Conditions: Myelodysplastic Syndrome (MDS)
Keywords: sabatolimab phase II MBG453 TIM-3 decitabine azacitidine oral decitabine INQOVI myelodysplastic syndrome (MDS) adult MDS
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
The main objective of this study was to assess the safety profile of MBG453 (sabatolimab) in combination with FDA approved hypomethylating agents (HMAs) of investigator's choice (IV Decitabine or Azacitidine /SC Azacitidine /Oral Decitabine (cedazuridine combination (INQOVI))).

Detailed description:
This was a single arm, nonrandomized, open label, Phase II multicenter study of i.v sabatolimab added to FDA approved HMA agents of Investigator's choice (i.v/s.c/oral) in adult patients with intermediate, high or very high risk MDS as per IPSS-R criteria.

There were 4 separate periods of this study:

1. Screening period (signing of written informed consent through day of enrollment),
2. Core phase for up to 12 months,
3. Extension phase for efficacy and/or survival status (up to 12 months after the core phase),
4. Post-treatment safety follow-up period monitoring for AEs for 30 days following the last dose of azacitidine or decitabine or INQOVI (oral decitabine), or 150 days following the last dose of sabatolimab, whichever was later.

During the conduct of the study there were 2 updates to the Novartis development strategy for sabatolimab. Based on the results from the Phase II STIMULUS MDS-1 study, recruitment was halted for CMBG453B1US01 (STIMULUS MDS-US) on 30-Sep-2022. Novartis confirmed the decision to halt recruitment was not based on any safety findings or safety concerns. Patients who were on study treatment or in follow-up were continued as per the protocol. Furthermore, on 11-Jan-2024, all sabatolimab investigators were notified by Novartis that, based on decision taken in Dec-2023, that the sabatolimab development program (which included study CMBG453B1US01) would be terminated. After the decision was made to discontinue the sabatolimab development program, participants already enrolled in the CMBG453B1US01 study were prepared for closure; these close out activities took approximately 9 months. The actual last patient last visit date was 1 Sep 2024.

Arms:
arm 1: MBG453 (sabatolimab) + HMA of investigator's choice (IV Decitabine or Azacitidine /SC Azacitidine /Oral Decitabine (cedazuridine combination (INQOVI)))

Interventions: intervention 1: MBG453 intervention 2: Azacitidine intervention 3: Decitabine intervention 4: INQOVI (oral decitabine)
Intervention descriptions: intervention 1: Solution for intravenous infusion intervention 2: Solution for subcutaneous injection or intravenous administration intervention 3: Solution for intravenous administration intervention 4: Tablet for oral administration

Protocol document:
Prot_000.pdf: 


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................6
List of figures.......................................................................................................................8
List of abbreviations ............................................................................................................9
Glossary of terms...............................................................................................................13
Amendment 2 (22-Dec-2022)............................................................................................14
Amendment 1 (01-Apr-2021) ............................................................................................16
Protocol summary:.............................................................................................................19
1
Introduction........................................................................................................................24
1.1
Background............................................................................................................24
1.2
Purpose...................................................................................................................33
2
Objectives and endpoints...................................................................................................33
3
Study design.......................................................................................................................34
3.1
Definition of end of study......................................................................................37
4
Rationale ............................................................................................................................38
4.1
Rationale for study design......................................................................................38
4.2
Rationale for dose/regimen and duration of treatment...........................................39
4.3
Rationale for choice of the combination drugs......................................................41
4.3.1
Rationale for HMA (IV/SC azacitidine or IV/oral decitabine) .............41
4.3.2
Rationale for MBG453 (sabatolimab)...................................................43
45
4.4
Purpose and timing of interim analyses.................................................................46
4.5
Risks and benefits ..................................................................................................46
4.6
Rationale for Public Health Emergency mitigations procedures...........................47
5
Study Population................................................................................................................48
5.1
Inclusion criteria ....................................................................................................48
5.2
Exclusion criteria ...................................................................................................48
6
Treatment...........................................................................................................................51
6.1
Study treatment ......................................................................................................51
6.1.1
Additional study treatments...................................................................53
6.1.2
Treatment arms/group ...........................................................................53
6.1.3
Guidelines for continuation of treatment...............................................53
6.1.4
Treatment duration ................................................................................53
6.2
Other treatment(s) ..................................................................................................54
6.2.1
Concomitant therapy .............................................................................54




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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
9.1.2
Withdrawal of informed consent...........................................................97
9.1.3
Lost to follow-up...................................................................................98
9.1.4
Early study termination by the sponsor.................................................98
9.1.5
Extension phase.....................................................................................98
9.1.6
Post treatment safety follow up period..................................................99
9.2
Study completion and post-study treatment...........................................................99
10 Safety monitoring and reporting......................................................................................100
10.1
Definition of adverse events and reporting requirements....................................100
10.1.1
Adverse events.....................................................................................100
10.1.2
Serious adverse events.........................................................................102
10.1.3
SAE reporting......................................................................................102
10.1.4
Pregnancy reporting.............................................................................103
10.1.5
Reporting of study treatment errors including misuse/abuse ..............104
10.2
Additional Safety Monitoring..............................................................................104
10.2.1
Steering Committee.............................................................................104
11 Data Collection and Database management ....................................................................105
11.1
Data collection .....................................................................................................105
11.2
Database management and quality control ..........................................................105
11.3
Site monitoring.....................................................................................................105
12 Data analysis and statistical methods...............................................................................106
12.1
Analysis sets.........................................................................................................106
12.1.1
Full Analysis Set (FAS).......................................................................107
12.1.2
Safety Set (SS).....................................................................................107
107
107
12.1.5
Efficacy/evaluable set..........................................................................107
12.2
Participant demographics and other baseline characteristics...............................107
12.3
Treatments (study treatment, concomitant therapies, compliance)......................107
12.4
Analysis of the primary endpoint.........................................................................108
12.4.1
Definition of primary endpoint............................................................108
12.4.2
Statistical model, hypothesis, and method of analysis ........................108
12.4.3
Handling of missing values/censoring/discontinuations .....................108
12.4.4
Supportive analyses.............................................................................108
12.5
Analysis of secondary endpoints..........................................................................108
12.5.1
Secondary objectives...........................................................................108
12.5.2
Safety objectives..................................................................................111


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
113
12.6
Interim analyses ...................................................................................................115
12.7
Sample size calculation........................................................................................115
13 Ethical considerations and administrative procedures.....................................................115
13.1
Regulatory and ethical compliance......................................................................115
13.2
Responsibilities of the investigator and IRB/IEC/REB.......................................115
13.3
Informed consent procedures...............................................................................116
13.4
Discontinuation of the study ................................................................................116
13.5
Publication of study protocol and results.............................................................116
13.6
Study documentation, record keeping and retention of documents.....................117
13.7
Confidentiality of study documents and patient records......................................117
13.8
Audits and inspections .........................................................................................117
13.9
Financial disclosures............................................................................................118
14 Protocol adherence...........................................................................................................118
14.1
Amendments to the protocol................................................................................118
15 References........................................................................................................................119
16 Appendices.......................................................................................................................125
16.1
Appendix 1: Clinically notable laboratory values and vital signs .......................125
16.2
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements.........................................................................................................126
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up....130
16.4
Appendix 4: Eligibility based on serologic markers for hepatitis B....................131




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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Table 16-6
Decision tree to determine eligibility based on serologic markers 
for hepatitis B ......................................................................................132


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
List of figures
Figure 1-1
TIM-3 ....................................................................................................28
Figure 1-2
TIM-3 Expression..................................................................................28
Figure 1-3
 Treatment-Related AEs in > 2% of Patients.........................................30
Figure 1-4
 Incidence rates of most frequent AEs with the Combination 
MBG453 (sabatolimab) + decitabine and MBG453 (sabatolimab) + 
Azacitidine.............................................................................................31
Figure 3-1
Study design ..........................................................................................36
 




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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
GCP
Good Clinical Practice
G-CSF
Granulocyte-Colony Stimulating Factor
GGT
Gamma-glutamyl-transferase
GLDH
Glutamate dehydrogenase
HAV
Hepatitis A virus
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HI
Hematologic improvement
Hgb
Hemoglobin
HI-E
Erythroid
HI-P
Platelet
HI-N
Neutrophil
HIV
human immunodeficiency virus
HMA
Hypomethylating agent
HSCT
Hematopoietic stem cell transplantation
IV
Intravenous
IA
Interim Analysis
ICF
informed consent form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
imAE
immune-mediated adverse event
INQOVI
Oral Decitabine
INR
International normalized ratio
IPSS-R
International Prognostic Scoring System
irAE
immune related adverse event
IRB
Institutional Review Board
IUD
Intrauterine Device
IUS
Intrauterine System
IWG
International Working Group
LC-MS
Liquid Chromatography Mass Spectrometry
LDH
lactate dehydrogenase
LFT
Liver function test
LMWH
Low Molecular Weight Heparin
LPLV
Last Patient Last Visit
mAB
Monoclonal antibody
MCH
mean cell hemoglobin


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
MCHC
mean corpuscular hemoglobin concentration
mCR
marrow Complete Remission
MCV
mean corpuscular volume
MDS
Myelodysplastic syndromes
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical dictionary for regulatory activities
Med Hx
Medical History
Mg
milligram(s)
mL
milliliter(s)
Ml
milliliter(s)
MRI
Magnetic Resonance Imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NK
Natural Killers
NR
not reached
ORR
Overall Response Rate
OS
Overall survival
PB
Peripheral Blood
PCR
Polymerase Chain Reaction
PD
pharmacodynamic(s)
PD-1
Programmed cell death protein 1
PFS
Progression free survival
PK
pharmacokinetic(s)
PR
Partial remission
PRO
Patient Reported Outcome
PS
Performance status
Q2W
Every 2 weeks
Q4W
Every 4 weeks
RBC
red blood cell(s)
RNA
Ribonucleic acid
PK
Pharmacokinetic(s)
PT
prothrombin time
QD
Once a day
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
R Value
ALT/ALP x ULN
RAP
The Report and Analysis Plan 
RBC
red blood cell(s)
REB
Research Ethics Board
RU
Resource Utilization
SC
Subcutaneous
SAE
serious adverse event
SSC
Steering committee
SD
Stable disease
SOC
Standard of Care
sTIM-3
Soluble T-cell immunoglobulin domain and mucin domain-3
SUSAR
Suspected Unexpected Serious Adverse Reactions
T3
Triiodothyronine (thyroid hormone)
T4
Thyroxine (thyroid hormone)
TBL
total bilirubin
TIM-3
T-cell immunoglobulin domain and mucin domain-3
TLS
Tumor lysis syndrome
TSH
Thyroid-Stimulating Hormone
ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Glossary of terms
Assessment
A procedure used to generate data required by the study
Combination drug
Any drug that is combined to a specified regimen
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)
Enrollment
Point/time of participant entry into the study and all screening procedures have 
been completed/ eligibility criteria met (C1D1) 
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with a 
purpose (e.g. screening, randomization, treatment, follow-up), which applies across all 
arms of a study.
Investigational 
drug
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance”
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage.
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 number assigned to each participant who enrolls in the study. When 
combined with the center number, a unique identifier is created for each 
participant in the study.
Period
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned.
Screen Failure
A participant who is screened but is not treated or enrolled
Stage
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, completion of treatment, etc.
Study completion
Point/time at which the participant came in for a final evaluation visit or when 
study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when participant permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature participant 
withdrawal.
Study treatment
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s)
Study treatment 
discontinuation
When the participant permanently stops taking study treatment prior to the 
defined study treatment completion date


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Amendment 2 (22-Dec-2022)
Amendment rationale
As of the release of this amendment, 39 subjects have been enrolled in this trial.
The purpose of this amendment is to clarify and provide an update on the development 
strategy of sabatolimab (MBG453). Novartis has decided to permanently halt recruitment in 
the ongoing CMBG453B1US01 (STIMULUS MDS-US) and STIMULUS MDS-3 trials based 
on a reevaluation of the development strategy for sabatolimab.  Patients who are currently on 
study treatment or in follow-up may continue in both studies as per the respective protocol.  
Novartis confirms the decision to halt recruitment is not based on any safety findings or safety 
concerns with sabatolimab, either in combination with a hypomethylating agent (HMA) or as 
part of a triplet combination with venetoclax and azacitidine. Novartis remains engaged in the 
development of sabatolimab and all other sabatolimab trials will continue as planned.
Recruitment was halted for the STIMULUS MDS-US study on 30-Sep-2022.
This protocol amendment will be shortening the timeline of the study as well as various 
administrative changes.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
•
Glossary of terms: Definition for enrollment was clarified.
•
Protocol summary : Timepoints for analysis and study periods were clarified. Data 
analysis and enrollment numbers were updated per adjustment.
•
Section 2 : Timepoints for analysis was clarified.
•
Section 3 : Timepoints and study periods were adjusted.
•
Section 4.4 : Timepoints for reporting was clarified.
•
Section 5 : Enrollment numbers were adjusted.
•
Section 6.1 : Dosing administration guidelines were updated.
•
Section 6.1.4 : Duration of study was adjusted.
•
Table 8-1 : Duration of study and assessments were adjusted.
•
Section 8.3 : Number of assessments was adjusted.
•
Table 8-7 : Number of assessments was adjusted.
•
Talbe 8-8 : Number of assessments was adjusted.
•
Section 12.8 : Enrollment numbers were adjusted.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
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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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Amendment 1 (01-Apr-2021)
Amendment rationale
As of the release of this amendment, 0 subjects have been enrolled in this trial.
The purpose of this amendment is to clarify, in particular, the inclusion criteria related to the 
eligibility for intensive chemotherapy and stem cell transplantation, as well as the exclusion 
criteria related to cardiac abnormalities. Additionally, as new treatment options may be 
available for patients with AML, study treatment beyond progression in case of acute leukemia 
(per WHO 2016, as defined as ≥20% blasts in bone marrow and/or peripheral blood) is not 
permitted any longer. Definitions of the RBC or platelet transfusion dependence and transfusion 
independence in Table 8-2 were updated. The same pre-specified period of observation (i.e., 8 
weeks) will be used to determine the transfusion status throughout the study. The interval of 8 
weeks is selected, as it is in line with the assessment of transfusions for hematologic 
improvement and is acceptable to evaluate the transfusion status of higher-risk MDS patients at 
baseline (IWG 2006, IWG 2018)(Cheson et al 2006, Platzbecker 2019). Transfusion 
independence will be defined as absence of any transfusion during a given period of 
observation. Furthermore, clarifications about the estimand definition and methods for 
statistical analyses of PRO data were added. In addition, the need for TLS risk monitoring was 
further emphasized.  
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
•
Glossary of terms: Definition for combination drug was added.
•
Protocol Summary: Key Inclusion criteria regarding assessment of eligibility for 
chemotherapy or stem cell transplantation updated. Key Exclusion criteria amended to 
exclude patients who received investigational treatment within 5 half-lives of this 
treatment ; removal of exception of patients with a history of adequately treated 
malignancy for which no anticancer systemic therapy is ongoing or required during the 
course of the study. ; and removal of diagnosis of therapy related myeloid neoplasms.
•
Section 3 : added statement clarifying that patients receiving treatment in the extension
phase are allowed any combination of the treatments.
•
Section 4.2 and 4.3.2 : Efficacy and safety data were updated based on new data acquired.
•
Section 4.5: Evaluation of risk due to COVID-19 pandemic added.
•
Section 4.6 : Rationale for Public Health Emergency mitigations procedures added
•
 Section 5.1: Inclusion criteria 4 was amended to specify that assessment of eligibility is at 
time of screening for chemotherapy or stem cell transplantation, and stem cell 
transplantation was included. Intensive was removed.
•
 Section 5.2 : Exclusion criteria 5 was amended to exclude patients who received 
investigational treatment within 5 half-lives of this treatment. Exclusion criteria 14 and 19  
amended to exclude patients who received a diagnosis of therapy related myeloid 
neoplasms or developed therapy related neoplasms.


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
•
Section 6.1.4 : added statement clarifying that patients receiving treatment in the extension 
phase are allowed any combination of the treatments. Added statement that patients who 
become eligible for HSCT will be discontinued from MBG453 treatment for clarity in this 
section.
•
Section 6.1.4.1 : Text updated to clarify that continuation of study treatment or 
components of study treatment beyond progression is not allowed in case of 
transformation to acute leukemia. Criteria for continuation of study treatment or 
components of study treatment beyond progression modified. Guidance for assessment of 
clinical benefit added.
•
Section 6.5 : Clarified that the ASCO guidelines include hematologic AEs. Table 6-2: 
Guidance for non-hematologic, non-immune-related toxicities was amended to clarify that 
this refers to any non-hematologic, non-immune-related toxicities that are at least possibly 
attributable to the investigational drug.
•
Section 6.5.1 : Added clarification that appendices include additional instructions for the 
follow-up for toxicities.
•
Section 6.7 : Public Health Emergency mitigations procedures added
•
Section 7 : Informed Consent will be obtained in case of continuing study treatment or 
components of the study treatment beyond progression in absence of transformation to 
acute leukemia. Public Health Emergency mitigations procedures added.
•
Section 8 : Public Health Emergency mitigations procedures added.
•
Section 8, Table 8-1 : Clarified listing of cytokines are examples. List of cytokines was 
removed. Clarification added that efficacy bone marrow sample can be an aspirate and/or 
a biopsy sample. Clarified cycles within the extension phase. Removed requirement of day 
30 PKs and IGs within the post-treatment safety FU phase and changed to investigator’s 
discretion.
•
Section 8.2 : Clarification added that the last available laboratory results during screening 
should be used to confirm eligibility. Rationale for collection of subjects' race and 
ethnicity data added.
•
Section 8.3: Transfusion independence and dependence definitions were updated in Table 
8-2. In addition, a clarification was added that bone marrow samples, blood smears and 
pathology reports from the diagnosis should be sent to the central laboratory even if done 
during regular work-up of the subject before study start.
•
Section 8.4 : Public Health Emergency mitigations procedures added.
•
Section 8.4.1, Table 8-5: Addition of cytokines types to be analyzed. Collection of 
Troponin I added as alternative for Troponin T.
•
Section 8.4.4: New section added to emphasize monitoring of patients for signs and 
symptoms of TLS under azacitidine treatment.
•
Section 8.5.1 : Public Health Emergency mitigations procedures added.
•
•
•
Section 9.1.1 : Progression of disease (including transformation to acute leukemia) was




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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Protocol summary:
Title
Single-arm, open label, phase II study of MBG453 (sabatolimab) added 
to FDA approved Hypomethylating agents of investigator’s choice 
(IV/SC/Oral) for patients with intermediate, high or very high risk 
myelodysplastic syndrome (MDS) as per IPSS-R criteria (US multi-center) 
(STIMULUS MDS-US)
Brief title
STIMULUS MDS-US
Sponsor and Clinical 
Phase
Novartis
Phase II
Investigation type
Biological
Study type
Interventional
Purpose and rationale
Complete remission with HMAs in patients with intermediate, high, and 
very high risk MDS is usually infrequent and transient, and prognosis 
remains poor for these patients. When standard of care based on HMA 
fails in these patients, treatment options in second line are limited.
Main objective of this proposed study is to describe and evaluate safety 
and efficacy of MBG453 (sabatolimab) 800 mg every 4 weeks on day 8 in 
combination with FDA approved HMAs of investigator’s choice (IV 
Decitabine or Azacitidine /SC Azacitidine /Oral Decitabine (cedazuridine 
combination (INQOVI)) (For IV and SC HMAs, sabatolimab (MBG453) 
can be administered on a day between days 5-8 as per investigator 
decision)) in a single-arm, non- randomized, open label, phase II multi-
center US study.
Primary Objective(s) 
To assess the safety profile of MBG453 (sabatolimab) 800 mg (every 4 
weeks) given in combination with HMAs (IV/SC/Oral) by 12 months
Secondary Objectives
1.
To evaluate complete remission with MBG453 (sabatolimab) in 
combination with HMAs (IV/SC/Oral) in participants with 
intermediate, high, or very high risk MDS by 12 months
2.
To evaluate PFS rate by 12 months with MBG453 (sabatolimab) 
combined with HMAs (IV/SC/Oral) in participants with intermediate, 
high or very high risk MDS
3.
To assess Overall Survival rate by 24 months
4.
To assess Leukemia-free survival rate by 12 months in each 
treatment
5.
To assess other response rates
6.
To assess duration of complete remission
7.
To assess time to complete remission
8.
To assess the improvement in RBC/platelets transfusion 
independence


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Study design
This is a single-arm, non- randomized, open label, phase II multi-center 
study of intravenous MBG453 (sabatolimab) added to FDA approved 
Hypomethylating agents of investigator’s choice (IV/SC/ Oral) in adult 
participants with intermediate, high or very high risk myelodysplastic 
syndrome (MDS) as per IPSS-R criteria.
There are four separate periods of this study: 
1. Screening period (signing of written informed consent through 
Day 1); 
2. Core phase for up to12 months 
3. Extension phase for efficacy and/or survival status (up to 12 
months after core phase)
4. Post treatment safety follow-up monitoring for adverse events 
(AEs) for 30 days following the last dose of azacitidine or 
decitabine or INQOVI (oral decitabine), or 150 days following 
the last dose of MBG453 (sabatolimab), whichever is later).
Study Population
This target population of this study will be adult patients (>18 years) to be 
treated in first-line setting, with intermediate, high or very high risk per 
IPSS-R prognostic risk categories for myelodysplastic syndrome who do 
not qualify according the medical judgment for chemotherapy or HSCT. 
Participants with chronic myelomonocytic leukemia (CMML) are not 
eligible for this trial. 
It is anticipated that approximately 39 patients will be enrolled in this 
study. Patients will be recruited from sites within the United States.
Patient population will consist of approximately 39 patients receiving the 
HMA of choice. No pre-treatment stratification is planned. The investigator 
or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are enrolled in the study.
Inclusion criteria (key)
Written informed consent must be signed by the patient prior to any 
screening procedures. Patients eligible for this study must meet all of the 
following criteria:
•
Signed informed consent must be obtained prior to participation in 
the study.
•
Age ≥ 18 years at the date of signing the informed consent form 
(ICF).
•
Morphologically confirmed diagnosis of a myelodysplastic syndrome 
(MDS) primary or secondary based on 2016 WHO classification 
(Arber et al 2016) by investigator assessment with one of the 
following Prognostic Risk Categories, based on the International 
Prognostic Scoring System (IPSS-R). Note: MDS diagnosis history 
will be recorded in the CRF:
•
Very high (> 6 points)
•
High (> 4.5 – ≤ 6 points)
•
Intermediate (> 3 – ≤ 4.5 points) 


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•
Not suitable at the time of screening for immediate myeloablative/ 
chemotherapy  or hematopoietic stem cell transplantation based on 
investigator assessment of age, comorbidities, local guidelines, 
institutional practice (any or all of these).
•
Eastern Cooperative Oncology Group (ECOG) performance status 
of 0, 1 or 2.
•
AST and ALT ≤ 3 × upper limit of normal (ULN).
•
Total bilirubin ≤ 2 × ULN (except in the setting of isolated Gilbert 
syndrome).
•
Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73m2 
(estimation based on Modification of Diet in Renal Disease (MDRD) 
formula, by local laboratory).
•
Patient is able to communicate with the investigator and has the 
ability to comply with the requirements of the study procedures.
Exclusion criteria (key)
Patients eligible for this study must not meet any of the following criteria:
•
Prior exposure to TIM-3 directed therapy at any time. Prior therapy 
with immune checkpoint inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-
PD-L1, or anti-PD-L2), cancer vaccines are allowed only if the last 
dose of the drug was administered more than 4 months prior to 
enrollment
•
Previous treatment for intermediate, high or very high risk 
myelodysplastic syndromes (based on IPSS-R) with chemotherapy 
or other antineoplastic agents including lenalidomide and 
hypomethylating agent (HMAs) such as decitabine or azacitidine or 
INQOVI (oral decitabine) (patients who had up to 1 cycle of HMAs 
can be included). However, previous treatment with hydroxyurea is 
permitted.
•
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).
•
Diagnosis of Chronic myelomonocytic leukemia (CMML), or primary 
or secondary myelofibrosis based on 2016 WHO classification 
(Arber et al 2016).
•
History of organ transplant or allogenic hematopoietic stem cell 
transplant
•
Participants with prior malignancy, except:
a.
Participants with history of lower risk MDS treated by supportive 
care (e.g. growth factors, TGF-beta agents) or untreated are 
eligible
b.
Participants with history of lower risk MDS who were treated 
adequately with lenalidomide and then failed are eligible
c.
Participants with history of adequately treated malignancy for 
which no anticancer systemic therapy (namely chemotherapy, 
radiotherapy or surgery) is ongoing or required during the 
course of the study. Participants who are receiving adjuvant 
therapy such as hormone therapy are eligible.
•
Participants with Myelodysplastic syndrome (MDS) based on 2016 
WHO classification (Arber et al 2016) with revised International 
Prognostic Scoring System (IPSS-R) ≤ 3




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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
The study analysis will be by 12 months post last patient first treatment 
and will be considered the primary analysis, and a CSR will be written. 
Additional analyses may be performed when all patients complete the 
extension phase and safety follow up.  In this case, a final CSR will be 
written.
All AEs, SAEs and other safety parameters will be summarized. No 
inferential tests for safety analyses will be performed. All primary, 
secondary 
 will be summarized descriptively. 
Categorical data will be presented in frequencies and percentages. For 
continuous data descriptive statistics (mean, standard deviation, median 
25th and 75th percentiles, min and max) will be provided. As appropriate, 
95% confidence intervals will also be reported. Kaplan Meier’s estimates 
will be reported for the time to event variables.
Detail analysis methods will be available in the Statistical Analysis Plan 
(SAP).
Approximately 39 patients will be enrolled for safety and efficacy 
assessment of this study. Novartis has decided to permanently halt 
recruitment based on a reevaluation of the development strategy for 
sabatolimab.  Patients who are currently on study treatment or in follow-
up may continue per the protocol.
Key words
Phase II, MBG453, TIM-3, decitabine, azacitidine, INQOVI (oral 
decitabine), myelodysplastic syndrome (MDS).


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
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). 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 hematopoietic diseases 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. 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, with median 
survival times of 8.8, 5.3, 3.0, 1.6 and 0.8 years, respectively and with 25% AML transformation 
rate of NR (not reached), 10.8, 3.2, 1.4, 0.73 years respectively (Greenberg et al 2012). 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). Current treatment guidelines for MDS recommend 
modification of the disease with hematopoietic stem cell transplantation (HSCT, treatment with 
a curative intent), hypomethylating agents (HMA: azacitidine or decitabine) or intensive 
chemotherapy (Fenaux et al 2014). Choice of therapy is mainly driven by the IPSS-R score, the 
overall general health status and clinical assessment of comorbidities. For patients eligible for 
intensive therapy, and for whom a donor is available for HSCT or for whom the marrow blast 
count requires reduction, intensive chemotherapy may be considered (Steensma 2018). HSCT 
remains the only curative option for MDS patients; however, many MDS patients are not 
candidate for HSCT (Passweg et al 2011; and see Section 4.3.1). In MDS patients without major 
co-morbidities who are classified as intermediate, high, very high risk by IPSS-R, and who do 
not qualify for HSCT or intensive chemotherapy, HMAs remain the first-line reference 
treatment. HMAs (azacitidine or decitabine) are generally administered for a minimum of 6 
cycles (repeat cycle after 4 weeks), and continued for as long as the patient benefits. HMAs 
(azacitidine or decitabine) have a similar safety profile. In clinical practice, bone marrow 
suppression is the most common adverse reaction in demethylation therapy, and is also the main 
reason for the dose-reduction or discontinuations of decitabine or azacitidine. Supportive care, 
including blood transfusions, is frequently required. HMAs have improved outcomes for 
patients with intermediate/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 HMA remains poor. Complete Remission 
rate (CR) with azacitidine or decitabine in higher-risk (IPSS; intermediate- & high, IPSS-R; 
intermediate, high & very high) MDS is rare. CR rate has been shown to be 9% for decitabine 
and 17 % for azacitidine in pivotal trials (Kantarjian et al 2006, Fenaux et al 2009). Other trials 


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
reported CR rate in MDS patients ranging from 7% to 25% with azacitidine and from 9% to 
35% with decitabine. (Saunthararajah 2013). 
Zeidan et al reported that azacitidine and decitabine used in monotherapy lead to similar 
clinical effectiveness and safety profiles retrospective study identified patients diagnosed with 
MDS between 2004 and 2011 in the US (SEER-Medicare linked database) who received ≥ 10 
doses of either HMA for comparing clinical effectiveness in daily practice of azacitidine 
versus decitabine. Azacitidine was used for treating approximately 80% of the patients (n = 
2,025). Survival from HMA initiation was estimated with Kaplan-Meier methods and 
adjustment was made for relevant covariates. No significant survival difference was found 
between azacitidine and decitabine in MDS patients, including in MDS patients with excess 
of blasts. However, it cannot be ruled out treatment outcome of a novel compound given in a 
combination regimen may vary with nature of the partner drug
Both DEC and AZA require IV infusion for 1 hour or subcutaneous (SC) injections daily for 
5-7 days of every 28-day treatment cycle. They both have limited oral bioavailability due to 
rapid degradation by cytidine deaminase (CDA) in the gut and liver. An orally bioavailable 
HMA option could reduce clinic visit frequency and reduce infusions/injections related adverse 
events and burden. ASTX727 is an oral tablet comprised of a fixed-dose combination (FDC) of 
CDA inhibitor cedazuridine (C) at 100 mg with DEC at 35 mg. In a phase 2 study, INQOVI 
(oral decitabine) (ASTX727) demonstrated pharmacokinetic (PK) AUC exposure similar to IV-
DEC at 20mg/m2 with comparable clinical activity and safety (Garcia-Manero, MDS Int’l 
symposium, 2019). At ASH 2019 phase 3 study (ASCERTAIN) demonstrated that INQOVI 
(oral decitabine), the oral FDC of cedazuridine/decitabine (100 mg/35 mg) resulted in an 
equivalent DEC exposure to IV-DEC at 20 mg/m2 over 5 days. Safety findings are consistent 
with those anticipated with IV-DEC with no clinically significant GI toxicity. Preliminary 
clinical activity is also consistent with published data from IV-DEC. INQOVI (oral decitabine) 
is an oral HMA alternative to IV-DEC (Garcia-Manero et al 2019). The FDA has granted a 
priority review designation to a new drug application (NDA) for cedazuridine plus decitabine 
(ASTX727; INQOVI (oral decitabine) for the treatment of adult patients with previously 
untreated intermediate- and high-risk myelodysplastic syndromes (MDS) or chronic 
myelomonocytic leukemia (CMML) (accessed at: Astex Pharmaceuticals announces U.S. Food 
and Drug Administration (FDA). In July 2020, INQOVI has received FDA approval for adult 
patients with MDS, including previously treated and untreated, de novo and secondary MDS 
with the following French-American-British subtypes (refractory anemia, refractory anemia 
with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic 
leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic 
Scoring System groups. CC486 (ONUREG) only has data in AML patients and is out of scope 
for this trial, which is why this molecule was excluded from this study.
Table 1-1
ASTX Oral Decitabine Safety: Most Common All Grades AEs in the 
First 2 Randomized Cycles (All Causality) – Garcia Manero et al ASH 
2019
None of the differences was statistically significant (All P values > 0.10)
GI AEs Grade ≥ 3 incidence <1% for each of ASTX727 and IV decitabine in Cycles 1 or 2


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Patients, n (%)
IV Decitabine Cycle 1 or 2
N=132*
ASTX727 Cycle 1 or 2
N=130*
Thrombocytopenia
50 (37.9%)
57 (43.8%)
Neutropenia
42 (31.8%)
46 (35.4%)
Anemia
42 (31.8%)
48 (36.9%)
Fatigue
22 (16.7%)
31 (23.8%)
Constipation
25 (18.9%)
21 (16.2%)
Nausea
21 (15.9%)
23 (17.7%)
Leukopenia
22 (16.7%)
25 (19.2%)
Diarrhea
14 (10.6%)
19 (14.6%)
Febrile neutropenia
10 (7.6%)
18 (13.8%)
Headache
18 (13.6%)
19 (14.6%)
The INQOVI label has updated Adverse Reactions (≥ 10%) in Patients Who Received INQOVI 
in Pooled Safety Population.
In this trial, participants with higher risk MDS (defined as intermediate risk, high risk & very 
high risk, will be enrolled. IPSS-R score at baseline is a crucial clinical indicator in the sense it 
will inform about the treatment outcomes and prognostic of each given Participant. Each level 
of risk (intermediate/high/very high) is associated with a different survival length and potential 
of leukemic transformation. From previously reported real world evidence studies, despite the 
availability of HMA therapies, the risk of death and AML transformation was high. Higher-risk 
MDS patients had the poorest prognosis, with a median overall survival time less than 1 year 
from HMA initiation and a median time to AML transformation of less than 2 years from HMA 
initiation (Stein et al 2019).
Novel targeted therapies and immune checkpoint inhibitors are being clinically studied in MDS. 
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 
Tcells 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 patients. 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 patients. Front-line MDS 
patients were treated with the combination azacitidine+nivolumab or ipilimumab, whereas 
relapsed MDS patients received single-agent nivolumab or ipilimumab. Twenty patients were 
treated with azacitidine+nivolumab, 21 with azacitidine+ipilumab, 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 patients treated with azacitidine combined with nivolumab, 


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
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 patients 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 (Garcia-Manero et al 2018). A Phase 
Ib/II study involving azacitidine and nivolumab has been conducted in 70 relapsed/refractory 
AML patients. 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 patients with hematologic improvement (HI) 
maintained > 6 months. The ORR was 58% and 22% in HMA-naive (n = 25) and HMA 
pretreated (n = 45) patients, respectively. Duration of response among responders was 5.2 
months. Three patients in CR/CRi underwent HSCT. Additionally, 6 patients 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%) patients (Daver et al 2019). A Phase Ib study 
reported that ipilimumab in patients with MDS after HMA failure is safe but has limited efficacy 
as monotherapy. However, prolonged stable disease was reported and some patients received 
allo HSCT. Prolonged stable disease for ≥ 46 weeks occurred in 7 patients (24% of the patients), 
including 3 patients with more than a year of stable disease. Five patients underwent allografting 
without excessive toxicity (Zeidan et al 2018).
T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is an inhibitory cell surface 
receptor with a key role in regulating adaptive and innate immune responses). TIM-3+ 
hematopoietic stem cells from patients with MDS display aberrant differentiation, increased 
proliferation and decreased apoptosis (Sakuishi et al 2011). TIM-3 is also preferentially 
expressed on leukemic stem cells and blasts, and expression of TIM-3 correlates with severity 
of MDS Therefore the blockade of TIM-3 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). 


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Figure 1-1
TIM-3
TIM-3 is an inhibitory cell surface receptor with a widespread and complex role in immune 
system regulation, with key roles in: Adaptive immune response (CD4+ and CD8+ effector T 
cells, regulatory T cells); and Innate immune response (macrophages, DCs, NK cells).
Figure 1-2
TIM-3 Expression
TIM-3 is expressed on the majority of leukemic progenitors in AML (CD34+/CD38- LSCs and 
CD34+/CD38+ leukemic progenitors), but not on normal HSCs (CD34+/CD38-). TIM-3 
expression is seen to correlate with the severity of MDS and progression to AML. TIM-3 
activation is involved in LSC self-renewal and activation, as well as immune escape in AML.
MBG453 (sabatolimab) is a high-affinity, humanized anti-TIM-3 IgG4 monoclonal antibody 
which blocks the binding of TIM-3 to phosphatidylserine (PtdSer) and partially blocks the 
binding of TIM-3 to Galectin-9. 
PK analyses were done in a ph 1-1b/2 study in pts with adv solid tumors (NCT02608268) and 
a ph 1b study in pts with high/very high risk MDS (HR-MDS) or AML who were ineligible for 
intensive chemotherapy (NCT03066648). Sabatolimab 400 mg Q2W was predicted to have the 
highest steady state Ctrough and TIM-3 occupancy rate when combined with HMA, and 800 mg 
was predicted to be an equivalent Q4W dosing regimen. No clear relationship was seen between 
sabatolimab dose or steady state exposure and safety/efficacy at the doses tested. These results 
support clinical development of the sabatolimab 400 mg Q2W and 800 mg Q4W dosing 
regimens (Borate et al ASH 2019).
In an early clinical trial, sabatolimab (MBG453) demonstrated a good safety/tolerability profile 
in pts with advanced solid tumors, also First in human trials have shown that MBG453 can be 


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
safely administered with decitabine in MDS/AML participants suggesting that MBG453 
(sabatolimab) may be combined with hypomethylating agents (decitabine or azacitidine) 
(Borate et al ASH 2019, EHA 2020). Preliminary clinical activity has been observed 
particularly in high and very high risk MDS participants and an ongoing phase I, II & III studies 
evaluating MBG453 (sabatolimab) plus decitabine & Azacitidine (IV/SC) in HR-MDS and 
acute myeloid leukemia (AML).
Therapy-related myelodysplastic syndromes (t-MDS) are defined as MDS occurring as a 
complication of cytotoxic chemotherapy and/or radiation administered for an antecedent 
neoplastic or non-neoplastic disorder (Kuendgen et al 2020). Kuendgen et al demonstrated that 
classification tools established in p-MDS were effective for stratifying subgropus in t-MDS and 
indicated the high prognostic relevance of cytogenetics in t-MDS.
For further details about sabatolimab (MBG453), refer to the Investigator's Brochure (IB) 
[MBG453 Investigator's Brochure] & below briefing section. 
Ongoing studies with MBG453 (sabatolimab)
1. There are three Phase I studies involving participants treated with MBG453 
(sabatolimab). :
a. In study [CMBG453X2101 / NCT02608268], 252 participants with solid tumors 
received MBG453 (sabatolimab) alone or MBG453 (sabatolimab) in combination 
with PDR001. MBG453 (sabatolimab) single-agent was administered as an IV 
infusion over 30 minutes at doses ranging from 80 to 1200 mg every 2 weeks (Q2W) 
or every 4 weeks (Q4W). 
Table 1-2
Incidence rates of most frequent AEs with single agent MBG453 
(sabatolimab – Solid Tumors
AEs
Single agent of MBG453 
(sabatolimab)2
CMBG453X2101
Solid tumors
All-grade AEs
Grade 3/4
Febrile neutropenia
0
0
Thrombocytopenia
2%
0
Neutropenia
1%
0
Nausea
5%
0
Fatigue
9%
0
Anemia
3%
1%
All-AEs suspected, Safety profile (CMBG453X2101) (2019) solid tumor, N=133


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Figure 1-3
Treatment-Related AEs in > 2% of Patients
CMBG453X2101. Curigliano G et al. AACR 2019. Oral presentation: CT183
b. In study [CPDR001X2105 / NCT03066648] there were 32 evaluable participants 
where MBG453 (sabatolimab) was administered as an intravenous (IV) infusion over 
30 minutes at doses of 240 mg Q2W, 400 mg Q2W and 800 mg Q4W in combination 
with decitabine 20mg QD IV for 5 days in participants with AML and high risk 
MDS.
Table 1-3
Incidence rates of most frequent AEs with the Combination MBG453 
(sabatolimab) + decitabine)
AEs
PDR001X2105
Combination (MBG453 (sabatolimab)+ 
decitabine) 1
MDS & AML
All-grade AEs
Grade 3/4
Febrile neutropenia
45%
44%
Thrombocytopenia
38%
16%
Neutropenia
35%
17%
Nausea
33%
3%
Fatigue
32%
3%


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Anemia
30%
25%
Borate, U et al ASH (2019), PDR001X2105 N=69 including both MDS and AML patients
Figure 1-4
Incidence rates of most frequent AEs with the Combination 
MBG453 (sabatolimab) + decitabine and MBG453 (sabatolimab) + 
Azacitidine
Most commonly reported TEAEs were consistent with those for HMA alone; no maximum 
tolerated dose was reached; no treatment-related deaths occurred ; and treatment 
discontinuation due to AE occurred in only 4 of 106 patients (2.3%)
Borate, U et al EHA (2020) PDR001X2105 including both MDS and AML patients
Table 1-4
Clinical safety and efficacy in pts with HR-MDS/AML treated with 
sabatolimab + HMA
HR-MDS
AML
Sabatolimab dose
240 mg 
Q2W
400 mg 
Q2W
800 mg 
Q4W
240 mg 
Q2W
400 mg 
Q2W
800 mg 
Q4W
Safety population, n
12
12
15
18
36
23
TEAEs grade ≥3a n (%)
Neutropenia
7 (58.3)
4 (33.3)
7 (46.7)
9 (50.0)
15 (41.7)
10 (43.5)
Thrombocytopenia
9 (75.0)
4 (33.3)
7 (46.7)
4 (22.2)
12 (33.3)
13 (56.5)
Febrile neutropenia
7 (58.3)
3 (25.0)
6 (40.0)
10 (55.6)
11 (30.6)
7 (30.4)
Anemia
5 (41.7)
1 (8.3)
5 (33.3)
3 (16.7)
10 (27.8)
8 (34.8)


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
Possible treatment-related imAEs 
grade ≥3b, n (%)
1 (8.3)
1 (8.3)
0
3 (16.7)
0
1 (4.3)
Efficacy evaluable pts, n
12
12
11
17
24
19
HR-MDS remission rate, n (%)
6 (50.0)
4 (33.3)
6 (54.5)
CR
2 (16.7)
3 (25.0)
3 (27.3)
mCR
4 (33.3)
1 (8.3)
3 (27.3)
PR
0
0
0
AML remission rate, n (%)
6 (35.3)
9 (37.5)
6 (31.6)
CR
3 (17.7)
4 (16.7)
1 (5.3)
CRi
3 (17.7)
4 (16.7)
3 (15.8)
PR
0
1 (4.2)
2 (10.5)
a Most common (≥15% of pts in either the HR-MDS or AML cohort) TEAEs grade ≥3.
b A total of 8 such events occurred in 6 pts. Three events (hypothyroidism, infusion-related reaction, and increased 
ALT) occurred in 1 pt with AML who received sabatolimab 240 mg Q2W. The other 5 events (arthritis, rash, possible 
HLH, increased ALT, and enterocolitis) each occurred in 1 pt.
CR, complete remission; CRi, CR with incomplete hematologic recovery; imAE, immune-mediated adverse event; 
mCR, marrow CR; PR, partial remission; TEAE, treatment-emergent adverse event; Q2W, every 2 weeks; Q4W, 
every 4 weeks.
CMBG453X2101 / NCT02608268 and CPDR001X2105 / NCT03066648 (ASH 2020)
c. As of Oct 2020, in planned study [CMBG453D12101 / NCT04283526] phase Ib for 
patients with primary myelofibrosis (PMF) or post-polycythemia vera myelofibrosis 
(PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF),the objective 
of the study is to characterize the safety, tolerability and recommended for each 
treatment combination (MBG453 + NIS793 ; MBG453 + NIS793 + decitabine ; and 
MBG453 + NIS793 + spartalizumab).
2. There are two Phase II studies for participants to be treated with MBG453 (sabatolimab) 
as of Oct 2020 :
a) ongoing CMBG453B12201 (STIMULUS-MDS1 / NCT03946670) Phase II study for 
intermediate, high and very high risk MDS that included dose of MBG453 
(sabatolimab) as 400mg Q2W to be given on day 8 and 22 in addition to HMAs 
(decitabine 20mg/m2 from D1 to D5 azacitidine 75mg/m2 from D1 to D7 or D1 to 
D5 + D8 & D9), 
b) ongoing CMBG453C12201 (STIMULUS-AML1 / NCT04150029) Phase II study is 
for AML unfit patients to receive MBG453 (sabatolimab) \ at day 8 in addition to 
HMAs + venetoclax. In part 1, patients will be enrolled at the starting MBG453 dose 
level of 400mg Q4W. If deemed safe, additional patients will then be rolled at the 
second MBG453 dose level of 800mg Q4W. In each cycle, azacitidine will be 
administered intravenous or subcutaneous at 75 mg/m2 on Days 1 to 5 and Days 8 
and 9 (or, at discretion of the investigator on Days 1-7, or Days 1-6 and Day 8 
respectively), and venetoclax will be administered orally at 400 mg daily.
3- CMBG453B12301 (STIMULUS-MDS2 / NCT04266301) - A randomized, double-blind, 
placebo-controlled phase III multi-center study of azacitidine with or without MBG453 
(sabatolimab) for the treatment of patients with intermediate, high or very high risk 
myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic 
Leukemia-2 (CMML-2). To compare OS in participants with intermediate-, high-, or very 


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high–risk MDS or CMML-2 treated with MBG453 (sabatolimab) 800 mg every 4 week + 
azacitidine vs. those treated with placebo + azacitidine.
1.2
Purpose
Complete remission with HMAs in patients with intermediate, high, and very high risk MDS is 
usually infrequent and transient, and prognosis remains poor for these patients. When standard 
of care based on HMA fails in these patients, treatment options in second line are limited.
Main objective of this proposed study is to describe and evaluate safety and efficacy of 
MBG453 (sabatolimab) 800 mg every 4 weeks on day 8 in combination with FDA approved 
HMAs of investigator’s choice (IV Decitabine or Azacitidine /SC Azacitidine /Oral Decitabine 
(cedazuridine combination (INQOVI)) (For IV and SC HMAs, sabatolimab (MBG453) can be 
administered on a day between days 5-8 as per investigator decision)) in a single-arm, non- 
randomized, open label, phase II multi-center US study.
2
Objectives and endpoints
Objectives and related endpoints are described in Table 2-1 below.
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective
•
To assess the safety profile of MBG453 
(sabatolimab) 800 mg (every 4 weeks) given 
in combination with HMAs (IV/SC/Oral) by 
12 months
Endpoint for primary objective
•
Incidence and severity of AEs and SAEs, 
changes in laboratory values and vital signs 
Secondary Objectives
1)
To evaluate complete remission with 
MBG453 (sabatolimab) in combination with 
HMAs (IV/SC/Oral) in participants with 
intermediate, high, or very high risk MDS 
by 12 months
2)
To evaluate PFS rate by 12 months with 
MBG453 (sabatolimab) combined with 
HMAs (IV/SC/Oral) in participants with 
intermediate, high or very high risk MDS
3)
To assess Overall Survival rate by 24 
months
4)
To assess Leukemia-free survival rate by 12 
months
5)
To assess other response rates
6)
To assess duration of complete remission
7)
To assess time to complete remission
8)
To assess the improvement in RBC/platelets 
transfusion independence
Endpoints for other secondary objectives
1)
Complete remission (CR) rate according to 
International Working Group (IWG) for 
MDS (2006) * as per investigator 
assessment by 12 months.
2)
PFS is defined as time from enrollment to 
disease progression (including 
transformation to leukemia per WHO 2016 
classification), relapse from CR according to 
IWG-MDS * or death due to any cause, 
whichever occurs first, as per investigator 
assessment ** by 12 months post LPFT.
3)
Overall survival, time from enrollment to 
death due to any cause during 12 months 
post LPFT.
4)
Time from enrollment to > 20% blasts in 
bone marrow/peripheral blood (per WHO 
2016 classification) or death due to any 
cause
5)
Percentage of CR/mCR/PR according to 
IWG-MDS as per investigator assessment


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Objective(s)
Endpoint(s)
6)
Time from the date of the first documented 
CR to the date of first documented relapse 
from CR or death due to any cause, 
whichever occurs first
7)
Time from enrollment to the first 
documented CR
8)
Number and percent of participants who are 
RBC/platelets transfusion independent after 
enrollment as per IWG-MDS
3
Study design
This is a single-arm, non- randomized, open label, phase II multi-center study of intravenous 
MBG453 (sabatolimab) added to FDA approved Hypomethylating agents of investigator’s 
choice (IV/SC/ Oral) in adult participants with intermediate, high or very high risk 
myelodysplastic syndrome (MDS) as per IPSS-R criteria.
The primary objective of this study is to assess the safety profile of MBG453 (sabatolimab) 800 
mg (every 4 weeks) given in combination with HMAs (IV/SC/Oral) by 12 months.




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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
1. Screening period (signing of written informed consent through Day of enrollment); 
2. Core phase for up to12 months 
3. Extension phase for efficacy and/or survival status (up to 12 months after core phase)
4. post treatment safety follow-up monitoring for adverse events (AEs) for 30 days following 
the last dose of azacitidine or decitabine or INQOVI (oral decitabine), or 150 days 
following the last dose of MBG453 (sabatolimab), whichever is later.
Approximately 39 patients who are evaluable for primary endpoints will be assessed.
Figure 3-1
Study design 


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Clinical Trial Protocol (Version No. 02)                                                   Protocol No. CMBG453B1US01
3.1
Definition of end of study
The end of the study (Last Patient Last Visit) is defined as once all patients discontinued study 
treatment and were transitioned to treatment outside the study and have completed the study 
which is targeted at the latest 29  months after the last patient was enrolled. The Last Patient 
Last Visit will include all the required safety follow-up visits.


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4
Rationale
4.1
Rationale for study design
The justification for a single arm, non-randomized phase II trial is to determine the safety of 
adding MBG453 (sabatolimab) every 4 weeks at day 8 to oral HMAs & at day 8 for IV and SC 
HMAs (For IV and SC HMAs, sabatolimab (MBG453) can be administered on a day between 
days 5-8 as per investigator decision) to on the primary safety & secondary efficacy endpoints
This prospective, non- randomized, study design of MBG453 (sabatolimab) combined with oral 
HMA (decitabine) complements other randomized placebo controlled MBG453 (sabatolimab) 
+ IV/ SC HMAs development studies. 
In this trial, participants with higher risk MDS (defined as very high risk, high risk, intermediate 
risk) will be enrolled. The choice of HMA (IV/SC/Oral) is left to the investigator's discretion 
in order to reflect the local approval and the local clinical practice. IPSS-R score at baseline is 
a crucial clinical indicator in the sense it will inform about the treatment outcomes and 
prognostic of each given Participant. Each level of risk (intermediate/high/very high) is 
associated with a different survival length and potential of leukemic transformation (see Section 
1.1). Azacitidine and decitabine used in monotherapy lead to similar clinical effectiveness and 
safety profiles (see Section 1.1). However, it cannot be ruled out treatment outcome of a novel 
compound given in a combination regimen may vary with nature of the partner drug.
The primary goal for treatment of higher-risk MDS patients (pts) is to improve overall survival 
(OS) and delay acute myeloid leukemia (AML) evolution. The IWG 2006 response criteria are 
used in clinical trials and in clinical practice for assessing efficacy of MDS therapies. These 
criteria were originally proposed by an international group of experts based on available data 
and consensus. In an ad hoc landmark analysis of the AZA-001 study using the 2006 IWG 
criteria, patients who achieved hematological improvement (HI), complete response (CR), 
marrow CR (mCR), or partial response (PR) demonstrated improved OS. 
Treatment response by IWG 2006 criteria and correlation with clinical outcomes has been 
evaluated in studies (Blood 2015, Leukemia Research 2016). In a study conducted with data 
from the MDS Clinical Research Consortium, HR-MDS patients treated with HMA who 
achieved CR had a longer median OS, as compared to patients who achieved PR, SD or HI 
(Leukemia Research 2016).
Due to its correlation with overall survival, the emerging goal for HR-MDS is to achieve 
complete remission (the bone marrow and blood cell counts return to normal). Only 40% to 
50% of patients typically will respond to HMAs, with a median duration of response < 1.5 years 
and eventually all patients will lose initial response. Outcome after HMA treatment failure is 
poor and represents an unmet need. Complete remission (CR) have shown to be associated with 
prolonged overall survival in MDS patients (Komrokji 2015).
In Komrokji 2015 study AZA001, for patients who were treated with HMA as first line therapy, 
the best response rates by IWG 2006 criteria were CR in 15%. 
In Garcia-Manero ASH 2019, CR rate for HR MDS/CMML study the oral decitabine data 
shows CR as 12%.


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4.2
Rationale for dose/regimen and duration of treatment
The proposed MBG453 (sabatolimab) dose in the study is 800 mg Q4W based on data 
accumulated from two phase I studies: [CMBG453X2101] and [CPDR001X2105]. 
[CMBG453X2101] in solid tumor patients has a wide MBG453 (sabatolimab) dose range 
(single agent MBG453 (sabatolimab) from 80 to 1200 mg every 2 weeks (Q2W) or every 4 
weeks (Q4W), with a lower 20 mg Q2W MBG453 (sabatolimab) dose additionally tested in 
combination with PDR001. Because of the data obtained in [CMBG453X2101], study 
[CPDR001X2105] started evaluating MBG453 (sabatolimab) at 240 mg Q2W and additionally 
tested 400 mg Q2W and 800 mg Q4W in combination with decitabine.
Clinical Pharmacology: The pharmacokinetics (PK) of MBG453 (sabatolimab) were similar 
between studies [CMBG453X2101] in solid tumor patients and [CPDR001X2105] in AML and 
high risk MDS patients. At lower doses (at 80 mg and below for Q2W dosing or at 240 mg and 
below for Q4W dosing), the PK was nonlinear, with faster elimination at lower concentrations. 
PK appeared linear with an approximate proportional dose-exposure (AUC and Cmax) 
relationship at doses of 240 mg and above for Q2W dosing and at doses of 800 mg and above 
for Q4W dosing. Accumulation of MBG453 (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. The dose of 800 mg Q4W has similar AUCtau as 400 mg Q2W 
at the steady state.
Clinical Efficacy: In study [CPDR001X2105], clinical benefit was seen across 3 dose levels 
tested at 240 mg Q2W, 400 mg Q2W and 800 mg Q4W in combination with hypomethylating 
agents, with CR or marrow CR in higher risk MDS participants and CR or CRi in newly 
diagnosed AML participants. Among responding higher-risk MDS participants, there were 
durable responses as long as 30 months (see section 4.3.2. No dose-response relationship was 
observed. In a preliminary exposure-response analysis, there was also no clear relationship 
between exposure and response, using steady state exposure metrics of AUCtau or Ctrough and 
efficacy metrics of clinical benefit (CR/mCR/CRi) or percent blast cell reduction.
Clinical Safety: In study [CMBG453X2101], as of 25-Jul-2019, a total of 133 participants with 
solid tumors have been treated with MBG453 (sabatolimab) single agent therapy. There were 
no adverse events attributed to study treatment with an incidence >10%. The most frequently 
reported adverse events attributed to study treatment included fatigue (9%), followed by 
decreased appetite and nausea (4.5% each). There were no DLTs during the first cycle. No 
participants discontinued study treatment due to treatment-related AEs.
In study [CPDR001X2105], as of 26-Jul-2019, a total of 123 participants with hematological 
malignancies have been treated with MBG453 (sabatolimab) as a single agent (n=26) or in 
combination with decitabine (n=81) or azacitidine (n=16). In the 26 participants treated with 
MBG453 (sabatolimab) single agent, there were no adverse events attributed to study treatment 
with an incidence >10%. The most frequently reported adverse event attributed to study 
treatment was a rash in two participants (8%). All other adverse events attributed to study 
treatment were single occurrences. There were no DLTs during the first cycle. No participants 
discontinued study treatment due to treatment-related AEs. In the 81 participants treated with 
MBG453 (sabatolimab) in combination with decitabine, the most frequent adverse events (all 
grades, >10%) attributed to study treatment have included thrombocytopenia, anemia, 


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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 16 participants treated with MBG453 (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, platelet count decrease. 
There were no DLTs during the first 2 cycles. No participants discontinued study treatment due 
to treatment-related AEs. No study treatment-related deaths were observed in any of the studies 
mentioned above.
Preliminary analysis revealed no relationship between dose, incidence and severity of adverse 
events across the different treatment groups. No relationship was observed between Cmax and 
the incidence of 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 
[MBG453 (sabatolimab) Investigator's Brochure] for additional information of AEs reported in 
participants with solid tumors or with hematologic malignancies treated with MBG453 
(sabatolimab) as a single agent or in combination with other drugs.
As per the latest data analysis (cut-off: 10-Apr-2020) of HR-MDS and AML patients treated 
with MBG453 + HMA combination; including 69 patients treated with MBG453+decitabine 
and 37 patients treated with MBG453+azacitidine combination from study [CPDR001X2105], 
MBG453 + HMA combination was safe and well tolerated. No Maximum Tolerated Dose 
(MTD) was reached and no new significant safety issues were observed. Most commonly 
reported treatment emergent adverse events were consistent with those for HMA alone. The 
majority (92%) of possible immune mediated adverse events (imAEs) related to study treatment 
were grade 1/2. No treatment related deaths were reported. 
Predicted target engagement: A population pharmacokinetic model of MBG453 (sabatolimab) 
concentration was fit to all participants from both studies to the predicted TIM-3 occupancy in 
the bone marrow by making assumptions about MBG453 (sabatolimab) biodistribution to the 
bone marrow and binding 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 3 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 a clear dose-response or exposure-response 
relationship for MBG453 (sabatolimab), 800 mg Q4W was selected as the dose regimen for this 
study.


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4.3
Rationale for choice of the combination drugs
4.3.1
Rationale for HMA (IV/SC azacitidine or IV/oral decitabine)
In MDS patients, HSCT is the only curative option. However, only a minority of MDS patients 
are candidates for HSCT and the intensive chemotherapy, which may be used prior to transplant 
(Steensma 2018, Platzbecker 2019).
Treatment strategies are generally non-intensive and risk-adapted (by IPSS-R), ranging from 
watchful surveillance, iron chelation and growth factors to lenalidomide and HMA.
Higher risk MDS patients who are non-transplant candidates are commonly treated with HMA 
therapy. HMAs (azacitidine and decitabine) represent the only approved therapeutic agents and 
constitute the current standard or care. Patients continue treatment if tolerated as long as they 
benefit. The main treatment goal is to delay or avoid disease progression and transformation to 
acute leukemia.
Both drugs (decitabine and azacitidine) are approved in the USA, whereas only azacitidine is 
approved for treating higher risk MDS in Europe. The pivotal Phase III trial of azacitidine 
(Fenaux et al 2009) reported a statistically significant survival benefit (median overall survival 
24.5 months versus 15.0 months) of azacitidine compared to conventional care including 
intensive chemotherapy. Decitabine approval in the US is mainly based on the findings from a 
Phase III clinical trial which demonstrated decitabine-treated participants achieved a 
significantly higher overall response rate (17%), including 9% complete remissions, compared 
with supportive care (0%) (p <0.001). An additional 12 participants who were treated with 
decitabine (13%) achieved hematologic improvement. Responses were relatively durable 
(median, 10.3 mos.) and were associated with transfusion independence (Kantarjian et al 2006). 
Azacitidine and decitabine have not been compared in clinical trials. However, a large 
retrospective study identified patients diagnosed with MDS between 2004 and 2011 in the US 
(SEER-Medicare linked database) who received ≥ 10 doses of either HMA for comparing 
clinical effectiveness in daily practice of azacitidine versus decitabine. Azacitidine was used for 
treating approximately 80% of the patients (n = 2,025). Survival from HMA initiation was 
estimated with Kaplan-Meier methods and adjustment was made for relevant covariates. No 
significant survival difference was found between azacitidine and decitabine in MDS patients, 
including in MDS patients with excess of blasts (Zeidan et al 2016).
Safety profiles of decitabine and azacitidine are similar. Azacitidine and decitabine are 
generally well tolerated and both have a manageable toxicity profile (Derissen et al 2013). The 
most common toxicity is myelosuppression, primarily neutropenia and thrombocytopenia. 
Adverse events related to myelosuppression typically occur in the third week of the treatment 
cycle and participants commonly achieve hematologic recovery prior to the next treatment cycle. 
Otherwise, a delay in starting the next cycle or a dose reduction may be necessary. During the 
clinical trials, hematologic adverse events were most frequently observed during the first two 
treatment cycles and nadir values for hematological parameters improved during subsequent 
cycles. The most common non-hematological adverse events corresponded to gastrointestinal 
toxicities (nausea, vomiting, diarrhea, and constipation) which generally occurred in the first 
week of the treatment cycle. These events were generally mild and transient. They could be 
managed with concomitant medications, including antiemetics and antidiarrheal.


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 Azacitidine and decitabine regimens used in this trial are the most studied regimens and 
recommended by international treatment guidelines.
In a phase 2 study, INQOVI (oral decitabine) (ASTX727) demonstrated pharmacokinetic (PK) 
AUC exposure similar to IV-DEC at 20mg/m2 with comparable clinical activity and safety 
(Garcia-Manero, MDS Int’l symposium, 2019). At ASH 2019 phase 3 study (ASCERTAIN) 
demonstrated that INQOVI (oral decitabine), the oral FDC of cedazuridine/decitabine (100 
mg/35 mg) resulted in an equivalent DEC exposure to IV-DEC at 20 mg/m2 over 5 days. Safety 
findings are consistent with those anticipated with IV-DEC with no clinically significant GI 
toxicity. Preliminary clinical activity is also consistent with published data from IV-DEC. 
INQOVI (oral decitabine)is an oral HMA alternative to IV-DEC (Garcia-Manero et al 2019). 
The FDA has granted a priority review designation to a new drug application (NDA) for 
cedazuridine plus decitabine (ASTX727; INQOVI) for the treatment of adult patients with 
previously untreated intermediate- and high-risk myelodysplastic syndromes (MDS) or chronic 
myelomonocytic leukemia (CMML).(accessed at: Astex Pharmaceuticals announces U.S. Food 
and Drug Administration (FDA); According to research presented as a late-breaking abstract at 
the 2019 ASH Annual Meeting, treatment with CC-486, an oral formulation of the 
hypomethylating agent azacitidine, improved overall survival (OS) and relapse-free survival 
(RFS) when used as maintenance therapy in patients with acute myeloid leukemia (AML) who 
were in remission after induction chemotherapy.
These efficacy results suggest that CC-486 could represent a new standard in this setting (post 
remission AML maintenance); however considering difference in pharmacokinetics between 
CC-486 & IV Azacitidine in addition to no current studies in Higher risk MDS – there are no 
plans for HR-MDS label inclusion for this molecule. (Garcia- Manero et al 2008, Cogle et al 
2015).
Table 4-1
ASTX Oral Decitabine Safety: Most Common All Grades AEs in the 
First 2 Randomized Cycles (All Causality) – Garcia Manero et al ASH 
2019
None of the differences was statistically significant (All P values > 0.10)
GI AEs Grade ≥ 3 incidence <1% for each of ASTX727 and IV decitabine in Cycles 1 or 2


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In July 2020, INQOVI has received FDA approval for adult patients with MDS, including 
previously treated and untreated, de novo and secondary MDS with the following French-
American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, 
refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and 
intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. 
Oral decitabine is also included within the NCCN guidelines.
4.3.2
Rationale for MBG453 (sabatolimab)
The large family of costimulatory molecules plays a crucial role in regulation of the immune 
response. These molecules modulate the immune system by phosphorylation cascades. Some 
of the coinhibitory members of this family, such as PD-1 and CTLA-4, already constitute 
clinical targets in oncology and, since 2011, have opened a new area of antitumor 
immunotherapy. Checkpoint inhibitors (such as nivolumab, ipilimumab, pembrolizumab) have 
been approved by health authorities (FDA and EMA in particular) for numerous cancer 
indications including hematologic malignancies, and they are used in daily clinical practice. A 
great deal of clinical trials are ongoing to assess these antibodies in new potential indications. 
Many novel antibodies targeting inhibitory receptors (such as e.g. TIM-3, VISTA, Lag-3) or 
activating costimulatory molecules (such as OX40, GITR) are also being investigated in clinical 
trials enrolling participants with solid tumors or hematological malignancies.
Abnormal upregulation of PD-L1, PD-L2, PD-1, and CTLA4 in CD34+ cells in MDS 
participants compared to healthy controls has been reported (Yang et al 2014), and their 
expression is further upregulated following epigenetic therapy with HMAs. Overexpression of 
these checkpoint receptors on T cells and ligands on AML/MDS blasts interferes with effective 
T- cell antitumor response and is associated with leukemic progression in preclinical models. 
Novel monoclonal antibodies targeting CTLA-4 (e.g. ipilimumab) or PD-1/PD-L1 (e.g. 
nivolumab, pembrolizumab, and atezolizumab) can reverse immune suppression and enables 
lymphocyte-mediated toxicity against blasts. Results of ongoing early clinical trials evaluating 
these agents in monotherapy or in combination with the hypomethylating agents in relapsed 
AML and frontline post-hypomethylating MDS are showing promising clinical activity and 
acceptable safety profile in participants treated with these agents alone or in combination to 
HMA (see Section 1.1).
Similarly to PD1 and CTLA4, MDS patients overexpress the immune checkpoint receptor, 
TIM-3, which inhibits immune recognition by cytotoxic T cells (Kikushige et al 2010). TIM-3 
expression levels on MDS blasts increases as MDS progresses to the advanced stage. It has 
been observed that the proliferation of TIM-3 + MDS blasts is inhibited by the blockade of 
TIM-3 using an anti-TIM-3 antibody (Asayama et al 2017). Hence, TIM-3 constitutes a relevant 
target for novel therapies in development in MDS and AML. MBG453 (sabatolimab) is a high- 
affinity, ligand-blocking, humanized anti-TIM-3 IgG4 antibody (stabilized hinge, S228P) 
which blocks the binding of TIM-3 to phosphatidylserine (PtdSer). Clinical trials of MBG453 
(sabatolimab) are ongoing in solid tumors and hematological malignancies.
Safety data indicate that the compound was well tolerated overall in 291 participants with solid 
tumors or hematological malignancies exposed to MBG453 (sabatolimab). Two trials are 
ongoing as of Oct 2020: one Phase I/II open label, multicenter study of the safety and efficacy 
of MBG453 (sabatolimab) as single agent and in combination with PDR001 in adult participants 


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with advanced malignancies [CMBG453X2101] and a Phase Ib multi-arm, open label study of 
PDR001 and/or MBG453 (sabatolimab) in combination with decitabine in participants with 
AML or high risk MDS [CPDR001X2105].
 In particular, the compound was well tolerated as a single agent or when it is administered 
intravenously in combination with decitabine to MDS/AML participants. Please refer to Section 
1.1 and the [MBG453 (sabatolimab) Investigator's Brochure] for more details.
Preliminary efficacy data reported in study [PDR001X2105] with higher risk MDS participants 
are showing high response rates. At the time of the latest analysis (cut-off: 10-Apr-2020), in the 
MBG453 + decitabine arm, 11 of 18 (61.1%) evaluable high risk and very high risk MDS 
patients have achieved a response (6 complete remissions [33.3%], 3 marrow complete 
remissions [16.7%], 2 stable diseases with hematologic improvement [11.1%]).  Median of 
exposure in this arm is approximately 8 months. Durability of response and clinical benefit is 
being observed with the longest responding higher-risk MDS subjects continuing on study for 
more than 30 months. In the MBG453 + azacitidine arm, 11 of 19 (57.9%) evaluable higher-
risk MDS patients have achieved a response (2 complete remissions [10.5%], 7 marrow 
complete remissions [36.8%], 2 stable diseases with hematologic improvement [10.5%]). Of 
note, data from this arm is less mature with duration of follow-up of approximately 3 
monthsRationale for combining MBG453 (sabatolimab) with HMA (IV/ SC azacitidine and IV/ 
oral decitabine)
Despite the fact that single-agent HMAs are available for the treatment of patients with higher 
risk MDS, alternative treatment strategies are urgently needed; because achieving complete 
remission with HMA alone in this difficult to treat population is a rare event and the duration 
of the clinical benefit is commonly transient. Furthermore, attempts to use HMA single-agent 
to increase the HSCT rate or as alternative treatment of cytarabine in higher risk MDS patients 
have been disappointing. In addition, many higher risk MDS patients eventually progress on 
HMAs and ultimately progress to AML.
Combining HMAs with novel agents may improve their clinical efficacy and overcome 
resistance. The fact that immune checkpoint inhibitors have been able to generate deep and 
durable response in various cancers including hematologic malignancies together with 
emerging preclinical and clinical data (see Section 15) strongly supports the evaluation of the 
novel anti-TIM-3 antibody MBG453 (sabatolimab) combined with HMAs in MDS.
Preclinical data suggest HMA enhances checkpoint expression and that a synergistic response 
may be produced by using a checkpoint inhibitor and a hypomethylating agent concomitantly. 
HMAs induce increased expression of other checkpoints in MDS patients, i.e. PD-1, PD-L1, 
PD-L2 and CTLA4, which may justify the use of check-point inhibitors in combination with 
HMAs (Yang et al 2014, Ørskov et al 2015). Another interesting biological finding is that 
demethylation of the TIM-3 promoter has been shown to be critical for the stable expression of 
TIM-3 on T cells, indicating that modulation of the expression of TIM-3 by hypomethylating 
agents (azacitidine or decitabine) could have important immunomodulatory implications (Chou 
et al 2016). Furthermore, decitabine has been shown to increase the activity of Natural Killer 
(NK) cells, which may play a role in anti-tumor immunity (Sohlberg et al 2015).
Emerging clinical data from the ongoing Phase I study [CPDR001X2105] enrolling high risk 
MDS Participants indicate that MBG453 (sabatolimab) plus decitabine combination is feasible, 






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there are dose modification and management guidelines, including for follow-up of toxicities, 
proposed by the protocol in relation to recent American Society of Clinical Oncology (ASCO) 
practices guidelines about management of immune-related adverse events in patients treated 
with checkpoint inhibitors (Brahmer et al 2018; see Section 6.5). Additionally, general 
guideline for non-hematologic non-immune-related toxicities that are clinically significant per 
investigator judgement and that are possibly attributable to the investigational drug is also 
provided (see Table 6-3).
The feasibility of starting a new clinical trial during a pandemic situation was assessed. The 
MBG453 (sabatolimab) benefit / risk ratio remains unchanged in light of the COVID-19 
pandemic. If a patient becomes infected with the virus, we recommend the patient recover 
before restarting the study drug.
Based on single agent data, there are no expected significant overlapping toxicities between 
INQOVI (oral decitabine) and MBG453 (sabatolimab) combination. Based on currently 
available data from phase I, there are no known significant overlapping toxicities between IV 
decitabine or IV/SC azacitidine and MBG453 (sabatolimab). However, there may be unforeseen 
risks from combining decitabine or INQOVI (oral decitabine) or azacitidine with MBG453 
(sabatolimab), which could be serious. In particular, since one focus of this study is to combine 
immunomodulatory agents in order to increase the anti- tumor immune response, there is the 
potential for increased toxicity secondary to increase in cytokine release syndrome due to 
activation of T cells and macrophages, and there may also be changes in immune function that 
could lead to increased autoimmunity or risk of infection or risk of immune-related adverse 
events. All participants enrolled will be monitored closely for these potential toxicities. 
Women of child-bearing 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 must agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria. If there is any question that the 
Participant will not reliably comply, they should not be entered or continue in the study.
No substantial additional risk for patients' safety due to the SARS-CoV-2 virus (Severe Acute 
Respiratory Syndrome Corona 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 patients can remain on 
study medication or not.
Approved HMAs labels are available at FDA website and MBG453 (sabatolimab) Investigator 
Brochure will be provided to sites as updates occur.
4.6
Rationale for Public Health Emergency mitigations procedures
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate.


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5
Study Population
This target population of this study will be adult patients (>18 years) to be treated in first-line 
setting, with intermediate, high or very high risk per IPSS-R prognostic risk categories for 
myelodysplastic syndrome who do not qualify according the medical judgment for 
chemotherapy or HSCT. Participants with chronic myelomonocytic leukemia (CMML) are not 
eligible for this trial. 
It is anticipated that approximately 39 patients will be enrolled in this study. Patients will be 
recruited from sites within the United States.
Patient population will consist of approximately 39 patients receiving the HMA of choice that 
is approved for frontline higher risk MDS.  No pre-treatment stratification is planned. Post study 
sub-group exploratory analysis will be evaluated. The investigator or designee must ensure that 
only patients who meet all the following inclusion and none of the exclusion criteria are enrolled 
in the study.
5.1
Inclusion criteria
Written informed consent must be signed by the patient prior to any screening procedures. 
Patients eligible for 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 a myelodysplastic syndrome (MDS) primary or 
secondary based on 2016 WHO classification (Arber et al 2016) by investigator 
assessment with one of the following Prognostic Risk Categories, based on the 
International Prognostic Scoring System (IPSS-R). Note: MDS diagnosis history will be 
recorded in the CRF:
•
Very high (> 6 points)
•
High (> 4.5 – ≤ 6 points)
•
Intermediate (> 3 – ≤ 4.5 points) 
4. Not suitable at time of screening for immediate myeloablative/ chemotherapy or 
hematopoetic stem-cell transplantation based on investigator assessment of age, 
comorbidities, local guidelines, institutional practice (any or all of these).
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
6. AST and ALT ≤ 3 × upper limit of normal (ULN).
7. Total bilirubin ≤ 2 × ULN (except in the setting of isolated Gilbert syndrome).
8. Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73m2 (estimation based on 
Modification of Diet in Renal Disease (MDRD) formula, by local laboratory).
9. Patient is able to communicate with the investigator and has the ability to comply with the 
requirements of the study procedures.
5.2
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:


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1. Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune 
checkpoint inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer 
vaccines are allowed only if the last dose of the drug was administered more than 4 
months prior to enrollment.
2. Previous treatment for intermediate, high or very high risk myelodysplastic syndromes 
(based on IPSS-R) with chemotherapy or other antineoplastic agents including 
lenalidomide and hypomethylating agent (HMAs) such as decitabine or INQOVI (oral 
decitabine) or azacitidine (patients who had up to 1 cycle of HMAs can be included). 
However, previous treatment with hydroxyurea is permitted.
3. History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, 
decitabine, INQOVI (oral decitabine) or MBG453 (sabatolimab)) or monoclonal 
antibodies (mAbs) and/or their excipients.
4. Current use or use within 14 days prior to enrollment 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.
5. Investigational treatment for MDS received within 4 weeks or 5 half-lives of this 
investigational treatment, whatever is longer prior to enrollment. In case of a checkpoint 
inhibitor: 4 months minimum prior to enrollment interval is necessary to allow enrollment.
6. Active autoimmune disease requiring systemic therapy (e.g. corticosteroids).
7. Live vaccine administered within 30 days prior to enrollment. (refer to Exclusion criteria 1 
regarding cancer vaccines)
8. Treatment with drugs that are metabolized by cytidine deaminase within 7 days prior to 
starting the study treatment.
9. 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).
10. Diagnosis of Chronic myelomonocytic leukemia (CMML), 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. Participants with active 
infection requiring parenteral antibacterial, antiviral or antifungal therapy which are 
controlled by treatment are eligible.
13. 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 >480 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) unless well controlled and clinically addressed in addition 
to follow-up with cardiologist or agreed by medical monitor


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14. Participants with prior malignancy, except:
a. Participants with history of lower risk MDS treated by supportive care (e.g. growth 
factors, TGF-beta agents) or untreated are eligible
b. Participants with history of lower risk MDS who were treated adequately with 
lenalidomide and then failed are eligible
c. Participants with history of adequately treated malignancy for which no anticancer 
systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or 
required during the course of the study. Participants who are receiving adjuvant 
therapy such as hormone therapy are eligible.
15. Human immunodeficiency virus (HIV) infection not controlled by standard therapy and/or 
with known history of opportunistic infection.
16. Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Participants whose disease is 
controlled under antiviral therapy should not be excluded. For additional guidance 
regarding Hepatitis B, please refer to Section 16.4.
17. Other co-morbidity that, in the opinion of the investigator, predisposes the participant to 
high risk of noncompliance with the protocol.
18. Participants with Myelodysplastic syndrome (MDS) based on 2016 WHO classification 
(Arber et al 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 3
19. Sexually active males unwilling to use a condom during intercourse while taking 
azacitidine or decitabine or INQOVI (oral decitabine) and for 3 months after stopping 
these drugs. 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. In addition, male participants must not donate sperm for the time period 
specified above, and their female partners will be instructed to use highly effective 
contraception.
20. Participant is pregnant or breastfeeding.
21. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during study treatment and for 3 months after the last dose of azacitidine or decitabine or 
INQOVI (oral decitabine) (or as per their respective local labels, whichever is longer) and 
150 days after the last dose of MBG453 (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
•
Male sterilization (at least 6 months prior to screening). For female participants on the 
study the vasectomized male partner should be the sole partner for that participant.
•
Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device (IUD) or intrauterine 


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system (IUS) or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child-bearing 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) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least 6 weeks 
before taking study treatment. 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 child-bearing potential.
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the ICF.
6
Treatment
6.1
Study treatment
In this study, the “study treatment” refers to the combination of study drugs: MBG453 
(sabatolimab) plus hypomethylating agent (IV/SC/Oral).
The term “investigational drug” refers to the Novartis study drug, MBG453 (sabatolimab). The 
choice of the HMA (as described in the following sections) will be selected by the investigator 
as per local standard of care (SOC). After study enrollment and investigator choice for HMA is 
decided [whether azacitadine (IV or SC) or decitabine (IV or oral)], type of HMA and mode of 
administration must not be changed during the study course. In case of emergency clinical care 
during the study course, it will be allowed for patients switching from oral to IV decitabine 
during inpatient as per investigator decision. Switching from IV to oral decitabine during 
emergency clinical care requires following the label to complete the IV cycle to reach steady 
state of decitabine levels.
All doses prescribed, dispensed to the participant and all dose changes during the study 
including the reason must be recorded on the appropriate electronic case report form (eCRF) 
page.
Table 6-1
Investigational drugs
Investigational 
Drug
(Name and 
strength)
Dose 
Administration
Pharmaceutical 
Dosage Form
Route of 
Administration
Obtained by
MBG453 
(sabatolimab)
400mg/4ml
800mg every 4 
weeks at day 8 (For 
IV and SC HMAs, 
sabatolimab 
(MBG453) can be 
Solution for 
infusion
Intravenous use
Sponsor


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administered on a 
day between days 
5-8 as per 
investigator 
decision)
Table 6-2
Study drugs
Study Drug 
(Name and 
strength)
Dose 
Administration
Pharmaceutical 
Dosage Form
Route of 
Administration
Obtained by
Decitabine 50mg 
single vial**
20mg/m2 D1-D5
Lyophilized 
powder
Intravenous use
Site
Decitabine Oral 
(INQOVI)
100mg 
cedazuridine / 
35mg decitabine 
QD D1 to D5
Tablet
Oral
Site
Azacitidine 100 mg 
single vial**
75mg/m2 D1-D7 or 
D1 to D5 + D8 & 
D9
Lyophilized 
powder
Intravenous or 
subcutaneous use
Site
**Other locally available dose strengths are acceptable
Azacitidine and decitabine regimens used in this protocol were selected because they are the 
most studied regimens and recommended by international treatment guidelines (National 
Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), 
Steensma 2018). Azacitidine and decitabine are considered as a Standard of Care in the 
population enrolled in this study and it should be administered according to standard local 
clinical practice.
Decitabine should be administered according to local standard clinical practice. A standard dose 
of decitabine (20 mg/m2) will be given intravenously every day for five consecutive days on 
Days 1-5 out of a 28 days cycle (see local decitabine US package insert) or 100mg/35mg QD 
D1 to D5 out of a 28 days cycle if using oral formulation. The food intake requirement for oral 
formulation should be consistent with approved oral decitabine label, no food should be 
consumed 2 hours before and 2 hours after each dose of oral decitabine. MBG453 (sabatolimab) 
infusions will be administered on Day 8 out of a 28 days cycle (For IV and SC HMAs, 
sabatolimab (MBG453) can be administered on a day between days 5-8 as per investigator 
decision) (Table 8-1).
Azacitidine should be administered according to local standard 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 US package 
insert). In keeping with standard clinical practice, the alternative schedule 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 also be permitted (alternative schedule). MBG453 (sabatolimab) infusions will be 


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administered on Day 8 out of a 28 days cycle (For IV and SC HMAs, sabatolimab (MBG453) 
can be administered on a day between days 5-8 as per investigator decision) (Table 8-1).
If the alternative schedule is selected for azacitidine by the investigator, azacitidine and 
MBG453 (sabatolimab) will be given on the same Day 8 (For IV and SC HMAs, sabatolimab 
(MBG453) can be administered on a day between days 5-8 as per investigator decision). 
Azacitidine should be administered first, followed by MBG453 (sabatolimab). 
An interval of 1 hour is recommended between the two dose administrations.
MBG453 (sabatolimab) will be administered via IV infusion over 30 minutes. Further 
instructions for the preparation and administration of MBG453 (sabatolimab) are described in 
Section 6.7 and in the [CMBG453B1US01 Pharmacy Manual].
6.1.1
Additional study treatments 
No other treatment beyond investigational drugs are included in this trial.
6.1.2
Treatment arms/group 
Not applicable.
6.1.3
Guidelines for continuation of treatment 
The study treatment consists of HMA plus MBG453 (sabatolimab). Planned duration of a cycle 
is 28 days. Treatment will continue until a protocol-defined reason for discontinuation is met 
(Section 9).
Per protocol, dose modifications including interruptions for toxicities are permitted (Section 
6.5).
6.1.4
Treatment duration
The planned duration of treatment with MBG453 (sabatolimab) is up to 24 months. After the 
12 month core phase, patients will have the option to transition to an extra 12 months in the 
extension phase (based on investigator decision). For patients that will receive treatment in the 
extension phase, they are allowed to continue treatment with MBG453 and 
azacitidine/decitibine/INQOVI 
(oral 
decitibine), 
azacitidine/decitibine/INQOVI 
(oral 
decitibine) alone, or MBG453 alone.
In addition, all patients who discontinued any study treatments (unless due to progression) may 
enter the extension phase. In the extension phase, patients who discontinued any study treatment 
due to reasons other than progression, death, lost to follow-up, or withdrawal of consent (i.e. 
transplantation, adverse events, etc.) will have hematology assessments, Patient Reported 
Outcomes (PRO) and response assessments at defined timepoints until documented disease 
progression, death, lost to follow-up, withdrawal of consent, or end of the extension phase, 
whichever comes first (Table 8-1). Patients who progress on study (core phase (first 12 months) 
or extension phase (maximum addition of 12 months)) will enter the post treatment safety 
follow up period. 
Participants who become eligible for hematopoietic stem cell transplant (HSCT) at any time 
during the course of the study will be discontinued from investigational study treatment 


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(MBG453 (sabatolimab)). 
 
Post treatment follow up is for safety collection and is up to 150 days post core phase or 
extension phase discontinuation (see Figure 3-1). Survival data will be collected until end of 
study inclusive of the post treatment follow up duration.
At any time during the study, continuation of treatment beyond progression (excluding 
transformation to acute leukemia) may be possible in selected participants (Section 6.1.4.1).
Participants may continue azacitidine or decitabine or INQOVI (oral decitabine) alone or 
MBG453 (sabatolimab) alone if the investigator considers this is in the best interest for the 
participant. In this case, the participants should continue to conduct the assessments outlined 
for treatment phase in Table 8-1.
6.1.4.1
Treatment beyond disease progression
Participants with immunotherapy may get clinical benefit despite initial evidence of disease 
progression. Participants will be allowed to continue the study treatment, (HMA and/or 
MBG453 (sabatolimab)) beyond disease progression through the extension phase if all four of 
the following criteria are met:
1. Absence of acute leukemia per WHO 2016 classification (as defined as ≥20% of blasts 
in bone marrow and/or peripheral blood) (Arber et al 2016)  
2. There is a clinical benefit observed per investigator assessment. The clinical benefit at 
the time of disease progression should consist of :
•
Improved or stable ECOG performance status and no cell lineage (neutrophils count, 
platelets count, hemoglobin) have worsened by >25% as compared to baseline status
•
And, at least one of the two following criteria:
•
Improvement or stabilization of cytopenia in at least one cell lineage (neutrophils 
count, platelets count, hemoglobin) as compared to baseline values, or
•
Reduction of RBC/platelet transfusion needs within the 8 weeks prior to evidence 
of disease progression as compared to transfusion needs reported prior to 
enrollment
3. No unacceptable toxicity is reported
4. The participant continues to follow all protocol requirements
In addition, treatment beyond disease progression should not jeopardize critical interventions 
to treat/prevent severe complications or prevent participants from receiving adequate care.
If the study treatment continues, the participants should continue to perform all assessments for 
extension phase as per Table 8-1.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
In general, the use of any concomitant medication/therapy deemed necessary for the care of the 
participant (e.g., such as anti-emetics, anti-diarrheal) is permitted, except when specifically 


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prohibited (see Section 6.2.2). The participant must be told to notify the investigational site 
about any new medications he/she takes after the start of the study drug.
Participants should not receive pre-medication to prevent infusion reaction before the first 
infusion of MBG453 (sabatolimab). If a participant experiences an infusion reaction, he/she 
may receive pre- medication on subsequent dosing days. The pre-medication should be chosen 
per institutional standard of care, at the discretion of the treating physician. If a participant 
experiences a Grade 3 or Grade 4 infusion reaction, the investigational drug should be 
discontinued.
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 or Grade 4 
anaphylactic/anaphylactoid reaction, the investigational drug should be discontinued.
MBG453 (sabatolimab) should be administered in a facility equipped for cardiopulmonary 
resuscitation. Appropriate resuscitation equipment should be available and a physician should 
be readily available.
Participants should receive appropriate prophylaxis (e.g., antiemetics) for HMA as per local 
practice.
Relevant prior and all concomitant medication and non-drug therapies will be collected. Blood 
transfusions taken within 16 weeks before enrollment and during the course of the study should 
be recorded in the appropriate case report form (CRF). Transfusion should be collected every 2 
months during post-treatment follow-up.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
enrolling a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis medical monitor to determine if the participant should continue study 
treatment.
Supportive therapy including prophylactic antibiotic and antifungal treatments, transfusions, 
will be administered at the discretion of the investigators according to their local standard of 
care. Transient use of Granulocyte Colony Stimulating Factor (G-CSF) is allowed according to 
the local standard of care, e.g., in the context of infection or septicemia. Erythropoietin 
stimulating agents (ESA) and Thrombopoietic agents are prohibited during the study.
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms.
Regarding the SARS-CoV-2 vaccination:
•
There is no contraindication for the use of an inactivated, viral-vector-, or mRNA based 
SARS-CoV-2 vaccine in cancer patients on sabatolimab therapy. Recognizing that 
multiple vaccines may have various mechanisms of action with different associated 
potential risks, please reach out to Novartis to discuss specific recommendations related to 
the use of SARS-CoV-2 vaccines in sabatolimab clinical trials.


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•
For patients enrolled in Novartis clinical trials who receive a COVID-19 vaccine which is 
permitted* for use by a local Health Authority, we will capture the vaccine as a 
concomitant medication (in the respective CRF page), and IRB/EC approval and inclusion 
in Informed Consent are not required. [*Permitted includes full approval, conditional 
approval, emergency use authorization, provisional/temporary/interim authorization by 
Health Authority i.e., outside of a COVID-19 clinical trial to evaluate the 
effectiveness/safety of a COVID-19 vaccine.] Exceptions may apply if a Health Authority 
considers the vaccine to be "investigational". As of 08-Dec-2020, there are no known 
exceptions.
•
Although there will be no mandate to vaccinate clinical trial participants against SARS-
CoV-2 prior to entry into a trial, patients will be advised to have vaccination against 
SARS-CoV-2, if available and recommended according to local practice.
•
For the patients already in the study, the decision and timing of vaccination for SARS-
CoV-2 should be made on a case-by-case basis and at the discretion of the treating 
physician. In immunosuppressed patients, vaccination failure is a known risk. Vaccination 
against COVID-19, unless these are live vaccines, is allowed during the study but should 
not be administered on the same day of study treatment administration as recommended 
by the ASCO guidelines (Schneider et al 2021).
•
No data are yet available on the efficacy and safety of vaccines against SARS-CoV-2 in 
patients with cancer treated with sabatolimab, including the ideal timing of administration.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Anticoagulation therapy is permitted if the participants are already at stable dose of warfarin or 
stable doses of low molecular weight heparin (LMWH) for ￿ 2 weeks at time of first dose and 
International Normalized Ratio (INR) should be monitored as clinically indicated per 
investigator’s discretion. Participants who develop a new requirement for anticoagulant 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 MBG453 
(sabatolimab).
6.2.2
Prohibited medication
During the course of the study, participants must not receive additional investigational drugs or 
devices, chemotherapy, or any other therapies that may be active against cancer or modulate 
the immune response.
Additionally, no immunosuppressive medication may be administered while on study drug 
unless given for the management of immune toxicity.
The use of systemic steroid therapy 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 replacement-dose steroids in the setting of adrenal 


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insufficiency or transient exacerbation of other underlying diseases such as chronic obstructive 
pulmonary disease requiring treatment for ≤ 3 weeks. 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 study administration. If more than 
10 mg/day prednisone is used, study drug should be 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. 
Inactivated vaccines, subunits recombinant, polysaccharide and conjugate vaccines and toxoid 
vaccines are allowed.  Vaccination against COVID-19 is allowed during screening and during 
the treatment phase, unless theseare live vaccines, but should not be administered on the same 
day of study treatment administration to avoid potential overlapping adverse events. Prior 
exposure to cancer vaccines are allowed except if the vaccine was administered within 4 
months prior to enrollment. Administration of any inactivated vaccines and any covid-19 
vaccines will be documented in the CRFs.
Erythropoietin stimulating agents and Thrombopoietic agents are prohibited during the study. 
Of note, transient use of Granulocyte Colony Stimulating Factor (G-CSF) is allowed according 
to the local standard of care, e.g., in the context of infection or septicemia
In addition, prohibited medication related to INQOVI (oral decitabine), decitabine and 
azacitidine 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 unless the participant is re-screened. The Participant identifier consists of the Center 
Number (Center No.), (as assigned by Novartis to the investigative site) with a sequential 
Participant No. suffixed to it, so that each patient’s participation 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.
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 patient fails to be enrolled or start treatment for any reason, the reason will be entered into 
the appropriate eCRF page. 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 patients.
6.3.2
Treatment assignment, randomization
Not applicable.
6.4
Treatment blinding
Not applicable. 


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6.5
Dose Modification
Dose escalation is not applicable.
For participants who do not tolerate the protocol-specified dosing schedule, dose modifications 
consisting in dose interruptions are either recommended or mandated in order to allow 
participants to continue the study treatment.
Dose modifications for HMA will be done according to local practice and US package insert. 
Dose modifications for MBG453 (sabatolimab) will be done according to ASCO guidelines 
about management of immune-related AEs including hematological AEs (Brahmer et al 2018). 
Additionally, the guidance indicated in Table 6-3 below provides instructions for infusion 
reaction, immune-related adverse events not covered by ASCO guidelines and a general 
guideline for non-hematologic non-immune-related toxicities that are clinically significant per 
investigator judgement and possibly attributable to the investigational drug. This general 
guideline will not apply in case of non-hematologic non-immune-related toxicities that are 
attributable to HMA or MDS and its complications.
General guidelines are to follow local practice, US package insert, and ASCO guidelines for 
HMAs. Further guidance is provided below.
Deviations to mandatory dose interruptions, reductions and/or permanent discontinuations are 
not allowed.
•
Dose modifications for MBG453 (sabatolimab) (See Table 6-3 and refer to Brahmer et 
al 2018)
Administration of MBG453 (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 and the cycle will be shifted 
accordingly. Dose reductions for MBG453 (sabatolimab) are not allowed; however, longer 
intervals for administration (Q8W instead of Q4W) are permitted in some clinical situations, as 
described in Table 6-3.
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 section 6.5.1) within 12 weeks after initiation of immunosuppressive therapy, 
MBG453 (sabatolimab) must be permanently discontinued.
•
Dose modifications for HMA
If azacitidine or decitabine or INQOVI (oral decitabine) treatment is deemed by the investigator 
to possibly have contributed to an observed adverse event, the dose or schedule of 
hypomethylating agent treatment may be modified within a cycle and/or for subsequent cycles 
or temporary/permanent interruptions of HMA treatment may be decided by the investigator 
according to local practice and/or the US package insert guiding azacitidine or decitabine or 
INQOVI (oral decitabine) use.
•
Permanent discontinuation of MBG453 (sabatolimab) and HMA
If the study treatment is interrupted for toxicities and the start of the subsequent study treatment 
cycle is delayed for more than 56 consecutive days (i.e. 2 planned consecutive cycles of study 


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treatment for both, HMA and MBG453 (sabatolimab)) the participant should be discontinued 
from study treatment.
•
Permanent discontinuation of only one component MBG453 (sabatolimab) or HMA
If one component only of the study treatment (HMA OR MBG453 (sabatolimab)) is 
discontinued for toxicities, then the treatment may continue with the other component of study 
treatment alone (MBG453 (sabatolimab) or HMA alone) as long as the participant benefits per 
investigator's judgement.
All dose changes must be recorded on the appropriate CRF.
Criteria for re-initiation of study drug MBG453 (sabatolimab) for adverse drug reactions
Table 6-3
Criteria for re-initiation of study drug MBG453 (sabatolimab) for 
adverse drug reactions
Worst Toxicity CTCAE v5.0 Grade
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 adequate pre-medication, then discontinue 
treatment
Grade 3 or 4
Discontinue MBG453 (sabatolimab)
For toxicities thought to be immune-related and not covered in the ASCO Guidelines for the 
management of immune-related adverse events in participants treated with immune checkpoint 
inhibitor therapy 
Grade 1
No change. Continue MBG453 (sabatolimab) at 
the same dose (800 mg) and schedule (Q4W)
Grade 2 or Grade 3 ≤7 days
Delay MBG453 (sabatolimab) until toxicity resolved 
to≤ Grade 1 or baseline. Then resume at the same 
dose (800 mg) and schedule (Q4W)
Grade 3 lasting >7 days but <21 days
Delay MBG453 (sabatolimab) until toxicity resolved 
to
≤Grade 1 or baseline. Then resume at the same dose 
(800 mg) but with a longer treatment interval (Q8W). 
Return to the initial treatment interval (Q4W) may be 
possible but only after discussion and agreement with 
Novartis Medical Lead
Grade 3 lasting ≥21 days Or Grade 4
Discontinue MBG453 (sabatolimab)
General guideline for non-hematologic, non-immune-related toxicities that are clinically significant** and at 
least possibly attributable to the investigational drug.
This guideline does not apply for toxicities attributable to HMA (decitabine or INQOVI (oral decitabine) or 
azacitidine) or the underlying MDS including its complications.


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Grade 1
No change. Continue MBG453 (sabatolimab) at the 
same dose (800 mg) and schedule (Q4W)
Grade 2 or Grade 3 ≤7 days
Delay MBG453 (sabatolimab ) until toxicity resolved 
to
≤Grade 1 or baseline. Then resume at the same dose 
(800 mg) and schedule (Q4W)
Grade 3 >7 days
Delay MBG453 (sabatolimab) until toxicity resolved 
to
≤Grade 1 or baseline. Then resume at the same dose 
(800 mg) but with a longer treatment interval (Q8W). 
Return to the initial treatment interval (Q4W) may be 
possible but only after discussion and agreement with 
Novartis Medical Lead
Grade 4
Discontinue MBG453 (sabatolimab)
All dose modifications should be based on the available information and worst preceding toxicity.
* Infusion related reaction or allergic reaction/anaphylaxis. See section 6.2.1 for instructions 
regarding prophylaxis.
** Per investigator judgement.
6.5.1
Follow-up for toxicities
Patients 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.
In addition to the instructions provided in this section, please refer to Section 16.2 (Appendix 
2) for further guidance on liver events, laboratory trigger definitions and follow-up 
requirements. For guidance on renal alert criteria, actions and events follow up, please refer to 
Section 16.3 (Appendix 3).
All patients must be followed up for AEs for 30 days following the last dose of azacitidine or 
decitabine or INQOVI (oral decitabine), or 150 days following the last dose of MBG453 
(sabatolimab), whichever is later.
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 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 patients with signs or 
symptoms of irAEs should be monitored and managed following the ASCO Guidelines for the 


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management of immune-related adverse events in participants treated with immune checkpoint 
inhibitor therapy. 
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 assessments outlined in Table 8-1 must be performed.
Tumor lysis syndrome
Tumor lysis syndrome (TLS) is a clinical entity frequently observed in 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 (Coiffier et al 2008). TLS is not frequent in MDS and no cases of TLS 
has been reported in the ongoing CPDR001X2105 for MDS participants receiving MBG453 
(sabatolimab) in combination with decitabine.
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. To minimize risk 
of TLS, participants with elevated uric acid or high tumor burden should receive allopurinol, or 
an alternative prophylaxis, 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 (e.g., febuxostat), and 
increased oral/ IV 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 (IV 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 3 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


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•
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 IV fluids, treatment with rasburicase, and hospital 
monitoring.
•
Laboratory TLS should be managed with IV fluids, laboratory blood tests every 6 to 8 
hours and inpatient 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 IV fluids, laboratory blood tests 
every 6 to 8 hours, cardiac monitoring, and treatment with 
rasburicase/allopurinol/febuxostat and inpatient care (consider intensive care unit 
(ICU)).
Patients 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 discussion between the sponsor and the investigator.
6.5.1.1
Follow up on potential drug-induced liver injury (DILI) cases
Guidelines for follow-up on potential DILI cases are described in Table 6-4 and Table 6-5.
Table 6-4
Follow-up of abnormal liver chemistry results
ALT
TBL
Liver Symptoms
Action
ALT increase without bilirubin increase:
If normal at 
baseline: ALT >3 x 
If elevated at baseline: 
ALT >2 x baseline or 
>200 U/L (whichever 
occurs first)
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 and CK in 
48- 72 hours (GLDH is 
recommended as well)
- Follow-up for symptoms
If normal at baseline: 
ALT >5 x ULN for 
more than two weeks
Normal
For participants with 
None
- Interrupt investigational drug


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If elevated at baseline: 
ALT >3 x baseline or 
>300 U/L (whichever 
occurs first) for more 
than two weeks
Gilbert’s syndrome: No 
change in baseline 
TBL
If normal at 
baseline: ALT >8 x 
Normal
None
ALT increase with bilirubin increase:
If normal at 
baseline: ALT >3 x 
If elevated at baseline: 
ALT >2 x baseline or 
>200 U/L (whichever 
occurs first)
TBL >2 x ULN (or INR 
>1.5)
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin
None
If normal at baseline: 
ALT >3 x ULN
If elevated at baseline: 
ALT >2 x baseline or 
>200 U/L (whichever 
occurs first)
Normal or elevated
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain
- Measure ALT, AST, ALP, 
GGT,
TBL, INR, albumin and CK in 
48- 72 hours (GLDH is 
recommended as well).
- Follow-up for symptoms.
- Initiate close monitoring and 
workup for competing 
etiologies.
- Investigational drug can be 
restarted only if another 
etiology is identified and liver 
enzymes return to baseline.
Table 6-5
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 Liver Function Tests 
(LFTs) within 48-72 hours, then monitor LFTs weekly 
until resolution to ≤ Grade 1 or to baseline
Grade 3 (>3.0 – 10 ULN)
Interrupt treatment. Repeat LFTs within 48-72 hours, 
then monitor LFTs weekly until resolution to <Grade 
1 or to baseline 
Grade 4 (> 10 x ULN)
Discontinue study treatment
If abnormalities are confirmed, close observation and follow-up are required:
1. A detailed history, including relevant information, such as cardiac disease, history of any 
pre-existing liver conditions or risk factors, blood transfusions, IV drug abuse, travel, 
work, alcohol intake, and full clinical examination for evidence of acute or chronic liver 
disease, cardiac disease and infection etc. should be performed.
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.




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6.7
Preparation and dispensation
MBG453 (sabatolimab)
MBG453 (sabatolimab) (800 mg) will be administered IV. Further instructions for the 
preparation and dispensation of MBG453 (sabatolimab) are described in the Pharmacy Manual.
All dosages for MBG453 (sabatolimab) prescribed to the participant and all dose changes 
during the study must be recorded on the Dosage Administration Record eCRF.
Decitabine (IV and INQOVI (oral decitabine))
For details on preparation refer to the US package insert instructions and/or IV decitabine or 
INQOVI (oral decitabine) package insert, if the drug is commercially available. All dosages for 
decitabine or INQOVI (oral decitabine) prescribed to the participant and all dose changes during 
the study must be recorded on the Dosage Administration Record eCRF.
Azacitidine
For details on preparation refer to the US package insert instructions and/or azacitidine package 
insert, if the drug is commercially available. All dosages for azacitidine prescribed to the 
participant and all dose changes during the study must be recorded on the Dosage 
Administration Record eCRF.
Public Health emergency
As per section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of IMP directly to a participant’s home may be permitted (if allowed by Local or 
Regional Health Authorities and Ethics Committees as appropriate) in the event the Investigator 
has decided that an on-site visit by the participant is no longer appropriate or possible, and that 
it is in the interest of the participant’s health to administer the study treatment even without 
performing an on-site visit. The dispatch of IMP from the site to the participant’s home remains 
under the accountability of the Investigator. Each shipment/provisioning will be for a maximum 
of X-months supply. In this case, regular phone calls or virtual contacts (every Y weeks or more 
frequently if needed) will occur between the site and the participant for instructional purposes, 
safety monitoring, drug accountability, investigation of any adverse events, ensuring 
participants continue to benefit from treatment and discussion of the participant´s health status 
until the participants can resume visits at the study site.
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 treatments must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 


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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.
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 field monitor or to the Novartis address provided in the investigator 
folder at each site.
6.7.1.2
Handling of additional treatment
Not applicable
6.7.2
Instruction for prescribing and taking study treatment
Refer to Section 6.1.
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board (IRB) / Institutional Ethics 
Committee (IEC) approved informed consent.
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her 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.
The date when a participant’s Informed Consent was actually obtained will be captured in their 
CRFs.
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 






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Table 8-1
Assessment Schedule
Period
Scr
Core
EOT7
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7 
(28d)
Cycle 8 (and beyond until 
Cycle 13) (28d) 7
Visit Name
Scr
eeni
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 (17, 
19, 21 
16 (18, 20, 22 
+)
EOT7
Days
-28 
to -1
D1
D81
D1
D8
1
D1
D8
1
D1
D81
D1
D8
1
D1
D81
D1
D8
1
D1
 D81
-
Informed consent
X
Demography
X
Inclusion / Exclusion 
criteria
X
Medical 
history/current 
medical conditions
X
Disease History
X
Prior antineoplastic 
therapies
X
Prior medications, 
surgery and medical 
procedures (including 
blood transfusions 
requirement)
X
Physical 
Examination
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Height
X


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Clinical Trial Protocol (Version No. 02)                                               
                        Protocol No. CMBG453B1US01
Period
Scr
Core
EOT7
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7 
(28d)
Cycle 8 (and beyond until 
Cycle 13) (28d) 7
Visit Name
Scr
eeni
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 (17, 19, 21 
+)
16 (18, 
20, 22 
EOT7
Days
-28 
to -1
D1
D81
D1
D8
1
D1
D8
1
D1
D81
D1
D8
1
D1
D81
D1
D8
1
D1
D81
-
BSA (use height from 
screening)
X
X
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
12-Lead ECG 
(triplicates)
S
If clinically indicated
S
Hematology
X2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X2
X
X
X
X
X
X
X
On cycle 9, 11, and 
13
X
Coagulation
X
X
X
X
X
X
X
X
On cycle 9, 11, and 
13
X
Thyroid function
X
X
X
On cycle 8
and 11
X


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Clinical Trial Protocol (Version No. 02)                                               
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Period
Scree
Core
EOT7
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7 
(28d)
Cycle 8 (and beyond until 
Cycle 13) (28d) 7
Visit Name
Scree
ning
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 (17, 
19, 21 
16 (18, 20, 22 
+)
EOT7
Days
-28 to 
-1
D1
D81
D1
D8
1
D1
D8
1
D1
D81
D1
D81
D1
D81
D1
D8
1
D1
D81
-
Virology hepatitis B 
and C
S
If clinically indicated
HIV serology (only 
if required per local 
regulation)
S
Serum Pregnancy 
Test (only women 
with child-bearing 
potential)
S
S
S
Urine Pregnancy 
Test OR Serum 
Pregnancy Test (only 
women with child-
bearing potential)
S
S
S
S
S
S
S
Urinalysis 
dipstick and 
sediment
S
If clinically indicated
Efficacy - Bone 
marrow aspirate 
and/or biopsy5
X3
X
X
On cycle 10 
and 13
       X


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Period Screening
Core
EOT7
Cycle
Cycle 1 
(28d)
Cycle 
2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7 
(28d)
Cycle 8 (and beyond until 
Cycle 13) (28d)7
Visit Name Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 (17, 
19, 21 
16 (18, 20, 22 
+)
EOT7
Days
-28 to -1
D1
D81
D
1
D8
1
D1
D8
1
D1
D81
D1
D81
D1
D81
D1
D8
1
D1
D81
-
Efficacy - 
Peripheral blood 
collection5
X
X
X
On cycle 10, 
13 and if 
clinically 
indicated
       X
Cytogenetics
X
Response 
assessment
X
On cycle 13
and if 
clinically 
indicated
X


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Period Screening
Core
EOT7
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7 
(28d)
Cycle 8 (and beyond until 
Cycle 13) (28d) 7
Visit Name Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 (17, 
19, 21 +)
16 (18, 20, 22 +)
EOT7
Days
-28 to -1
D1
D81
D1
D8
1
D1
D8
1
D1
D81
D1
D81
D1
D81
D1
D8
1
D1
D81
-


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Clinical Trial Protocol (Version No. 02)                                               
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Period Screening
Core
EOT7
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7 
(28d)
Cycle 8 (and beyond until 
Cycle 13) (28d) 7
Visit Name Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 (17, 
19, 21 +)
16 (18, 20, 22 
+)
EOT7
Days
-28 to -1
D1
D81
D1
D8
1
D1
D8
1
D1
D81
D1
D8
1
D1
D81
D1
D8
1
D1
D81
-
Azacitidine 
infusion or 
SC
If chosen: on Days 1- 7 of each cycle OR on Days 1-5 and then on Day 8 and Day 9: IV or SC 75mg/m2
Decitabine 
infusion
If chosen: on Days 1-5 of each cycle
Oral decitabine/ 
cedazuridine
If chosen: on Days 1-5 of each cycle
Infusion 
MBG453 
(sabatolimab) 
X1
X1
X1
X1
X1
X1
X1
X1
Adverse Events
X
Continuous


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Period Screening
Core
EOT7
Cycle
Cycle 1 
(28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7 
(28d)
Cycle 8 (and beyond until 
Cycle 13) (28d) 7
Visit Name Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 (17, 
19, 21 +)
16 (18, 20, 22 
+)
EOT7
Days
-28 to -1
D1
D81
D1
D8
1
D1
D8
1
D1
D81
D1
D81
D1
D81
D1
D8
1
D1
D81
-
Concomitant 
medications and 
medical 
procedures 
(including blood 
transfusions 
requirement)
X
Continuous
Antineoplastic 
therapies, HSCT 
and transfusions 
X
Disposition
X
X
Survival Follow 
up


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Period
Extension
Cycle
Cycle 
1 (28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7 
(28d)
Cycle 8 
(28d)
Cycle 9 
(28d)
Cycle 
10 (28d)
Cycle 
11 (28d)
Cycle 
12 (28d)
Cycle 13 
(28d)
Visit Name
Ext 1
Ext 2
Ext 3
Ext 4
Ext 5
Ext 6
Ext 7
Ext 8
Ext 9
Ext 10
Ext 11
Ext 12
Ext 13
Hematology
X
If clinically 
indicated
X
If clinically 
indicated
X
If clinically 
indicated
X
If clinically 
indicated
X
Chemistry
If clinically indicated
Coagulation
If clinically indicated
Thyroid function
If clinically indicated
Virology hepatitis B 
and C
If clinically indicated
HIV serology (only if 
required per local 
regulation)
If clinically indicated
Urine Pregnancy Test 
OR Serum Pregnancy 
Test (only women with 
child-bearing 
potential)
S
S
S
S
S
S
S
S
S
S
S
S
S
Urinalysis dipstick and 
sediment
If clinically indicated


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          Protocol No. CMBG453B1US01
Period
Extension
Cycle
Cycle 
1 (28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7 
(28d)
Cycle 8 
(28d)
Cycle 9 
(28d)
Cycle 
10 (28d)
Cycle 
11 (28d)
Cycle 
12 
(28d)
Cycle 13 
(28d)
Visit Name
Ext 1
Ext 2
Ext 3
Ext 4
Ext 5
Ext 6
Ext 7
Ext 8
Ext 9
Ext 10
Ext 11
Ext 12
Ext 13
Efficacy - Bone marrow 
aspirate and/or biopsy5
X
If clinically indicated
X
If clinically indicated
X
Efficacy - Peripheral 
blood collection5
X
If clinically indicated
X
If clinically indicated
X
Response assessment
If clinically indicated  (for example if progression or relapse is suspected)
Azacitidine infusion or 
SC
If chosen and continuing treatment: on Days 1- 7 of each cycle OR on Days 1-5 and then on Day 8 and Day 9: IV or SC 75mg/m2


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Clinical Trial Protocol (Version No. 02)                                               
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Period
Extension
Cycle
Cycle 
1 (28d)
Cycle 2 
(28d)
Cycle 3 
(28d)
Cycle 4 
(28d)
Cycle 5 
(28d)
Cycle 6 
(28d)
Cycle 7 
(28d)
Cycle 8 
(28d)
Cycle 9 
(28d)
Cycle 
10 (28d)
Cycle 
11 (28d)
Cycle 
12 
(28d)
Cycle 13 
(28d)
Visit Name
Ext 1
Ext 2
Ext 3
Ext 4
Ext 5
Ext 6
Ext 7
Ext 8
Ext 9
Ext 10
Ext 11
Ext 12
Ext 13
Decitabine infusion
If chosen and continuing treatment: on Days 1-5 of each cycle
Oral 
decitabine/cedazuridine
If chosen and continuing treatment: on Days 1-5 of each cycle
Infusion Drug 
Dispensation MBG453 
(sabatolimab)8
If continuing treatment : on D8 of every cycle
Adverse Events8
Continuous
Concomitant  
medications and 
medical procedures 
(including blood 
transfusions 
requirement)
Continuous
Antineoplastic 
therapies, HSCT and 
transfusions since 
discontinuation of 
study treatment8
Disposition
X
Survival Follow up
X
X
X


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Clinical Trial Protocol (Version No. 02)                                               
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Period
Post-treatment Safety FU
Cycle
Visit Name
D30
D150 and beyond
Days
-
-
Serum Pregnancy Test (only women with child-bearing potential)
S (D150 only)
Urine Pregnancy Test OR Serum Pregnancy Test (only women with 
child-bearing potential)
S (D30, D60, D90, D120 after the last dose of MBG453 (sabatolimab))
Adverse Events9
Continuous until D30 or D150
Concomitant medications and medical procedures (including blood 
transfusions requirement)
Continuous
Antineoplastic therapies, HSCT and transfusions since 
discontinuation of study treatment
Continuous
Survival Follow up
Every 6 cycles




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8.1
Screening
Screening
All participants must provide signed ICFs prior to performing any study specific procedures. 
Participants will be evaluated against all study inclusion and exclusion criteria.
After signing the study ICFs, screening assessments should be completed within 28 days prior 
to enrollment (Table 8-1). A patient who has a laboratory tests result(s) that does not satisfy the 
entrance criteria may have the test(s) repeated. These test(s) may be repeated as soon as the 
investigator believes the re- test result(s) is/are likely to be within the acceptable range to satisfy 
the entrance criteria, but may be completed within approximately 3 weeks of the original 
screening visit date. In this case, the Participant will not be required to sign another ICF, and 
the original participant ID number assigned by the investigator will be used. In the event that 
the laboratory test(s) cannot be performed within 3 weeks of the original screening visit, or the 
re-test(s) do not meet the entrance criteria, or other eligibility criteria have changed and are not 
met anymore, the patient is considered a screen failure, and must be discontinued from the study.
A new ICF will need to be signed if the investigator chooses to re-screen the patient after a 
patient has screen failed, and the Participant ID number will change. All required screening 
activities must be performed when the patient is re-screened for participation in the study. An 
individual patient may only be re-screened once for the study. Once the number of patients 
screened and enrolled is likely to ensure target enrollment, the Sponsor may close the study to 
further screening. In this case, the patients who screen failed will not be permitted to re-screen. 
Bone marrow and peripheral blood pathology specimens (i.e. bone marrow slides, bone marrow 
biopsy block if applicable, peripheral blood samples) 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.
8.1.1
Eligibility screening
Participant eligibility will be checked once all screening procedures are completed.
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 enrollment will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. 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 SAE 
section for reporting details, Section 10.1.3). 
8.2
Participant demographics/other baseline characteristics
Demographics and other baseline characteristics data to be collected on all participants include:




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•
Blood should be collected for phenotypic and molecular assessments
Subject race and ethnicity are collected and analyzed to identify variations in safety or efficacy 
due to these factors as well as to assess the diversity of the study population as required by 
Health Authorities.
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 subject’s eCRF.
8.3
Efficacy
Efficacy assessments will be performed according to the IWG and WHO criteria for MDS 
(Cheson et al 2000, Cheson et al 2006, Arber et al 2016, Platzbecker et al 2018). Response 
criteria in MDS are described in Table 8-2. Investigators will assess locally at their site and 
document response/progression at each time point as per the visit schedule. For efficacy 
analyses, baseline is defined as the last non-missing assessment on or before the date of 
enrollment.
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 criteria in MDS
 (Platzbecker et al 2018, 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


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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**


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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 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 Hematological Improvement per IWG-MDS criteria in MDS (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 
9


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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 MDS (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 any 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 aspirate or biopsy and peripheral blood will be collected per Table 8-1 for 
assessment of disease. The bone marrow and peripheral blood pathology specimens (i.e. bone 
marrow aspirate slides, bone marrow biopsy block if applicable, peripheral blood samples) 
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 
subject 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. All enrolled participants has to be followed for efficacy, 
regardless whether treatment received or not. Bone marrow assessments will be performed at 
screening and pre-dose during treatment period at C4D1, C7D1, C10D1, C13D1, and EOT and 
hematology assessments will be performed at screening, D1 and D8 of each cycle until end of 
treatment and if clinically indicated at any time during the study. Screening bone marrow 
aspirates or biopsies (BMA/BMB) must be collected within 28 days of informed consent. If a 
participant's screening BMA/BMB was collected >28 days before informed consent, then the 
participant must agree to have a repeat BMA/BMB performed. Clinical suspicion of relapse or 
disease progression at any time after enrollment will require a disease evaluation promptly, 


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rather than waiting for the next scheduled assessment. In case of an unscheduled or delayed 
disease evaluation for any reason, subsequent assessments should be performed according to 
the original planned schedule.
More frequent efficacy assessments may be performed at the investigator’s discretion, if 
medically indicated, and recorded as an unscheduled visit in the eCRFs.
Extension phase
Patients completing core phase of 12 months and requiring continuation of study treatment (by 
investigator decision) beyond 12 months  will enter the extension phase. For patients that will 
receive treatment in the extension phase, they are allowed to continue treatment with MBG453 
and azacitidine/decitibine/INQOVI (oral decitibine), azacitidine/decitibine/INQOVI (oral 
decitibine) alone, or MBG453 alone.
Additionally, for participants who discontinue any study treatment for reasons other than 
documented disease progression, death, lost to follow-up, or withdrawal of consent, will enter 
extension phase. 
Efficacy assessments (hematology and bone marrow aspirate/biopsy) should follow Table 8-1. 
Response assessments must continue to be performed every 3 cycles as per hematology 
assessment and at least every 6 cycles as per bone marrow assessment or as clinically indicated 
until documented disease progression/relapse (per IWG criteria Table 8-2), death, lost to 
follow-up, or withdrawal of consent.
8.3.1
Appropriateness of efficacy assessments 
Not applicable.
8.4
Safety
Safety assessments are specified below Table 8-3 with the assessment schedule detailing when 
each assessment is to be performed.
For safety evaluations, baseline is defined as assessments done on C1D1 prior to the first dose 
of study treatment. For assessment which are not done at C1D1 as per Table 8-1, baseline is 
defined as the last available assessment prior to C1D1.
The investigator will report any vital signs considered clinically significant in the eCRF. For 
details on AE collection and reporting, refer to AE Section 10.1.1.
As per section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur (every Y weeks or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again.
If participants cannot visit the site to have serum pregnancy tests, urine pregnancy test kits may 
be used. Relevant participants can perform the urine pregnancy test at home and report the result 
to the site. It is important that participants are instructed to perform the urine pregnancy test 
first and only if the test result is negative proceed with the administration of the study treatment. 


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A communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g. following Country specific measures).
If participants cannot visit the site for protocol specified safety lab assessments, an alternative 
lab (local) collection site may be used.
Table 8-3
Assessments & Specifications
Assessment
Specification
Physical examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular and neurological.
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 will be measured at screening.
Body weight (in indoor clothing, but without shoes) will be measured and BSA 
will be calculated as specified in Table 8-1.
Performance status:
ECOG Performance status scale will be used as described in Table 8-4 and collected as specified 
in Table 8-1. 
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.


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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 hematology.
Laboratory values obtained during the Screening phase will be used to assess participant’s 
eligibility.
Novartis must be provided with a copy of the certification and a tabulation of the normal ranges 
and units for all local laboratories used to in the trial.
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
There are no specific notable range criteria for this study; however, the local laboratory will 
flag laboratory values falling outside of the normal range, on the local report (as applicable) 
(which the investigator should sign off) as per local practice, and the investigator will report any 
values considered clinically significant in the eCRF.
Table 8-5
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood 
cells, White blood cells, RBC Morphology, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands), Blasts, 
Other (absolute value preferred, %s are acceptable)
Chemistry
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl- 
transferase (GGT), Lactate dehydrogenase (LDH),Calcium, 
Magnesium, Phosphorus, Sodium, Potassium, Creatinine, Creatine 
kinase, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Total 
Cholesterol, Total Protein, Blood Urea Nitrogen (BUN) or Urea, Uric 
Acid, Amylase, Lipase, Glucose (fasting), Troponin T
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)
Cytokines***
IFN-γ, IL-6, IL-1, TNF-α
Urinalysis dipstick and sediment*
Dipstick examination includes specific gravity, pH, glucose, 
protein, blood, bilirubin, ketones and WBC as clinically indicated
Pregnancy Test*
Serum / Urine pregnancy test (refer to 'Pregnancy and 
assessments of fertility' section)




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8.4.3
Pregnancy and assessments of fertility
Female patients
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 72 hours before 
the first dose of study treatment.
During the study, a urine/serum pregnancy test should be done locally at Day 1 of each cycle 
(except if for Cycle 1 a pregnancy test was performed within 72 hours of the first dose) and at 
EOT visit. Additionally, during the post treatment safety follow up, women of child bearing 
potential will be tested monthly with urine or serum pregnancy tests up to Day 90 after the last 
dose of azacitidine or decitabine or INQOVI (oral decitabine). They will also be tested monthly 
with urine or serum pregnancy tests up to Day 150 after the last dose of MBG453 (sabatolimab), 
and a serum pregnancy test should be performed on Day 150 after the last dose of MBG453 
(sabatolimab). If the participant is not coming to the clinic during the safety follow-up period, 
the test can be performed at home or at a local doctor’s office, and the results will be 
communicated to the site staff.
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.
Women of childbearing potential should employ the use of highly effective contraception 
during study treatment, for 3 months after the last dose of azacitidine or decitabine or INQOVI 
(oral decitabine) (or as per their respective local labels, whichever is longer) and 150 days after 
the last dose of MBG453 (sabatolimab). Highly effective contraception methods are defined in 
Section 5.2.
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.
Male Patients
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 or decitabine or INQOVI (oral decitabine) and for 3 months after stopping these 
drugs. In addition, male participants should not donate sperm for the time period specified above.


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Prior to starting treatment, male participants are advised to seek consultation on sperm storage 
and female participants of child-bearing potential should seek consultation regarding oocyte 
cryopreservation.
8.4.4
Additional safety monitoring and considerations
Due to the known risk of TLS with azacitidine treatment, during this study, subjects should be 
closely monitored (including relevant laboratory tests) for signs and symptoms of TLS. High 
risk patients may need additional measures like i.v. hydration and hospitalization; events should 
be managed per local guidelines. Refer to Section 6.5.1 for guidance on minimizing the risk 
of TLS and procedures to be followed before initiation of a treatment cycle and during the 
treatment cycle. 
8.4.5
Graft versus Host Disease
For transplanted patients during post-treatment follow up, 
 
 
8.4.6
Appropriateness of Safety Measurements
The safety assessments selected are standard for this indication/participant population.


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9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Discontinuation of study treatment 
Study treatment is consider discontinued if stopped earlier than the protocol planned duration. 
Either the participant or the investigator can initiate study treatment discontinuation.
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Study treatment must be discontinued under the following circumstances:
•
Participant/guardian decision
•
Pregnancy


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•
Use of prohibited treatment as per recommendations in the prohibited treatment (see 
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 judgement of the
•
investigator, taking into consideration the participant’s overall status, prevents the 
participant from continuing participation in the study
•
Protocol-defined reasons for discontinuation (see Section 6.1.4)
•
Progression of disease (including transformation to acute leukemia per WHO 2016 
classification, as defined as ≥20% blasts in bone marrow and/or peripheral blood), unless 
specific criteria to continue study treatment, in case there is no acute leukemia reported, as 
per Section 6.1.4.1, are met
•
Termination of the study by Novartis
•
Participants who are scheduled for hematopoietic stem-cell transplant (HSCT) or 
chemotherapy at any time during the course of the study
•
Transition to commercial supplies
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 Section 9.1.2). Where possible, they should return for the assessments 
indicated in the Assessment Schedule. If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the 
participant/pre-designated contact as specified in the lost to follow-up section (Section 9.1.3). 
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.
For participants who discontinue treatment for reasons other than pregnancy, death, lost to 
follow-up, or withdrawal of consent, efficacy assessments must continue to be performed every 
2 months as per hematology assessment and at least every 6 months as per bone marrow 
assessment or as clinically indicated until the end of the study, death, lost to follow-up, or 
withdrawal of consent.
In some circumstances participants may be allowed to continue to receive study treatment 
beyond disease progression as per criteria described at Section 6.1.4.1. These participants will 
continue assessments as outlined in the assessments section (Section 8), and will complete the 
EOT visit only after permanent discontinuation of study treatment.
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:


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•
Does not want to participate in the study anymore, and
•
Does not allow further collection of personal data
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.
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 withdrawal. A final 
evaluation at the time of the participant’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a participant’s samples until the time of withdrawal) according to applicable 
law.
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.
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 
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 (provide instruction for contacting the 
participant, when the participant should stop taking drug, when the participant should come for 
a final visit) and 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.
9.1.5
Extension phase
Patients completing core phase of 12 months and requiring continuation of study treatment (by 
investigator decision) beyond 1 year will enter the extension phase. For patients that will receive 
treatment in the extension phase, they are allowed to continue treatment with MBG453 and 


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azacitidine/decitibine/INQOVI 
(oral 
decitibine), 
azacitidine/decitibine/INQOVI 
(oral 
decitibine) alone, or MBG453 alone.
Additionally, for participants who discontinue any study treatment for reasons other than 
documented disease progression, death, lost to follow-up, or withdrawal of consent, will enter 
the extension phase. 
Efficacy assessments (hematology and bone marrow aspirate/biopsy) should follow Table 8-1. 
Response assessments must continue to be performed every 3 cycles as per hematology 
assessment and at least every 6 cycles as per bone marrow assessment or as clinically indicated 
until documented disease progression/relapse (per IWG criteria Table 8-2), death, lost to 
follow-up, or withdrawal of consent.
Drug will be supplied as per section 6.1.4 Also patients who will receive HSCT will be included 
in the extension phase. Patients will be followed up for efficacy and safety as per Table 8-1 up 
to 24 months post last patient first treatment. Once they complete the extension phase or end 
treatment due to progression or any reason excluding HSCT, death, lost to follow up, or 
withdrawal of consent, patients will enter the post-treatment safety follow up. Participants on 
the extension period can be contacted by telephone every 6 cycles (24 weeks) to follow-up on 
their survival status.
9.1.6
Post treatment safety follow up period
Post treatment safety follow up period is for 150 days for safety and until end of study for 
survival follow up.
All patients on the study should enter the post treatment safety follow up period. Patients can 
enter the post treatment safety follow up period any time during the study based on 
discontinuation or completion of prior core phase or extension phase. Reasons for entering the 
post treatment safety follow up period can be completing the extension phase or ending 
treatment due to progression. Any new antineoplastic therapies and transfusions that have been 
started since the previous contact will be collected. HSCT information will also be collected 
during these phone calls and 
 will be collected as part of the safety follow up. 
Participants on the post treatment safety follow up period can be contacted by telephone every 
6 cycles (24 weeks) to follow-up on their survival status.
9.2
Study completion and post-study treatment
Study completion (Core) will occur when the last patient completes the 12 month core phase 
and safety follow-up or discontinues early.
The end of the study (Last Patient Last Visit) is defined as once all patients discontinued study 
treatment and were transitioned to treatment outside the study and have completed the study 
which is targeted at the latest 29 months after the last patient was enrolled. The Last Patient 
Last Visit will include all the required safety follow-up visits.
At the end of the study, every effort will be made, in alignment with local regulations, to 
continue provision of MBG453 (sabatolimab) outside this study through an alternative setting to 
participants who are receiving treatment with MBG453 (sabatolimab) and in the opinion of the 
investigator are still deriving clinical benefit. Options for continued treatment with MBG453 


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(sabatolimab) may include access to commercially available drug, or managed access program, 
or a roll-over study
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 adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are reported by 
the participant during, between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The adverse events will be assessed and graded according to 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


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•
Dose Reduced/increased
•
Drug interrupted/withdrawn
6. 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.
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.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
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 a separate 
adverse event.
Adverse event monitoring should be continued for at least:
•
30 days following the last dose of azacitidine or decitabine or INQOVI (oral decitabine), 
or 150 days following the last dose of MBG453 (sabatolimab), whichever is later (After 
the safety follow-up on site visit on Day 30, participants will be followed via telephone 
call for the Day 90 and Day 150 (or onsite visit if patient happens to be visiting the site).
 OR
•
Until the start of a new post treatment antineoplastic medication if sooner than the 150 
days mentioned above. If a patient 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 MBG453 (sabatolimab).
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 inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
•
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
•
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent
•
social reasons and respite care in the absence of any deterioration in the participant’s 
general condition
•
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission
•
is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgement 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 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.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent to 30 days after the date of the last actual administration of HMA 


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or 150 days after the last dose of MBG453 (sabatolimab), whichever is later and it must be 
reported to Novartis safety within 24 hours of learning of its occurrence. Any SAEs experienced 
after the 150 day safety follow-up period should only be reported to Novartis safety database if 
the investigator suspects a causal relationship to study treatment.
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
The following SAE reporting timeframes apply:
1. Screen Failures (e.g. a participant who is screened but is not treated or enrolled) 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 the time the participant signs ICF to 30 days 
after the date of the last actual administration of HMA or 150 days after the last dose of 
MBG453 (sabatolimab), whichever is later or stopped study treatment
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. 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.
Disease progression (including fatal outcomes) has to be documented as an efficacy assessment 
and should not be reported as a serious adverse event, except if the investigator considers that 
the disease progression is related to study treatment.
If the SAE is not previously documented in the Investigator’s Brochure or US Package Insert 
(new occurrence) and is thought to be related to the study treatment, a Novartis Chief Medical 
Office & Patient Safety (CMO & PS) Department associate may urgently require further 
information from the investigator for health authority reporting. Novartis may need to issue an 
Investigator Notification (IN) to inform all investigators involved in any study with the same 
study treatment that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
10.1.4
Pregnancy reporting
If a female subject becomes pregnant, the study treatment should be stopped, and subject 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 in a female study participant 
after signing the informed consent must be reported to Novartis within 24 hours of learning of 
its occurrence. The pregnancy should be followed up to 12 months after the estimated date of 
delivery to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 


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form and should include an assessment of the possible relationship of the pregnancy outcome 
and the study treatment. Any SAE experienced during pregnancy must be reported.
Pregnancy data will not be collected for the female partners of any male participants 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 (European Medicines Agency (EMA) definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse 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
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1.1 and Section 10.1.2). 
10.2
Additional Safety Monitoring
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure (IB). Additional safety information collected between IB updates will be 
communicated in the form of Investigator Notifications. This information will be included in 
the patient informed consent and must be discussed with the patient during the study as needed.
10.2.1
Steering Committee
The Steering Committee (SC) will be established comprising of investigators participating in 
the trial and an MDS patient not on the trial.
The Study Steering Committee will ensure transparent management of the study according to 
the protocol through recommending and approving modifications as circumstances require. The 
Study Steering Committee will review protocol amendments as appropriate. Together with the 
clinical trial team, the Study Steering Committee will also develop recommendations for 
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
Yes
Yes
Yes, even if not 
associated with a SAE


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publications of study results including authorship rules. The details of the role of the steering 
committee will be defined in the steering committee charter. 
Other members may be added after consultation with SSC members. 
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 electronic data capture (EDC) system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs, allow modification 
and/or verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel or designated CRO will review the data entered by investigational staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
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 lock can only be 
made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative or designated CRO 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 


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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.
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant’s file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed.
12
Data analysis and statistical methods
Data from all participating centers will be combined. Data from all centers participating in this 
study will be aggregated for analyses. A contract Research organization will conduct all 
analyses and will report data from all centers.
The primary analysis of the primary endpoint will be performed after all patients have 
completed 12 months follow-up from the first dose of study medication or discontinued earlier. 
A final Clinical Study Report (CSR) will be produced once all patients complete the study.
All AEs, SAEs and other safety parameters will be summarized. No inferential tests for safety 
analyses will be performed. All primary, secondary 
 variables will be 
summarized descriptively. Categorical data will be presented in frequencies and percentages. 
For continuous data descriptive statistics (mean, standard deviation, median 25th and 75th 
percentiles, min and max) will be provided. As appropriate, 95% confidence intervals will also 
be reported. Kaplan Meier’s estimates will be reported for the time to event variables.
Detail analysis methods will be available in the Statistical Analysis Plan (SAP).
12.1
Analysis sets
The analysis sets to be used are defined as below. The FAS will be used as the primary efficacy 
analysis set. The Safety Set will be used for all the safety analysis. 
The screened patients comprises all patients who have signed informed consent/assent and 
screened in the study. The enrolled comprises all patients who are enrolled in the study. 
Enrollment is defined as the point at which the patient meets all inclusion/exclusion criteria.




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12.4
Analysis of the primary endpoint
12.4.1
Definition of primary endpoint
Primary objective is to assess the safety profile of MBG453 (sabatolimab) 800 mg (every 4 
weeks) given in combination with HMAs (IV/SC/ Oral) by 12 months. For all primary safety 
analyses, the Safety Set will be used, unless stated otherwise. Additionally, safety profile will 
be assessed beyond the primary time point until the end of the study.
The variables for the primary analysis are incidence and severity of AEs and SAEs, and changes 
in laboratory values and vital signs.
12.4.2
Statistical model, hypothesis, and method of analysis
No formal hypothesis testing is planned for this study. Analyses of the primary endpoints are 
described in Section 12.5.2. 
12.4.3
Handling of missing values/censoring/discontinuations
Missing data for measures of safety will not be imputed.
12.4.4
Supportive analyses 
Subgroup analyses will be performed on the -primary and secondary endpoints of CR and PFS.
The following subgroup analyses may be performed considering patient’s baseline status:
•
IPSS-R (Intermediate, High & V. High) 
•
HMA (Oral, IV, SC) 
Data will be only summarized within each subgroup.
Additionally, as the study will be ongoing during COVID 19 pandemic, in order to address the 
impact of COVID-19 (if any) the following will be explored:
•
Discontinuation
•
Protocol deviation
•
Disease status
•
Dose interruption/missing data
•
AEs and labs
As appropriate, a sensitivity analysis may be performed on the primary safety evaluating the 
impact of COVID-19 on the study.
12.5
Analysis of secondary endpoints
12.5.1
Secondary objectives
For all secondary efficacy analyses, the Full Analysis Set (FAS) will be used for all patients 
by 12 months, unless stated otherwise. 


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12.5.1.1 Complete remission rate
Complete remission rate will be assessed according to International Working Group (IWG) for 
MDS (2006) with MBG453 (sabatolimab) in combination with HMAs (IV/SC/Oral) in 
Participants with intermediate, high, or very high risk MDS by 12 months.
Proportion of patients achieving CR by 12 months will be presented together with an exact 95% 
confidence interval. 
Patients who discontinue early before achieving response will be considered as non-responders. 
Similarly patients with transplant or patients with progression before achieving response will 
be considered as non-responders. As appropriate, additional sensitivity analyses will be 
performed excluding discontinued patients, transplant patients and patients with progression 
before documentation of CR. 
12.5.1.2 Progression Free Survival
Progression Free Survival (PFS) rate by 12 months is defined as time from the enrollment date 
to disease progression (including transformation to leukemia per WHO 2016 classification), 
relapse from CR according to IWG-MDS or death due to any cause, whichever occurs first, as 
per investigator assessment during core phase by 12 months post last patient first treatment.  
For patients without progression, the time is censored at the latest date the patient was known 
to be alive and without progression (on or before the cut-off date).
PFS will be analyzed using the Kaplan-Meier Product-Limit method. Patients who do not 
progress will be censored at the last adequate assessment. Estimates of the 25th, median and 
75th percentile of the PFS and their 95% confidence intervals will be provided, if applicable.
12.5.1.3 Overall Survival
Overall Survival (OS) rate by 24 months is defined as the proportion of patients alive time from 
theenrollment date to death due to any cause during 12 months.
 If a patient is not known to have died, then OS will be censored at the latest date the patient 
was known to be alive (on or before the cut-off date). All deaths will be taken into account 
whatever 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 analyzed using the Kaplan-Meier Product-Limit method. Patients who do not die 
will be censored at the last adequate assessment. Estimates of the 25th, median and 75th 
percentile of the OS and their 95% confidence intervals will be provided, if applicable.
12.5.1.4 Leukemia-free survival
Leukemia-free survival (LFS) is the time from the enrollment date to ≥ 20% blasts in bone 
marrow/peripheral blood (per WHO 2016 classification) or death due to any cause. 
For a patient without event, the time is censored at the latest date the patient was known to be 
alive and without leukemia (on or before the cut-off date).
LFS will be analyzed using the Kaplan-Meier Product-Limit method. Patients who are not 
known to be alive without leukemia will be censored at the last adequate assessment. Estimates 


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of the 25th, median and 75th percentile of the PFS and their 95% confidence intervals will be 
provided, if applicable.
12.5.1.5 Other Response Rates
CR/mCR/PR according to IWG-MDS will be as per investigator assessment. Number and 
percentage patients with all other responses rates will be summarized.
12.5.1.6 Duration to Complete Remission
Duration of Complete Remission (DOR) is the time from the date of the first documented CR 
to the date of first documented relapse from CR or death due to any cause, whichever occurs 
first.
The start date is the date of first documented CR and the end date is defined as the date of the 
first documented relapse from CR or death due to any cause. Participants continuing without 
event will be censored at the date of their last adequate response assessment. 
DOR will be listed and summarized. Median duration and 95% Confidence interval will be 
reported.
12.5.1.7 Time to Complete Remission
Time to Complete Remission is defined as the time from the date of enrollment to the first 
documented CR.
Time to complete remission will be analyzed using the Kaplan-Meier Product-Limit method. 
Patients who are known to be without CR will be censored at the last adequate assessment. 
Estimates of the 25th, median and 75th percentile of the PFS and their 95% confidence intervals 
will be provided, if applicable.
12.5.1.8 Improvement in RBC/platelets transfusion independence
Number and percent of patients who are RBC/platelets transfusion independent after the date 
of the first dose of study medication as per IWG-MDS.
RBC/Platelets transfusion independence rate is defined as the proportion of participants having 
received <0 units RBC/Platelets transfusions during at least 8 consecutive weeks after 
enrollment (Table 8-2). The number and percentage of patients will be shown for the overall 
FAS and then also in only those with transfusion dependence at baseline. Percentages will be 
provided with exact 95% Clopper-Pearson confidence intervals. 
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.


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12.5.2
Safety objectives
12.5.2.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment received.
The overall observation period will be divided into three mutually exclusive segments:
•
pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
•
on-treatment period: from day of first dose of study medication to last dose of study 
medication and up to 30 days after last dose.
•
Post-treatment period: starting at day 31 after last administration of study treatment 
(MBG453 or HMA)
•
Note : for patients who discontinue MBG453 investigational study treatment to receive 
transplant, they will not be included in the safety set (post discontinuation) and only be 
followed up for 
 transplant related mortality.
12.5.2.2 Adverse events (AEs)
All information obtained on adverse events will be displayed by treatment and participant.
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). Separate summaries will be provided for study medication related 
adverse events, deaths, serious adverse events, adverse events leading to treatment 
discontinuation, and adverse events leading to dose adjustment. The number (and percentage) 
of participants with 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, adverse events leading to treatment discontinuation, and adverse events leading 
to dose adjustment.
The incidence of adverse events will be summarized by system organ class and or preferred 
term, severity (based on CTCAE grades), type of adverse event, relation to study treatment.
Serious adverse events and non-serious adverse events will be tabulated.
Selected summaries of adverse events will be produced for the overall safety period. All deaths 
(on-treatment and post-treatment) will be summarized.
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, post-treatment and overall 
safety period will be flagged.


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12.5.2.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI 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. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE v5, results will be categorized as 
low/normal/high (or other project-specific ranges, if more suitable) based on laboratory normal 
ranges.
The following summaries will be generated separately for hematology and biochemistry tests: 
For laboratory tests where grades are defined by CTCAE v5
•
Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline.
•
Shift tables to compare baseline CTCAE grades to the worst on-treatment grade 
For laboratory tests where grades are not defined by CTCAE v5
•
Shift tables using the low/normal/high/low and high (or project specific) classification to 
compare baseline to the worst on-treatment value.
Listing of all laboratory data with values flagged to show the corresponding CTCAE v5 grades 
if applicable and the classifications relative to the laboratory normal ranges will be presented.
12.5.2.4 Other safety data ECG
A 12-lead ECG including PR, QRS, QT, QTcF, QTcB and RR intervals will be obtained for 
each patient during the study. 
As appropriate, the number and percent of patients with notable ECG value will be tabulated 
by category. In addition, a listing of patients with at least one notable ECG value will be 
produced.
Vital signs
Data on vital signs will be tabulated and summarized descriptively as follows:
•
Change from baseline to the worst on-treatment result
•
Number and frequency of patients who shift from non-notable at baseline to notable post- 
baseline (details about the definition of notable abnormal results will be given in the SAP)
All information collected will be listed and notable values will be flagged.








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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 field 
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
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e., all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents. The date when a patient’s Informed Consent was 
actually obtained will be captured in their eCRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential must be informed that taking the study medication 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 requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they must 
not be entered in the study.
13.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 9.1.4.
13.5
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov. In 
addition, after study completion (defined as last patient last visit) and finalization of the study 
report the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 
Health Authority websites (e.g. clinicaltrials.gov, FDA 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.


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13.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the Sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study electronic case report form (eCRF) is the primary data 
collection instrument for the study. The investigator must ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, must be consistent with the 
source documents or the discrepancies must be explained. All data requested on the eCRF must 
be recorded. Any missing data must be explained. For electronic CRFs an audit trail will be 
maintained by the system.
The investigator/institution must maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution must take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) must be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
13.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
13.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.


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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.
13.9
Financial disclosures
Financial disclosures must be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
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 Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented. 
All significant protocol deviations will be recorded and reported in the CSR.
14.1
Amendments to the protocol
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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Chen X, Liu S, Wang L, et al (2008) Clinical significance of B7-H1 (PD-L1) expression in 
human acute leukemia. Cancer Biol Ther; 7(5): 622-7.
Cheson BD, Bennett JM, Kantarjian H, et al (2000) Report of an international working group 
to standardize response criteria for myelodysplastic syndromes. Blood; 96(12): 3671-4.
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; 108(2): 419-25.
Chou FC, Kuo CC, Chen HY, et al (2016) DNA demethylation of the TIM-3 promoter is 
critical for its stable expression on T cells. Genes Immun; 17(3): 179-86.
Clopper CJ and Pearson ES (1934) The use of confidence or fiducial limites illustrated in the 
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Cogle C, Scott B, Boyd T, et al (2015) Oral Azacitidine (CC-486) for the Treatment of 
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MBG453 + spartalizumab (PDR001) in patients (pts) with advanced malignancies. AACR 
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Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A 
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16
Appendices
MBG453, as a mAB, is not expected to have many interactions, unlike small molecules that are 
metabolized by the CYP450 enzymes and may induce or inhibit some of these enzymes or other 
transporters. Therefore, there is no long list of prohibited meds that need to be listed in an 
appendix. Please refer to section 6.2.2.
16.1
Appendix 1: Clinically notable laboratory values and vital signs 
There are no specific notable range criteria for this study; however, the local and central 
laboratory will flag laboratory values falling outside of the normal range, on the local and 
central laboratory report (as applicable) (which the investigator should sign off) as per local 
practice, and the investigator will report any values considered clinically significant in the eCRF. 
The investigator will also report any vital signs, local ECG values considered clinically 
significant in the eCRF.


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16.2
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements
Table 16-1
Liver event and laboratory trigger definitions 
Definition/ threshold
LIVER LABORATORY TRIGGERS
3 x ULN <ALT / AST ≤ 5 x ULN
1.5 x ULN <TBL ≤ 2 x ULN
LIVER EVENTS
ALT or AST >5 × ULN
ALP >2 × ULN (in the absence of known bone pathology)
TBL >2 × ULN (in the absence of known Gilbert syndrome)
ALT or AST >3 × ULN and INR >1.5
Potential Hy’s Law cases (defined as ALT or AST >3 × ULN and 
TBL >2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to >2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST >3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: Hepatic failure, fibrosis and cirrhosis, and other liver damage- related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms TBL: total 
bilirubin; ULN: upper limit of normal
Table 16-2
Follow up requirements for liver laboratory triggers with liver 
symptoms 
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea
Discontinue the study treatment 
immediately
Hospitalize, if clinically
ALT, AST, TBL, Alb, PT/INR, ALP
and GGT until resolutionc (frequency at 
investigator discretion)
appropriate
Establish causality
Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in the
appropriate CRF


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Criteria
Actions required
Follow-up monitoring
ALT or AST
>8 × ULN
Discontinue the study 
treatment immediately
Hospitalize if clinically 
appropriate
Establish causality
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP
and GGT until resolutionc (frequency at 
investigator discretion)
>3 × ULN and INR >1.5
Discontinue the study treatment 
immediately
Hospitalize, if clinically 
appropriate
Establish causality
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP
and GGT until resolutionc (frequency at 
investigator discretion)
>5 to ≤8 × ULN
Repeat LFT within 48 hours
If elevation persists, continue 
follow-up monitoring
If elevation persists for more 
than 2 weeks, discontinue the 
study drug
Establish causality
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP
and GGT until resolutionc (frequency at 
investigator discretion)
>3 × ULN accompanied by 
symptomsb
Discontinue the study 
treatment immediately
Hospitalize if clinically 
appropriate
Establish causality
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP
and GGT until resolutionc (frequency at 
investigator discretion)


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Criteria
Actions required
Follow-up monitoring
ALP (isolated)
>2 × ULN (in the absence of 
known bone pathology)
Repeat LFT within 48 hours
If elevation persists, 
establish causality
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
TBL (isolated)
>2 × ULN (in the absence of 
known Gilbert syndrome)
Repeat LFT within 48 hours
If elevation persists, 
discontinue the study drug 
immediately
Hospitalize if clinically 
appropriate
ALT, AST, TBL, Alb, PT/INR, ALP
and GGT until resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
Establish causality
Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in the
appropriate CRF
>1.5 to ≤2 × ULN (patient is 
asymptomatic)
Repeat LFT within the next 
week
If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
Jaundice
Discontinue the study 
treatment immediately
Hospitalize the patient
ALT, AST, TBL, Alb, PT/INR, ALP
and GGT until resolutionc (frequency at 
investigator discretion)
Establish causality
Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in the
appropriate CRF
Any AE potentially indicative 
of a liver toxicity*
Consider study treatment 
interruption or
Investigator discretion
discontinuation
>3 to ≤5 × ULN (patient is 
asymptomatic)
Repeat LFT within the next 
week
If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks


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Hospitalization if clinically
Criteria
Actions required
Follow-up monitoring
aElevated ALT/AST >3 × ULN and TBL >2 × ULN but without notable increase in ALP to >2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia cResolution is 
defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at three 
subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 months, 
(4) liver transplantation, and (5) death.
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.


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


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•
Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumorlysis
Table 16-4
Renal Event Follow Up
FOLLOW-UP OF RENAL EVENTS
Assess, document and record in CRF:
Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial cells
Blood pressure and body weight
Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and uric acid
Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc.) in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until:
Event resolution: (sCr within 10% of baseline or PCR <1 g/g Cr, or ACR <300 mg/g Cr) or
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization 
at a new level with ±50% variability over last 6 months.
Analysis of urine markers in samples collected over the course of the DIN event
16.4
Appendix 4: Eligibility based on serologic markers for hepatitis B
Please consider the general guidelines below, investigators may consult specialists to decide 
participant’s eligibility in case of borderline results.
Protocol exclusion criterion:
•
Positive serology for hepatitis B surface antigen (HBsAg)
•
Positive serology for hepatitis B core antibody (HBcAb), except if both criteria are met:
1.
HBV DNA negative
2.
Hepatitis B monitoring is implemented: HBsAg and HBV DNA should be tested 
every 6 weeks for the first 6 months and every 12 weeks thereafter, until the end of 
study.


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Table 16-5
Eligibility based on serologic markers for hepatitis B
Table 16-6
Decision tree to determine eligibility based on serologic markers for 
hepatitis B 

SAP_001.pdf: 


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 Document History – Changes compared to previous final version of SAP. 
 
Date 
Time 
point 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
 07-
09-
2023 
Before 
Interim 
analysis 
or DBL 
As 
protocol 
was 
amended due to the 
halt in recruitment 
for the STIMULUS 
MDS-US study on 
30-Sep-2022. 
 
 shortening the timeline of 
the study as well as various 
administrative changes. 
Amendment 01 
(Based on 
protocol incl. 
amendment 02 
from 08-Feb-2023) 
Section 1.1 
Study design 
Section 
1.2 
Study objectives 
and endpoints 
Section 
2.2.1 
Subgroup 
of 
interest 
Section 
2.5.4 
Supportive 
analyses 
Section 
2.7.1.2 
Progression Free 
Survival 
Section 
2.7.1.3 
Overall Survival, 
Section 2.7.1.8 
Improvement in 
RBC/platelets 
transfusion 
independence 
Section 
2.8.4.1 
ECG and cardiac 
imaging 
data 
Section 3 Sample 
size calculation 
 05-
11-
2024 
Before 
Final 
analysis 
or Final 
DBL 
 
 
 
Objectives 
and 
endpoints 
Survival follow-up 
missed  
 
 
 
 
Overall survival endpoints 
were updated from 12 months 
to 24 months 
survival follow-up added to 
summarize. 
 
 
 
 
 
Section 1.2 study 
objectives 
& 
endpoints 
Section 2.31 


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Date 
Time 
point 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
Typo corrected 
Typo 
corrected 
from 
randomization to enrollment. 
 
Typo 
corrected 
from 
randomization to enrollment. 
 
Dropped text ‘Placebo’  
 
2.7.1.1 Complete 
remission rate: 
 
2.7.1.2
 
Progressi
on Free Survival 
2.8 
Safety 
analyses 
 
 
 
As 
per 
CTT 
discussion, 
CRF 
collected Visits to 
be 
used 
instead 
windowing. 
CRF 
visits 
might 
be 
delayed, which is 
not unusual from a 
medical perspective. 
Additionally, 
the 
"End of Treatment" 
visits are patient-
specific based on the 
study design.  
 
 
 
 
For ePRO analysis, visit 
window will not be used and 
dropped from SAP. 
5 Appendix 
Calculations for 
the date of last 
exposure 
to 
HMA drugs were 
updated 
Section 
5 
Appendix 
28-
11-
2024 
After 
DBL 
Due 
to 
inconsistency 
in 
objectives/endpoints 
for final analysis 
The objectives and endpoints 
analysis related to time to 
event is updated to 12 months 
post LPFT and also for 
Section 1.2 & 
section 2.7 


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Date 
Time 
point 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
complete available data of the 
study. 
The primary objective i.e., 
safety 
profile 
will 
be 
analyzed considering all the 
data (not by 12 months, as 
agreed by the CTT). 
 
07-
02-
2025 
After 
DBL 
From 
the 
recent CTT 
discussion, it was 
decided to align the 
objectives 
and 
endpoints with the 
protocol v02 (which 
is 
available 
in 
CT.gov.in)   
 
 
Per the clinical trial 
safety 
disclosure 
requirement to keep 
all analyses inline 
with the protocol. 
Objectives and endpoints 
will be aligned with the 
protocol v02. The primary 
objective i.e., safety profile 
will be analysed considering  
by the 12 months data (i.e., 
LPFT+12months). 
For 
Overall survival by 12 
months (LPFT+12months) 
and 
24 
months 
(LPFT+24months) data will 
be analysed.  
For safety disclosure the text 
mentioned in section 2.8.1 
should be added  
 
 
Section 1.2 & 2.7 
 
 
 
 
 
 
 
 
Section 2.8.1 
 
 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 5 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 8 
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 ................................................................................ 15 
2.2 
Analysis sets .......................................................................................................... 16 
2.2.1 
Subgroup of interest .............................................................................. 17 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 18 
2.3.1 
Subject disposition ................................................................................ 18 
2.3.2 
Demographic and other baseline characteristics ................................... 18 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 19 
2.4.1 
Study treatment / compliance ................................................................ 19 
2.4.2 
Prior, concomitant and post therapies ................................................... 20 
2.5 
Analysis of the primary objective .......................................................................... 20 
2.5.1 
Primary endpoint ................................................................................... 20 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 21 
2.5.4 
Supportive analyses ............................................................................... 21 
2.6 
Analysis of the key secondary objective ............................................................... 21 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 21 
2.7.1 
Secondary endpoints ............................................................................. 21 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 28 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 28 
2.8 
Safety analyses ....................................................................................................... 29 
2.8.1 
Adverse events (AEs) ............................................................................ 29 
2.8.2 
Deaths .................................................................................................... 31 
2.8.3 
Laboratory data ..................................................................................... 32 
2.8.4 
Other safety data ................................................................................... 32 
 
 33 
 
 33 
 
 34 


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 35 
 
 35 
 
 36 
 
 36 
2.10 
Interim analysis ...................................................................................................... 37 
3 
Sample size calculation ..................................................................................................... 37 
4 
Change to protocol specified analyses .............................................................................. 37 
5 
Appendix ........................................................................................................................... 38 
5.1 
Date of first administration of investigational drug /HMA ................................... 38 
5.2 
Date of last administration of of investigational drug /HMA ................................ 38 
5.3 
Date of first administration of study treatment (combination) .............................. 38 
5.4 
Date of last administration of study treatment (combination) ............................... 38 
5.5 
Date of last exposure to HMA and investigational drug and date of last 
exposure to study treatment (combination) ........................................................... 38 
5.6 
Duration of study treatment (combination) used to calculate the dose intensity 
and the relative dose intensity ................................................................................ 39 
5.7 
Windows for multiple assessments ........................................................................ 39 
5.8 
Last contact date .................................................................................................... 40 
5.9 
Imputation rules ..................................................................................................... 40 
5.10 
AEs coding/grading ............................................................................................... 41 
5.11 
Laboratory parameters derivations ........................................................................ 41 
5.12 
Statistical models ................................................................................................... 41 
5.12.1 
Primary analysis .................................................................................... 41 
5.12.2 
Key secondary analysis ......................................................................... 41 
6 
Reference ........................................................................................................................... 42 
 


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List of abbreviations 
 
 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ATC 
Anatomical Therapeutic Chemical  
 
 
BLQ 
Below the Limit of Quantitation  
BMI 
Body mass index 
BOR 
Best Overall Response 
BP 
Blood pressure 
CI 
Confidence interval 
CR 
Complete Remission 
CSR 
Clinical study report 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DMS 
Document Management System 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
eCRF 
Electronic Case Report/Record Form 
eCRS 
Electronic case retrieval strategy 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
EOT 
End of treatment  
 
  
 
 
FAS 
Full Analysis Set 
Hgb 
Hemoglobin 
HLT 
High level terms 
HGLTs 
High level group terms 
HMA 
Hypomethylating agent (Decitabine-IV, INQOVI (oral decitabine) and 
Azacitidine-IV or SC) 
HSCT 
Hematopoietic stem cell transplantation 
IV 
Intravenous 
 
 
IPSS-R 
International Prognostic Scoring System 
IRT 
Interactive Response Technology 
INQOVI 
Oral Decitabine 
IWG 
International Working Group 
LPLV 
Last Patient Last Visit 


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mCR 
marrow Complete Remission 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical dictionary for regulatory activities 
 
 
NCI 
National Cancer Institute 
NGS 
Next Generation Sequencing 
NMQ 
Novartis MedDRA queries 
OS 
Overall survival 
ORR 
Overall Response Rate 
 
  
PD 
Pharmacodynamics 
PFS 
Progression free survival 
 
 
 
 
 
 
PR 
Partial remission 
PRO 
Patient Reported Outcome 
PT  
Preferred term 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
 
 
RBC 
Red blood cell(s) 
SC 
Subcutaneous 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SMQ 
Standardized MedDRA queries 
SOC 
Standard of Care 
TFL 
Tables Figures Listings 
TIM-3 
T-cell immunoglobulin domain and mucin domain-3 
TEAE 
Treatment emergent adverse event 
 
 
WHO 
World Health Organization 
1 
Introduction 
This statistical analysis plan (SAP) describes the planned analyses for the  final Clinical Study 
Report (CSR) of the study CMBG453B1US01, single-arm, open label, Phase II study 
evaluating the efficacy and safety of MBG453 in combination with hypomethylating agents 
(HMAs) in subjects with IPSS-R intermediate, high or very high-risk myelodysplastic 
syndrome (MDS). 


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A final analysis will be performed when all subjects complete the long-term extension phase 
and safety follow up. In this case a final CSR will be written. 
In addition, as specified in the section 12.6 of the study protocol, interim analyses may be 
performed for publication or any regulatory purpose, e.g., an interim analysis can be performed 
after all subjects have completed 6 months follow-up from enrollment (cycle 1 day 1) or 
discontinued earlier. 
This SAP is created for all the analysis including final analyses and a separate document for 
tables, figures and listings (TFL) will be created.   
The main purpose of this document is to provide a summary of the statistical methodology that 
will be used for this clinical study; this includes a detailed description of data summaries. 
‘Analyses plan’ in this document refers to the related statistical analysis sections in CSR. 
The analysis described here will be conducted by ), Novartis, using statistical software SAS® 
Version 9.4 according to the Statistical methods and data analysis Section 12 of the study 
protocol which will be available in Appendix 16.1.1 of the CSR. Important information will be 
given in the following sections and further details are provided, as applicable, in the Appendix 
16.1.9 of the CSR. 
Unless otherwise specified, the statistical methodologies including the analysis sets, analysis 
models, algorithms, and conventions are following the Oncology study amended protocol 
CMBG4531US01 version 02. 
1.1 
Study design 
This is a single-arm, non-randomized, open label, phase II multi-center study of intravenous 
MBG453 (Sabatolimab) added to FDA approved HMAs of investigator’s choice (IV/SC/ Oral) 
in adult subjects with intermediate, high or very high risk myelodysplastic syndrome (MDS) as 
per IPSS-R criteria. 
Study treatment will be administered for 12 months within the core phase of the study. After 
the 12 months core phase, subjects may enter the extension phase (based on investigator 
decision). 
For subjects that will receive treatment in the extension phase, they are allowed to continue 
treatment with MBG453 only, HMA only or MBG453+HMA. 
In addition, all subjects who discontinued (at core phase) study treatment (unless due to 
progression) may enter the extension phase. In the extension phase, subjects who discontinued 
study treatment due to reasons other than progression, death, lost to follow-up, or withdrawal 
of consent (i.e. transplantation, adverse events, etc.) will have hematology assessments, Patient 
Reported Outcomes (PRO) and response assessments at defined time points until documented 
disease progression, death, lost to follow-up, withdrawal of consent, or have reached the end of 
extension phase, whichever comes first. Subjects who progress on study [core phase (first 
12 months) or extension phase (additional 12 months)] will enter the post treatment safety 
follow-up period. 


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Post treatment follow-up is for safety collection and is up to 150 days post core phase or 
extension phase discontinuation. Survival data will be collected until end of study inclusive of 
the extension and post treatment follow-up duration. 
Subjects who become eligible for hematopoietic stem cell transplant (HSCT) or intensive 
chemotherapy at any time during the course of the study will be discontinued from study 
treatment. However, they may continue into the extension phase for safety. 
The study treatment consists of cycles of MBG453 in combination with HMA administered to 
the subjects until treatment discontinuation as described in the protocol. The planned duration 
of a cycle is 28 days. 
Planned number of subjects 
Novartis has decided to permanently halt recruitment based on a re-evaluation of the 
development strategy for sabatolimab. Subjects who are currently on study treatment or in 
follow-up will be continued per the protocol. 
A total of 39 subjects were enrolled in this study. Subjects were recruited from sites within the 
United States. No pre-treatment stratification is planned. The investigator or designee must 
ensure that only subjects who meet all the inclusion and none of the exclusion criteria are 
enrolled in the study. 
There are 4 types of periods/phases: Screening phase, core phase, extension phase and post 
treatment safety follow-up 
Screening phase: A signing of written informed consent obtained through day 1 of enrollment 
(from up to 28 days of period prior to core phase start date). 
Core phase: A 12 months of treatment period is a core phase  
Extension phase: Extension phase for efficacy and/or survival status (up to 24 months of last 
subject enrolling) or in addition to core phase (12 months), an additional 12 months of treatment 
period is extension phase. 
Post treatment safety follow up: Post treatment safety follow-up monitoring for adverse 
events (AEs) for 30 days following the last dose of azacitidine or decitabine or INQOVI (oral 
decitabine), or 150 days following the last dose of MBG453 (sabatolimab), whichever is later. 


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 Figure 1-1 
Study design 
 
  
1.2 
Study objectives and endpoints 
Main objective of this proposed study is to describe and evaluate safety and efficacy of 
MBG453 (sabatolimab) in combination with FDA approved HMAs of investigator’s choice in 
a single-arm, non randomized, open label, phase II multi-center US study. 
Objectives and related endpoints are described in Table 1-1 below. 
Table 1-1 
Objectives and related endpoints 
Cut-off date: For analysis of the primary and secondary objectives and endpoints, 12 
months post LPFT will be considered as cut-off date. Additionally, for OS of 24 months, 
the cut-off date will be considered as 24 months post LPFT. 
Objective(s) 
Endpoint(s) 
Primary Objective 
1. To assess the safety profile of MBG453 
(sabatolimab) 800 mg (every 4 weeks) given in 
combination with HMAs (IV/SC/Oral) by 12 
months 
Endpoint for primary objective 
Incidence and severity of AEs and SAEs, changes in 
laboratory values and vital signs 


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Secondary Objectives 
1) To evaluate complete remission rate with 
MBG453 (sabatolimab) in combination 
with HMAs (IV/SC/Oral) in subjects with 
intermediate, high, or very high risk MDS 
by 12 months. 
2) To evaluate PFS rate by 12 months with 
MBG453 (sabatolimab) combined with 
HMAs (IV/SC/Oral) in subjects with 
intermediate, high or very high risk MDS. 
 
 
3) To assess Overall Survival rate by 24 
months. 
 
4) To assess Leukemia-free survival rate by 
12 months. 
 
 
5) To assess other response rates.  
 
 
 
6) To assess duration of complete remission. 
 
7) To assess time to complete remission. 
 
8) To assess the improvement in RBC/platelets 
transfusion independence. 
Endpoints for other secondary objectives 
1) Complete remission (CR) rate according to 
International Working Group (IWG) for MDS 
(2006) * as per investigator assessment by 12 
months. 
 
2) PFS is defined as time from enrollment to disease 
progression (including transformation to leukemia 
per WHO 2016 classification), relapse from CR 
according to IWG-MDS*  or death due to any 
cause, whichever occurs first, as per investigator 
assessment **by 12 months post LPFT. 
 
3) Overall survival, time from enrollment to death 
due to any cause during 12 months post LPFT. 
4) Time from enrollment to ≥ 20% blasts in bone 
marrow/peripheral blood (per WHO 2016 
classification) or death due to any cause. 
5) Percentage of CR/ mCR/ PR and according to 
IWG-MDS as per investigator assessment.. 
 
6) Time from the date of the first documented CR to 
the date of first documented relapse from CR or 
death due to any cause, whichever occurs first. 
7) Time from enrollment to the first documented 
CR.. 
 
8) Number and percent of subjects who are 
RBC/platelets transfusion independent after 
enrollment as per IWG-MDS. 


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Notes: 
*According to IWG-MDS 
** Indicates as per investigator assessment by 12 months post LPFT. 
 
 
 


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2 
Statistical methods 
2.1 
Data analysis general information 
The analysis outlined in this document will be performed by, Novartis. SAS® version 9.4 or 
higher will be used for generating tables, figures and listings (TFLs). It is planned that the data 
from all subjects and centers will be used.  
Note: After termination of MBG453 program, the clinical team agreed to go ahead with only 
one final CSR instead of separate CSR's for primary and the full study.  
 
General analysis conventions 
Data will be summarized for demographics and other baseline characteristics as well as efficacy 
data for the Full Analysis Set (FAS), safety and any other data (unless specified otherwise) for 
the Safety Set.  
Categorical data (e.g. gender, race, etc.) will be presented in frequencies and percentages. A 
row (category) denoted “Missing” will be included in count tabulations if a non-zero count of 
missing values is present. Percentages will be calculated using the number of subjects in the 
relevant population or subgroup as the denominator. If a count of zero is obtained, the zero 
count will still be displayed. 
For continuous data descriptive statistics (n, mean, standard deviation, median 25th and 75th 
percentiles, min and max) will be provided. As appropriate, 95% confidence intervals (CI)  
will also be reported. Kaplan Meier’s estimates will be reported for the time to event 
variables. If not otherwise specified, p-values and confidence interval will be presented as 
two-sided. Unless otherwise stated, the default level of significance will be set to 5% (two-
sided, family-wise type-I-error). 
Summary statistics will also be presented graphically wherever applicable. 
The following number of decimal places will be used: mean and median to 1 more decimal 
place than the raw data; minimum and maximum to the same number of decimal places as the 
raw data and SD to 2 more decimal places than the raw data. p-value: 4 decimal places; if p-
value is less than 0.0001, display < 0.0001. 
• Standard error and standard deviation: data precision + 2 decimal places 
• Mean, quartile, percentile and median: data precision + 1 decimal place 
• Minimum and maximum: same as data precision 
• Percentages: 1 decimal place, 0% will be displayed as 0 and 100% will be displayed as 
100. 
• Confidence interval (CI): data precision + 2 decimal place. 
• p-value: 4 decimal places 


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All tables and listings will be presented by one treatment arm of the study. All data will be listed 
by center and subject number, unless stated otherwise. 
2.1.1 
General definitions  
2.1.1.1 
Study treatment and study drug 
MBG453 (sabalotimab) is given with a combination of “HMAs” (INQOVI,azacitidine and 
decitabine) throughout this document and in the analyses. The treatment arm is MBG453 + 
HMAs. 
Study treatment refers to the combination of MBG453 with HMAs. 
Study drug refers to the individual components: MBG453 or HMAs. 
2.1.1.2 
Baseline assessment  
For safety evaluations, the last available assessment prior to administration of MBG453 (on day 
8) in combination with HMA (in any day between day 5-8) Study Day 1 (cycle 1 day 1) should 
be used as the baseline assessment. No assessments prior to Screening assessments will be used.  
For all other parameters, baseline is defined as the last non-missing assessment on or before the 
enrollment (cycle 1 day 1) date. 
If subjects have no assessment as defined above, the baseline results will be missing. 
2.1.1.3 
Date of first administration of study treatment   
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 (MBG453 with 
HMAs) is administered. 
2.1.1.4 
Date of last administration of study treatment   
The date of last administration of study treatment (or end date of study treatment) is defined as 
the last date when a non-zero dose of any component of the study treatment (MBG453 with 
HMAs) is administered. 
2.1.1.5 
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. 
2.1.1.6 
Study day 
The study day describes the day of the event or assessment date, relative to the reference start 
date (enrollment date or 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 all the parameters will be the start of study treatment.  
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. 
2.2 
Analysis sets 
The analysis sets to be used as defined below. The FAS will be used for efficacy analysis. The 
Safety Set will be used for all the safety analysis.  
Full Analysis Set  
The FAS comprises all enrolled subjects to whom took any component of the study treatment. 
Safety Set 
The Safety Set includes all subjects who received at least one dose of any component of the study 
treatment (MBG453 + HMA).  
  
 
 
 
1. 
 
2. 
 
 
3. 
 
 
 
 
 
Subject Classification 
Subjects may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in 
Table 2-1. 
Table 2-1 Subject classification based on protocol deviations and non-protocol 
deviations criteria 
Analysis  
Protocol deviations leading 
to exclusion 
Non 
Protocol 
deviations 
leading to exclusion 


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FAS 
No written informed consent 
None 
Safety Set 
No written informed consent 
No dose of any component of 
study treatment 
 
 
 
 
 
 
 
 
Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the study will not be included in the analyses. The date on which a 
subject 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. 
2.2.1 
Subgroup of interest 
Subgroup analyses will be performed on the primary and secondary endpoints (CR and PFS). 
For sub-group analysis of primary (All AE/SAE) and secondary endpoints (CR and PFS) will 
be summarized with counts and percentage for the subgroups below. 
The following subgroups based on the subject baseline assessment may be performed in this 
study: 
 
 
• IPSS-R (Intermediate, High & V. High) 
• HMA (Oral, IV, SC)  
Additionally, as the study will be ongoing during COVID 19 pandemic, in order to address the 
impact of COVID-19 (if any) the sensitivity analysis may be performed as appropriate: 
• Discontinuation 
• Protocol deviation 
• Disease status 
• Dose interruption/missing data 
• AEs and labs 
As appropriate, a sensitivity analysis may be performed on the primary safety evaluating the 
impact of COVID-19 on the study. 


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2.3 
Subject disposition, demographics and other baseline 
characteristics 
2.3.1 
Subject disposition 
Number and percentage of subjects screened, completed and discontinued along with reason 
for discontinuation will be summarized for each study periods (core phase, extension phase, 
post-treatment safety follow-up and survival follow-up period). 
The number (%) of subjects in the FAS who started treatment core phase (i.e. core phase: 12 
months of treatments), are still on treatment in core phase, who entered and discontinued the 
extension phase (i.e. next 12 months of core phase), who entered, discontinued post-treatment 
follow-up and survival follow-up will be summarized together with the respective reasons for 
core treatment phase/ extension phase/ post-treatment follow-up/ end of study discontinuation. 
All disposition information will be listed. 
Protocol deviations 
The number and percentage of subjects in the FAS with any protocol deviation will be tabulated 
by deviation category. All protocol deviations will be listed. 
2.3.2 
Demographic and other baseline characteristics  
Demographics (date of birth (Age), sex, height and weight, BMI, predominant race and 
ethnicity), ECOG Performance Status by grade will be summarized descriptively using FAS 
and listed, unless stated otherwise. 
Details on MDS diagnosis (initial diagnosis, WHO classification, current disease status (de 
novo or secondary) and cytogenetic abnormalities) will be tabulated and time since diagnosis 
will be summarized by each risk classification. 
Disease history (MDS), including date of diagnosis, confirmation of MDS diagnosis, IPSS-R 
risk classification for MDS subjects at time of screening, prior antineoplastic therapies. 
Medical history 
Medical history (e.g., important medical, surgical, and allergic conditions from the subject’s 
medical history which could have an impact on the subject’s evaluation) / current medical 
conditions (e.g., all relevant current medical conditions which are present at the time of signing 
informed consent). Ongoing medical conditions, symptoms and diseases which are recorded on 
the Medical History eCRF must include the toxicity grade when applicable. 
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. 


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2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The duration of exposure will be summarized for study treatment and for each study drug 
(MBG453 (sabatolimab) and HMA (separately and combined together for all HMA)). The 
dose intensity (computed as the ratio of actual cumulative dose received and actual duration of 
exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned 
dose intensity) will be summarized for each study drug MBG453 and for HMA individual 
component by descriptive statistics. 
For MBG453, the actual cumulative dose in mg is the sum of “dose administered” from the 
eCRF of all cycles during the exposure of MBG453. For HMA (azacitidine, decitabine and 
INQOVI (oral decitabine), 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. The actual cumulative dose in mg/m2 is 
then the sum of all cycles.  The following formula is used for BSA: 
BSA (m2) = √Weight (kg) ∗Height at screening (cm)/3600 (Mosteller formula) 
 
The duration considered for the derivation of the dose intensity and the relative dose 
intensity will be derived from the start date of study drug to the end of the last cycle initiated 
irrespective of date of death, last contact date for withdraw consent and cut-off date: the last 
exposure to study treatment (combination) will be the planned end date (Day 28) of the last 
cycle initiated with MBG453 and/or HMA, whichever is the latest. Details are provided in 
section 5. Appendix. 
The relative dose intensity is then comparing the actual dose intensity during subject’s exposure 
with the protocol planned dose of 800 mg Q4W for MBG453 and 20 mg/m2 for decitabine, 75 
mg/m2 for azacitadine and Decitabine Oral (INQOVI) (100mg cedazuridine / 35mg decitabine), 
e.g. if a subjects received 300 mg Q2W on average throughout the study, the relative dose 
intensity for this subject is 0.75. 
Dose réductions, interruptions or permanent discontinuations 
The number and percentage of subjects with any dose changes of MBG453 (incl. interruptions, 
or permanent discontinuations) and the reasons will be presented. 
The number and percentage of subjects with any dose changes (incl. reductions, interruptions, 
or permanent discontinuations) and the reasons (e.g. AE, dosing error, dispensing error, and 
physician decision) will be taken from the ‘Study Treatment eCRF’ and summarized by HMA. 
The total duration of interruptions by subject 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). 


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2.4.2 
Prior, concomitant and post therapies 
Prior and concomitant medications 
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. 
Each medication has the start and end dates recorded on the eCRF. Prior medications are defined 
as those medications which were taken and stopped prior to first dose of study treatment. 
Concomitant medications are defined as any medication given at least once between the day of 
first dose of study treatment and the last day of study visit, including those which were started 
pre-baseline and continued into the treatment period. 
All concomitant medications will be listed and summarized in alphabetic order according to 
Anatomical Therapeutic Chemical (ATC) classification system and PT. All summaries will be 
performed on the Safety set. 
  
Prior anti-neoplastic therapies 
Prior anti-neoplastic medications, radiotherapy or surgery will be summarized using the FAS. 
Medications will be summarized by ATC class and preferred term. Radiotherapies and surgeries 
will be summarized by system organ class and preferred term. 
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD); 
antineoplastic surgery will be coded using MedDRA. 
Transfusions 
All transfusions of blood products (incl. those not related to MDS) prior and after start of study 
treatment will be listed. Only MDS related transfusions of platelet and red blood cells will be 
summarized using the FAS. For that, the number of transfusion episodes will be normalized by 
time (e.g. fixed 8-weekly interval) prior to and on-treatment. 
Post treatment anti-neoplastic therapies and HSCT 
Anti-neoplastic medications after discontinuation of study treatment during follow-up within 
the study will be summarized by ATC class and preferred term. HSCTs will be also summarized 
with the source, the type of transplant and the allogenic donor type if applicable. Both analyses 
will be using the FAS. 
2.5 
Analysis of the primary objective 
The primary objective of this study is to assess the safety profile of MBG453(sabatolimab) 
800mg (every 4 weeks) given in combination with HMAs (IV/SC/Oral). 
2.5.1 
Primary endpoint 
The primary variables for this study are incidence of AEs and SAEs, and changes in laboratory 
values and vital signs. 


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Note: As primary objective of the study is safety objective and detailed analysis will be 
described in section 2.8, safety analysis  
2.5.2 
Statistical hypothesis, model, and method of analysis  
No formal hypothesis testing is planned for this study.  
2.5.3 
Handling of missing values/censoring/discontinuations 
Missing data for safety and efficacy endpoints will not be imputed. 
2.5.4 
Supportive analyses 
Subgroup analysis may be performed as described in section 2.2.1. 
2.6 
Analysis of the key secondary objective 
There is no key secondary objectives for this study and hence this section is not applicable. 
2.7 
Analysis of secondary efficacy objective(s) 
For all secondary efficacy analyses, the Full Analysis Set (FAS) will be used for all subjects, 
unless stated otherwise. 
2.7.1 
Secondary endpoints 
Following are the secondary endpoints to be considered for analysis by 12 months post LPFT 
and for complete available data for the study. Additionally for OS analysis by 24 months post 
LPFT will also be analyzed. 
A listing of all responses assessments by subject will be provided including BOR, PFS time, 
PFS event (yes/no), OS time, death date and duration of CR. Bone marrow blasts percentage 
will also be listed. In addition, for some selected laboratory parameters and for bone marrow 
blasts percentage, trends over time will be displayed via boxplots and corresponding tables 
displaying the summary statistics for these selected timepoints to be produced. 
2.7.1.1 
Complete remission rate:  
Complete remission rate will be assessed according to International Working Group (IWG) 
for MDS (2006) with MBG453 (sabatolimab) in combination with HMAs (IV/SC/Oral) in 
subject with intermediate, high, or very high risk MDS. 
Proportion of subjects achieving CR will be presented together with an exact 95% confidence 
interval. 
A sensitivity analysis may be performed for CR by considering IWG-MDS & modified IWG-
MDS of Peripheral blood. 
If any subject who achieved CR and discontinued/lost to follow-up within 12 months will be 
considered as Responder. 


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If any subject who achieved CR and undergone to Bone Marrow Transplantation (BMT) 
within 12 months will be considered as Responder. 
Subjects who discontinue early before achieving response will be considered as non-
responders. Similarly subjects with transplant or subjects with progression before achieving 
response will be considered as non-responders. As appropriate, additional sensitivity analyses 
will be performed excluding discontinued subjects, transplant subjects and subjects with 
progression before documentation of CR. 
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 and 
peripheral blood every 3 cycles for core phase during the first 07 cycles and every 6 cycles for 
extension phase and all transfusions records as detailed in Table 2-6 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 secondary endpoint rules by 
Novartis as below: 
• CR = at least one determination of CR without progression or relapse from CR within the 
four 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). 
• SD = at least one SD assessment and not qualifying for CR, mCR or PR. 
• PD = progression after enrollment and not qualifying for CR, mCR, PR or SD. 
• UNK = all other cases (i.e., not qualifying for confirmed CR or mCR or PR and without SD 
or progression). 
Details on the definition of response categories which are to be captured in the eCRF by the 
investigator were defined in Table 8-2 of the protocol that was copied into Table 2-6 below. 
Table 2-6 Modified response classification per IWG criteria in MDS  
Response category 
Definition# 


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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*10
9/L AND 
3. Neutrophils ≥ 1.0*10
9/L AND 
4. Blasts 0% 
Note: the subject 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 subjects 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.] 
• 
Return to baseline bone marrow blast percentage 
• 
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 
• 
Decrease of ≥ 50% from maximum remission/response*** levels in 
platelets AND platelets <100*109/L 
• 
Decrease from maximum remission/response*** levels in Hgb 
concentration by ≥1.5g/dL AND Hgb <10 g/dL  
• 
Becoming transfusion dependent** 
 


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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 subject 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. 
Subjects 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 Hematological Improvement per IWG-MDS criteria in MDS (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 subjects 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 subjects 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 


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#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 MDS (e.g. bleeding, surgical procedure, 
hemolysis, infections) should not be taken into account for the following: 
Transfusion dependence: 
1. At baseline: subjects having received ≥ 3 units of transfusion within the 8 consecutive 
weeks prior to baseline.  
2. Post-baseline: subjects having received ≥ 3 units of transfusion within any 8 
consecutive weeks during the course of the study. 
Transfusion independence: 
1. At baseline: subjects having received 0 units of transfusion within any 8 consecutive 
weeks prior to baseline.  
2. Post-baseline: subjects having received 0 units of transfusion within any 8 
consecutive weeks during the course of the study. 
2.7.1.2 
Progression Free Survival 
Progression Free Survival (PFS) is defined as time from the date of enrollment (cycle 1 day 1) 
to disease progression (including transformation to leukemia per WHO 2016 classification), 
relapse from CR according to modified IWG-MDS or death due to any cause, whichever 
occurs first, as per investigator assessment. 
For subjects without progression, the subject time is censored at the latest date where the 
subject was known to be alive, without progression and without relapse from CR (on or before 
the cut-off date). 
PFS will be analyzed using the Kaplan-Meier Product-Limit method. Estimates of the 25th, 
median and 75th percentile of the PFS and their 95% confidence intervals will be provided, 
Kaplan-Meier curves will be produced, if applicable. 
For subjects without PFS event, PFS is censored at last adequate assessment. This is the last 
response assessment conducted that is not considered as unknown. 
The following events could occur after enrollment and may affect the interpretation of the 
results: 
• 
Start of further anti-neoplastic therapy: For a subject without an event before the 
time he/she receives any further anti-cancer therapy, PFS would be censored at the date of the 
last adequate assessment prior to start of further anti-neoplastic therapy. 


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• 
Hematopoietic Stem cell transplantation (HSCT): A subject with an event, regardless 
of whether it occurred before or after the time he/she receives a HSCT, would be considered as 
having an event at the date when the event is observed.  
• 
Stopping study treatment (including due to toxicities): All events will be taken into 
account when they occur, regardless of any study treatment interruption or permanent 
discontinuation. 
• 
Discontinuation from study due to lost to follow-up or withdrawal of consent: For 
subject without an event prior to discontinuation due to lost to follow-up or withdrawal of 
consent, PFS will be censored at the last adequate assessment date.  
For PFS, an event occurring after two or more consecutive missing response assessments (not 
done or unknown) is censored in the analysis of PFS 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 every 3 cycles (12 weeks +/- 2 weeks) during the first 12 cycles 
and every 6 months (+/-1 month) thereafter. Therefore, for the first 12 cycles, any distance 
larger than D2 = 2*14 weeks = 28 weeks between last adequate assessment and the event means 
that there are two missing assessments. For the period beyond 12 cycles, any distance larger 
than D2 = 2*7 months = 14 months (56 weeks) means that there are two missing assessments. 
The PFS censoring reason will be summarized as:  
1. Ongoing without event 
2. New anti-neoplastic therapy 
3. Withdrew consent 
4. Lost to follow-up 
5. Event documented after two or more missing response assessments. 
6. Discontinuation due to subject/physician/guardian’s decision 
 
2.7.1.3 
Overall Survival 
Overall Survival (OS) rate is defined as the proportion of subjects alive time from the date of 
enrollment (cycle 1 day 1) to date of death due to any cause. 
If a subject is not known to have died, then OS will be censored at the latest date the subject 
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. 


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The OS censoring reason will be summarized as ‘Alive’ or ‘Lost to follow-up’. Subjects 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, subjects will have the censoring reason ‘Alive’. 
OS will be analyzed using the Kaplan-Meier Product-Limit method. Estimates of the 25th, 
median and 75th percentile of the OS and their 95% confidence intervals will be provided, 
Kaplan-Meier curves will be produced, if applicable. 
2.7.1.4 
Leukemia-free survival 
Leukemia-free survival (LFS) is the time from the date of enrollment (cycle 1 day 1) to ≥ 20% 
blasts in bone marrow/peripheral blood (per WHO 2016 classification) or death due to any 
cause. 
For a subject without event, the subject is censored at the latest date the subject was known to 
be alive and without leukemia (last adequate assessment, bone marrow and/or hematology 
assessment on or before the cut-off date). 
LFS will be analyzed using the Kaplan-Meier Product-Limit method. Estimates of the 25th, 
median and 75th percentile of the PFS and their 95% confidence intervals will be provided, 
Kaplan-Meier curves will be produced, if applicable. 
2.7.1.5 
 Response Rates 
Response rate is defined as the proportion of subjects with best overall response of either 
complete remission (CR)/marrow remission (mCR)/partial remission as per investigator 
assessment according IWG- MDS at any time during the study (on or before cut-off date) 
(Table 2-6). The number and percentage of subjects with all other responses rates will be 
summarized. 
2.7.1.6 
Duration of Complete Remission 
Duration of Complete Remission (DOR) is the time from the date of the first documented CR 
to the date of first documented relapse from CR or death due to any cause, whichever occurs 
first. 
The start date is the date of first documented CR and the end date is defined as the date of the 
first documented relapse from CR or death due to any cause. Duration of CR for Subjects 
without event will be censored at the date of their last adequate response assessment.  
DOR will be analyzed using the Kaplan-Meier method. Estimates of the 25th, median and 75th 
percentile of the DOR and their 95% confidence intervals will be provided, Kaplan-Meier 
curves will be produced, if applicable. 
• DOR applies only to subjects who have CR (responded). 


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2.7.1.7 
Time to Complete Remission 
Time to Complete Remission is defined as the time from the date of enrollment (cycle 1 day 
1) to the first documented CR. 
Time to complete remission will be analyzed using the Kaplan-Meier Product-Limit method. 
Subjects who are known to be without CR will be censored at study-maximum follow-up time 
(i.e. Last Subject Last Visit (LPLV) for final analysis, for analysis of cut-off date min (LPLV, 
Cut-off date)) for subjects with a PFS event (i.e. disease progression or death due to any 
cause), or at the date of the last adequate assessment for subjects without a PFS event. 
Estimates of the 25th, median and 75th percentile of the time to CR and their 95% confidence 
intervals Kaplan-Meier plots will be provided, if applicable. Improvement in RBC/platelets 
transfusion independence 
The number and percent of subjects who are RBC/platelets transfusion independent after the 
date of enrollment as per IWG-MDS will be provided. 
RBC/Platelets transfusion independence rate is defined as the proportion of subjects having 
received <0 units (no RBC/Platelets transfusions) during at least 8 consecutive weeks after 
enrollment (Table 2-6). The number and percentage of subjects will be shown for the overall 
FAS and then also in only those with transfusion dependence at baseline. Percentages will be 
provided with exact 95% Clopper-Pearson confidence intervals. Bar graphs will be provided. 
For subjects 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. 
2.7.2 
Statistical hypothesis, model, and method of analysis 
No formal hypothesis testing is planned for this study. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Missing data for safety and efficacy endpoints will not be imputed. 
For the determination of CR, only assessments post enrollment and prior start of any other anti-
neoplastic therapy or HSCT are considered.  
For the determination of PFS events, only assessments post enrollment and prior start of any 
other anti-neoplastic therapy are considered. If disease progression/relapse from CR or death is 
documented after two or more missing response assessments, PFS will be censored at the last 
adequate response assessment prior to the event. 
For PFS and duration of CR, an adequate response assessment is considered any disease 
assessment indicating response status apart from “unknown” or “not done”. 


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A subject whose disease has not progressed or died by the date of the analysis cut-off will have 
their PFS censored at the time of the last adequate tumor evaluation performed on or before the 
cut-off date. Clinical deterioration will not be considered as documented disease progression.  
Further details were already described in Section 2.7.1. 
2.8 
Safety analyses 
For all safety analyses, the safety set will be used.  
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. laboratory 
shift tables). In particular, summary tables for adverse events (AEs) will summarize only on-
treatment events, with start date during the on-treatment period (treatment-emergent AEs). 
The overall observation period will be divided into three mutually exclusive segments: 
• Pre-treatment period: from day of subject’s informed consent to the day before first 
administration of study treatment 
• On-treatment period: from day of first dose of study treatment to last dose of study 
treatment and up to 30 days after last administration of study treatment. 
• Post-treatment period: starting at day 31 after last administration of study treatment 
(MBG453 or HMA). 
Overall safety period: from date of first administration of study treatment to 30 days after the 
date of the last administration of HMA or 150 days after the last dose of MBG453 whichever 
is later. 
 
2.8.1 
Adverse events (AEs) 
All information obtained on adverse events will be listed. 
Treatment emergent adverse event (TEAE) defined as any adverse event which started on or 
after the day of first dose of study treatment and before 30 days after last dose of study treatment.  
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period. The number (and percentage) of subjects with treatment emergent AEs 
will be summarized by primary system organ class, preferred term and maximum severity 
(based on CTCAE grades).  
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT). A 
subject with multiple occurrences of an AE will be counted only once in the respective AE 
category. A subject 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. 
 
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 


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that started during the pre-treatment, on-treatment, post-treatment and after the overall safety 
period will be flagged. 
Separate summaries will be provided for study treatment related adverse events, death, serious 
adverse events, non-serious adverse events, adverse events leading to treatment discontinuation, 
and adverse events leading to dose adjustment by primary system organ class and preferred 
term. 
Selected summaries of adverse events will be produced for the overall safety period. All deaths 
(on-treatment and post-treatment) will be summarized. 
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, post-treatment and overall 
safety period will be flagged. Subjects who are having AE after transplantation or antineoplastic 
therapies will be listed & flagged. 
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 MBG453 + HMA arm. 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 and all AEs by HMA 
• 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 
• SAEs with fatal outcome and separately those considered related to study treatment 
• AEs leading to study treatment or MBG453/HMA discontinuation and by HMA 
• Related to study treatment AEs leading to study treatment discontinuation 
• AEs leading to dose adjustment/interruption for (MBG453/HMA) and study treatment 
• AEs requiring additional therapy 
• COVID-19 related adverse events by MedDRA COVID-19 (SMQ) terms. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT). A 
subject with multiple occurrences of an AE will be counted only once in the respective AE 
category. A subject 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 addition, all AEs and SAE by SOC and PT will be also provided on the overall safety period. 


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Adverse events for safety follow up period (day 31-150 after last dose of study drug) will be 
described by system organ class and preferred term. 
For the legal requirements of ClinicalTrials.gov, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
incidence greater than X% and on <on-treatment/treatment emergent> serious adverse events 
and SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
 
• A single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• More than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT." 
2.8.1.1 
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 MBG453. 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, number and percentage of subjects 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 and percentage of subjects 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. 
Of note, AESI will be included only in the final CSR. 
2.8.2 
Deaths 
Separate summaries for on-treatment and all deaths (including post-treatment deaths not in the 
AE CRF but in the survival CRF) will be produced showing deaths reasons by SOC and 
preferred term. 


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All deaths (including those from the pre- and post-treatment periods) will be listed and those 
collected during the pre-treatment, post-treatment and overall safety period will be flagged. A 
separate listing of deaths prior to starting treatment will be provided for all screened subjects. 
2.8.3 
Laboratory data 
Grading of laboratory values will be assigned programmatically as per NCI 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. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE v5, results will be categorized as 
low/normal/high classifications based on laboratory normal ranges.  
The following summaries will be generated separately for hematology and biochemistry tests: 
For laboratory tests where grades are defined by CTCAE v5. 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will 
be counted only once for the worst grade observed post-baseline. 
• Shift tables to compare baseline CTCAE grades to the worst on-treatment grade. 
We will be plan two shift tables (i) One for up to end of core treatment period and (ii) 
another from Day 1 to end of extension period. 
For laboratory tests where grades are not defined by CTCAE v5 
• Shift tables using the low/normal/high/low and high classification to compare baseline 
to the worst on-treatment value. 
Listing of all laboratory data with values flagged to show the corresponding CTCAE v5 grades. 
If applicable and the classifications relative to the laboratory normal ranges will be presented. 
Data summaries will be provided in SI units. The summary of laboratory evaluations will be 
presented for three groups of laboratory tests: Hematology, Chemistry and Urinalysis. On 
presenting summary statistics, laboratory data will be grouped and displayed in an alphabetical 
order within the Hematology and Chemistry groups. 
All laboratory data will be listed by subject and visit. If normal ranges are available, 
abnormalities will be flagged.  
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
No ECG data collected in eCRF only collected in source, if clinically significant ECG findings 
is recorded on the CRF as either medical history, current medical conditions or adverse events 
as appropriate.  


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2.8.4.1.1  Cardiac Imaging Data 
No cardiac imaging data collected. Hence Not applicable  
2.8.4.2 
Vital signs 
Notable vital sign values during on-treatment period in subjects with non-notable values at 
baseline (e.g. systolic BP >90 and <180 mmHg for analysis of systolic BP) 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  
- 
 
 
 
   
 
   
 
 
 
 
 


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.  
 
.  
 
. 
 
 
 
 
 
: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
• 
 
• 
 




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, 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
 
 
 
 
  


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2.10 
Interim analysis 
 
An interim analysis was performed after all subjects who have completed 6 months follow-up 
from enrollment (cycle 1 day 1)  or discontinued earlier for publication purpose. 
Final Analysis will be performed when all subjects complete the core and extension phase and 
safety follow-up or discontinued early. A final CSR will be written. 
3 
Sample size calculation 
This is an open label, non-randomized, single-arm combination study to assess safety and 
efficacy of MBG453 (sabatolimab) given with HMAs of investigator’s choice (IV/ SC/ Oral). 
The primary objective of the study is to assess safety profile of this combination drug by 12 
months. 
Given the above expected incidence rates of AEs with the combination (Table 1-3 of protocol), 
a sample size of 81 evaluable subjects is estimated based on a two sided 95% confidence 
interval for an incidence rate of an AE using the large sample normal approximation that will 
extend 0.10 from the observed incidence rate of an AE (precision or margin of error of 10%) 
for an expected incidence rate of 30%. 
Thus, with the estimated sample size of 90 subjects there is at least 90% probability to detect 
an AE with a true incidence rate of 2.5%. Considering drop-out rate of 10%, approximately 
90 subjects will be enrolled for safety and efficacy assessment of this study. 
Novartis has decided to permanently halt recruitment based on a re-evaluation of the 
development strategy for sabatolimab. Subjects who are currently on study treatment or in 
follow-up will be continue per the protocol. At the time of this amendment, 39 subjects have 
been enrolled into the study. 
4 
Change to protocol specified analyses 
• 
 
 
• No supportive/subgroup/sensitivity analysis performed due to MBG program 
closing/due to fewer sample size. Additionally it is mentioned in protocol that 
subgroup analysis may be performed.  Hence it is agreed to not have these analysis. 


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5 
Appendix 
5.1 
Date of first administration of investigational drug /HMA 
The date of first administration of investigational drug /HMA is defined as the first date when 
a non-zero dose of investigational drug /HMA is administered and recorded on the study 
treatment eCRF page.  
5.2 
Date of last administration of of investigational drug /HMA 
The date of last administration of the investigational drug /HMA is defined as the last date when 
a non-zero dose of the respective investigational drug /HMA is administered and recorded on 
the study treatment eCRF page. So both, first and last date of investigational drug /HMA, are 
derived separately for each drug which is part of the study treatment. 
5.3 
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 (MBG453 
(sabatolimab) in combination with HMAs (IV/SC/Oral)) is administered. 
5.4 
Date of last administration of study treatment (combination) 
The date of last administration of study treatment (or end date of study treatment) is defined as 
the last date when the last non-zero dose of any last component of the study treatment (MBG453 
(sabatolimab) in combination with HMAs (IV/SC/Oral)) is administered. 
5.5 
Date of last exposure to HMA and investigational drug and date 
of last exposure to study treatment (combination)    
One planned cycle length is 28 days. HMA drugs are planned to be administered every cycle 
between Day 1 and Day 9 with different schedules. MGB453 is administered every 4 weeks, 
on Day 8 out of a 28 days cycle, unless there was a toxicity leading to a dosing interval increase.  
As treatment is given in cycles, the date of last administration of study treatment is not 
considered the date of last exposure but instead the planned end date of the last cycle in which 
the last non-zero dose was given.  
The date of last exposure to MBG453 is therefore calculated as: 
• Minimum (last date of administration of investigational drug + 27 days, date of death, 
last contact date in case subject is lost to follow-up), as MBG453 injections is given 
Q4W (in case of change to Q8W, the cycle would end after 55 days) 
The date of last exposure to HMA drugs is calculated as: 
The date of last exposure to azacitidine 
• Minimum (last date of administration of  azacitidine + 20 days, date of death, last contact 
date in case subject is lost to follow-up) as azacitidine is given daily every cycle during 


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7 days at the beginning of each cycle (between Day 1 to Day 9) (total cycle length 28 
days). 
     The date of last exposure to decitabine 
• Minimum (last date of administration of decitabine + 22 days, date of death, last contact 
date in case subject is lost to follow-up) as decitabine is given daily every cycle during 
5 days at the beginning of each cycle (between Day 1 to Day 5) (total cycle length 28 
days). 
The date of last exposure to study treatment (combination) is calculated as  the minimum 
date between the end date of the last cycle initiated with any component of the study treatment, 
the date of death and the last contact date in case subject is lost to follow-up. The end date of 
the last cycle initiated is the planned end date (Day 28) of the last cycle initiated where MBG453 
and/or HMA were last administered or the date of the last administration of a non-zero dose of 
any last component of the study treatment (MBG453, HMA), whichever is the latest. 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.  
The planned end date of a cycle (Day 28) will be applicable even if this date goes beyond the 
data cutoff date (it should not be truncated to the date of data cutoff).  
5.6 
Duration of study treatment (combination) used to calculate the 
dose intensity and the relative dose intensity  
For the calculation of the dose intensity and relative dose intensity, the cycle-based exposure to 
study treatment (combination) will be derived from the date of first administration of study 
treatment (combination) to the actual or planned end date of the last cycle initiated (whichever 
is the latest) irrespective of date of death, last contact date for withdraw consent and cut-off 
date.  
The start date of the first cycle initiated is the first date when a non-zero dose of HMA.  
The end date of the last cycle initiated is the planned end date (Day 28) of the last cycle initiated 
where MBG453 and/or HMA were last administered or the date of the last administration of a 
non-zero dose of any component of the combination, whichever is the latest.  
The duration of study treatment in days used to derive the dose intensity and the relative dose 
intensity will be calculated as follow: end date of the last cycle initiated – date of first 
administration of study treatment (combination) + 1.  
The planned end date of a cycle (Day 28) will be applicable even if this date goes beyond the 
data cutoff date, the date of death or the date of last contact date for withdraw consent (it should 
not be truncated to the date of data cutoff, the date of death or the date of last contact date).  
5.7 
Windows for multiple assessments 
Note: As per CTT discussion, It was suggested to use CRF visits for ECOG and ePROs and 
remove the visit window from the SAP. It is acknowledged that CRF visits might be delayed, 


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which is not unusual from a medical perspective. Additionally, the "End of Treatment" visits 
are subject-specific based on the study design. These point should be mentioned in the footnotes 
of the respective tables. 
5.8 
Last contact date  
The last contact date will be used for censoring of subjects 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 5-1). The cut-off date will not be used for last contact date, unless the 
subject 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 subjects not known to have died at the analysis cut-off 
using the last complete date among the following: 
Table 5-1 
Last contact date data sources  
Source data 
Conditions 
Date of enrollment  
 
No condition 
Last date subject was known to be alive from 
Survival Follow-up page  
 
Subject 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 
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 
5.9 
Imputation rules 
A project level study macro to be considered for imputation rules from GPS as mentioned below 
path. 
CMBG453b1/util 


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5.10 
AEs coding/grading 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. The latest MedDRA version will be used and will be described in the footnote of 
relevant outputs. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE). The CTCAE represents a comprehensive grading system for reporting the acute and 
late effects of cancer treatments. CTCAE grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1). The 
CTCAE grade of 5 (death) is not used; rather, ‘fatal’ is collected as AE outcome and death 
information is also collected on a separate eCRF page. 
5.11 
Laboratory parameters derivations 
 Not applicable 
5.12 
Statistical models  
5.12.1 
Primary analysis 
There is no hypothesis testing planned for this study.  
5.12.2 
Key secondary analysis 
There is no key secondary analysis planned for this study. 
 
 
 


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6 
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