episode will also be described. Further analyses to summarize transfusion 
independence and dependence are described in the efficacy section. 
2.5
Analysis of the primary objectives
The primary objective of the Safety run-in (Part 1) of the study is to determine whether 
sabatolimab 400 mg and 800 mg are safe (i.e. not meeting overdose criteria) when added in 
combination with azacitidine and venetoclax.
The primary objective of the Expansion (Part 2) is to determine the complete remission rate 
(CR) of sabatolimab (800 mg Q4W) in combination with azacitidine and venetoclax. This 
analysis will include all participants’ data from cohort 2 of the Safety run-in (Part 1) and 
Expansion (Part 2).


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2.5.1
Primary endpoints and estimand
2.5.1.1
Safety run-in (Part 1)
For the Safety run-in part, the primary endpoint is the incidence of DLTs during the first 2 
cycles of treatment for participants in the DDS. The number and percentage of DLTs occurring 
during the DLT evaluation period will be summarized by system organ class and preferred term 
in the DDS, and the DLTs will be listed
Details on the definition of DLT which are to be captured in the Adverse Event eCRF were 
defined as described in (Table 6-4 of study protocol).
2.5.1.2
Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2)
The primary endpoint is the proportion of participants included in the FAS and assigned to 
sabatolimab at the 800 mg Q4W dose level (in both safety run-in and expansion parts) who 
achieved a complete remission (CR) as per investigator assessment.
Response assessment rules 
Response assessment will be performed by the investigator according to the assessment 
schedule depicted in protocol Table 8-1 based on available bone marrow assessment (C3D1, 
C7D1, C10D1, C13D1 and then C19D1, C25D1 and then every 12 cycles), hematology data (at 
D1, D8, D22 of the first 2 cycles and then D1 and D8 of each cycle until end of treatment and 
then every 12 weeks) and all transfusions records as detailed in s using the modified version of 
the published response criteria IWG for MDS. Moreover, response assessments can be 
performed at any time if clinically indicated, e.g. for confirmation of response but also for any 
suspicion of progression/relapse. These assessments are recorded as an unscheduled visit in the 
eCRFs and will be considered for the overall determination of response and progression/relapse 
with the respective assessment date.
The investigator does not determine best overall response, he/she is assessing only the response 
based on the given bone marrow and peripheral blood data, the history of transfusions and
myeloid growth factor received within the last 2 weeks. 
The best overall response (BOR) will be derived based on the CR primary endpoint rules by 
Novartis as below:

CR = at least one determination of CR without progression or relapse from CR within the 
four weeks after CR 

mCR = at least one determination of mCR (and not qualifying for a CR).

PR = at least one determination of PR (and not qualifying for a CR, mCR).

HI = at least one determination of HI (and not qualifying for a CR, mCR, PR)

SD = at least one SD assessment and not qualifying for CR, mCR, PR or HI).

PD = progression after start of treatment and not qualifying for CR, mCR, PR, HI or SD.

UNK = all other cases (i.e., not qualifying for confirmed CR or mCR or PR or HI and 
without SD or progression).
Details for the definition of response categories (captured in the eCRF by the Investigator) as 
defined in Table 8-2 of the protocol, are described in Table 2-2 below. 


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Table 2-2
Modified response classification per IWG-MDS criteria (Platzbecker et             
al 2019, Cheson et al 2006, Cheson et al 2000)
Response category
Definition#
Complete remission (CR)
Bone marrow:
<= 5% blasts with normal maturation of all 
cell lineages. (Note: Persistence of dysplasia 
will be noted but does not preclude 
achievement of complete remission [CR])
Peripheral blood:
1. Hgb ≥ 10 g/dl AND
2. Platelets ≥ 100*109/L AND
3. Neutrophils ≥ 1.0*109/L AND
4. Blasts 0%
(Note: the participant must not receive RBC 
or platelet transfusions, myeloid growth 
factor within 2 weeks before this disease 
assessment)
marrow Complete remission (mCR)
Bone marrow:
<= 5% blasts and blast count decrease by ≥ 
50% compared to baseline
Peripheral blood/transfusion: Marrow CR 
may be achieved with or without improved 
blood counts or with or without transfusions
Partial remission (PR)
All CR criteria except
Bone marrow: ≥ 50% decrease from 
baseline in blasts in bone marrow AND blast 
count in bone marrow > 5%
Stable Disease (SD)
Failure to achieve at least PR, but no 
evidence of progression for >8 weeks
Relapse from CR
Only in participants with a CR
At least 1 of the following criteria is met: 
[in absence of another explanation not due to 
MDS, such as acute infection, bleeding, 
hemolysis, etc. Note that observation of 
peripheral blasts is not a sufficient criterion 
for relapse. However, in that case, a bone 
marrow examination should be made to 
determine whether relapse has occurred]


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1. Return to baseline bone marrow blast 
percentage
2. Decrease of ≥ 50% from maximum 
remission/response*** levels in neutrophils 
AND 
neutrophils 
<1.0*109/L. 
Note: 
neutrophils counts during periods of active 
infection 
will 
not 
be 
considered 
in 
determining the maximum
3. Decrease of ≥ 50% from maximum 
remission/response*** levels in platelets 
AND platelets < 100*109/L
4. 
Decrease 
from 
maximum 
remission/response*** 
levels
in 
Hgb 
concentration by ≥ 1.5g/dL AND Hgb < 10 
g/dL
5. Becoming transfusion dependent**
Disease progression
At least 1 of the following criteria is met:
[in absence of another explanation not due to 
MDS, such as acute infection, bleeding, 
hemolysis, etc. Note that observation of 
peripheral blasts is not a sufficient criterion 
for progression. However, in that case, a bone 
marrow examination should be made to 
determine whether relapse has occurred]
Bone marrow according to the number of 
blasts of the participant at baseline:
1. Less than 5% blasts at baseline: ≥ 50% 
increase in blasts over baseline to > 5% blasts
2. 5% - < 10% blasts at baseline: ≥ 50% 
increase over baseline to > 10% blasts
3. 10% - < 20% blasts at baseline: ≥ 50% 
increase over baseline to > 20% blasts.
Participants with more than 20% of blasts 
will be considered to have transformation to 
acute leukemia per 2016 WHO classification 
(Arber et al, 2016)
Peripheral blood:
1. Decrease of ≥ 50% from maximum 
remission/response*** levels in neutrophils 


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AND 
neutrophils 
< 
1.0*109/L. 
Note: 
neutrophils counts during periods of active 
infection 
will 
not 
be 
considered 
in 
determining the maximum
2. Decrease of ≥ 50% from maximum 
remission/response*** levels in platelets 
AND platelets < 100*109/L
3. 
Reduction 
from 
maximum 
remission/response*** levels in Hgb by ≥ 
2g/dL AND Hgb < 10g/dL
Becoming transfusion dependent**
Occurrence 
of 
acute 
leukemia, 
or 
extramedullary leukemia per investigator's 
judgement
Modified Hematologic Improvement per IWG-MDS criteria (Cheson et al 2006)
HI category
Definition# (HI must last at least 8 weeks)
Erythroid response (HI-E) 
(pretreatment*, <11 g/dL)
1. Hgb increase from baseline by ≥ 1.5 g/dL, 
in at least 2 consecutive Hgb measurements 
and maintained over at least 8 weeks
2. Relevant reduction from baseline of units 
of RBC transfusions by an absolute number 
of at least 4 RBC transfusions/8 weeks 
compared with the pre-treatment transfusion 
number in the previous 8 weeks. Only RBC 
transfusions given for a Hgb of < 9 g/dL pre-
treatment will count in the RBC transfusion 
response evaluation.
Platelet response (HI-P) (pretreatment*, 
<100 x 109/L)
1. Absolute increase from baseline of ≥ 30 x 
109/L for participants starting with > 20 x 
109/L platelets
2. Increase from baseline from < 20 x109/L 
to > 20 x109/L and by at least 100% for 
participants starting with < 20 x 109/L 
platelets
Neutrophil response (HI-N)
(pretreatment*, <1.0 x 109/L)
At least 100% increase and an absolute 
increase from baseline of > 0.5 x 109/L
#If not defined otherwise, all of the criteria apply. Words that are written in italics highlights 
the modifications from the IWG criteria described in the reference publications.
*Pretreatment counts correspond to the baseline (not influenced by transfusions)


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**Definition of transfusion dependence and independence for red blood cells (RBC) and/or platelets 
are described below.
***maximum remission/response levels correspond to the best values reported in post baseline.
Transfusions Status Definitions for RBC/platelets
Transfusions for intercurrent diseases not due to study indication (e.g. bleeding, 
surgical procedure, hemolysis, infections) should not be taken into account for the 
following:
Transfusion dependence:
1. At baseline: participants having received ≥ 3 units of transfusion within the 8 consecutive 
weeks 
prior 
to 
baseline.
2. Post-baseline: participants having received ≥ 3 units of transfusion within any 8 
consecutive weeks during the course of the study
Transfusion independence:
1. At baseline: participants having received 0 units of transfusion within the 8 consecutive 
weeks prior to baseline.
2. Post-baseline: participants having received 0 units of transfusion within any 8 consecutive 
weeks during the course of the study.
Primary estimand
The primary clinical question of interest is the following:
Is sabatolimab 800 mg Q4W in combination with fixed doses of azacitidine (75 mg/m2 Day 1-
7) and venetoclax (400 mg Day 1-14) associated with improved efficacy (i.e. CR rate >= 50%) 
for participants with high or very high risk MDS?
The primary endpoint (combining data from cohort 2 of the Safety run-in (Part 1) and the 
Expansion (Part 2) (i.e. sabatolimab 800 mg (Q4W)) is the proportion of participants achieving 
a complete remission (CR) as per investigator assessment.
The primary efficacy estimand is described by the following five attributes:

Population: Adult participants as described by inclusion/exclusion criteria not eligible for 
intensive chemotherapy nor for HSCT with high or very high risk MDS (IPSS-R criteria) 
(Greenberg et al 2012) as per inclusion/exclusion criteria and as assessed locally by the 
investigator.

Variable: Best overall response among all disease response assessments as assessed by 
investigator per modified IWG MDS criteria (Cheson et al 2006) up to new anti-cancer 
therapy (including HSCT).

Treatment: Study treatment initiates sabatolimab 800 mg Q4W + azacitidine (75 
mg/m2 Day 1-7) + venetoclax (400 mg Day 1-14). Participants will continue treatment 


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until a reason of treatment discontinuation is met (e.g. progression, unacceptable toxicity, 
HSCT).

Intercurrent events:

Study treatment modification: all CR will be taken into account regardless of any 
study treatment component interruption, dose adjustment or permanent 
discontinuation.

Concomitant medications and supportive care: A participant may receive blood 
transfusion as supportive care and prophylactic treatment as clinically indicated (e.g. 
antiemetics, antibiotics, antifungals). All CR will be taken into account regardless of 
any concomitant medication administration including prohibited medications.

New anti-cancer therapy/HSCT: CR achieved after initiation of a new anti-cancer 
therapy or HSCT will not be taken into account.

Summary measures: The CR rate and the 95% confidence interval (CI).
2.5.2
Statistical hypothesis, model, and method of analysis
2.5.2.1
Safety run-in (Part 1)
DLT analysis
A Bayesian model will be used to assess whether sabatolimab at the two tested dose levels is 
not meeting overdose criteria when added to azacitidine and venetoclax in participants from the 
DDS. The relationship between dose and the probability of DLT is modeled using a logistic 
regression model. Detail of the characteristics of this Bayesian model is provided in Appendix 
Section 16.1 of the protocol.
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 [33%, 100%] (i.e. excessive toxicity).
2.5.2.2
Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2)
CR primary analysis 
As Novartis decided to halt the enrollment in the expansion part, only the CR rate by the dose 
level of sabatolimab with exact 95% confidence interval will be reported in the abbreviated 
CSR.
2.5.3
Handling of missing values/censoring/discontinuations
2.5.3.1
Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2)
For the determination of CR, only assessments after first dose of study treatment and prior to 
the start of any other anti-neoplastic therapy/HSCT as per investigator evaluation are considered. 
An adequate response assessment is considered any disease assessment indicating response 
status apart from “unknown” or “not done”. Participants who discontinued trial prior to the first 
efficacy assessment (i.e. C3D1) will be reported with best response as ‘Unknown’.


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2.6
Analysis of secondary objective(s)
The secondary objectives are to assess the overall response rate (ORR), CR/mCR rate, duration 
of CR, time to CR/mCR, duration of response, duration of CR/mCR, overall survival (OS), 
event free survival (EFS), progression free survival (PFS), leukemia free survival (LFS), 
RBC/platelets transfusion independence, changes from baseline in fatigue, pharmacokinetic, 
immunogenicity and safety.
2.6.1
Efficacy
2.6.1.1
Safety run-in (Part 1)
CR+mCR and overall response (ORR) rates
CR+mCR rate is defined as the proportion of participants with best overall response of either 
complete remission (CR) or marrow complete remission as per investigator assessment. 
CR/mCR rate will be provided with exact 95% confidence interval (Clopper and Pearson 
1934).
ORR rate is defined as the proportion of participants with best overall response of hematological 
improvement (HI) or better as per investigator assessment. ORR rate will be provided with
exact 95% confidence interval (Clopper CJ and Pearson ES 1934). CR/mCR and ORR will be 
provided by dose level of sabatolimab.
Improvement of RBC/platelets transfusion independence
RBC/Platelets transfusion independence rate is defined as the proportion of participants having
received no RBC/Platelets transfusions during at least 8 consecutive weeks after start of 
treatment. The number and percentage of participants will be shown for the FAS and then also 
in only those with transfusion dependence at baseline. Percentages will be provided with exact 
95% confidence interval (Clopper and Pearson 1934). Shift tables will be provided to describe 
the transfusion status at baseline versus the best transfusion status postbaseline.
For participants with at least one period of transfusion independence post-baseline, the total 
duration of all transfusion independence periods (which all individually must be at least 8 
weeks) will be also summarized. The duration of each period of transfusion independence is 
defined from the end date of the last transfusion received until the date transfusions are given 
again or last date of treatment administration in case transfusions had not (re-)started during 
treatment.
The total duration of all transfusion independence periods is the sum of each period of the 
transfusion independence. The data will be summarized by dose level of sabatolimab.
2.6.1.2
Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2)
All time-to-event endpoints (including duration of CR, time to CR/mCR, duration of response, 
duration of CR/mCR, OS, EFS, PFS and LFS) will be derived and stored in analysis datasets, 
and the individual time and specific event / censoring type will be listed. However, the amount 
of available follow-up data and number of events will determine if standard KM tables and/or 
graphics will be produced, which will be further discussed in the TFL shell. 


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Bone marrow blasts percentage will be listed. In addition, for some selected laboratory 
parameters and for bone marrow blasts percentage, trends over time (baseline and on-treatment 
timepoints during the first 6 cycles of treatment including C7D1 assessment) will be displayed 
via boxplots, and corresponding tables displaying the summary statistics for these selected 
timepoints will be produced.
CR+mCR rate 
CR+mCR rate is defined as the proportion of participants treated with sabatolimab at 800 mg 
Q4W with best overall response of either complete remission (CR) or marrow complete 
remission as per investigator assessment. CR/mCR rate will be provided with exact 95% 
confidence interval (Clopper CJ and Pearson ES 1934). The same rules applied to the primary
endpoint (i.e. CR rate) will be applied to the CR/mCR rate.
Overall Response Rate (ORR) 
ORR rate is defined as the proportion of participants treated with sabatolimab at 800 mg Q4W 
with best overall response of hematological improvement (HI) or better as per investigator 
assessment. ORR rate will be provided with exact 95% confidence interval (Clopper and 
Pearson 1934). The same rules applied to the primary endpoint (i.e. CR rate) will be applied 
to CR/mCR rate.
Duration of CR
The duration of CR will be derived for participants treated with sabatolimab at 800 mg Q4W 
who achieve CR per modified IWG-MDS Cheson 2006 (prior to any new antineoplastic therapy, 
including HSCT) as per investigator assessment and is defined from the first occurrence of CR 
until relapse, progression, or death due to any reason.  Relapse, progression or death occurring 
after HSCT will be considered as event for the duration of CR. The date of the event will be the 
date of relapse, progression, or death whichever occurs first. If participant did not relapse nor 
progress/die, the duration of response will be censored at the last adequate response assessment.
If the participant has started a new antineoplastic therapy without prior documented relapse or 
progression, the duration of CR is censored at the last adequate assessment prior to the start of 
that therapy, and thus any subsequent relapse/progression/death will not be considered as an 
event for duration of CR.
Duration of CR will be estimated using the Kaplan-Meier Method. The median duration of CR 
along with 95% Confidence interval will be presented.
Duration of CR/mCR 
The duration of CR/mCR will be derived for participants treated with sabatolimab at 800 mg 
Q4W who achieve CR or mCR (prior to any new antineoplastic therapy, including HSCT) as 
per investigator assessment and is defined from the first occurrence of CR or mCR until relapse, 
progression or death due to any reason. Relapse, progression or death occurring after HSCT will 
be considered as event for the duration of CR/mCR, the date of the event will be the date of 
relapse, progression, or death whichever occurs first. If the participant did not relapse, progress 
or die, the duration of CR/mCR will be censored at the last adequate response assessment. If 
the participant started a new antineoplastic therapy, without prior documented relapse or 


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progression, the duration of CR/mCR is censored at the last adequate assessment prior to the 
start of that therapy and thus any subsequent relapse/progression/death will not be considered 
as an event for duration of CR/mCR.
Duration of CR/mCR will be estimated using the Kaplan-Meier Method. The median duration 
of CR/mCR along with 95% Confidence interval will be presented.  
Duration of response 
The duration of response will be derived for participants treated with sabatolimab at 800 mg 
Q4W who achieve HI or better (prior to any new antineoplastic therapy, including HSCT) as 
per investigator assessment and is defined from the first occurrence of CR, mCR, PR or HI until 
relapse, progression or death due to any reason.
Relapse, progression or death occurring after HSCT will be considered as an event for the 
duration of response. The date of the event will be the date of relapse, progression, or death 
whichever occurs first. If the participant did not relapse, progress or die, the duration of response 
will be censored at the last adequate response assessment. If the participant started a new 
antineoplastic therapy without prior documented relapse or progression, the duration of 
response is censored at the last adequate assessment prior to the start of that therapy and thus 
any subsequent relapse, progression, or death will not be considered as an event for duration of 
response.
Duration of response will be estimated using the Kaplan-Meier method. The median duration 
of response along with 95% confidence interval will be presented.
Time to CR/mCR 
The time to CR/mCR will be derived for all participants treated with sabatolimab at 800 mg 
Q4W and is defined from start of treatment to first occurrence of CR/mCR (prior to any new 
antineoplastic therapy, including HSCT). For participants who reached CR /mCR after HSCT
or a new antineoplastic therapy, the time to CR/mCR will be censored at the time of HSCT or 
initiation of new antineoplastic therapy.
For participants who did not reach CR/mCR, a). if they did not progress, die or progress to acute 
myeloid leukemia either, the time to CR/mCR will be censored at the last adequate response 
assessment; or b). if they progressed, died or the disease progressed to acute myeloid leukemia, 
the time to CR/mCR will be censored at the maximum follow-up (last participant last visit).
Time to CR/mCR will be estimated using the Kaplan-Meier method. The median time to 
CR/mCR along with 95% confidence interval will be presented.
Event-free survival (EFS) 
Event-free survival (EFS) is defined from the date of start of treatment to:

Lack of complete remission within the maximum of first 6 months or 6 cycles
(including C7D1 assessment) of start of treatment

Progression/Relapse

Death from any cause
Whichever occurs first.


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Participants treated with sabatolimab at 800 mg Q4W who failed to achieve CR within 6 cycles 
of treatment will have their EFS event documented at start of treatment. If participant
discontinued treatment due to any reason (including death) prior to 6 cycles and without CR 
will be considered as EFS event documented at start of treatment date.
Progression/Relapse, or death events after HSCT, and transfusion of blood products, will be 
taken into account. However, Progression/Relapse, or death, occurring after initiation of new 
antineoplastic therapy, will not be considered an event and EFS will be censored at the last 
adequate response assessment prior to the new antineoplastics therapy. 
In case of two or more missing assessments prior to documented progression, relapse or death, 
EFS will be censored at the last adequate response assessment prior to the documentation of 
relapse or death.
EFS will be estimated using the Kaplan-Meier method. The median EFS along with 95% 
confidence interval will be presented.
Progression free survival (PFS) 
PFS is defined as the time from start date of treatment to date of relapse, progression (including 
transformation to acute leukemia per WHO 2016 classification) or death due to any cause. If a 
participant is not known to have relapsed, progressed nor died, then PFS will be censored at the 
last adequate response assessment (on or before the cut-off date). Progression/relapse or death 
occurring after a). HSCT, b). interruptions or c). discontinuation of study treatment due to any 
reason will be taken into account. However, Progression/Relapse, death occurring after 
initiation of new antineoplastic therapy will not be considered an event and PFS will be 
censored at the last adequate response assessment.
In case of two or more missing assessments prior to documented progression, relapse or death, 
PFS will be censored at the last adequate response assessment prior to the documentation of 
progression, relapse or death.
PFS will be estimated using the Kaplan-Meier method. The median PFS along with 95% 
confidence interval will be presented.
Leukemia Free survival (LFS) 
LFS is defined as the time from start of treatment to transformation to acute leukemia as per 
investigator assessment defined as the following:

≥ 20% blasts in bone marrow/ peripheral blood (per WHO 2016 classification)

Diagnosis of extramedullary acute leukemia

Death due to any cause
whichever occurs first.
If a participant is known to not have progressed to leukemia as defined by the criteria mentioned 
above, then LFS will be censored at the last bone marrow/peripheral blood assessments (on or 
before the cut-off date). Any of the three events (i.e. ≥ 20% blasts in bone marrow/peripheral 
blood, diagnosis of extramedullary acute leukemia or death) occurring after HSCT,
interruptions, or discontinuation of study treatment due to any reason will be taken into account. 
However, events occurring after initiation of new antineoplastic therapy will not be considered 


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an event and LFS will be censored at the last adequate assessment of bone marrow and/or 
peripheral blood, or diagnosis of extramedullary acute leukemia prior to initiation of new 
antineoplastic therapy.
In case of two or more missing assessments prior to documented progression to leukemia, LFS 
will be censored at the last adequate assessment (bone marrow and/or hematology assessment) 
prior to the documentation of progression to leukemia.
LFS will be estimated using the Kaplan-Meier method. The median LFS along with 95% 
confidence interval will be presented.
Overall Survival (OS) 
OS is defined as the time from start date of treatment to date of death due to any cause. If a 
participant is not known to have died, then OS will be censored at the latest date the participant
was known to be alive (on or before the cut-off date). All deaths will be taken into account 
whenever the death occurred, i.e. even after new anti-neoplastic therapy, HSCT, interruptions, 
or discontinuation of study treatment due to any reason.
The OS censoring reason will be summarized as ‘Alive’ or ‘Lost to follow-up’. Participants not
known to have died will have the censoring reason ‘Lost to follow-up’ if the reason for 
discontinuation from study is ‘Lost to follow-up’ or ‘Withdrawal of consent’. Otherwise, 
participants will have the censoring reason ‘Alive’.
OS will be estimated using the Kaplan-Meier method. The median OS along with 95% 
confidence interval will be presented.
Improvement of RBC/platelets transfusion independence 
RBC/Platelets transfusion independence rate is defined as the proportion of participants having 
received no RBC/Platelets transfusions during at least 8 consecutive weeks after start of 
treatment. The number and percentage of participants will be shown for the FAS and then also 
in only those with transfusion dependence at baseline. Percentages will be provided with exact 
95% confidence interval (Clopper and Pearson 1934). Shift tables will be provided to describe 
the transfusion status at baseline versus the best transfusion status postbaseline.
For participants with at least one period of transfusion independence post-baseline, the total 
duration of all transfusion independence periods (which all individually must be at least 8 
weeks) will be also summarized. The duration of each period of transfusion independence is 
defined from the end date of the last transfusion received until the date transfusions are given 
again or last date of treatment administration in case transfusions had not (re-)started during 
treatment.
The total duration of all transfusion independence periods is the sum of each period of the 
transfusion independence.
2.6.1.3
Handling of missing values/censoring/discontinuations for PFS, LFS 
and EFS 
For participants without PFS/EFS/LFS events, PFS/LFS/EFS are censored at the last adequate
assessment (response assessment for PFS/EFS, bone marrow/hematology assessment for LFS). 


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This is the last response/bone marrow/hematology assessment conducted that is not considered 
as unknown. 
An event occurring after two or more consecutive missing response assessments (not done or 
unknown) is censored in the analysis at the last adequate response assessment before the event 
date and reason for censoring then summarized as ‘Event documented after two or more missing 
response assessments’. 
An exact rule to determine whether there are two missing assessments is therefore needed.  This 
rule 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:

Pre-dose on C3D1, then

From C7D1, bone marrow assessments will be performed every 3 cycles (12 weeks)
until C13D1 (C7D1, C10D1, C13D1), then

Every 6 cycles (24 weeks) until C25D1 (C19D1 and C25D1) and thereafter every 12 
cycles (48 week, visit: C37D1, C49D1 etc.) and as clinically indicated during the 
treatment period).

At least every 12 months during follow-up for efficacy
As per the protocol, a window of +/- 1 week from the planned visit date is allowed for BMA 
procedures. During the post-treatment and survival follow-up phases, a visit window of +/- 2 
weeks is allowed.  
The censoring reason will be summarized as:
1. Ongoing without event
2. New anti-cancer therapy
3. Withdrew consent
4. Lost to follow-up
5. Event documented after two or more missing response assessments
6. Discontinuation due to participant/physician/guardian’s decision
2.6.2
Safety
Safety analyses will be summarized for the safety set and by dose level of sabatolimab (400 mg 
Q4W, 800 mg Q4W) and for all participants (“All participants” column).
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, tables for adverse events (AEs) will summarize 
only on-treatment events, with a start date during the on-treatment period (treatment-emergent 
AEs).


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The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from the day of participant’s informed consent to the day before first 
administration of study treatment
2. On-treatment period: from date of first administration of study treatment to 30 days after 
the date of 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 first administration of study treatment to 
150 days after the last dose of sabatolimab.
2.6.2.1
Adverse events (AEs)
AE summaries will include all AEs occurring during on-treatment period (until 30 days after
last administration of study treatment). When specified, some AEs summaries will include all
AEs occurring during the overall safety period.
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 
AEs will be summarized by primary system organ class, preferred term and maximum severity
(based on CTCAE grades).
All AEs reported in the AE eCRF page will be listed along with the information collected on
those AEs, e.g. toxicity grade, relationship to study treatment, outcome, action taken etc. AEs
that started during the pre-treatment, post-treatment and after the overall safety period will be
flagged in listings.
AEs will be summarized by number and percentage of participants having at least one AE, 
having at least one AE in each primary system organ class (SOC) and for each preferred term 
(PT). 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 preferred term 
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 system organ class will be presented alphabetically and the
preferred terms will be sorted within primary SOC in descending frequency. The sort order for
the preferred term will be based on their frequency in the sabatolimab 800 mg Q4W. 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 treatment, outcome or action taken:

AEs (all AEs (by SOC and by PT) and separately those considered related to study
treatment

SAEs and separately those considered related to study treatment

SAEs with number of occurrences (an occurrence is defined as > 1 day between start and
prior end date of record of same preferred term).

Non-SAEs


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
SAEs with fatal outcome and separately those considered related to study treatment

AEs leading to study treatment or sabatolimab discontinuation

Related to study treatment AEs leading to study treatment discontinuation

AEs leading to dose adjustment/interruption for sabatolimab,venetoclax or azacitidine

AEs requiring additional therapy

COVID-19 related adverse events by MedDRA COVID-19 (SMQ) terms.
In addition, all AEs and SAE by SOC and PT will be also provided for the overall safety period. 
Adverse events for the safety follow up period (day 31-150 after last dose of sabatolimab) will 
be described by system organ class and preferred term.
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 reason for deaths by SOC and 
preferred term. All AEs, deaths, and serious adverse events (including those from the pre- and 
post-treatment periods) will be listed and those collected during the pre-treatment, 
posttreatment and overall safety period will be flagged in listings. A separate listing of deaths 
prior to starting treatment will be provided for all screened participants.
2.6.2.2
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 compound sabatolimab. These groupings are defined using 
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) may also be used. A NMQ is 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. It 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 on treatment period will be summarized together with the individual preferred 
terms in that grouping. In addition, number (%) of participants with at least one AESIs by 
maximum CTC grade, related AESIs, serious AESIs as well as action taken and outcome of the 
respective AESI will be summarized. 
2.6.2.3
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 reasons for deaths by the primary 
reason 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.
2.6.2.4
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 


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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
Liver function parameters of interest are total bilirubin, ALT, AST and alkaline phosphatase. 
The number (%) of participants with the worst post-baseline values as per Novartis Liver 
Toxicity guidelines will be summarized.
All CTCAE grade 3 or 4 laboratory toxicities will be listed.
2.6.2.5
Other safety data
Safety data listed in this section will be analyzed and summarized for the safety set and 
presented by dose level of sabatolimab (400 mg Q4W, 800 mg Q4W) and for all participants 
(“All participants” column), and by visit/sampling time point.
2.6.2.6
ECG and cardiac imaging data
ECGs are collected as 12-lead triplicate using the ECG machines supplied by the central 
laboratory and then transmitted electronically to the central laboratory for central review by an 
independent reviewer. These central ECGs are done at screening, C1D1 pre-dose, C1D8 post-
dose, C3D8 post-dose and at end of treatment; however, additional ECGs can be done if 
clinically indicated.
Notable ECG values during on-treatment period in participants with normal values at baseline 
(for the respective QTc value) will be summarized using the following criteria:
Table 2-3
Notable ECG values
ECG parameter (unit)
Clinically notable criteria
QTcF (ms)
Increase >30 and <=60 ms
Increase >60 ms
New >450 to <=480 ms
New >480 to <=500 ms
New >500 ms
HR (bpm)
Increase >25% and HR >100 bpm
Decrease >25% and HR<50 bpm
PR (ms)
Increase from baseline >25% and to a value > 200 ms
New value of > 200 ms
QRS (ms)
Increase from baseline >25% and to a value > 120 ms
New values of QRS > 120 ms


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In addition, local ECGs are performed but not used for summary of QTc values. If abnormalities 
are observed based on these local ECGs, these abnormalities are to be reported and thus 
summarized as AEs.
2.6.2.7
Vital signs
Notable vital sign values during on-treatment period will be summarized using the following 
criteria:
Table 2-4
Notable vital sign values
Vital sign (unit)
Clinically notable criteria
above normal value 
below normal value
Systolic blood pressure 
(mmHg)
>= 180 with increase from baseline 
of >= 20
<= 90 with decrease from baseline 
of >= 20
Diastolic blood pressure 
(mmHg)
>= 105 with increase from baseline
of >= 15
<= 50 with decrease from baseline 
of >= 15
Pulse rate (bpm)
>= 100 with increase from baseline 
of > 25%
<= 50 with decrease from baseline 
of > 25%
Weight (kg)
Increase >= 10% from baseline
Decrease  >= 10% from baseline
Body temperature (°C)
>= 39.1 
-
2.6.3
Pharmacokinetic
2.6.3.1
Sabatolimab and venetoclax drug concentrations
Pharmacokinetic analyses will be summarized for the sabatolimab
or venetoclax 
pharmacokinetic analysis set. Sabatolimab and venetoclax concentration data will be listed by 
participant, and visit/sampling time point. Descriptive summary statistics for sabatolimab and 
venetoclax concentrations will be provided by the dose level of sabatolimab, visit/sampling 
time point. Concentrations at EOT, 30-day safety follow-up and 150-day safety follow-up visit 
will not be included in the summary table for sabatolimab. In the case of predose samples, the 
actual dose would reflect the prior dose the participant received.  The summary table for
venetoclax concentration data only includes the patients whose prior dose (D7 dose) was 400 
mg at each sampling time point. Summary statistics will include 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%. Sabatolimab and venetoclax concentration data obtained 
from samples collected outside of PK sample collection window as defined per protocol will be 
flagged and excluded for the summary statistics. PK parameters (the minimum observed plasma 
or serum drug concentration (Cmin or Ctrough) and the maximum (peak) observed plasma or 
serum drug concentration (Cmax)) will be estimated and reported. Missing values for any PK 
parameters or concentrations will not be imputed and will be treated as missing.


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All concentration data for sabatolimab vs. time profiles with median will be displayed 
graphically, excluding concentrations at EOT, 30-day safety follow-up and 150-day safety 
follow-up visit. All concentration data for venetoclax by timepoints will be displayed 
graphically.  The concentrations collected before dose administration on Day 8 of Cycle 3 and 
beyond are Ctrough for sabatolimab. If the sabatolimab pre-dose sample is collected more than 
+/- 3 days from the 28 day dose cycle, this concentration would be removed from the graph and 
summary. If the venetoclax pre-dose sample is collected more than +/- 3 hours from the 24 
hours daily dose interval after the prior dose on Day 7, this concentration would be removed 
from the graph and summary. End of infusion concentration will be reported as Cmax.
2.6.3.2
As the half-life of venetoclax is approximately 26 hours, the sample 
collected at Cycle 1 Day 8 will be considered as the venetoclax trough 
concentration at steady state before any dose administration of 
sabatolimab.Population pharmacokinetic analysis
If data permit, a mixed-effects model may be applied to the serum sabatolimab concentration-
time data from this study along with other studies to generate post-hoc estimates of 
pharmacokinetic parameters using appropriate software to characterize sabatolimab exposure 
and to determine the effects of intrinsic (i.e. demographic factors) and extrinsic covariates (e.g. 
combination partners) on sabatolimab exposure. 
The population pharmacokinetic analyses will not be conducted for the abbreviated final CSR. 
If there are sufficient data for analysis, the details of the population pharmacokinetic analyses 
may be provided in a separate reporting and analysis plan, and the results may be reported in a 
separate population pharmacokinetic report.
2.6.4
Immunogenicity
2.6.4.1
Sample ADA Status
Each IG sample is assessed in a three-tiered anti-drug anti-body (ADA) testing approach. All 
IG samples are analyzed in the initial screening assay (first tier). Samples testing negative in 
the screening assay are not subject to a confirmatory assay. Samples testing positive in the 
screening assay are then subjected to the confirmatory assay to demonstrate that ADA are 
specific for the therapeutic protein product (second tier). The titer of confirmatory positive 
samples will be subsequently determined in the titration assay (third tier). Samples identified as 
positive in the confirmatory assay are considered ADA positive. Samples can test negative in 
either the screening or confirmatory assay but for analysis purposes they are not differentiated. 
The following properties of each sample will be provided in the source data:

Result of the assay according to a pre-specified confirmatory cut point: ADA positive (yes) 
or ADA negative (no)

Titer (for positive samples): numerical representation of the magnitude of ADA response.

When titer values are below the titer cut point with minimal required dilution (MRD) and 
the result is reported as ‘Titer value 50 (MRD)’, it is interpreted as a POSTIVE sample with 
titer equal to 50. Drug tolerance level: highest drug concentration that does not interfere 
with the ADA detection method


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
Fold titer change (i.e. x-fold): threshold for determining treatment boosted
Determinant samples are defined as samples which are not unevaluable (where unevaluable = 
sample where assay is not available).
The following definitions apply only to determinant samples:

ADA-negative sample: Determinant sample where the assay is ADA negative and MBG453 
PK concentration at the time of IG sample collection is less than the drug tolerance level.

ADA-positive sample: Determinant sample where the assay is ADA positive. 

ADA-inconclusive sample: Sample where assay is the ADA is negative and MBG453 PK 
concentration at the time of the IG sample collection is greater than or equal to the drug 
tolerance level or missing
The following definitions apply only to post-baseline ADA-positive samples with a 
corresponding determinant baseline sample. To be classified as treatment-boosted or treatment-
unaffected, both the post-baseline and baseline titer must be non-missing:

treatment-induced ADA-positive sample: ADA-positive sample post-baseline with ADA-
negative sample at baseline.

treatment-boosted ADA-positive sample: ADA-positive sample post-baseline with a titer 
that is at least the fold titer change greater than the ADA-positive baseline titer.

treatment-unaffected ADA-positive sample: ADA-positive sample post-baseline with a titer 
that is less than the fold titer change greater than the ADA-positive baseline titer.
NOTE: PK concentrations which are flagged for exclusion will still be used to determine ADA-
inconclusive and ADA-negative samples.
Listings will be provided of sample ADA status (including titer for positive samples).
2.6.4.2
Participant ADA status
Any IG sample collected after 150 days of the last dose of sabatolimab will not be used for 
summaries or derivations and will only be included in the listing.
Participant ADA status is defined as follows:

Treatment-induced ADA-positive participant: participant with ADA-negative sample at 
baseline and at least one treatment-induced ADA-positive sample.

Treatment-boosted ADA-positive participant: participant with ADA-positive sample at 
baseline and at least one treatment-boosted ADA-positive sample.

Treatment-unaffected ADA-positive participant: participant with ADA-positive sample at 
baseline, no treatment-boosted ADA-positive samples, and at least one treatment-unaffected 
ADA-positive sample.

Treatment-reduced ADA-positive participant: participant with ADA-positive sample at 
baseline and at least one post baseline determinant sample, all of which are ADA-negative 
samples.


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!
ADA-negative participant: participant with ADA-negative sample at baseline and at least 
one post baseline determinant sample, all of which are ADA-negative samples.
!
Inconclusive participant: participant who does not qualify as treatment-induced ADA-
positive, treatment-boosted ADA-positive, treatment-unaffected ADA-positive, treatment-
reduced ADA-positive, or ADA-negative.
Listings will be provided of participant ADA status.
2.6.5
Patient-Reported outcome: MDS symptoms and fatigue (Part II only)
Not applicable.
PPD


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2.8
Interim analysis
No formal interim analysis is planned for this trial. However, two safety review meetings during 
the safety run-in part and a periodic safety review by the Steering Committee will occur 
approximately every 6 months in the expansion cohort.
In the Safety run-in (Part 1), the first safety review meeting will be conducted after participants 
included in the first cohort (N=6 with at least 3 evaluable participants treated with sabatolimab
at the 400 mg Q4W) have completed 2 cycles of treatment. If the 400 mg Q4W dose of 
sabatolimab is considered to be safe in combination with venetoclax and azacitidine guided by 
the Bayesian analysis based on the incidence of dose limiting toxicity (DLT) data as well as all 
available safety, clinical pharmacology and tolerability data, a second cohort with 12 
participants will be opened (sabatolimab at 800 mg Q4W). Otherwise the study will be stopped.
After completion of 2 cycles of treatment with at least 9 evaluable participants, the second safety 
review meeting will take place. The decision will be made based on DLT observation and the 
Bayesian model to open the Expansion (Part 2) (or not) at this dose level (sabatolimab at 800 
mg Q4W) in combination with venetoclax and azacitidine. If sabatolimab 800 mg Q4W is 
considered to be safe, then Expansion (Part 2) will be opened at the same dose level (800 mg 
Q4W). Otherwise, the study will be stopped.
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 and medical history
!
Concomitant medications
!
Patient disposition
!
Protocol deviations
!
Duration of exposure to study treatment, Dose intensity and relative dose intensity, 
Number (%) of participants with any dose changes (incl. 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
!
Posterior distribution for the risk of DLT for new participants at the dose level tested (see
Section 2.5.2.1)
!
Laboratory data and vital signs abnormalities
!
Blast counts from bone marrow and investigator’s response assessment
Due to the recruitment halt, safety review meetings after the safety run-in part will not be 
conducted.
PPD


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2.9
Sample size calculation
2.9.1
Safety run-in (Part 1)
No formal statistical power calculations to determine sample size were performed for this part 
of the study. However, the operating characteristics are reasonable based on the sample size for
this part of the study. In case the starting dose (sabatolimab 400 mg Q4W (N=6)) with the fixed 
dose combination of azacitidine plus venetoclax is confirmed to be safe and tolerated for at least 
3 evaluable participants, another cohort will be opened at 800 mg of sabatolimab Q4W (N=12) 
with fixed dose of venetoclax plus azacitidine with at least 9 evaluable participants. Otherwise, 
the study will be stopped.
In total, the Safety run-in (Part 1) is expected to enroll approximately 18 participants (6 
participants for cohort 1 (sabatolimab (400 mg Q4W) and 12 participants for cohort 2 (800 mg 
(Q4W)) in order to have at least 12 evaluable participants (3 evaluable participants in cohort 1 
and 9 evaluable participants in cohort 2).
2.9.2
Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2) (CR primary 
analysis)
The sample size calculation is based on the Complete Remission (CR) rate (primary efficacy 
endpoint) for participants treated with sabatolimab 800 mg Q4W from Safety run-in (Part 1) 
and Expansion (Part 2). 
Based on available data (Wei et al 2019), the CR rate with the combination azacitidine and 
venetoclax is expected to be around 39%. The first criteria to declare the trial successful is to 
test if the CR rate with sabatolimab in combination with azacitidine and venetoclax is at least 
50% (statistical significance).
The Bayesian formulation of this dual criterion design can be expressed as below:

Bayesian statistical significance: probability for a positive treatment effect (i.e. CR 
rate > 39% | data) ≥ 0.975.

Clinical relevance: posterior median of CR rate ≥ 50%.
With the two criteria stated above the minimally required sample (nmin) size is 67 and the sample 
size was set to 70 including participants from cohort 2 of the Safety run-in (Part 1) and the 
Expansion (Part 2). Thus, the total sample size is comprised of 76 participants (including the 6 
participants treated at 400 mg Q4W in cohort 1 of the Safety run-in (Part 1). For 70 participants 
(included for the primary efficacy analysis), the table below shows data scenarios (number of 
participants achieving complete remission) with respective inferential results and decisions.
The minimum number of participants with CR to declare this trial successful (both statistical 
significance and clinical relevance met) is 36 out of 70 participants (51.4%).
Based on simulations (Table 2-5), a total of 36 responders out of 70 participants is required for 
trial success, with estimates of 51.4% for the posterior median CR rate and 98.3% for the 
posterior probability for a positive effect (CR > 39%). If the number of participants with CR is 
less than 36, both criteria are not met (NO-GO).


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Table 2-5
Data scenarios, inferential results and decisions (n=70)
True CR rate
Posterior median CR
Posterior probability for a 
positive effect (CR>39%)
Decision for trial 
success
30/70 (42.9%)
43.0%
0.754
Failed
31/70 (44.3%)
44.4%
0.823
Failed
32/70 (45.7%)
45.8%
0.879
Failed
33/70 (47.1%)
47.2%
0.920
Failed
34/70 (48.6%)
48.6%
0.950
Failed
35/70 (50.0%)
50.0%
0.970
Failed
36/70 (51.4%)
51.4%
0.983
Successful
A non-informative Beta (1,1) prior with mean 50% has been used in these calculations.
Operating characteristics for various true CR rates are presented in the table below. The type-I 
error under the null value (CR rate = 38.6%) is 2.0% and power is 80% assuming a true CR of 
55.7 %.
Table 2-6
Operating characteristics for true CR rate (n=70)
True CR rate
Probability of success (Go)
Probability of futility (No Go)
27/70 (38.6%)*
0.020
0.980
28/70 (40.0%)
0.035
0.965
29/70 (41.4%)
0.056
0.944
30/70(42.9%)
0.094
0.906
31/70 (44.3%)
0.140
0.860
32/70 (45.7%)
0.204
0.796
33/70 (47.1%)
0.272
0.728
34/70 (48.6%)
0.355
0.645
35/70 (50%)
0.452
0.548
36/70 (51.4%)
0.546
0.454
37/70 (52.9%)
0.644
0.356
38/70 (54.3%)
0.721
0.279
39/70 (55.7%)**
0.800
0.200
*For a true CR rate of 38.6% (null value), the probability for a trial success is 2.0% (type-I error).
**For a true CR rate of 55.7%, the probability for a trial success is 80% (power).
These calculation were made using the software R (version 3.6.1) using the RBestT package.
3
Change to protocol specified analyses
As Novartis decided to halt the enrollment in the expansion part in September 2022, the 
following analyses as per protocol will not be performed due to data limitations:
!
The primary analysis of CR rate
!
The analysis of Patient-Reported outcome: MDS symptoms and fatigue
P
P


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4
Appendix - General definitions
Date of first administration of study treatment (sabatolimab or azacitidine or 
venetoclax)
The date of first administration of any study treatment component (sabatolimab or azacitidine 
or venetoclax) is defined as the first date when a non-zero dose of the respective study drug is 
administered and recorded on the study treatment eCRF page. 
Date of last administration of study treatment (sabatolimab or azacitidine or 
venetoclax)
The date of last administration of any study treatment component (sabatolimab or azacitidine 
or venetoclax) is defined as the last date when a non-zero dose of the respective study drug 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.
Date of first administration of study treatment (combination)
The date of first administration of study treatment (or start date of study treatment) is defined 
as the first date when a non-zero dose of any component of the study treatment (sabatolimab, 
Azacitidine or venetoclax) is administered.
Date of last administration of study treatment (combination)
The date of last administration of study treatment (or start 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, Azacitidine or venetoclax) is administered.
Date of last exposure to study treatment component (sabatolimab or 
azacitidine or venetoclax)
One planned cycle length is 28 days and the start date of a cycle is defined as the first 
administration of azacitidine within a cycle. Azacitidine is planned to be administered daily 
every cycle during 7 days at the beginning of each cycle (between Day 1 to Day 9). Sabatolimab
is administered every 4 weeks (Q4W), on Day 8 of each cycle, unless there was a toxicity 
leading to a dosing interval increase. Venetoclax is planned to be administered once a day from 
day 1 to day 14 of the 28-day cycle.
The date of last exposure to sabatolimab is therefore calculated as:
Minimum (last date of administration of sabatolimab + 27 days, date of death, last 
contact date in case participant is lost to follow-up), as sabatolimab injections are given 
Q4W.
The date of last exposure to azacitidine is calculated as:
Minimum (last date of administration of azacitidine + 20 days, date of death, last contact 
date in case participant is lost to follow-up) as the 7 doses of azacitidine are given in the 
beginning of each cycle.
The date of last exposure to venetoclax is calculated as:


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Minimum (last date of administration of venetoclax + 14 days, date of death, last contact 
date in case participant is lost to follow-up) as the 14 doses of venetoclax are given in 
the beginning of each cycle (in case of regimen change to “one week on, three weeks 
off” in the last cycle, last date of administration of venetoclax +  21 days will be 
considered.)
End date of the last cycle initiated
The end date of the last cycle initiated is the maximum date between:

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 or 
venetoclax) is administered,

The actual date of the last administration of a non-zero dose of any last component 
of the study treatment.
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)
For the calculation of the duration of exposure to study treatment (combination), the date of last 
exposure to study treatment (combination) will be derived as the minimum date between:

The latest one of the date of last exposure to any study treatment component 
(sabatolimab or azacitidine or venetoclax),

Date of death,

Last contact date in case participant is lost to follow-up.
The duration of exposure to study treatment (combination) will be calculated as follow: 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: end date of the last cycle initiated - 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:


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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) and 
patient-reported outcomes (PRO).
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.
Baseline
For efficacy evaluations and PROs, 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 the start of study treatment is taken as “baseline” assessment. If participants
have no value as defined above, the baseline result will be missing. 
Windows for multiple assessments
Time windows will be defined for descriptive summary of ECOG and PRO data (EORTC 
QLQC30,
 by visit and the longitudinal data analysis. If more 
than one assessment is available in the same time window, the assessment closest to the planned 
date will be considered. If two assessments are obtained with the same time difference 
compared to the scheduled visit day, the assessment obtained prior to the visit will be considered. 
Data obtained at the end of treatment visit will be classified as other assessment in the 
corresponding time window. For participants who discontinue treatment for reasons other than 
progressive disease, withdraw consent or death, EORTC QLQ-C30 
5L will 
continue being collected every 6 months during this follow-up period until disease progression.
Table 4-1
Time windows for PRO and ECOG data
Assessment
Target day of 
assessment
Time Window Definition
Baseline 
On or before Study Day 
1[a]
≤ Study Day 1
During treatment phase 
    Cycle 2 Day 1
Study Day 29
Study Days 2 to 42
    Cycle 3 Day 1
Study Day 57
Study Days 43 to 70
    Cycle k day 1
Study Day = 28*(k-1) + 1
Study Day 


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Assessment
Target day of 
assessment
Time Window Definition
     (with k=4, 5, 6, 7, 8 etc...)
28*(k-1) +1 -14 to 28*(k-1) +14 
For last cycle of dosing: from 28*(k-
1) +1 -14 to end of treatment visit 
date +7
“Note: EOT data will be included if 
obtained within 7 days of permanent 
discontinuation of study treatment”
After treatment discontinuation (only EORTC QLQ-C30 
)
Post treatment follow-up   
Every 6 months 
For the first time window: [upper 
bound of the last previous time 
windows with assessment + 1; 
PRO assessment date + 84 days] 
Otherwise: [PRO assessment 
date -/+ 84 days] 
[a] Study Day 1 = randomization date will be baseline (except for 
 for which there is no 
baseline)
Last contact date 
The last contact date will be used for censoring of participants in the analysis of overall survival.
The last contact date is defined as the latest complete date from the below list on or before the 
data cut-off date:
Table 4-2
Last contact date data sources
Source data
Conditions
Date of start of treatment
Non-missing dose
Last date participant was known to be alive from 
Survival Follow-up page 
Participant status is reported to be alive or 
unknown
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term
Start/End dates from drug administration record 
Non-missing dose 
Response assessment date
Response marked as ‘done’
Laboratory/PK collection dates
Sample collection marked as ‘done’
Vital signs date
At least one non-missing parameter value
ECOG performance status date
Non-missing performance status
Start/End dates of AE 
Non-missing verbatim term


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The cut-off date will not be used for last contact date, unless the participant was seen or 
contacted on that date. No date post cut-off date will be used.
Completely imputed dates (e.g. the analysis cut-off date programmatically imputed to replace
the missing end date of a dose record) will not be used to derive the last contact date. Partial 
date imputation is allowed for event (death)/censoring only if coming from the ‘Survival’ eCRF.
The last contact date will be derived for participants not known to have died at the analysis cut-
off using the last complete date among the following:
5
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.

Platzbecker U (2019) Treatment of MDS. Blood p. 1096-1107.

Platzbecker U, Fenaux P, Adès L, et al (2018) Proposals for revised IWG 2018 
hematological response criteria in patients with MDS included in clinical trials. Blood; 
[Epub ahead of print].

Pollyea D. et al. Venetoclax in combination with hypomethylating agents induces rapid, 
deep, and durable responses in patients with AML ineligible for intensive therapy. 2018 
Dec 2; Oral Abstract #285: 60 ASH Annual Meeting and Exposition, San Diego, CA.

Cheson BD, Greenberg PL, Bennett JM, et al (2006) Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood p. 419-25.\
 

Fayers PM (2001) Interpreting quality of life data: population-based reference data for the 
EORTC QLQ-C30. Eur J Cancer; 37(11): 1331-4.